relatório actividade

Transcrição

RELATÓRIO
DE
ACTIVIDADE
2014
Relatório de Actividade
Introdução
Produção Científica
Research Groups
Cancer Biology
Cancer Drug Resistance
Cancer Genetics
Differentiation and Cancer
Expression Regulation in Cancer
Genetic Diversity
Genetic Dynamics of Cancer Cells
Glycobiology in Cancer
Population Genetics
Post-Graduation Unit
Outreach Activities
Science Diffusion
Public Awareness of Cancer
IPATIMUP Diagnostics
Innovation & Translation
Ipatimup Innovation
Ipatimup Translation
Internal Services
Animal Model Service
Cell Lines Bank
In vivo CAM Assays
Proteomics Service
Sequencing Service
Core Services
Informatics
Programs Office
Risk Management System
Secretary General
Slides Digitalization Service
Technical Body
ANNEXES
Recent PhDs
Research Projects
Scientific Papers
Members of Ipatimup at Editorial Boards
Relatório das actividades comemorativas dos 25 anos
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Introdução
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Introdução
O ano de 2014 foi marcado por dois acontecimentos/processos fundamentais na vida do Ipatimup: as comemorações dos 25 anos de
actividade científica e profissional do instituto e das suas gentes e a consolidação da Unidade de Investigação i3S da Universidade do
Porto, da qual o Ipatimup é membro fundador.
Ao longo do ano de 2014, o Ipatimup organizou uma vasta programação de comemorações dirigida ao grande público, à comunidade
científica em que o Instituto está inserido e a profissionais médicos e associação de doentes, para dar a conhecer todas as suas
valências profissionais. Os graus de adesão dos públicos-alvo e o interesse dos meios de comunicação social surpreenderam pela
positiva os elementos do Ipatimup que conceberam e asseguraram os numerosos eventos sempre com grande entusiasmo (anexo:
Relatório das actividades comemorativas dos 25 anos).
O Programa de Comemorações incluiu seis eventos permanentes: a exposição fotográfica itinerante “Olhares com Memória”, sobre
o património edificado e humano do Ipatimup ao longo dos 25 anos de existência, que percorreu lugares emblemáticos da cidade,
como a Câmara Municipal do Porto e a Casa da Música; uma campanha de outdoors, pela qual o Instituto conquistou a cidade,
ajudando a conhecer melhor a sua missão; o filme “O que é o Ipatimup?”, que deu a conhecer o que 25 figuras públicas da ciência,
da cultura e da política da cidade do Porto e do país pensavam sobre nós; o filme “Trocado em Miúdos”, no qual o trabalho de
investigação realizado no Ipatimup foi explicado pelo olhar imaginativo e inocente das crianças; a inauguração da página do Instituto
no Facebook.
A abertura do programa de comemorações dos 25 anos realizou-se em Março, com um jantar na Casa da Música, congregando
quem trabalha no Ipatimup e personalidades da cidade, ciência e empresas mecenas. Em Abril, assinalamos o visitante 35 mil do
Laboratório Aberto que, em seis anos de vida, foi “utilizado” por milhares de crianças de escolas do ensino básico e secundário.
Destacamos, pelo impacto obtido junto da comunidade, a exposição “Cancro, Ciência e Cidade: Os Passos da Ciência nos
Paços de Concelho”, realizada em Maio na Câmara Municipal do Porto: a partir da história do Ipatimup e das descobertas dos
seus investigadores, partilhamos conhecimento sobre a prevenção e o diagnóstico precoce de diferentes tipos de cancro e as
características genéticas e hábitos da população portuguesa. A notoriedade conseguida por esta exposição deu origem ao convite,
feito pela Fundação Calouste Gulbenkian, para uma segunda edição em Lisboa, que se concretizou já em Janeiro de 2015. Durante
esta exposição foi lançado o livro “Cancro ponto e vírgula” que foi totalmente concebido no Ipatimup e que contou com o apoio
financeiro da Fundação Calouste Gulbenkian. Este livro ilustra a capacidade que o Ipatimup tem de divulgar ciência e assim
promover estilos de vida saudável, que vão ter impacto nas taxas de incidência do cancro, no diagnóstico precoce e na vigilância da
doença.
No Dia Internacional da Tireóide, o Ipatimup organizou uma sessão pública de informação e divulgação das doenças da tireóide. Foi
possível realizar testes de TSH e ecografia tireoideira gratuitos. Inscreveram-se 150 pessoas para fazerem os rastreios e, para além
destas, estiveram presentes mais 150 para as conferências.
Em Junho, tivemos um evento dirigido especificamente para a comunidade científica, o GLYCO-T 2014: 9th International Symposium
on Glycosyltransferases, realizado nas instalações da Fundação Eng. António de Almeida, com a presença de mais de 200
investigadores, europeus, dos EUA, Israel, China e Japão.
Em Julho e Setembro, realizámos dois eventos em mais dois lugares emblemáticos da cidade, a Casa das Artes – Conferência sobre
Ancestralidade e Multiculturalismo – e o Mercado do Bom Sucesso – Comer com Sucesso, uma palestra sobre alimentação saudável
e como isso pode ajudar a prevenir o cancro com um Chef e o coordenador da Plataforma Nacional contra a Obesidade, da Direcção
Geral da Saúde.
Também em Setembro, organizámos a apresentação do livro da Prof. Maria de Sousa “Meu dito, meu escrito - Futuros e Desafios
na Ciência: Ouvir os novos com ouvidos cansados. Ou um encontro de velhos e novos sangues para a continuidade da estrutura de
um país científico”. Ouvimos investigadores com idades entre os 30 e os 40 anos, falarem sobre o futuro da investigação científica
em Portugal e sobre o que esperam vir a ser as suas vidas como investigadores nos próximos 20 anos. Destacamos as palestras do
ex-reitor da Universidade do Porto, Prof. Marques dos Santos e dos Doutores Nuno Azevedo e Luís Portela.
Em Outubro, realizou-se a XVI edição das Conferências do Equinócio, promovidas pelo Prof. Rui Mota Cardoso desde 1997, como um
dia anual para reflexão e discussão interdisciplinar de temas de Medicina, Ciência e Investigação. A edição de 2014 foi organizada
pelo Prof. João Lobo Antunes.
Durante os dias 14 e 15 de Novembro de 2014, o Ipatimup abriu as suas portas à comunidade. Nestes “Dias Abertos” estudantes,
famílias e população em geral espreitaram o dia-a-dia de um instituto científico, assim como o funcionamento dos seus laboratórios
de investigação e de diagnóstico. O número de visitantes atingiu o impressionante número de 1.000 pessoas e contou com o
apoio da Junta de Freguesia de Paranhos. Tal como nos eventos anteriormente referenciados, a iniciativa chamou a atenção da
generalidade dos meios de comunicação social, que deram grande cobertura nacional aos “Dias Abertos” do Ipatimup.
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Ainda em Novembro, organizaram-se mais dois eventos em locais de referência da cidade do Porto. O Teatro Nacional de S. João
estreou a peça “Biodegradáveis”, inspirada na observação do dia a dia de um investigador. A Câmara Municipal do Porto convidou
o Prof. Sobrinho Simões para um palestra que decorreu no Teatro Municipal Rivoli, para debater o tema do cancro e genética com o
Prémio Nobel da Química de 2004, Prof. Aaron Ciechanover.
Fechámos a programação em Dezembro, com a inauguração do Marco do escultor Zulmiro de Carvalho, implantado nos jardins
do Ipatimup, representativo do percurso sólido do Instituto, da sua visão para o futuro e da sua integração no ambiente da
Universidade, Centros Hospitalares e na própria Cidade. Sem dúvida o Marco representa a marca que o Ipatimup deixa no
desenvolvimento profissional dos seus elementos bem como a sua importância na vida de todos que participam na sua construção
e consolidação como escola de ciência de Ciências da Vida e da Saúde. Foi, no mesmo dia, encerrada e literalmente enterrada
a “Cápsula do Tempo”, que será aberta daqui a 25 anos. Na Cápsula foram colocados o livro dos 25 anos, os depoimentos de 25
personalidades e de 25 “anónimos” sobre o que pensam hoje do Ipatimup e como prevêm que virá a ser encarado o cancro daqui a
três décadas. São depoimentos para memória futura, constituindo uma voz comum de expectativas que servirão de inspiração às
novas gerações de cientistas.
Para além da referenciação específica nos diferentes eventos, não podemos deixar de, neste Relatório, reiterar o especial
agradecimento às empresas, entidades e personalidades amigas que tornaram possível a comemoração dos 25 anos: Amorim
Investimentos e Participações, SGPS, SA; Arsopi, Indústrias Metalúrgicas Arlindo S. Pinho, S.A.; Astrazeneca – Produtos
Farmacêuticos, Lda; Banco Carregosa; Banco Espírito Santo, SA; Banco BPI, SA; Banco Santander Totta, SA; Bayer Portugal, SA; BIALPortela & Ca., SA; Câmara Municipal do Porto; Casa das Artes; Fundação Calouste Gulbenkian; Fundação Casa da Música; Fundação
GlaxoSmithKline para as Ciências da Saúde; Fundação Manuel António da Mota; Janssen-Cilag Farmacêutica, Lda; Rosalina Machado;
Santa Casa da Misericórdia do Porto; Sonae SGPS; Unicer Bebidas de Portugal, SGPS, SA.
No final do ano de 2014 foram divulgados os resultados da candidatura do Instituto de Inovação e Investigação em Saúde da
Universidade do Porto (i3S), como nova Unidade de Investigação encabeçada pela Universidade do Porto e contando com a
associação em consórcio da Universidade com o IBMC, INEB e Ipatimup. A candidatura foi classificada como “Excepcional”, tendo
obtido a pontuação de 25/25 pelo painel de avaliação da European Science Foundation contratado pela FCT (Fundação para a
Ciência e Tecnologia). Vale a pena reproduzir uma breve passagem do relatório de avaliação: “The site visit team is convinced that
the proposed program with the centralization of the RGs and core facilities in a new building, which the panel toured, is a unique
and ambitious operation, giving the unit the possibility of becoming a leading research centre, not only in Portugal, but also in
Europe.” O i3S foi uma das 11 Unidades de Investigação que obtiveram a classificação de “Excepcional”.
No ano de 2014 intensificaram-se as obras de construção do novo edifício do i3S mas esta adaptação não afectou o funcionamento
normal do Ipatimup, tanto na sua actividade cientifica como na sua actividade profissional como prestador de serviços à
comunidade.
Relativamente ao i3S (Instituto de Inovação e Investigação em Saúde) intensificaram-se os trabalhos de implementação da estrutura
científica e organizativa da unidade de investigação. O Conselho de Gestão e Orientação (CGO) do i3S em articulação com elementos
do Ipatimup, IBMC, INEB e membros da Faculdade de Medicina da Universidade do Porto, criaram vários grupos de trabalho para
estudo da organização das plataformas científicas e tecnológicas comuns, bem como de outros serviços de suporte à investigação,
como serão as unidades de divulgação, inovação e transferência de tecnologia, assim como as unidades de informática e gestão de
infra-estruturas.
No âmbito da actividade científica regular do Ipatimup o Instituto manteve em pleno funcionamento os seus 10 grupos de
investigação com resultados que consideramos excelentes tanto pelo número e qualidade de artigos científicos, número de
prémios e número de estudantes que apoiamos em diferentes fases da sua carreira científica ou profissional (estágios profissionais
e de mestrado, estudantes de doutoramento e pós-doutoramento). Foram publicados ou aceites para publicação 171 artigos,
ultrapassando o número obtido em 2013. Destes artigos, 20 foram publicados ou aceites em revistas indexadas com impacto
superior a 6 e 67 foram publicados ou aceites em revistas com impacto entre 3 e 6. Tendo em conta a distribuição por quartis, a
maioria (53%; 90/171) dos artigos pertencem ao Q1 e cerca de 20% (n=34) pertence ao Q2.
Em 2014, doutoraram-se 7 elementos do Ipatimup, 6 pela Universidade do Porto através de duas das suas Faculdades e 1 pela
Universidade de Leeds. Três estudantes de pós-doutoramento obtiveram posições Investigador FCT, para iniciar funções no
Ipatimup como instituição de acolhimento, cujos contratos se iniciarão em 2015.
O Ipatimup ganhou o prémio APIFARMA pela excelência da sua investigação médica. Este prémio é mais um estímulo para consolidar
a forte ligação que o Ipatimup já tem com a Industria Farmacêutica tanto a nível nacional como internacional. A Unidade de
Translação e Inovação, que foi uma aposta do Ipatimup, tem desempenhado um papel fundamental nesta ligação crucial ao mundo
empresarial.
À vice-presidente do Ipatimup, Prof.ª Raquel Seruca, foram atribuídos a medalha de Mérito (Grau Ouro) da cidade do Porto e o
Prémio Femina, este último pela qualidade do seu desempenho na área da Ciência.
O Ipatimup foi homenageado pelo Rotary Club Porto Portucale Novas Gerações, clube Rotário da cidade do Porto.
Um estudante de doutoramento do Ipatimup (Dr. João Vinagre) recebeu o Prémio Pulido Valente Ciência, que distingue o melhor
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trabalho publicado em 2014 no domínio das Ciências Biomédicas e feito por investigadores com menos de 35 anos, em laboratórios
portugueses.
No final de 2014 um estudo liderado por uma investigadora do Ipatimup (Doutora Sónia Melo) teve amplo reconhecimento público
da sua importância nos meios de comunicação social e convite para uma palestra na TEDx que tem por lema segundo as palavras
da própria organização, “ideias que merecem ser disseminadas”. O estudo identifica o mecanismo que leva as células cancerígenas
a transferir, através de vesiculas que são secretadas para o “meio ambiente”, informação molecular que influencia e reprograma o
comportamento das células normais vizinhas. Esta descoberta abre novas possibilidades na detecção e monitorização do cancro,
através de métodos de diagnóstico não-invasivos. Em Janeiro de 2015, a Doutora Sónia Melo recebeu o prémio L’Oréal para a
Ciência, destinado a dar continuidade a este trabalho.
Uma das investigadoras do Ipatimup (Doutora Joana Paredes) ganhou o prémio da Associação Laço para iniciar um estudo sobre
novas terapias biológicas do cancro da mama metastático.
Iniciaram-se em 2014 os 4 projectos exploratórios alocados às 4 posições Investigador FCT obtidas no concurso de 2013. Iniciouse ainda um projecto de investigação em consórcio financiado pela Agência Nacional de Inovação, dois protocolos de estudos
clínicos com o Grupo de Estudo da Doença Inflamatória Intestinal (GEDII) e um projecto com a empresa bio farmacêutica AbbVie.
Este projecto resulta de uma parceria entre a empresa, a Unidade de Investigação de Translação do Ipatimup e o Hospital de Santo
António, visando a implementação de um projecto inovador e multidisciplinar para o estudo da doença inflamatória do intestino
(DII).
O Ipatimup ganhou ainda um projecto financiado pela União Europeia – Programa Eramus+, dedicado à formação avançada em
Anatomia Patológica, “Cytological Training at European Standard through Telepathology”.
A Fundação Calouste Gulbenkian elegeu o Ipatimup como parceiro de referência para programas de cooperação com Moçambique
e Angola. Iniciou-se o estudo “Epidemiologia das hemoglobinopatias: variabilidade genética da hemoglobina e de enzimas
eritrocitárias na Província do Bengo”, no âmbito do desenvolvimento do Centro de Investigação em Saúde de Angola. Celebrou-se
ainda um protocolo entre a Fundação Calouste Gulbenkian, o Ipatimup e o Hospital Central de Maputo para implementação do
projecto “Atenção Integrada ao doente oncológico no Hospital Central de Maputo – Reforço da Capacidade Institucional – 20142016”.
A Fundação Calouste Gulbenkian financiou também um projecto apresentado a concurso pela Unidade de Prevenção do Cancro do
Ipatimup, “Hyper-healthy youth through prevention education”.
O Ipatimup concorreu a dois concursos de reequipamento científico abertos pelo Programa Operacional Regional do Norte e
foram aprovados dois projectos, para reforço e consolidação da capacidade infra estrutural do IPATIMUP, enquanto player do
sistema regional de inovação”. Estes projectos permitiram a actualização tecnológica em sequenciação de Sanger, next generation
sequencing, proteómica, microscopia avançada e citometria e tornaram-se particularmente importantes numa óptica financeira,
pois permitiram, para além da compra de equipamento, assegurar os custos de contratos de manutenção imprescindíveis e os
recursos humanos incluídos nas equipas técnicas.
O Ipatimup participou em oito programas doutorais da Universidade do Porto, destacando-se, desde 1996, o GABBA - Graduate
Program on Basic and Applied Biology Areas – em conjunto com as Faculdades de Medicina e de Ciências da Universidade do Porto,
o ICBAS e o IBMC. Participou na segunda edição, em 2014/2015, do BiotechHealth - Programa Doutoral em Biotecnologia Molecular
e Celular Aplicada às Ciências da Saúde – em conjunto com o ICBAS e a Faculdade de Farmácia da Universidade do Porto, o INEB, o
IBMC, o REQUIMTE e o Centro Hospitalar do Porto.
O Ipatimup continuou a acolher e a apoiar a Associação Portuguesa de Investigação em Cancro- ASPIC, enquanto rede científica
nacional ligada à instituição europeia com maior visibilidade na área do cancro, a EACR - European Association for Cancer Research.
Depois de uma Conferência kick-off realizada no Porto em Novembro de 2013, a ASPIC teve o seu primeiro congresso internacional
em 25 e 26 de Novembro de 2014, na Fundação Calouste Gulbenkian. Uma das Investigadores do Ipatimup (Doutora Ana Sofia
Ribeiro) recebeu a distinção atribuída ao melhor poster da conferência.
O Ipatimup continuou a manter uma estreita colaboração com o Health Cluster Portugal (HCP) - Pólo de Competitividade em Saúde,
quer isoladamente, quer em articulação com o IPO-Porto (Consórcio IPATIMUP–IPO) e o Centro Hospitalar de S. João (Protocolo
de colaboração). A Unidade Ipatimup Translação encontra-se a gerir o processo que levará à inclusão do IPATIMUP, em conjunto
com o Hospital de S. João e o IPO-Porto, na infra-estrutura europeia de Medicina Translacional (EATRIS), uma organização sem fins
lucrativos compreendendo centros académicos de excelência europeus em investigação translacional.
O Prof. Sobrinho Simões escreveu o livro “O Cancro”, editado pela Fundação Francisco Manuel dos Santos.
O Ipatimup promoveu, em Novembro de 2014, a última site visit anual do seu External Advisory Board. Destacamos três pareceres
que constam do Executive Summary da site visit: “Research Groups mostly are in good shape, scientifically productive and with
innovative plans for the future.”; “Translation unit has been a success in bringing in new collaborations with the biomedical industry.”;
“Outreach contributes to the positive image IPATIMUP has for the public at large”.
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No ano de 2014, o IPATIMUP atingiu o número de 169 artigos publicados em revistas internacionais indexadas. Dos 169 artigos,
foram publicados 20 em revistas com Factor de Impacto (FI) superior a 6; 65 em revistas com FI entre 3 a 6; 59 em revistas com FI
entre 1 e 3.
Os gráficos seguintes ilustram a evolução do número de artigos publicados e de citações desde 2004, de acordo com o Factor de
Impacto das respectivas revistas:
Papers
90
80
70
60
50
40
30
20
10
0
2004
2005
2006
2007
2008
<1
2009
1-3
2010
3-6
2011
2012
2013
2014
2012
2013
2014
>6
Citations per year
2000
1800
1600
1400
1200
1000
800
600
400
200
0
2004
2005
2006
2007
2008
<1
2009
1-3
2010
3-6
2011
>6
9
10
2014
2014
Research Groups
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Cancer Biology
Objectives
The general subject of study of the group is the identification of molecular mechanisms of human cancer with potential applications
in the diagnosis, prognosis and therapy, using as biologic models, thyroid and other neuroendocrine tumors. Besides the component
of translational research, the group has basic research interests such as oncogenic signaling, survival mechanisms and mechanisms/
molecules involved in mobility and invasion. Within this frame, a particular attention is paid to:
• Signaling induced by genetic alterations in tyrosine kinase receptors and signal transducing molecules involved in the MAPK and
the PI3K/mTOR pathway;
• Survival mechanisms of cancer cells, including telomerase reactivation and apoptosis dysregulation;
• Molecular mechanisms of metabolic alterations secondary to mitochondrial DNA mutations/deletions or to mutations in nuclear
genes encoding metabolic enzymes.
In addition the group has scientific interest in some aspects of cell cycle, tumor-microenvironment interactions and motility/
invasiveness processes in cancer.
Main research topics:
1. Oncobiology and genetics of familial and sporadic thyroid tumors
2. Clinico-pathologic and molecular characterization of thyroid cancers (PTC and Hurthel cell tumors) and of some neuroendocrine
tumors (GEP-NET, paraganglioma, melanoma)
3. Role of mitochondrial alterations in the etiopathogenesis of sporadic, familial and radiation-induced thyroid tumors
4. Role of mitochondrial alterations in the cancer-associated metabolic switch
Main Achievements
Clinico-pathological studies on thyroid tumors
The incidence of papillary thyroid microcarcinoma (PTmC) has been increasing everywhere due to the improvement of imaging and
morphological diagnoses and probably also due to environmental alterations. Despite this, the mortality caused by thyroid cancer
has not increased, reflecting the low clinical aggressiveness of most papillary thyroid carcinomas (PTCs) and the quality of the
available treatment. Despite this overall good prognosis of the most frequent endocrine malignancy, 10-15 % of papillary thyroid
carcinomas (PTCs) turn refractory to radioactive iodine therapy. The increased incidence of thyroid cancer, and in particular of
(very) small PTCs has led to the search for solid prognostic biomarkers that predict the behavior of such tumors. We published two
critical review papers addressing the most interesting issues from a practical standpoint: 1) Are there any specific morphological
or molecular features distinguishing PTmC from PTC? Is it possible to predict the clinical behavior of PTmC in fine needle aspiration
biopsy and in surgical specimens, using morphological and/or molecular markers? (Soares P, et al Int J Surg Pathol. 2014); and 2)
Despite the huge amount of genetic information on thyroid tumors, very few new markers revealed diagnostic or prognostic value
per se. BRAF mutation can have some value if associated to other clinico-pathological parameters, or in the particular setting of
iodine refractory tumors. Others, such as TERTp mutations can prove interesting in the future as predictive biomarkers (Soares P et
al., Virchows Arch. 2014).
Clinico-pathological studies on rare variants of thyroid tumors
In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as
paragangliomas. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin
expression and raise difficult diagnostic problems. We have described a neuroendocrine carcinoma resembling a paragangliomalike MTC displaying unequivocal signs of vascular invasion. A diagnosis of C-cell-derived primary neuroendocrine carcinoma
of the thyroid without calcitonin expression was made. The diagnosis of atypical MTC was confirmed by the demonstration of
immunoreactivity for CGRP. We concluded that the tumor was a C-cell-derived carcinoma (“atypical MTC”) in which the loss of
calcitonin expression reflects a genetic and/or epigenetic interference with the calcitonin-encoding gene (Nakazawa T, Int J Surg
Pathol. 2014).
A case of primary squamous-cell carcinoma (SCC) of the thyroid which had been initially diagnosed as an anaplastic carcinoma (ATC)
has been described. Clinically, primary SCCs of the thyroid and ATCs are similar. The distinction is often difficult particularly when
based on the cytological analysis of FNA material (Bolfi F, Case Reports in Pathology, 2014).
Clinico-pathological and molecular studies in thyroid inflammatory disorders
Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto’s thyroiditis and Graves’ disease, both characterized by
reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating
hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are
key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential
risk factors for AITD. We report significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the
relevance of polymorphisms in inflammation-related genes in the etiopathogenesis of AITD (Durães C., PLoS One. 2014)
The association between selenium and inflammation and the relevance of selenoproteins in follicular thyroid cell physiology have
pointed to a putative role of selenoproteins in the pathogenesis of autoimmune thyroid diseases. We found a significant association
between the SEPS1 -105 GA and AA genotypes and HT. Our findings support the existence of a link between SEPS1 promoter genetic
variation and HT risk (Santos LR. J Clin Endocrinol Metab. 2014)
We also described a case of Riedel thyroiditis (RT) using immunohistochemistry and electron microscopy to clarify its pathogenesis
and its relationship with IgG4-related disease. The increased number of lymphatic vessels in RT is reported for the first time. Our
findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and
physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic
vessels in the pathogenesis of RT (Cameselle-Teijeiro J, Virchows Arch. 2014).
Dissecting molecular pathways in thyroid tumors
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Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma
2014
(FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently
reported. In a series of MTCs we analyzed the presence of RET, H-RAS, and K-RAS mutations and evaluated the mTOR pathway
activation. We confirmed the presence of RAS mutation in sporadic MTCs and reported, for the first time, an association between
such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an
indicator of invasive MTC (Lyra J., Eur J Endocrinol. 2014).
Dissecting the genetics of human cancers
We have identify TERTp mutations as common events in human cancers and TERT promoter mutations may be one of the
mechanisms that underlies telomerase reactivation in several types of human tumors. In the following of our findings we have
performed several works establishing the prognostic role of these mutations in thyroid and melanoma (Melo M, J Clin Endocrinol
Metab. 2014; Pópulo H., J Invest Dermatol.2014). We also reported for the first time the presence of TERTp mutations in GIST
(Campanella NC, Eur J Hum Genet. 2014) and published a systematic review of the recent data in this topic (Vinagre J., Virchows
Arch. 2014)
Radiation and cancer
The reactivation or re-expression of telomerase (TERT) is a widespread feature of neoplasms. TERT promoter mutations were
recently reported that were hypothesized to result from UV radiation. In a retrospective study, we assessed TERT promoter
mutations in 196 cutaneous basal cell carcinomas (BCCs), including 102 tumors from X-irradiated patients, 94 tumors from patients
never exposed to ionizing radiation treatment. We sought to evaluate the effects of UV and X-ray irradiation on TERT mutation
frequency. TERT mutations were detected in 27% of BCCs from X-irradiated patients, 51% of BCCs from non-irradiated patients,
and 22% of melanoma patients. TERT mutations were significantly increased in non-X-irradiated BCC patients compared with
X-irradiated BCC patients; the mutations also presented a different mutation signature. In non-irradiated patients, TERT mutations
were more frequent in BCCs of sun-exposed skin, supporting a possible causative role of UV radiation. Our results suggest that
various carcinogenic factors may cause distinct spectrum of TERTp mutations in BCC (H Populo, Boaventura P et al, JID. 2014).
Mitochondrial alterations and cancer
Using cybrid cell lines harboring either wild-type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbor the
pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)], we have shown that mtDNA-driven OXPHOS dysfunction
correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer
cell mitochondria and the extracellular matrix. tRNAmut cybrids displayed increased motility and migration capacities, which were
associated with altered integrin-ß1 N-glycosylation, in particular with higher levels of ß-1,6-N-acetylglucosamine (GlcNAc) branched
N-glycans. This integrin-ß1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-ß1 and also with
increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate than WT cybrids, however,
when injected in nude mice, tRNAmut cybrids produced larger tumors and showed higher metastatic potential than WT cybrids.
These results were published in the journal Human Molecular Genetics (Nunes et al, EJHG 2014).
In the project entitled “The Metabolic Needs of Epithelial to Mesenchymal Transition”, we have characterized the metabolic
alterations in epithelial and mesenchymal cells, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This analysis
revealed several specific metabolic pathways that are specifically associated with the mesenchymal phenotype and may be
important for the cells to lose their epithelial morphology and enter a mesenchymal state. This project is being carried out by a PhD
student, in collaboration with Dr. John Blenis at Weill Cornell Medical College.
Mitochondrial alterations and epigenetic modifications
In this year, we observed that mtDNA mutations induces a metabolic reprograming of the cell, namely changes in Krebs Cycle and
OXPHOS activity, and changes in the metabolism of lipid, , glutathione, CoA, methionine and cysteine as well as changes in the Redox
state of the cell.
We also showed that mutations in mtDNA genes and nuclear genes encoding mitochondrial proteins were able to induce changes in
the epigenetic landscape of the cell, namely changes in DNA methylation and protein acetylation through changes in cell metabolic
flux. We observed that mitochondrial dysfunction caused by depletion of mtDNA, leads to the readjustment of several cellular
processes through the acetylation of several proteins, allowing the cell to survive and maintain its homeostasis.
Mitochondrial fusion and fission proteins and its role in oncocytic cell transformation
Both IHC and in vitro protein analyses showed an overall increase in the levels of “mitochondrial-shaping” proteins in oncocytic
thyroid tumors. Furthermore, overexpression of the pro-fission protein Drp1 was found to be associated with malignant oncocytic
thyroid tumors. Interestingly, genetic and pharmacological blockage of Drp1 activity was able to influence thyroid cancer cells
migration/invasion ability, a feature of tumor malignancy. In this study we show that unbalanced mitochondrial dynamics
characterize the malignant features of thyroid oncocytic cell tumors, and participate in the acquisition of the migrating phenotype
(Silva AF et al,PLOS ONE, in press). We have also reviewed the molecular basis of mitochondrial dynamism concerning shape,
transport and cell migration (Silva AFCell Mol Life Sci. 2014).
Internationalization/Networking
National Collaborations
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Ana Teixeira - Animal Cell Technology Laboratory, Institute of Experimental and Technological Biology, Oeiras, Portugal
Arnaldo Videira - ICBAS, Porto, Portugal.
Carlos Palmeira - Centre for Neuroscience and Cell Biology (CNC), Coimbra, Portugal.
Cristina Rego - Faculty of Medicine and Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Isabel Bento - Instituto de Tecnologia Química e Biológica (ITQB), Oeiras, Portugal.
Isabel Torres – Department of Endocrinology, Portuguese Institute of Oncology, Porto, Portugal
Margarida Almeida, Departamento de Comunicação e Arte, Universidade de Aveiro
Maria Oliveira - Biomaterials Division, NEWTherapies Group, Institute of Biomedical Engineering, Porto
Micaela Fernandes - Instituto Tecnológico e Nuclear/Instituto Superior Técnico, Lisboa.
Miguel Godinho, Institute Gulbenkian of Science
Nuno Carinhas - Institute of Experimental and Technologic Biology (IBET), Oeiras.
Pedro Vaz and Octávia Monteiro Gil, IST-ID (CTN), Lisbon.
Raquel Soares - Biochemistry Department, Faculty of Medicine of the University of Porto
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Rui Carvalho - CNC, Coimbra
Rui Vaz –Department of Neurosurgery, Hospital S. João, Porto
International Collaborations
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Lothe RA, Skotheim RI- Department of Cancer Prevention of the Institute for Cancer Research of the Norwegian Radium Hospital
of Oslo University Hospital.
Keshav K. Singh - Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, USA
John Blenis – Department of Cell Biology, Harvard Medical School, Boston, USA
Keshav Singh - Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, USA.
Dhan Kalvakolanu - Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore.
Daniele de Sanctis - European Synchrotron Radiation Facility (ESRF), Grenoble, France.
Cameselle-Teijeiro JM and Clara Alvarez - University of Santiago de Compostela, Santiago de Compostela.
Etel Gimba - Universidade Federal Fluminense and Instituto Nacional do Câncer, Rio de Janeiro – Brazil
Leandro Alves, Denise Pires de Carvalho – Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro,
Brasil
Robert Hofstra - University Medical Center Groningen, Holland.
Luca Scorrano - Department of Cell Physiology and Metabolism of the University of Geneve
Mike Atkinson - Collaboration in European grant call OPERRA
Professor Gavin Vinson - Queen Mary University of London, UK
Future Research
Tert promoter mutations in human cancer: cellular and clinical implications.
We will continue to focus our efforts in the understanding of the effect of these mutations in terms of cancer cell biology, as well
as in the diagnostic and prognostic value of these alterations. This work will use several tumor models (thyroid, melanoma, glioma,
BCC, cSCC, hepatocarcinomas, neuroendocrine tumors, bladder, etc.). We are also developing methods for detection of these
alterations in several types of biological materials.
Non-canonical BRAF signalling in thyroid cancer: Cellular and animal models
We will continue our studies in non-canonical BRAF signaling, namely in the AKT/mTOR pathway, will be pursued by exploring the
relationship between BRAF/mTOR activation in thyroid tumors and the expression of genes involved in iodine metabolism (NIS). We
have also recently started a project concerning the role of BRAF mutations in tumor microenvironment modification, namely the
changes in matrix proteins such as osteopontin. We have been developing an animal model of BRAF induced thyroid cancer - BRAFtransgenic zebrafish - in collaboration with Miguel Godinho from IGC.
Studies in familial forms of thyroid cancer
We pursue our studies to select a series of Portuguese families with FNMTT (familial non-medullary thyroid tumors) aiming to
identify genes predisposing to FNMTT. We have select three informative families with several member affect with non-medullary
thyroid tumors, and we sent, for whole exome sequencing analysis, DNA from blood of these individuals to an external collaborator
(Robert Hofstra). We receive the data from genome sequencing and we are currently analyzing it.
Radiation and cancer
We are still following-up a cohort of individuals that suffered epilation by scalp X-ray irradiation for tinea capitis treatment. We will
continue to collect clinical data, concerning the atherosclerotic risk evaluation and the evaluation of cancer risk in the tinea capitis
cohort in collaboration with RORENO. Additional studies will be conducted in order to identify and characterize immunological and
genetic risk factors for radiation-associated diseases namely the study of IL6-polymorphisms in the tinea capitis cohort. We intend
to study telomere length in PBMC and tumour lesions as possible biomarkers of exposure to radiation / late radiation-induced
disease (cardiovascular disease and cancer).
Cancer metabolism and epigenetic changes
We want to clarify the mechanism(s) involved in the epigenetic changes observed, and how these changes contribute to tumor
progression.
We will pursuit our hypothesis that oncogenic pathways regulate metabolism, and in this way affect cell behavior linked to migration
and invasion. We are using three complementary models: a) Cybrid cell lines, where we aim to modulate the metabolic pathways
that are unique to OXPHOS-deficient cybrids and assess the way they control their increased migratory and invasive properties.b)
C-met-induced cell migration and invasion, where we intend to determine which enzymes are crucial for c-met-induced cell
migration and invasion. C)Epithelial to Mesenchymal Transition model, where we aim to discriminate the metabolic events that are
essential for the phenotypic transition.
Mitochondrial dysfunction and cancer
In a previous study, of a small series of thyroid tumors, we showed that mtDNA mutations, namely pathogenic mtDNA mutations in
mitochondrial Complex I, are common and contribute to the etiopathogenesis of Hürthle cell tumors, now we are collecting data
from 500 cases of thyroid cancer of the TCGA database in order to confirm the previous results.
Participation in PhD Programs
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Valdemar Máximo, Jorge Lima and Manuel Sobrinho-Simões.Metabolism and Cancer integrated in the Oncobiology module of
the Doctoral Programme in Molecular Medicine and Oncology (IPATIMUP, February 2014)
Paula Soares, Jorge Lima, Valdemar Máximo and Manuel Sobrinho-Simões.Cell Growth (proliferation, apoptosis and
metabolism) integrated in the Oncobiology module of the 13th Edition of the GABBA Doctoral Programme (IPATIMUP, April
2013)
Paula Soares, Valdemar Máximo, Jorge Lima and Manuel Sobrinho-Simões.Oncobiology II – PhD Programs in Medicine and
Molecular Oncology and in Biomedicine, FMUP.
Paula Soares, Valdemar Máximo, Jorge Lima and Manuel Sobrinho-Simões.Oncobiology - PhD Program in Pathology and
Molecular Genetics, ICBAS.
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Paula Soares, Valdemar Máximo, João Vinagre.Cell cycle and Apoptosis II - PhD Program in Pathology and Molecular Genetics,
ICBAS and Medicine and Molecular Oncology and in Biomedicine, FMUP.
Valdemar Máximo Coordinator, in partnership with Professor Fátima Carneiro, of the Oncobiology II Course units of the PhD
Programmes in Medicine and Molecular Oncology and Biomedicine - FMUP.
Manuel Sobrinho-Simões Coordinator of the PhD Programme in Medicine and Molecular Oncology - FMUP.
Participation in Master Programs
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Paula Soares, Valdemar Máximo, João Vinagre. Cell Cell cycle and Apoptosis I - Master Program in Medicine and Molecular
Oncology, FMUP.
Paula Soares, Valdemar Máximo, Jorge Lima and Manuel Sobrinho-Simões . Oncobiology I, Master Program in Medicine and
Molecular Oncology, FMUP
Valdemar Máximo. Coordinator, in partnership with Professor Fátima Carneiro, of the Oncobiology I Course unit of the Master
Course in Medicine and Molecular Oncology - FMUP.
Paula Soares, Jorge Lima Endocrinology module of the Master in Molecular Medicine and Oncology
Invited Talks
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Soares P, Prazeres H, Domingues R, Cavaco B. . Divulgação do diagnóstico Molecular em Endocrinologia. . XV Congresso
Português de Endocrinologia/65ª Reunião Anual da SPEDM. Vilamoura, Portugal. 01/2014.
Paula Soares.. Telomerase promoter mutations in cancer: an emerging molecular biomarker?. 1st ASPIC International Congress.
Lisboa, Portugal. 25/11/2014.
Paula Soares. . Thyroid Cancer: From oncogenic activation to immortalization. XXIX Reunião Anual da Federação de Sociedade
de Biologia Experimental (FeSBE). Caxambu, Brasil. 27/08/2014.
Paula Soares. Medullary thyroid carcinoma: molecular pathology of sporadic and hereditary forms. Sao Paulo Advanced
School in Oncogenesis and Translational Medicine;Oncogenesis and Translational Medicine Conference. Ribeirão Preto , Brasil.
17/02/2014.
Paula Soares. Tumores neuroendocrinos e medicina de translação: racional para o uso de terapias moleculares. 13º Congresso
da Sociedade Portuguesa de Oncologia. Porto, Portugal. 23/11/2014.
Boaventura, P. Tinea capitis in portugal - past and present concerns. Dark.Risk 2nd Annual Meeting. Belgrade, Sérvia.
20/10/2014.
Paula Soares. Biologia do Cancro. Curso de Formação Avançada Oncologia Molecular: Biologia do Cancro e Terapias Emergentes.
IPO-Coimbra, Portugal. 10/10/2014.
Catarina Eloy. Thyroid pathology - difficult and cytologically indetermined cases on surgical samples.. European Congress of
Cytology. Geneve, Suiça. 17/09/2014.
Helena Pópulo. Oncogénese do melanoma: aspetos relevantes na prática clínica.. 2º Simpósio de melanoma. Coimbra, Portugal.
01/11/2014.
Helena Pópulo. Alterações moleculares em melanoma: mutações no promotor do gene TERT. Perspetivas em oncologia II. Porto,
Portugal. 14/02/2014.
Catarina Tavares, Paula Soares. Challenges assessing sodium iodide transporter (NIS) expression in thyroid tumors. Center for
Research in Molecular Medicine and Chronic Diseases. Santiago de Compostela, Spain. 24/11/2014.
Sobrinho-Simões M. A investigação e a prática médica em oncologia. Universidade do Minho. Braga,Portugal. 28/03/2014.
Sobrinho-Simões M. Tumores da Tireoide. Hospital Amadora Sintra. Sintra, Portugal. 16/05/2014.
Sobrinho-Simões M. O bicho-Homem: Quem é, de onde veio e para onde vai?. A ciência por quem a faz e por quem a ensina..
Maia, Portugal. 8/9/2014.
Sobrinho-Simões M. O Envelhecimento numa perspectiva celular e molecular. Envelhecimento e Cancro. Porto, Portugal.
10/10/2014.
Sobrinho-Simões M. Novas perspectivas do diagnóstico do cancro oral: deteção de marcadores tumorais. Congresso da Ordem
dos Médicos Dentistas. Porto, Portugal. 07/11/2014.
Sobrinho-Simões M. Da Investigação à Prática Clínica em Oncologia . 13º Congresso Nacional de Oncologia. Porto, Portugal.
14/11/2014.
Sobrinho-Simões M. “Enigma de los tumores foliculares en la histologia tiroidea”
Differential diagnosis of follicular patterned thyroid tumours . Differential diagnosis of follicular patterned thyroid tumours .
Valencia, Spain. 22/05/2014.
Sobrinho-Simões M. “L’ apport des biomarqueurs dans les cancers de la glande thyroïde“ . 1er Congrès de la Société
Académique Algérienne de Biopathologie et Cancer (SAABC). Argélia. 31/05/2014.
Sobrinho-Simões M. Papillary carcinoma and its variants - Thyroid tumours with a follicular pattern of growth including UMPs
• Rare flowers including hereditary follicular cell derived carcinomas, small cell tumours, sarcomas and metastases; Prognosis
of thyroid carcinoma: Role of histopathology and of molecular pathology; Poorly differentiated and undifferentiated (anaplastic)
carcinoma of the thyroid. Thyroid Pathology for the Practising Pathologists. Paris, France. 26/05/2014.
Sobrinho-Simões M. Follicular patterned tumours: Do ancillary techniques help the histopathologist?. European Congress of
Pathology. Londres, Inglaterra. 31/08/2014.
Sobrinho-Simões M. How to diagnose malignancy in well differentiated thyroid tumours? The importance of understanding.
Biological malignancy versus Clinical malignancy - Rare tumours of (in) the thyroid. 5th BWP. Ghent, Bélgica. 23/10/2014.
Sobrinho-Simões M. Interesting/Difficult cases - Follicular patterned lesions; Prognostic and molecular markers in thyroid
neoplasms. Recent developments in papillary and follicular carcinoma; Poorly differentiated and undifferentiated carcinomas;
Papillary carcinoma. Classical and difficult variants; Follicular neoplasm: Benign or malignant ? 24th National Pathology
Congress. Trabzon, Turquia. 19/11/2014.
Sobrinho-Simões M. Anatomia Patológica dos Tumores Tiroideus. O que há de novo? . Sociedade Galega de Endocrinologia.
Corunha, Espanha. 25/11/2014.
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Oral Presentations
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Catarina Tavares, Catarina Salgado, Rui Batista, Helena Pópulo, Manuel Sobrinho-Simões, Paula Soares. . Estudo da relação
entre mutação do BRAF e expressão do transportador sódio/iodo (NIS) no cancro da tiróide.. Reunião de Outono do Grupo de
Estudos da Tiróide - Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Coimbra, Portugal. 01/11/2014.
Boaventura, P., Fontes, P., Soares, P., Cirnes,L., Bastos, S., Graça, P., Azevedo, J.. Um jogo interactivo para a prevenção da
obesidade em adolescentes. CONGRESSO INTERNACIONAL Presente e Futuro: Realidade Clínica, Social e Económica na Diabetes,
TOTUSALUS. Porto, Portugal. 11/2014.
Fontes, P., Boaventura, P., Azevedo, J. . Mobile games to improve healthier lifestyle amongst youth: “are we there yet” or should
we move forward?. Workshop on ACE 2014 “Designing Systems for Health and Entertainment: what are we missing?”. Funchal,
Portugal. 11/11/2014.
Boaventura, P., Fontes, P., Azevedo, C., Fins, J., Gomes, G., Leitão,R., Bastos, S., Graça, P., Cirnes, L., Soares, P., Azevedo, J.. Art
and mobile devices in health literacy: obesity prevention in adolescence. ECREA Preconference “Games and Society”. Lisboa,
Portugal. 11/11/2014.
Boaventura P., Mendes A., Teixeira-Gomes J., Soares P. Hiperparatiroidismo Primário numa Coorte de Indivíduos Irradiados na
Infância para o Tratamento da Tinea Capitis. 3ª Reunião Ibérica de Cirurgia Endócrina. Porto, Portugal. 09/2014.
Ricardo Celestino , Torfinn Nome, Ana Pestana, Eva Sigstad , Ragnhild A. Lothe , Trine Bjøro, Manuel Sobrinho-Simões, Rolf I.
Skotheim, Paula Soares.. Differential gene expression in follicular thyroid carcinomas showing different degrees of invasiveness..
38th Annual Meeting of the European Thyroid Association . Santiago de Compostela, Spain. 10/09/2014.
Eloy C, Sapia S, Sobrinho-Simões M. The grey zone between small cell carcinoma and Ewing family tumours of the thyroid..
European Congress of Pathology. London, UK. 27/09/2014.
Miguel Melo, Adriana Gaspar da Rocha, João Vinagre, Rui Batista, Joana Peixoto, Ricardo Celestino, Catarina Salgado, Catarina
Eloy, Jorge Lima, Teresina Amaro, Cláudia Lobo, Margarida Moura, Branca Cavaco, Valeriano Leite, José Manuel CameselleTeijeiro, Francisco Carrilho, Manuela Carvalheiro, Valdemar Máximo, Manuel Sobrinho-Simões, Paula Soares. As mutações
do promotor da TERT são um indicador major de mau prognóstico em carcinomas diferenciados da tiróide. XV Congresso
Português de Endocrinologia/65.ª Reunião Anual da Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo.
Vilamoura, Portugal. 24/01/2014.
Adriana Rocha et al.. Otimização da análise molecular de um painel de genes a partir de material de biopsia aspirativa
de tireóide. Reunião de Outono do Grupo de Estudos da Tiróide - Sociedade Portuguesa de Endocrinologia, Diabetes e
Metabolismo, Grupo de Estudos da Tiróide da Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Coimbra,
Portugal. 01/11/2014.
Ferreira LB; Tavares C; Pestana A; Castro P; Batista R; Celestino R; Prazeres H; Simoes MS; Gimba ERP; Soares P. Relevância
da Expressão das Isoformas da Osteopontina no Cancro da Tireoide. Reunião de Outono do Grupo de Estudos da Tiróide Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo, Grupo de Estudos da Tiróide da Sociedade Portuguesa de
Endocrinologia, Diabetes e Metabolismo. Coimbra, Portugal. 01/11/2014.
Campanella NC, Celestino R, Pestana A, Scapulatempo-Neto C, Brito MJ, Gouveia A, Lopes JM, Guimarães DP, Soares P, Reis RM..
TERT increased transcriptional activity and oncogenic TERT promoter mutations in GIST. 13º Congresso Nacional em Oncologia.
Porto, Portugal. 14/11/2014.
Liliana Santos et al.. Genética e metabolismo das seleproteínas nas doenças autoimunes da tiróide e patologias associadas.
Reunião de Outono do Grupo de Estudos da Tiróide - Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo, Grupo
de Estudos da Tiróide da Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo. Coimbra, Portugal. 1/11/2014.
Liliana Santos et al., . Selenoprotein genetics and metabolism in autoimmune thyroid disorders and associated diseases.. XIX
Curso Pós-graduado de Endocrinologia Diabetes e Metabolismo. Porto, Portugal. 16/03/2014.
Prizes
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Nathalia Cristina Campanella, Ricardo Celestino, Ana Pestana, Cristovam Scapulatempo-Neto, Maria José Brito; António
Gouveia; José Manuel Lopes, Denise Peixoto Guimarães, Paula Soares, Rui M. Reis.TERT increased transcriptional activity and
oncogenic TERT promoter mutations in GIST.
2º prémio Comunicações Orais. 13º Congresso da Sociedade Portuguesa de Oncologia, Novembro 2014, Porto
Vinagre J, Almeida A, Pópulo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L, Melo M, da Rocha AG, Preto
A, Castro P, Castro L, Pardal F, Lopes JM, Santos LL, Reis RM, Cameselle-Teijeiro J, Sobrinho-Simões M, Lima J, Máximo V, Soares
PFrequency of TERT promoter mutations in human cancers.
(Nat Commun. 2013;4:2185.)
Prèmio SPGH melhor trabalho em genética. 18.ª Reunião da SPGH, Novembro 2014, Lisboa
Melo M et al;As mutações do promotor da TERT são um indicador major de mau prognóstico em carcinomas diferenciados da
tiróide.
1º Prémio de Investigação Clínica XV Congresso Português de Endocrinologia/65ª Reunião Anual da Sociedade Portuguesa de
Endocrinologia, Diabetes e Metabolismo, 2014
Boaventura P., Mendes A., Teixeira-Gomes J., Soares P.Hiperparatiroidismo Primário numa Coorte de Indivíduos Irradiados na
Infância para o Tratamento da Tinea Capitis
Prémio melhor comunicação oral. 3ª Reunião Ibérica de Cirurgia Endócrina, Setembro de 2014, Porto.
2014
Objectives
The Cancer Drug Resistance group is mainly focused on translating basic science findings related to drug resistance into validation
of potentially new molecular targets for cancer therapy, such as anti-apoptotic molecules and some microRNAs, using several in
vitro models for different cancer types. Also, in an attempt to counteract cancer drug resistance, we are involved in testing newly
synthesized compounds (“small molecules”) in particular sets of cancer cell lines.
Main Achievements
Studying the role of microRNAs in Drug Resistance/Drug response
This work, performed in collaboration with Hospital São João, aimed at investigating the role of selected microRNAs (miRs) in drug
resistance/drug response of acute myeloid leukemia cells. We studied the role of miR-128 in DNA damage of HL-60 acute myeloid
leukemia cells and their response to chemotherapeutic drugs (Seca et al., Current Pharmaceutical Biotechnology 2014). In addition,
we have published a book chapter about “miRNAs in cancer drug resistance and drug sensitivity” (Seca H. et al., 2014).
Studying the role of P-glycoprotein (P-gp) in the intercellular transfer of multidrug resistance
Studies on the significance of P-gp found in extracellular vesicles isolated from drug resistant cells have been initiated. In particular,
we have initiated studies on how the intercellular transfer of P-gp from drug-resistant cells to drug-sensitive cells, mediated by
extracellular vesicles, may be responsible for the transfer of drug resistance (ongoing work).
Additionally, we have been studying the significance of cellular multidrug resistance to the type of extracellular vesicles shed by cells
and to their protein cargo (ongoing work).
Furthermore, the known interactions between P-gp and microRNAs have been reviewed (Lopes-Rodrigues V. et al., Int J Cancer,
2014).
Searching for small molecules with antitumor potential and anti-Pgp activity
In an attempt to counteract cancer drug resistance, the group was involved in testing newly synthesized compounds in cancer cell
lines. Most of this work was carried out as collaboration with CEQUIMED-UP. We have identified some compounds that interfere
with apoptosis (Pereira C. et. al., Eur J Pharmaceut Sci 2014) and we have been involved in the evaluation of potential inhibitors of
steroid sulfatase (Costa E.V. et al., Current Topics in Medicinal Chemistry 2014). Additional work showed that one hit compound
interferes with autophagy (in preparation for publication). Furthermore, we are testing potential inhibitors of P-gp synthesis
(ongoing work).
Finally, in collaboration with REQUIMTE, we have been searching for small molecule modulators of p53 family proteins (project
having ICETA-Porto/UP as the Proponent Institution, PI Prof. Lucília Saraiva, PTDC/SAU-FAR/110848/2009).
Searching for natural products with antitumor potential
Several studies have been carried out, in collaboration with Instituto Politécnico de Bragança, to identify natural products with
antitumor potential. Several publications resulted from this work (dos Santos T. et al., J. Funct Foods 2014; Oliveira et al., Food and
Function 2014; Lima et al., Industrial Crops and Products 2014; Reis et al., Food and Function 2014; Ferreira et al., Phytochemistry in press; Bizarro et al., submitted for publication).
International collaborations
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European COST Action BM1202 “European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD)” - M.H.
Vasconcelos was a substitute member of the Management Committee.
Department of Food, Environmental and Nutritional Sciences, University of Milan, Italy (Prof. Sabrina Dallavalle) - Collaboration
through COST Action CM1106.
Dublin City University and National Institute for Cellular Biotechnology, Ireland (Dr. Robert O’Connor) - Collaboration through a
PhD student (V. Rodrigues).
Facultad de Farmacia, Universidad Complutense de Madrid, Spain (Dr. Patricia Morales Gómez) - Collaboration through a PhD
student (F. Reis).
National collaborations
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CEQUIMED-UP (Prof. Madalena Pinto, Prof. Emília Sousa)
Collaboration through a PhD student project (V. Rodrigues) and a post-doc project (R.T. Lima).
Hospital São João (Prof. José Eduardo Guimarães)
Collaboration through a visiting researcher (R. Bergantim).
Instituto Politécnico de Bragança (Prof. Isabel Ferreira)
Collaboration through a PhD student (F. Reis).
REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences of FFUP (Prof. Lucília Saraiva)
Collaboration through one project financed by FCT (PTDC/SAU-FAR/110848/2009).
Future Research
Studying the role of P-gp and microRNAs in the intercellular transfer of cancer drug resistance by extracellular
vesicles
We aim to confirm if P-gp and some of the microRNAs that are responsible for cancer drug resistance (including regulators of P-gp
expression) are functionally transferred via extracellular vesicles, from drug-resistant to drug-sensitive tumor cells (PhD project of D.
Sousa).
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2014
Studying the significance of a cellular multidrug resistance phenotype to the type of extracellular vesicles shed
by cells
We aim to conclude these studies (PhD project of V. Rodrigues) and initiate a pilot study on the possibility of developing a biomarker
of multidrug resistance for diagnostic purposes.
Confirming and understanding the association between multidrug resistance (mediated by P-gp) and cellular
resistance to apoptosis
We aim to confirm if there is an association between multidrug resistance mediated by P-gp and cellular resistance to apoptosis; in
addition, to understand the mechanisms involved (PhD project of V. Rodrigues).
Identifying novel inhibitors of cancer multidrug resistance
We aim to identify inhibitors of P-gp synthesis (PhD project of V. Rodrigues).
Investigating the mechanism of action of hit small molecules which induce programmed cell death
We aim to further investigate the mechanism of action of one hit molecule from the CEQUIMED-UP library, which has potent human
tumor cell growth inhibitory potential. In addition, we aim to continue our collaboration with Prof. Lucília Saraiva in order to identify
small molecules which are modulators of p53 family proteins (post-doctoral project of R.T. Lima).
Identifying natural products with antitumor potential
We aim to continue identifying natural products with antitumor potential, particularly as inducers of cell death (PhD project of F.
Reis).
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M. Helena Vasconcelos. Programa de doutoramento em Ciências da Saúde da Faculdade de Medicina da Universidade de
Coimbra (participação no Curso “Cancer and Oncobiology”).
M. Helena Vasconcelos. Programa Doutoral em Segurança e Saúde Ocupacionais, Faculdade de Engenharia da Universidade do
Porto (participação na Unidade Curricular “Seminários Multidisciplinares”).
M. Helena Vasconcelos. Programa Doutoral GABBA, “Programa Graduado em Áreas da Biologia Básica e Aplicada” da
Universidade do Porto (participação no módulo de “Oncobiologia”).
M. Helena Vasconcelos and Raquel T. Lima. International Doctoral Programme on Cellular and Molecular Biotechnology Applied
to Health Sciences (BiotechHealth) – membros do corpo docente.
M. Helena Vasconcelos and Raquel T. Lima. Programa doutoral de Patologia e Genética Molecular no Instituto de Ciências
Biomédicas Abel Salazar da Universidade do Porto. Orientação de estudante de doutoramento.
M. Helena Vasconcelos and Raquel T. Lima. Doutoramento em Ciências Farmacêuticas da Faculdade de Farmácia da
Universidade do Porto. Orientação de estudante de doutoramento.
M. Helena Vasconcelos. Programa de doutoramento em Farmácia da Universidade Complutense de Madrid, Espanha. Coorientação de estudante de doutoramento.
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R.T. Lima. Mestrado em Medicina Legal, Instituto de Ciências Biomédicas Abel Salazar.
M. Helena Vasconcelos. Mestrado em Genética Molecular, Departamento de Biologia, Universidade do Minho (participação no
curso de pós-graduação “Mammalian and yeast as complementary cell models in programmed cell death”).
M. Helena Vasconcelos. Mestrado em Química Farmacêutica, Faculdade de Farmácia da Universidade do Porto (participação na
Unidade Curricular “Bioensaios”).
Invited Talks
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M. Helena Vasconcelos. “Apoptose e estratégias focadas na apoptose”. Curso de oncologia molecular: biologia do cancro e
terapias emergentes. Coimbra, Portugal. 07/11/2014.
Raquel T. Lima. “Autogafia e estratégias focadas na autofagia”. Curso de oncologia molecular: biologia do cancro e terapias
emergentes. Coimbra, Portugal. 07/11/2014.
M. Helena Vasconcelos. “The role of extracellular vesicles in cancer drug resistance”. 2nd Geivex Symposium “Extracellular
vesicles: from the bench to the clinics”. Terragona, Spain. 10/10/2014.
2014
Cancer Genetics
Objectives
Epithelial homeostasis mostly depends on cellular junctions, which control highly integrated networks and constitute key protein
receptors in outside-in cellular signaling, with significant consequences on cell behavior.
The long term goal of the Group is to uncover how epithelial cell-cell and cell-matrix junctions, as well as the surrounding
microenvironment, can influence cancer progression.
Specifically, and based on three common epithelial-derived cancers (gastric, breast and colorectal), the group aims at establishing
the contribution of adhesion molecules (E- and P-cadherins), infections (Helicobacter pylori and the microbiota), and non-neoplastic
components of the tumor tissue (fibroblast-like cells, the cancer cell secreted peptides and the elements of the extracellular matrix),
to altered epithelial homeostasis and to cancer development.
The accomplishment of these research goals will contribute to the development of new tools for cancer screening, prevention and
patient surveillance, as well as therapeutic strategies based on the modulation of cancer cell interactions.
Main Achievements
E-cadherin-integrin-ECM crosstalk in gastric cancer
Cell-cell and cell-extracellular matrix adhesions are crucial physical interactions for tissue homeostasis and architecture. Cadherins
are central molecules in cell-cell junctions, whereas integrins play a major role in the interaction between cells and the extracellular
matrix (ECM). In cancer, E-cadherin loss and integrin dysfunction are frequent events and have been implicated in the initiation,
progression and metastasis of solid tumours. Aiming at disclosing the molecular mechanisms underlying the regulation of
E-cadherin-integrin-ECM crosstalk in gastric cancer, and using an in vitro cell model, we showed that the expression of E-cadherin
leads to decreased expression of Integrin b4 and Integrin b1. We verified that Laminin g2, which is known to interact with both b1
and b4 integrins, is also downregulated in the presence of E-cadherin. Furthermore, we demonstrated that modulation of Laminin
g2 by siRNA enhances E-cadherin expression through a mechanism involving its trafficking machinery. Arf6, a key protein involved in
E-cadherin endocytosis and recycling is decreased. Simultaneously, the inhibition of Laminin g2 stimulates the expression of PIPKIg,
which is described to bind to E-cadherin promoting its transport to the plasma membrane. We present evidence of a direct influence
of E-cadherin in the expression of integrins and ECM components and the reverse, the effect of an ECM component in E-cadherin
expression and in its intracellular trafficking.
Ectopic laminin expression at the Ecad+/Ecad- interface promotes invasion and survival
We used two independent models (in vivo and in vitro) to understand what triggered laminin 332 overexpression in the context
of silencing of E-cadherin and to unveil the functional significance of its deregulation. In the Drosophila tissue context, cells
with reduced E-cadherin start dying and expressing MMP1 to degrade the basement membrane whereas, at the invasive front,
cells sense sharp differences in E-cadherin levels and ectopically express Laminin A (the fly orthologue of LAMA3). In the fly, this
phenomenon seems to be linked to integrin signaling and non-autonomous JNK activation. This was further validated with human
cell lines. We demonstrated that AGS parental cells (negative for E-cadherin) overexpressed Laminin g2 (332), MMP2, integrins
(b1 and b4) when compared to the same line stably transfected with E-cadherin. We concluded that, at the interface, the cells
expressing Laminin and integrin are those that lost E-cadherin. Laminin g2 overexpression leads to an increase in the invasive
capacity and an increase in cell survival, in accordance with pSrc and pAKT upregulation and caspase 3 dowregulation. In summary,
Laminin expression at the Ecad+/Ecad- interface is key for Ecad- cells to invade and survive.
The gastric molecular program that allows cell survival upon loss of E-cadherin-mediated adhesion
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome caused by germline mutations in the
E-cadherin encoding gene, CDH1. What is striking is that CDH1 germline mutations confer more than 80% lifetime risk to specifically
develop gastric cancer, despite that E-cadherin is expressed in all epithelial tissues. We hypothesized that CDH1 biallelic inactivation
is only tolerated in gastric epithelium due to a favorable gastric-specific expression program that allows cell-autonomous survival.
We have characterized the survival response of gastric, breast, and colon epithelium upon in E-cadherin downregulation by siRNA.
The results obtained corroborate our hypothesis that stomach epithelium is more resistant to loss of adhesion acquiring cellautonomous survival capacity. Moreover, basal cell death levels upon apoptosis induction with staurosporine and taxol indeed
suggest there must be a favorable gastric-specific expression program that allows and creates the tissue specific conditions to
overcome apoptosis. Accordingly, we evaluated the expression profiles and functional significance in resistance to apoptosis
induction of a series of candidate stomach-specific genes previously selected using bioinformatics tools. Our data supports a role for
S100P and CTSE in a gastric-specific molecular program that may ultimately encompass oncogenic potential. Furthermore, through
a proteomic profiler approach, we observed a striking upregulation of anti-apoptotic proteins upon CDH1 downregulation in gastric
epithelium. We have subsequently performed functional analysis of candidate molecules and found that PON2 and XIAP may be part
of the survival molecular program underlying gastric-specific resistance to E-cadherin loss. Currently, we are further characterizing
the molecular relationship between these anti-apoptotic proteins and the gastric-specific S100P and CTSE proteins, and how they
may interact and contribute to cancer transformation.
Functional evaluation of new E-cadherin germline missense mutations
Four new E-cadherin germline missense mutations were found in gastric cancer patients, and reported to our laboratory in order
to evaluate their pathogenicity through in vitro assays and in silico bioinformatic analysis. For in vitro functional characterization,
we performed slow aggregation and matrigel invasion assays in cells transiently transfected the vectors encoding WT or the
hE-cadherin mutants. Bioinformatic prediction of the impact of each mutation was performed using SIFT, Polyphen-2 and FoldX
programmes.
New bioimaging approach to distinguish WT from mutant forms of E-cadherin
We developed a bioinformatic tool that uses immunofluorescence images to quantify protein expression level and also to map the
protein at intra- and intercellular spaces. The output of the software can be analyzed by statistical methods or by constructing a
virtual cell that mimics the whole cell population examined. Using this approach, we were able to discriminate cells expressing wildtype E-cadherin from those expressing mutant forms of the protein. When compared to WT cells, we verify that mutant cells display
decreased fluorescence intensity at the membrane and present aberrant protein peaks corresponding to protein accumulation in
the perinuclear region.
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New bioimaging approach to determine cell cycle stage in single and cell populations using DAPI and FUCCI
analyses in WT and mutant forms of E-cadherin
We developed in collaboration with ISR-IST a bioinformatic tool that uses DAPI fluorescence images to determine the cell cycle
stage. The analysis is based on the quantification of the area and intensity of DAPI staining nuclei of in situ images of cell stably
expressing E-cadherin. To validate the method we used FUCCI (fluorescence ubiquitination cell cycle indicator), which is a two-color
sensor tool that enables the visualization of the cell cycle progression and division in live cells. Upon validation we found that the
bioimaging tool using DAPI staining only has an accuracy of 80% in the cell cycle staging of in situ images.
Genetic variants in the IL1A gene region contribute to gastric carcinoma susceptibility in European populations
In the context of sporadic gastric cancer, we have analysed the influence of human genetic variation on disease risk. Although
evidence points to the IL1 region as a genetic susceptibility region involved in gastric carcinoma risk (e.g. polymorphisms in the
IL1B and IL1RN genes), definite functional variants reproducible across populations of different genetic background have not been
discovered so far. Therefore, a high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to
identify haplotype tagSNPs. 87 SNPs were genotyped in a Portuguese case-control study (358 cases, 1485 controls) for the discovery
analysis. A replication study, including a subset of those tagSNPs (n=43), was performed in an independent analysis containing
individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for
overall gastric carcinoma and anatomopathological subtypes.
The most robust association was observed for SNP rs17042407, which is located 16Kb upstream of the IL1A gene. Although several
other SNP associations were observed, only the inverse association of rs17042407 allele C with intestinal type gastric carcinoma
was observed in both studies, retaining significance after multiple testing correction (p=0.0042) in the combined analysis. The
haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the
rs17042407 variant and gastric carcinoma, particularly of the intestinal type (p=3.1x10-5) and non-cardia localisation (p=4.6x10-3).
These results confirm the association of IL1 gene variants with gastric carcinoma and reveal a novel SNP and haplotypes in the IL1A
region associated with intestinal type gastric carcinoma in European populations (Durães et al. International Journal of Cancer,
2014).
Strain-specific sequences at the Helicobacter pylori cagA promoter influence CagA expression and interleukin-8
secretion
CagA is an important H. pylori virulence factor and a major contributor for gastric carcinoma development. Sequence heterogeneity
in the promoter region of the cagA gene which was linked to high CagA expression and worse gastric histopathology has been
recently identified. We have characterized the H. pylori cagA promoter region, to assess the relationship between variation in this
region and CagA expression, and to investigate the influence of cagA promoter variation and CagA expression on interleukin (IL)-8
secretion in Portuguese strains. We have confirmed that the cagA promoter showed high heterogeneity among strains, including
variation in sequence and copy number of several motifs. CagA protein expression was associated with a particular nucleotide
sequence at the -10 motif (p=0.012) and with the presence of the +59 motif (p=0.003). Moreover, the levels of IL-8 secreted by
gastric cells were correlated with the levels of CagA expression (rp=0.391; p=0.009), as well as with the presence of the +59 motif
in the cagA promoter (p<0.001). Further studies are needed to confirm the usefulness of specific regions on the cagA promoter as
markers to predict gastric carcinoma risk (Ferreira et al. In preparation).
Helicobacter pylori cagA and vacA genotyping cannot be used for identifying high-risk gastric carcinoma
patients in Macau, China
H. pylori virulence factors are associated with the clinical outcome of the infection. The aim of this study was to investigate the
relationship between H. pylori cagA and vacA genotypes, including the vacA mid (m)- and intermediate (i)-regions, and gastric
carcinoma development, in a population of Chinese patients from Macau. The results showed that the great majority of the H. pylori
strains in this population were vacA s1/i1 and cagA-positive, independently of the clinical outcomes of the infection. Furthermore,
and although the vacA m-region was more variable among H. pylori Chinese strains, no relationship was observed between vacA
m-region genotypes and gastric carcinoma. Therefore, these factors cannot be used for identifying high-risk patients in this
geographic region (Pinto-Ribeiro I et al. Helicobacter 2014).
Helicobacter pylori’s cholesterol uptake impacts resistance to docosahexaenoic acid
Docosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid with anti-inflammatory and antitumor effects, that directly inhibits
H. pylori growth in vitro and in mice (Correia et al. PLOS One 2013). We investigated if DHA affects also H. pylori growth by reducing
the availability of membrane cholesterol in the epithelial cell for H. pylori uptake. Levels of cholesterol in gastric epithelial cells and
of cholesteryl glucosides in H. pylori were determined by thin layer chromatography and gas chromatography. The consequences
of cholesterol depletion in epithelial cells on H. pylori growth were assessed in liquid cultures. We showed that H. pylori uptakes
cholesterol from epithelial cells. In addition, DHA lowered cholesterol levels in epithelial cells, decreased its de novo synthesis,
leading to a lower synthesis of cholesteryl glucosides by H. pylori. A previous exposition of H. pylori to cholesterol influenced
the bacterium response to the direct inhibitory effect of DHA. Overall, our results suggest that a direct effect of DHA on H. pylori
survival is modulated by its access to epithelial cell cholesterol, supporting the notion that cholesterol enhances the resistance
of H. pylori. The cholesterol-dependent resistance of H. pylori to antimicrobial compounds raises new important aspects for the
development of new anti-bacterial strategies (Correia et al. International Journal of Medical Microbiology 2014).
Water exposure modulates Helicobacter pylori virulence properties
While the influence of water in H. pylori culturability and membrane integrity has been extensively studied, there are little data
concerning the effect of this environment on virulence properties. Therefore, we studied the culturability of water-exposed H.
pylori and determined whether there was any relation with the bacterium’s ability to adhere, produce functional components of
pathogenicity and induce inflammation and alterations in apoptosis in an experimental model of human gastric epithelial cells. H.
pylori partially retained the ability to adhere to epithelial cells even after complete loss of culturability. However, the microorganism
is no longer effective in eliciting in vitro host cell inflammation and apoptosis, possibly due to the non-functionality of the cag type
IV secretion system. These H. pylori-induced host cell responses, which are lost along with culturability, are known to increase
epithelial cell turnover and, consequently, could have a deleterious effect on the initial H. pylori colonization process. The fact
that adhesion is maintained by H. pylori to the detriment of other factors involved in later infection stages appears to point to a
modulation of the physiology of the pathogen after water exposure and might provide the microorganism with the necessary means
to, at least transiently, colonize the human stomach (Guimarães et al. Memórias do Instituto Oswaldo Cruz 2014).
Helicobacter pylori detection using advanced locked nucleic acid (LNA) probes
Nucleic acid mimics robustly recognize DNA and RNA sequences and can be used for developing probes for fluorescence in
situ hybridization (FISH). We investigated the effect of different chemical modifications in fluorescent probes on their ability to
successfully detect the complementary target and discriminate mismatched base pairs by FISH. Different types of FISH probes were
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designed for detection of Helicobacter pylori and H. acinonychis. This is also the first study where unlocked nucleic acids (UNA)
were used as chemistry modification in oligonucleotides for FISH methodologies. The effectiveness in detecting the specific target
and in mismatch discrimination appears to be improved using locked nucleic acids (LNA)/2’OMe or peptide nucleic acid (PNA) in
comparison to LNA/DNA, LNA/unlocked nucleic acids (UNA) or DNA probes. Further, the use of LNA modifications together with
2’OMe monomers allowed the use of shorter fluorescent probes, improved mismatch discrimination, and increased the window of
hybridization temperatures (Fontenete et al. Applied Microbiology and Biotechnology, Accepted).
Characterization of the gastric microbiota in patients with chronic gastritis and gastric carcinoma
To determine the influence of the stomach microbiota in H. pylori-associated gastric carcinogenesis, we have characterized the
microbiota of chronic gastritis and gastric carcinoma patients, using the next generation sequencing platform Ion PGM. We have
found that the majority of the gastric microbiota was distributed in five main Phyla, Proteobacteria, Firmicutes, Actinobacteria,
Bacteroidetes, and Fusobacteria. The most representative Phylum in the stomach was the Proteobacteria. The abundance of
Helicobacter sp. was significantly lower in patients with gastric carcinoma than in patients with chronic gastritis. Analysis of the
phylogenetic diversity between groups of individuals in a principal coordinate analysis showed distinct microbiota profiles in the two
groups of patients.
P-cadherin signals through the laminin receptor alpha-6 beta-4 integrin to induce stem cell and invasive
properties in basal-like breast cancer cells
P-cadherin is a poor prognostic factor in breast cancer and its expression induces cancer stem cell and invasive properties to basallike breast cancer cells. We demonstrated that P-cadherin inhibition led to a significant decreased adhesion of cancer cells to the
basement membrane substrate laminin, as well as to a major reduction in the expression of the laminin receptor alpha-6 beta-4
integrin. Remarkably, the expression of this heterodimer was required for the invasive capacity and increased mammosphere
forming efficiency induced by P-cadherin expression. Moreover, we still demonstrated that P-cadherin downstream signaling, in
response to laminin, involves the activation of FAK, Src and AKT kinases. The association between the expression of P-cadherin,
alpha-6 beta-4 integrin and the active FAK and Src phosphorylated forms was validated in vivo (Vieira et al. Oncotarget 2014).
The basal epithelial marker P-cadherin associates with breast cancer cell populations harbouring a hypoxiaresistant phenotype
Using a large series of primary human breast carcinomas, we demonstrated that P-cadherin overexpression was significantly
associated with the expression of HIF-1a, GLUT1, CAIX, MCT1 and CD147, independently of the molecular subtype. Interestingly,
using the basal-like breast cancer cell models BT20 and SUM149, we were able to validate some of these associations. We showed
that the induction of HIF-1a by CoCl2 was accompanied by a significant increase of P-cadherin expression at the cell membrane.
By real-time PCR, we still demonstrated that P-cadherin silencing leads to a decrease of the mRNA levels of GLUT1 and CAIX, not
altering the transcripts of HIF-1a, MCT1 and CD147. Moreover, we could also find that the cancer cell fractions harboring high
levels of P-cadherin were the same exhibiting more GLUT1 and CAIX expression. In conclusion, our results establish a link between
aberrant P-cadherin expression and the breast cancer cell populations harboring a hypoxia-resistant phenotype (Sousa et al. BMC
Cancer 2014).
High-throughput molecular profiling of a P-cadherin overexpressing breast cancer model reveals new targets
for the anti-cancer bacterial protein azurin
Azurin is a bacterial protein from Pseudomonas aeruginosa which exerts an inhibitory activity in cancer cells. In P-cadherinoverexpressing models, azurin decreases the invasion of cancer cells. We performed a microarray analysis to compare the
expression profile of azurin treated cells with different P-cadherin expression levels. Azurin up-regulated apoptosis mediated by
p53 protein, endocytosis and vesicle-mediated transport. In the contrary, in invasive MCF-7/AZ.Pcad cells, azurin decreased the
expression of genes associated with cell surface receptors and signal transduction, as well as biological adhesion. Further, azurin
decreased adhesion of cells to proteins from the extracellular matrix (ECM) and altered protein expression of integrins alpha 6, beta
4 and beta 1 and interfered with the ability of these cells to form mammospheres. Altogether, our results further enlighten the anticancer effects mediated by azurin in P-cadherin overexpression breast cancer models (Bernardes et al. The International Journal of
Biochemistry & Cell Biology 2014).
Interactions between tumor and stromal cells that contribute to colorectal cancer progression
The maintenance of the architecture and homeostasis of the colonic epithelium results from a very controlled spatial organization
of signals emanating from a crosstalk between epithelial and mesenchymal cells residing in close proximity to the epithelium.
Deregulation of this fine-tuned crosstalk promotes tumor development. We focused on how KRAS activation in colonic cells
modulate epithelial-stromal crosstalk and creates a pro-tumoral microenvironment. In a panel of colorectal cancer cell lines (DLD1KRASG13D, HCT116KRASG13D, SW480KRASG12V, HT29KRASWT, RKOKRASWT, Caco2KRASWT) we characterized the expression
of proteins from intestinal homeostasis-related signaling pathways, namely sonic hedgehog (Shh), BMP7, and TGFbeta1 proteins,
all known to be pro-tumorigenic. Our preliminary results show that all the cell lines express variable levels of the three molecules,
independently of the presence of a KRAS mutation. However, only two cell lines, SW480 and Caco2, were found to express high
levels of the three molecules simultaneously. Further studies will elucidate the importance of these signaling pathways in colorectal
cancer progression.
New Strategies for Colorectal Cancer Therapy: a MAPK- and PI3K-Targeted Approach
At present, the therapeutic option for patients with metastatic CRC (mCRC) involves the use of EGFR antibodies but only a small
percentage of patients benefit from such therapies. Thus, it is urgent to unravel new strategies for CRC therapy and explore putative
biomarkers predictive of therapy outcome. Interestingly, we verified that inhibition of MEK1/2 and PI3K modulated cell viability/
proliferation, cell cycle and apoptosis differentially in human colorectal cancer cells with distinct mutational status for KRAS, BRAF
and PI3K. Furthermore, the analysis of a multitude of proteins by the use of antibody arrays revealed specific alterations in a wide
spectrum of kinases and apoptosis-related proteins upon MEK1/2 and/or PI3K silencing. More importantly, our data demonstrates a
pivotal role for PI3K in the survival of CRC cells.
National collaborations
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Arsénio Fialho, IBB-Instituto Superior Técnico, Lisboa
Fátima Baltazar, ICVS, University of Minho, Braga
Florence Janody, IGC, Oeiras
Isabel Amendoeira, HSJ, Porto
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Isabel Rocha, CEB, University of Minho, Braga
João Miguel Sanches, ISR, Instituto Superior Técnico, Lisboa
Manuel A. Santos, CESAM, University of Aveiro, Aveiro
Manuela Lacerda, IPOFG-CROC, Coimbra
Maria Oliveira, INEB, Porto
Mónica Bettencourt-Dias, IGC, Oeiras
Nuno Azevedo, FEUP, Porto
Nuno C. Santos, IMM, FMUL, Lisboa
Paula Alves, IBET, Oeiras
Pedro Granja, INEB, Porto
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Célia Carlini, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Dulciene Queiroz, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
David Huntsman, British Columbia Cancer Agency, Vancouver, Canada
Vanessa Ramirez, Calderón Guardia Hospital, San José, Costa Rica
Lene J Rasmussen, University of Copenhagen, Copenhagen, Denmark
Eliette Touati, Institute Pasteur, Paris, France
Françoise Bono, Sanofi-Aventis Rechérche, Toulouse, France
Sebastian Suerbaum, Hannover Medical School, Hannover, Germany
Franco Roviello, University of Siena, Siena, Italy
Carlos Gonzalez, Catalan Institute of Oncology, Barcelona, Spain
Fernando Casares, Centro Andaluz de Biología del Desarrollo, Sevilla, Spain
Jorge Cameselle-Teijeiro, Complexo Hospitalar Universitario, Vigo, Spain
Ola Söderberg, University of Uppsala, Uppsala, Sweden
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Leen-Jan van Doorn, DDL Diagnostic Laboratory, Voorburg, The Netherlands
Marjolijn Ligtenberg, University Nijmegen Medical Centre, Nijmegen, The Netherlands
Robert Hofstra, University of Groningen, Groningen, The Netherlands
Göran Landberg, University of Manchester, Manchester, UK
John Atherton, University of Nottingham, Nottingham, UK
Robert Clarke, Paterson University of Manchester, Manchester, UK
David Mooney, Harvard University, Cambridge, USA
Kevin Haigis, Massachusetts General Hospital, Boston, USA
Judy Lieberman, Harvard Medical School, Boston, USA
Patricia Steeg, Center for Cancer Research, NCI, Bethesda, USA
Future Research
In the gastric cancer setting:
To identify key players involved in the cell-ECM crosstalk in the context of E-cadherin mutations associated to Hereditary Diffuse
Gastric Cancer (HDGC);
To identify ECM components/composition that modulate the expression of integrins or associated molecules;
To study the consequences of integrin switch and ECM modulation with respect to cellular behavior;
To disclose the molecular mechanisms underlying the mutant E-cadherin-integrin-ECM associated cellular effects;
To evaluate if E-cadherin loss induces basal extrusion from an epithelium;
To identify the tensional forces that induce basal extrusion of E-cadherin defective cells;
To understand the crosstalk between tensional forces, cytoskeleton, and nuclear position;
To validate the role of PON2, XIAP, the gastric-specific S100P and CTSE in E-cadherin-related survival/apoptosis in the stomach, using
chick embryonic tissues.
In the gastric cancer setting mediated by Helicobacter pylori infection:
To determine host cell signaling pathways that lead to up-regulation of matrix metalloproteinase 10 in gastric epithelial cells induced
by H. pylori infection;
To dissect the signaling pathways involved in receptor tyrosine kinase activation induced by H. pylori and to investigate the
respective functional consequences;
To identify H. pylori factors involved in disturbance of cell-cell adhesion complexes;
To extend the characterization of the stomach microbiota to patients at different stages of gastric carcinogenesis, in order to
evaluate the influence of bacteria other than H. pylori in gastric carcinoma development.
In the breast cancer setting:
To identify key signaling pathways induced by P-cadherin expression, namely its role in cancer cell metabolism, survival, invasion, as
well as miRNAs expression;
To study the role of P-cadherin in the seeding of metastasis;
To study the role of soluble P-cadherin in the disruption of the BBB;
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To identify cancer stem cell markers with relevance in brain metastatic colonization;
To study the impact of P-cadherin expression in the DNA damage/repair signaling triggered by radio/chemotherapy in normal and
cancer cells;
To study the role of P-cadherin in cell polarity, namely in tight junction stability/assembly and in mitotic spindle orientation;
To find new therapeutic strategies to inhibit P-cadherin expression or associated signaling pathways;
To identify new mechanisms of CDH3 gene regulation in normal epithelial tissues and cancer.
In the colon cancer setting:
To determine if the survival of KRAS, BRAF and PI3K mutant CRC cells are all modulated by PI3K activation and validate the relevance
of PI3K activity and downstream targets in primary cultures of CRC tissues.
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Raquel Seruca, Ceu Figueiredo, Joana Paredes, Ana Sofia Ribeiro, André Vieira, Marina Leite, Rui Ferreira, Sofia Fernandes,
Sérgia VelhoPrograma Graduado em Áreas da Biologia Básica e Aplicada (GABBA), Universidade do Porto
Coordenação e participação no módulo de Oncobiologia; Orientação de estudantes
Raquel Seruca, Ceu Figueiredo, Joana ParedesInternational Doctoral Programme on Cellular and Molecular Biotechnology
Applied to Health Sciences (BiotechHealth)
Raquel Seruca, Ceu Figueiredo, Joana ParedesPrograma de Doutoramento em Biomedicina (FMUP)
Participação no Módulo de Oncobiologia; Orientação de estudantes
Ceu Figueiredo, Joana ParedesDoutoramento em Patologia e Genética Molecular, Instituto de Ciências Biomédicas Abel Salazar
(ICBAS), Universidade do Porto
Orientação de estudantes
Joana Paredes
Programa de Pós-Graduação Ciência para o Desenvolvimento (PGCD), Universidade de Cabo Verde, Cidade da Praia, Cabo Verde
Participação no módulo “The working cell (cell cycle, cytoskeleton and cancer)”
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Raquel Seruca, Ceu Figueiredo, Joana ParedesMestrado em Medicina e Oncologia Molecular, Faculdade de Medicina da
Universidade do Porto
Participação do Módulo de Oncobiologia; Orientação de estudantes
Ceu Figueiredo, Joana ParedesMestrado em Oncologia, Instituto de Ciências Biomédicas Abel Salazar - Orientação de
estudantes
Ceu Figueiredo, Joana ParedesMestrado Integrado em Medicina, Faculdade de Medicina da Universidade do Porto - Orientação
de estudantes
Invited Talks
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Ceu Figueiredo. The stomach microbiota in gastric carcinogenesis. VI International Symposium of Helicobacter pylori: Natural
history and implications for human health. Instituto de Investigaciones en Salud (INISA), University of Costa Rica. San José, Costa
Rica. 03/12/2014.
Ceu Figueiredo. Gastric microbiota and bacterial metabolism in gastric cancer. Plenary Symposium “Only H. pylori in the
stomach?” 27th International Workshop on Helicobacter and Microbiota in Inflammation and Cancer, European Helicobacter
Study Group (EHSG). Rome, Italy. 12/09/2014.
Ceu Figueiredo. H. pylori-mediated proteolytic activity in the gastric epithelium. Plenary Symposium “H. pylori-associated
gastric carcinogenesis”. 22nd United European Gastroenterology Week (UEGW). Vienna, Austria. 21/10/2014.
Rui Ferreira. Helicobacter pylori infection and gastric carcinoma development. V Jornadas Nacionais de Ciências Biomédicas
from the Faculty of Health Sciences of the University of Beira Interior. Covilhã, Portugal. 14/03/2014.
Ana Sofia Ribeiro. Cadherins, Cancer Stem Cells and Metastasis. Speed Dating and Cancer: basic biology and beyond. Coimbra,
Portugal. 21/02/2014.
Joana Paredes. E- cadherin and P-cadherin: their crosstalk in breast cancer cells. 5th French Cell Adhesion Club Symposium.
Marseille, France. 16/05/2014.
Joana Paredes. Identifying intermediate “metastable” phenotypes during breast cancer epithelial-mesenchymal transition.
Advanced Summer School 2014 – The self-renewal/differentiation interface. Barcelona, Spain. 30/06/2014.
Joana Paredes. Cancer stem cells. Curso de Pós-Graduação em Oncologia Molecular: Biologia do Cancro e Terapias Emergentes.
Instituto Português de Oncologia Francisco Gentil – Centro Regional de Oncologia de Coimbra. Coimbra, Portugal. 17/10/2014.
Joana Paredes. Carcinogénese Mamária. Curso Ibérico de Formação em Senologia. Unidade de Senologia de Santarém.
Santarém, Portugal. 24/10/2014.
Joana Paredes. The crosstalk between cadherins (and integrins) in breast cancer. Centre de Recherches en Oncologie Biologique
et Onco-Pharmacologie (UMR_S 911 CRO2). Aix-Marseille Université, France. 06/11/2014.
Joana Paredes. Brain metastasis and glioblastomas: different diseases, common biological traits?. VII Congresso Nacional da
Associação Portuguesa de Neuro-Oncologia. Lisboa, Portugal. 21/11/2014.
Oral Presentations
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Ribeiro AS, Nobre AR, Monteiro J, Carvalho F, Vieira AF, Sousa B, Albergaria A, Seruca R, Santos NC, Paredes J. E-cadherin
represses cell-cell adhesion mediated by E-cadherin in breast cancer cells: an AFM analysis. 3rd Bioimaging Symposium. Porto,
Portugal. 16/10/2014.
Prizes
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Joana Paredes - Grant Laço 2014 - Dasatinib as an option to treat P-cadherin-overexpressing poor prognosis breast cancer
Ribeiro AS, Nobre AR, Monteiro J, Carvalho F, Vieira AF, Sousa B, Albergaria A, Seruca R, Santos NC, Paredes J.Targeting
P-cadherin/Src induced mechanotransduction signaling: dasatinib as a promising therapeutic approach for invasive breast
cancer. ASPIC Best Poster Award. - 1st ASPIC Meeting, Lisbon, Portugal. November 2014.
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Differentiation and cancer
Objectives
Our main objectives are to understand the mechanisms whereby differentiation abnormalities, that are the first step of some
carcinogenic processes, predispose and progress to cancer and ultimately identify novel biomarkers and therapeutic targets that
may improve cancer diagnosis, screening, prevention, patient stratification and treatment. Two research lines have been followed: 1.
To understand the pathophysiology of gastric carcinogenesis and 2. To characterize the glycoproteome remodeling in precancerous
and cancerous lesions.
Main Achievements
SOX2 and CDX2 in gastric precancerous and cancerous lesions
We have shown that SOX2, a transcription factor associated with embryonical and adult stem cells, is expressed in the normal
gastric mucosa and in a subgroup of intestinal metaplasia, the incomplete type. On the opposite, it is frequently lost in dysplastic
lesions (Camilo et al, Histopathology, 2015). We have further shown that, in gastric carcinomas, SOX2 expression predicts worse
patient prognosis and the SOX2 locus is frequently subjected to copy number gain (Camilo et al, BMC Cancer, 2014). On the other
hand, we have also shown that CDX2 is expressed in all dysplastic lesions, suggesting a continuum between intestinal metaplasia
and dysplasia in the gastric setting. In gastric carcinomas, CDX2 expression marks a better patient prognosis possibly linked to its
function in differentiation.
Downregulation of CDX2 expression using a nanoparticle delivery system
We have developed a strategy to downregulate CDX2 expression using siRNAs delivered through a chitosan nanoparticle-based
approach. We demonstrated the efficacy of this system in cell lines and characterised their ability to cross the mucus barrier of
several gastrointestinal epithelia, showing that they are able to cross the gastric mucus but not the intestinal mucus barrier (Sadio et
al, PlosOne, 2014).
MUC16 glycoprofile as an improved cancer biomarker
We have applied the Proximity Ligation Assay to improve current biomarker detection in ovarian cancer. We demonstrated that
MUC16-STn glycoform has improved specificity and sensitivity over current methods to diagnose and monitor ovarian cancer
(Ricardo et al, Mol Onc, 2015).
Generation of new experimental tools
We have generated several new experimental tools to be used in the future: a new cellular model with CDX2 knock-out using a
genome editing approach; a new antibody against MUC16; a new mouse model with MEX3A knock-out.
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Faculty of Health Sciences of the University of Copenhagen - Ulla Mandel and Henrik Clausen - Collaboration has been
fundamental for characterization of carbohydrate antigens and glycosyltransferases using unique monoclonal antibodies.
Lara Silva finished a joint PhD thesis in 2014. We regularly collaborate in pos-graduate teaching activities at the University of
Copenhagen – PhD Glycobiology Course.
INSERM, Nantes – Jacques Le Pendu - This collaboration has been critical for the prosecution of the study of Secretor and Lewis
phenotypes/genotypes, due to the unique expertise of Jacques Le Pendu in the field. We are currently folllowing an interesting
possibility of cooperation of Helicobacter pylori in glycoengeneering the host for certain Calicivirus strain infections. A joint
publication was obtained in 2014 (Ruvoën-Clouet N et al, J Infect Dis, 2014).
University of Uppsala - Ola Soderberg - This collaboration has allowed the successful establishment of Proximity-Ligation
assays for identification of glycopeptide structures in situ. We are following-up the implementation of this strategy to detect
glycopeptides in serum as an improved cancer monitoring strategy.
INSERM, Grenoble - Marc Billaud - This collaboration is essential for the study of MEX3A, identified for the first time in humans
by this group. Joint publications were previously obtained. Currently we are following up a joint study on the involvement of
MEX3A in polarity and metabolism regulation in vitro and in a knock-out mouse model. A joint application to Infrafrontier FP7
mouse program has secured financing for the establishment of a MEX3A knock-out mouse model.
Faculty of Health Sciences of the University of Copenhagen - Eric Paul Bennett - This collaboration has been fundamental for the
establishment of a novel cellular system with CDX2 knock-out using a genome editing approach, with co-supervision of a PhD
student, Rita Pinto.
Instituto de Oncologia de Lisboa, Portugal - Paula Chaves - We are collaborating with the group in Lisbon using Barrett’s
oesophagus as a parallel model to intestinal metaplasia.
University of Helguero , Mexico - Luisa Silva - This collaboration has allowed detection of glycopeptides using biosensors which
led to a joint publication (Silva ML, et al, Biosensors & bioelectronics, 2014) and to a successful H2020-RISE proposal which was
declined due to alteration of the rules that led us to decide it was not any more interesting to pursue.
Instituto de Oncologia de Lisboa, Portugal - Ana Félix - This collaboration has allowed to study MUC16 glycoforms in a series of
ovarian cancer.
Future Research
SOX2 and stemness features in gastric cancer
We will further characterize the expression of SOX2 and association with clinicopathological features of the tumors in enlarged
series of patients from IPO-Coimbra and Hospital S. João. We will extend this study to other tumors types namely colonic (in
collaboration with the Oslo Cancer Center) and ovarian tumors. We will address in vitro and in vivo the relevance of SOX2 for
therapy resistance. For this we will use, in addition to standard cell lines, a manipulated cellular model with CDX2 knock-out that
acquires SOX2 expression and stemness markers.
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MEX3A biological functions - impact on polarity and metabolism
Based on preliminary data showing that MEX3A regulates the mTOR pathway, which might explain its role in polarity regulation and
suggests the involvement in metabolism, we will further explore this research line. For that, we will use cell lines and a knock-out
mouse model (financed by Infrafrontier FP7 mouse program).
MUC16 glycoprotein in ovarian cancer
We will expand the previous study on MUC16 glycoform identification to other ovarian cancer types and will expand to serum
detection.
We will address the interaction of MUC16 with mesothelin in the dissemination of ovarian cancer to the peritoneum. For this, cell
lines (with and without normal glycosylation) and mouse models will be used.
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Raquel Almeida, Leonor David, Rita Barros GABBA (Graduate program in areas of Basic and Applied Biology of the University of
Porto)
Raquel Almeida, Leonor David Programa Doutoral em Biomedicina da Faculdade de Medicina da Universidade do Porto
Raquel Almeida, Leonor David Workshop on Cancer Research: biological and molecular basis
Local: IPATIMUP Instituição: IPATIMUP/ICBAS Âmbito: Curso de formação contínua
Raquel Almeida, Leonor David Programa Doutoral de Medicina e Oncologia Molecular da Faculdade de Medicina da
Universidade do Porto.
Raquel Almeida, Leonor David Programa Doutoral em Patologia e Genética Molecular, ICBAS
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Raquel Almeida, Leonor David Mestrado em Medicina e Oncologia Molecular, FMUP
Invited Talks
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Raquel Almeida. Intestinal metaplasia of the stomach: a model of tissue regeneration with aberrant differentiation. . .. INSERM/
UJF U823, Grenoble, France . 04/03/2014.
Raquel Almeida. Tissue regeneration with aberrant differentiation.. .. Faculty of Pharmacy, University of Porto, Portugal.
20/05/2014.
Raquel Almeida. Tissue regeneration with aberrant differentiation - stem cell reprogramming. .. Instituto Português de
Oncologia - Lisboa, Portugal. 04/06/2014.
Leonor David. HPV in precursor lesions and epidermoid carcinoma of the conjunctiva.. Symposium on “Ocular tumours: From
genetics to treatment”. Porto, Portugal. 16/06/2014.
Oral Presentations
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Bruno Pereira. At the crossroads of post-transcriptional regulatory networks: the role of the RNA-binding protein MEX3A in
gastrointestinal cancer.. I3S 4th Annual Meeting 2014. Póvoa de Varzim, Portugal. 30/10/2014.
Rita Pinto. Establishment of an inducible CDX2 KO/KI model using zinc-finger nucleases: Impact on the intestinal phenotype.. 1st
ASPIC International Congress. Lisboa, Portugal. 26/11/2014.
Prizes
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Bruno Pereira. - Meeting Bursary to attend the EACR conference Goodbye Flat Biology: 3D models and the tumour
microenvironment
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Expression Regulation in Cancer
Objectives
AIM 1: Identification of germline and somatic defects underlying familial aggregation of GC.
We plan to map inherited genetic determinants in large and well defined cohorts of GC families gathered in collaboration with
national and international researchers working on hereditary GC. The approach is centered on the careful analysis of the clinical
history and histopathology of tumors from these families followed by targeted NGS at the germline and somatic level. The functional
relevance of alterations found is subsequently assessed through a pipeline of bioinformatics and wet lab tools, using segregation
analysis, independent/validation cohorts and in vitro and in vivo methodologies.
AIM 2: Extracellular vesicles role in cancer cell behaviour and as markers of cancer recurrence
2.1 Extracellular Vesicles and Epithelial-to-Mesenchymal Transitions (EMT/MET): The general aim of this project is to disclose
which factors, within extracellular vesicles (exosomes) secreted by cells undergoing EMT/MET, have functional autocrine/
paracrine effects that induce maintenance of a phenotype or reprogramming of recipient cells (cancer and other) to successfully
complete the process of metastasization.
2.2 Non-invasive monitoring of Gastric Cancer through the analysis of Circulating Exosomes. The general aim of this project is to
develop a pilot study to identify, monitor and evaluate the functional relevance of specific molecular markers of GC in exosomes
isolated from patients’ plasma.
AIM 3: Gastric cancer intra-tumour heterogeneity models and treatment
3.1 Characterization of intra-tumour heterogeneity in GC and identification of specific gastric tumour subgroups according to the
presence of specific molecular markers.
3.2 Generation and characterization of in vitro and in vivo GC models that mimic intra-tumour heterogeneity with the aim of
generating knowledge to identify effective combination therapy approaches for personalized therapy of gastric cancer patients.
AIM 4: Characterization of an in vitro epithelial-to-mesenchymal transition (EMT/MET) model.
4.1 Understand the biological and molecular processes underlying the reacquisition of epithelial phenotypes by cells which have
undergone EMT. Such processes will be of relevance for cancer progression.
4.2 Characterization of the role of a recently described gene (Dies1) in transdifferentiation processes.
Main Achievements
Aim 1: Familial gastric cancer: genetic susceptibility, pathology, and implications for management.
H Pinheiro and C Oliveira have reviewed the current knowledge concerning familial gastric cancer with particular emphasys in
hereditary diffuse gastric cancer, its pathophysiology and clinical management in two different manuscripts:
1) Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and
implications for management. Lancet Oncol. 2015 Feb;16(2):e60-e70. doi: 10.1016/S1470-2045(14)71016-2. Review.
2) Pinheiro H, Oliveira C, Seruca R, Carneiro F. Hereditary diffuse gastric cancer - pathophysiology and clinical management.
Best Pract Res Clin Gastroenterol. 2014 Dec;28(6):1055-68. doi: 10.1016/j.bpg.2014.09.007. Epub 2014 Sep 28. PubMed PMID:
25439071.
Aim 1: Germline mutations in MAP3K6 are associated with familial gastric cancer.
H Pinheiro and C Oliveira have participated in a collaborative study that examined a large family from Canada with Familial Gastric
Cancer (FGC) without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase
kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6
was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with nonCDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T,
p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and
evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual.
These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing
the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6
variants as a predisposing factor for FGC.
This work has been published in an original manuscript:
Gaston D*, Hansford S*, Oliveira C, Nightingale M, Pinheiro H, Macgillivray C, Kaurah P, Rideout AL, Steele P, Soares G, Huang
WY, Whitehouse S, Blowers S, LeBlanc MA, Jiang H, Greer W, Samuels ME, Orr A, Fernandez CV, Majewski J, Ludman M, Dyack
S, Penney LS, McMaster CR, Huntsman D, Bedard K. Germline mutations in MAP3K6 are associated with familial gastric cancer.
PLoS Genet. 2014 Oct 23;10(10):e1004669. doi: 10.1371/journal.pgen.1004669. eCollection 2014 Oct. PubMed PMID: 25340522;
PubMed Central PMCID: PMC4207611.
Aim 1: Rescue of wild-type E-cadherin expression from HDGC nonsense-mutated cancer cells by a suppressortRNA.
The group has evaluated suppressor-tRNAs potential to replace CDH1 premature stop codons (PTCs) with a cognate amino acid,
inducing readthrough and generating full-length proteins. The use of suppressor-tRNAs in HDGC patients could therefore constitute
a therapeutic option for nonsense mutation carriers, delaying the development of gastric cancer. Using site-directed mutagenesis,
we developed an arginine suppressor-tRNA vector to correct one HDGC nonsense mutation. E-cadherin-deficient cell lines were
transfected with plasmids carrying simultaneously the suppressor-tRNA and wild-type or mutant CDH1 mini-genes. RT-PCR, western
blot, immunofluorescence, flow cytometry and proximity ligation assay (PLA) were used to establish the model, and monitor
mRNA and protein expression and function recovery from CDH1 vectors. Cells expressing a CDH1 mini-gene, carrying a nonsense
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mutation and the suppressor-tRNA, recovered full-length E-cadherin expression and its correct localization and incorporation into
the adhesion complex. This was the first demonstration of functional recovery of a mutated causative gene in hereditary cancer by
cognate amino acid replacement with suppressor-tRNAs. Of the HDGC families, 21.3% are candidates for correction with suppressortRNAs to potentially delay cancer onset.
This work has been published in an original manuscript:
Bordeira-Carriço R, Ferreira D, Mateus DD, Pinheiro H, Pêgo AP, Santos MA, Oliveira C. Rescue of wild-type E-cadherin expression
from nonsense-mutated cancer cells by a suppressor-tRNA. Eur J Hum Genet. 2014 Sep;22(9):1085-92. doi:10.1038/ejhg.2013.292.
Epub 2014 Jan 15. PubMed PMID: 24424122; PubMed Central PMCID: PMC4135406.
Aim 2: Extracellular Vesicles and Epithelial-to-Mesenchymal Transitions
J Carvalho have established and optimized several methods for extracellular vesicles’ isolation and characterization and we are
currently applying several functional assays (in vitro and in vivo) to disclose the role of extracellular vesicles in EMT/EMT.
Aim 2: Biological Properties of Extracellular Vesicles and Their Physiological Functions.
J Carvalho and C Oliveira, together with several members of the European Network on Microvesicles and Exosomes on Health and
Disease have reviewed the currently available knowledge on the biological properties of extracellular vesicles and their physiological
functions.
This extensive review was already accepted for publication in the Journal of Extracellular Vesicles.
Aim 2: Extracellular Vesicles - powerful markers of cancer EVolution
J Carvalho and C Oliveira published their opinion on extracellular vesicles and their role as markers of cancer evolution in:
Carvalho J and Oliveira C. Extracellular Vesicles - powerful markers of cancer EVolution. Front Immunol. 2015 Jan 12;5:685. doi:
10.3389/fimmu.2014.00685. eCollection 2014.
Aim 2: Non-invasive monitoring of Gastric Cancer through the analysis of Circulating Exosomes
J Carvalho and C Oliveira have established a collaboration with a cancer hospital IPOFG-Coimbra to develop a pilot study based on
molecular analyses of exosomes isolated from plasma of Gastric Cancer patients. At this point, we have obtained approval from the
Ethics Committee of the hospital and GC patients are currently under follow-up. We have also optimized several protocols related
with isolation and characterization of exosomes from plasma samples. Additionally, we have submitted this project to the “Prémios
Maratona da Saúde 2014”.
Aim 3: Gastric Cancer Biomarkers with therapeutic value
GM Almeida and C Oliveira have reviewed the currently available knowledge on gastric cancer biomarkers with particular emphasis
on those with therapeutic target potential. This has been published:
Durães C, Almeida GM, Seruca R, Oliveira C, Carneiro F. Biomarkers for gastric cancer: prognostic, predictive or targets of
therapy? Virchows Arch. 2014 Mar;464(3):367-78.
Aim 3: Generation of intra-tumour heterogeneity GC in vivo model
GM Almeida has developed a xenograft mouse model that partially mimics the heterogeneity found in gastric tumours by injecting
a mixture of five different gastric cancer cell lines in the back of nude mice. Tumour growth kinetics was evaluated and the resulting
heterogeneity found in the obtained tumours and metastasis assessed. The full characterization of this model is still ongoing,
however it will soon be ready to test a variety of therapeutic agents.
Aim 4: MET entails its own set of novel and/or differentially active molecular circuitries, generating cells with
features distinct from the original epithelial state
P Oliveira and J Carvalho used an in vitro TGFß1-induced EMT/MET model, to demonstrate that MET is able to generate a
heterogeneous population of cells (Reverted-Epithelial or RE cells) with a biological signature not necessarily mirroring that of EMT.
These RE-cells displayed novel functional properties, such as increased self-renewal potential and in vivo tumourigenesis ability.
Moreover, whole-transcriptome analysis revealed de novo activation of several pathways, such as Toll-like receptor signalling,
further confirmed in RE-cells-derived tumours. Considering the increasing evidences towards tumours as a heterogeneous entities,
our model is a valuable tool for the discovery of novel pathways of relevance for tumour progression.
These results are included in a research article in preparation.
Aim 4: Characterization of the role of a recently described gene (Dies1) in transdifferentiation processes
Dies1 has been described as a gene with a crucial role in differentiation of embryonic stem cells. P Oliveira has been studying
the role of this gene and its regulatory mechanisms in an EMT/MET and cancer contexts. We have shown that this gene may be
necessary for re-epithelization of cells and it is regulated by promoter methylation. Moreover in gastric cancer samples we have
seen that expression of this gene is downregulated.
These results and others are included in a research article in preparation.
Bioinformatics data analysis and data mining for collaboration projects
During the year of 2014, several projects of bioinformatics data analysis have been conducted. In particular, we have collaborated
with:
1) Joana Paredes’ team (Cancer Genetics group, Ipatimup): data re-analysis of a microarray gene expression experiment for selection
of differentially expressed microRNAs and cDNAs as well as data mining of TCGA database;
2) Celso Reis’ group (Glycobiology in Cancer, Ipatimup): data mining for discovery of regulatory regions within the NFKB gene
(research article submitted);
3) Translational Unit at Ipatimup: assessment of mutations in several genes for all gastric cancer cell lines available at Ipatimup’s Cell
Line Bank;
4) Manuel Santos’s group at University of Aveiro: bioinformatics data analysis of cell line exomes with mutated tRNAs (NGS);
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5) Didier Cabanes’ Group at IBMC: re-analysis of RNA-seq experiments performed using Listeria monocytogenes (WT and mutants)
for assessment of differential expressed genes.
6) João Barata’s group at IMM: bioinformatics data analysis of gene expression microarrays of cell lines treated with citokines;
Career Development Program applications and Outcomes
P Ferreira applied for a iFCT position: “Understanding the impact of acquired and germline genetic variants in the complexity of
gastric cancer”.
Recommendation for 5-years funding from January 2015 to work in the Expression Regulation in Cancer Group
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International Gastric Cancer Linkage Consortium (IGCLC) 2014 - C Oliveira and H Pinheiro have participated in “Second
Consensus Meeting on Hereditary Gastric Cancer (IGCLC)” held on 19-21 March 2014 at the Radboud University Medical Center
in Nijmegen, the Netherlands. In this meeting the HDGC guidelines have been discussed, updated and will be published in 2015.
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Protocol with Instituto Português de Oncologia, Francisco Gentil - Coimbra - Carvalho and C Oliveira have established a
collaboration with IPOFG-Coimbra to develop a prospective study with longitudinal and cross-sectional molecular analyses of
exosomes isolated from plasma of Gastric Cancer patients.
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2nd GEIVEX Symposium - Extracellular Vesicles: From the bench to the clinics - J Carvalho and C Oliveira have participated in
the Second Symposium of the Grupo Español de Innovación e Investigación en Vesículas Extracelulares held on 9-10th 2014 in
Tarragona, Spain. In this meeting we have discussed the possibility of organizing an Iberian Society of Extracellular Vesicles.
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European COST Action CM1106 - GM Almeida has participated in two meetings: 2nd Workshop on “Chemical approaches to
targeting drug resistance in cancer stem cells”; Tenerife, Spain, 14-15 October 2014;
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2nd Working Group Meeting on “Chemical approaches to targeting drug resistance in cancer stem cells”; Budapest, Hungary,
27-28 March 2014.
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European COST Action BM1202 - C Oliveira and J Carvalho are Management Committee member (C Oliveira) and Management
Committee substitute member (J Carvalho) of the BMBS COST Action BM1202 “European Network on Microvesicles and
Exosomes in Health and Disease (ME-HAD)” (http://www.cost.eu/domains_actions/bmbs/Actions/BM1202?management).
Within the scope of this COST Action, C Oliveira has actively participated in two meetings: 1) Work group and Management
Committee Meeting, 03/05/2014, Rotterdam, Holland; 2) Autumn Meeting of the Cost action European Network on
Microvesicles and Exosomes in Health and Disease, 27/09/2014, Palermo, Italy.
Future Research
Hereditary Diffuse Gastric Cancer - beyond CDH1 coding mutations
The identification of novel HDGC causes, to use in secondary prevention, helping to decrease the high mortality in the 50% of
affected families without genetic diagnosis is seriously needed.
Our data demonstrate that, regardless of carrying a germline CDH1 defect, >90% of tumours arising in HDGC families display
aberrant E-cadherin expression, and that >70% of CDH1-mutation negative HDGC families show germline monoallelic CDH1
downregulation, indistinguishable from that of carriers of causative CDH1 truncating mutations. These evidences imply CDH1 in the
ethiology of more HDGC cases than previously expected. Our main goal is to disclose the mechanism by which this happens using
NGS, gene editing, in silico, in vitro and in vivo methodological approaches.
Extracellular vesicles (exosomes) in EMT/MET and Gastric Cancer
Project 1 - Extracellular vesicles and EMT/MET: Working under the hypothesis that cancer cells metastatic behaviour is partially
attributable to signals enclosed in secreted extracellular vesicles (mainly exosomes), we will profile cancer-derived exosomes
content and explore their role in reprogramming spreading of EMT/MET phenotypes.
Project 2 - Non-invasive monitoring of Gastric Cancer through the analysis of Circulating Exosomes: We hypothesize that exosomes
isolated from plasma of GC patients contain specific GC molecular markers, making them adequate to monitor tumor heterogeneity/
dynamics and drug sensitivity, likely to change during the therapeutic process and anticipate disease relapse. We will start the
collection of primary tumours and isolation of exosomes from plasma samples of GC patients.
Uncovering novel biomarkers for GC
Bioinformatics Analysis of Data resulting from DNAseq, RNAseq and Methylseq of 50 gastric cancer samples and paired normal.
Our aim with this project is to, after proper data analysis and integration, uncover novel biomarkers useful for GC prognosis and
therapeutics.
Improving GC patient therapeutic approaches
We hypothesize that the lack of effective GC therapies is partially due to the presence of intra-tumour heterogeneity. We will
therefore continue to study intra-tumour heterogeneity in GC patient samples and use in vitro and in vivo models that mimic such
heterogenenity in order to identify combination of therapies that can effectively eliminate the different sub-populations of tumour
cells. The ultimate aim is to contribute towards the development of therapeutic regimens that can offer a significant improvement in
gastric cancer patients’ survival.
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C Oliveira: Member of the Ph.D. Dissertation Committee of Germana Domingues. Univ. Lisbon, Portugal; 2014
C Oliveira: Invited Jury member (examiner): Ph.D. Dissertation of Joana Costa. Univ. Lisbon, Portugal; 2014
C Oliveira: Member of the Ph.D. Dissertation Committee of Irina Amorim. Univ. Porto, Portugal; 2014
C Oliveira: Invited Jury member (examiner): Ph.D. Dissertation of Ana Ramos. Univ. Coimbra, Portugal; 2014
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J Carvalho: Lecturer in the Oncobiology Module GABBA program. “Cancer cell communication and Exosomes”. Porto, Portugal,
April 2014
P Oliveira: Lecturer in the Oncobiology Module GABBA program. “DNA/RNAomics applications in Cancer”. Porto, Portugal, April
2014
C Oliveira: Lecturer in the Oncobiology Module GABBA program. “DNA/RNAomics applications in Cancer”. Porto, Portugal, April
2014
C Oliveira: Lecturer in the Oncobiology Module GABBA program. “Metastable phenotypes in Epithelial Cancer”. Porto, Portugal,
April 2014
C Oliveira: Programa de Doutoramento em Medicina e Oncologia Molecular, Faculdade de Medicina da Universidade do Porto.
Oncobiology Module. Porto, February 2014
C Oliveira: Member of the scientific committee, Supervisor and Lecturer of the FCT-funded PhD Programs:
Graduate Program in Areas of Basic and Applied Biology (GABBA)
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Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences (BiotechHealth)
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J Carvalho: Invited Jury member (examiner): Masters Dissertation of Ana Curinha. Master on Cellular and Molecular Biology
from University of Aveiro, Portugal, December 2014
P Oliveira: Co-supervisor of the Master Thesis entitled “Establishment of a 3D model of EMT/MET induction using molecularly
designed ECM-like hydrogels” by Sara Jorge Moreira da Rocha (Mestrado Integrado em Bioengenharia - Universidade do
Porto)
C Oliveira: Invited Jury member (examiner): Masters Dissertation of Rui Barranha. Univ. Porto, Portugal; 2014
C Oliveira: Member of the Masters Dissertation Committee of Inês Reis. Univ. Porto, Portugal; 2014
C Oliveira: Lecturer in the “The role of Bioinformatics in basic and applied research”. Sessão de Apresentação do Mestrado em
Bioinformática e Biologia Computacional. Faculdade de Ciência s da Universidade de Lisboa. Lisbon, Portugal, May 2014
C Oliveira: Supervisor of the Masters Thesis entitled “Dies1 gene expression and regulation in gastric cancer” by Inês Reis
(Mestrado em Oncologia - ICBAS)
Invited Talks
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C Oliveira. “Genomics and Transcriptomics in cancer research”. . 4rd Workshop on Cancer Research. IPATIMUP Porto, Portugal.
14/05/2014.
C Oliveira. “Next Generation Sequencing (NGS): Principles and clinical aplications”. . 6th Scientific Meeting of the Portuguese
Society of Clinical Chemistry and Laboratorial Medicine. Coimbra, Portugal. 05/04/2014.
C Oliveira. C Oliveira. “Germline and somatic determinants in gastric cancer: a focus on E-cadherin”. . “Through the looking
glass: the reversion of EMT”. Oncology Meetings: Gastric Cancer - State of Art. . 1st ASPIC International Congress. University of
Minho, Braga, Porto, Portugal. Lisbon, Portugal. 28/03/2014.25/11/2014.
J Carvalho. Epithelial to Mesenchymal Transition, Exosomes and Cancer. Curso Oncologia Molecular: Biologia do Cancro e
Terapias Emergentes. Coimbra, Portugal. 07/11/2014.
P Oliveira. Genomics of Gastric Cancer. 6as. Jornadas de Iniciação à Investigação Clínica. Centro Hospital do Porto, Portugal.
27/06/2014.
C Oliveira. “Hereditary GI cancer: New genes, old diseases”. UEG – United European Gastroenterology Week. Vienna Austria.
20/10/2014.
C Oliveira. “Germline and somatic determinants of gastric cancer: Next Generation Sequencing and Functional Genomics”..
Ministry of Health - MD Anderson Cancer Center Joint Conference on Gastric and Hereditary Cancer. Lisbon Academic Medical
Center, Lisbon, Portugal. 21/11/2014.
C Oliveira. “The role and cargo of EVs in epithelial-mesenchymal-epithelial transitions and gastric cancer progression”. . II
GEIVEX SYMPOSIUM: Extracellular vesicles, from the bench to the clinics. Satellite Meeting of the Portuguese Groups on
Extracellular Vesicles. Taragona, Spain. 10/10/2014.
C Oliveira. “The role and cargo of EVs in epithelial-mesenchymal-epithelial transitions and gastric cancer progression”.
Autumn Meeting of the Cost action European Network on Microvesicles and Exosomes in Health and Disease . Palermo, Italy.
27/09/2014.
C Oliveira. “Can you use next generation sequencing data from tumours to rationally select targeted therapy approaches?”.
BioP5med Unworkshop. IGC - Oeiras, Lisbon, Portugal. 14/07/2014.
C Oliveira. “Germline and somatic determinants in gastric cancer: a focus on E-cadherin”. ONCOBIOLOGY - genes and tumoral
microenviroment Seminar Series. Medical Sciences Faculty - NOVA University, Lisbon Portugal. 06/06/2014.
Oral Presentations
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H Pinheiro. “Identification of rare CDH1 non-coding variants in Hereditary Diffuse Gastric Cancer”. 1st ASPIC International
Congress. Lisbon, Portugal. 25/11/2014.
H Pinheiro. “Identification of rare CDH1 non-coding variants in Hereditary Diffuse Gastric Cancer”. 2nd Consensus Conference
on hereditary gastric cancer. Nijmegen, The Netherlands. 20/03/2014.
Prizes
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C Oliveira - The NSFCF - No Stomach for Cancer Foundation Award 2014 - “Defining the Contribution of Mutations in CDH1 NonCoding Regions and Other Known Susceptibility Genes to Hereditary Gastric Cancer”; Collaboration and Partnership with David
Huntsman from the BCCA, Vancouver Canada and the International Gastric Cancer Linkage Consortium (IGCLC); (07/2014-06/2016)
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Genetic Diversity
Objectives
The group aims to establish a bridge between human population and clinical genetics. We study evolution, genetic drift, migration,
expansion, bottleneck and selection, which are the major forces designing the genetic diversity across the world. Then we apply the
evolutionary based studies to the identification of candidate genes/variants which model human adaptation and health.
We continue to perform phylogeographic analyses based on mitochondrial DNA (mtDNA) diversity at a worldwide scale,
contributing information to the main human migrations, responsible for setting up the worldwide genetic distribution. We are also
showing that this knowledge is essential to disentangle between neutral and pathologic variants, estimate times of emergence of
polymorphisms, describe geographic dispersions, and applying that knowledge in the clinical field, namely in the cancer area.
We are conducting genome-wide association studies (GWAS) applied to dengue infection, under the FP7 project Denfree, in
collaboration with colleagues from Paris, Cuba and Thailand. We have been contributing with admixture-mapping methods,
which take advantage of the ancestry information to improve statistical power to identify candidate genes. We are also using chip
technology to identify selection patterns in African populations, many related with infectious diseases.
We are strengthening the research line in proteolysis genes by performing Sanger and/or next-generation sequencing in informative
gene families with potential implications in human health conditions. We are identifying targets of natural selection driven by
involvement in male reproduction and response against pathogens, while simultaneously exploring how these genes may contribute
to the development of different complex diseases such as male infertility, chronic obstructive pulmonary disease or lung cancer.
Main Achievements
Global human frequencies of predicted nuclear pathogenic variants and the role played by protein
hydrophobicity in pathogenicity potential
Mitochondrial proteins are coded by nuclear (nDNA) and mitochondrial (mtDNA) genes, implying a complex cross-talk between the
two genomes. Here we investigated the diversity displayed in 104 nuclear-coded mitochondrial proteins from 1,092 individuals from
the 1000 Genomes dataset, in order to evaluate if these genes are under the effects of purifying selection and how that selection
compares with their mitochondrial encoded counterparts. Only the very rare variants (frequency < 0.1%) in these nDNA genes are
indistinguishable from a random set from all possible variants in terms of predicted pathogenicity score, but more frequent variants
display distinct signs of purifying selection. Comparisons of selection strength indicate stronger selection in the mtDNA genes
compared to this set of nDNA genes, accounted for by the high hydrophobicity of the proteins coded by the mtDNA. Most of the
predicted pathogenic variants in the nDNA genes were restricted to a single continental population. The proportion of individuals
having at least one potential pathogenic mutation in this gene set was significantly lower in Europeans than in Africans and Asians.
This difference may reflect demographic asymmetries, since African and Asian populations experienced main expansions in middle
Holocene, while in Europeans the main expansions occurred earlier in the post-glacial period. [Pereira et al. 2014 Sci. Rep. 4:7155].
Genetic stratigraphy of key demographic events in Arabia
At the crossroads between Africa and Eurasia, Arabia is necessarily a melting pot, its peoples enriched by successive gene flow
over the generations. Estimating the timing and impact of these multiple migrations are important steps in reconstructing the
key demographic events in the human history. However, current methods based on genome-wide information identify admixture
events inefficiently, tending to estimate only the more recent ages, as here in the case of admixture events across the Red Sea
(~8–37 generations for African input into Arabia, and 30-90 generations for “back-to-Africa” migrations). An mtDNA-based founder
analysis, corroborated by detailed analysis of the whole-mtDNA genome, affords an alternative means by which to identify, date and
quantify multiple migration events at greater time depths, across the full range of modern human history, albeit for the maternal
line of descent only. In Arabia, this approach enables us to infer several major pulses of dispersal between the Near East and Arabia,
most likely via the Gulf corridor. Although some relict lineages survive in Arabia from the time of the out-of-Africa dispersal, 60 ka,
the major episodes in the peopling of the Peninsula took place from north to south in the Late Glacial and, to a lesser extent, the
immediate post-glacial/Neolithic. Exchanges across the Red Sea were mainly due to the Arab slave trade and maritime dominance
(from ~2.5 ka to very recent times), but had already begun by the early Holocene, fuelled by the establishment of maritime networks
since ~8 ka. The main “back-to-Africa” migrations, again undetected by genome-wide dating analyses, occurred in the Late
Glacial period for introductions into eastern Africa, whilst the Neolithic was more significant for migrations towards North Africa.
[Fernandes et al. 2015 Plos One, in press].
60,000 years interactions between Central and Eastern Africa documented by major African mitochondrial
haplogroup L2
Mitochondrial DNA (mtDNA) haplogroup L2 originated in Western Africa but is nowadays spread across the entire continent. L2
movements were previously postulated to be related to the Bantu expansion, however, L2 expansions eastwards probably occurred
much earlier. By reconstructing the phylogeny of L2 (44 new complete sequences) we provide insights on the complex net of
within-African migrations in the last 60 thousand years (ka). Results show that lineages in Southern Africa cluster with western/
central African lineages at a recent time scale, whereas, eastern lineages seem to be substantially more ancient. Three moments
of expansion from a Central African Source are associated to L2: (1) one migration at 70-50 ka into eastern or southern Africa, (2)
post-glacial movements (15-10 ka) into Eastern Africa; and (3) the southwards Bantu Expansion in the last 5 ka. The complementary
population and L0 phylogeography analyses indicate no strong evidence of mtDNA gene flow between eastern and southern
populations during the later movement, suggesting low admixture between Eastern African populations and the Bantu migrants.
This implies that, at least in the early stages, the Bantu expansion was mainly a demic diffusion with little incorporation of local
populations. [Silva et al. submitted]
Adaptive Evolution and Divergence of SERPINB3: A Young Duplicate in Great Apes
A series of duplication events led to an expansion of clade B Serine Protease Inhibitors (SERPIN), currently displaying a large
repertoire of functions in vertebrates. Accordingly, the recent duplicates SERPINB3 and B4 located in human 18q21.3 SERPIN cluster
control the activity of different cysteine and serine proteases, respectively. Here, we aim to assess SERPINB3 and B4 co-evolution
with their target proteases in order to understand the evolutionary forces shaping the accelerated divergence of these duplicates.
Phylogenetic analysis of primate sequences placed the duplication event in a Hominoidae ancestor (~30 Mya) and the emergence
of SERPINB3 in Homininae (~9 Mya). We detected evidence of strong positive selection throughout SERPINB4/B3 primate tree and
target proteases, cathepsin L2 (CTSL2) and G (CTSG) and chymase (CMA1). Specifically, in the Homininae clade a perfect match
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2014
was observed between the adaptive evolution of SERPINB3 and cathepsin S (CTSS) and most of sites under positive selection were
located at the inhibitor/protease interface. Altogether our results seem to favour a co-evolution hypothesis for SERPINB3, CTSS and
CTSL2 and for SERPINB4 and CTSG and CMA1. A scenario of an accelerated evolution driven by host-pathogen interactions is also
possible since SERPINB3/B4 are potent inhibitors of exogenous proteases, released by infectious agents. Finally, similar patterns
of expression and the sharing of many regulatory motifs suggest neofunctionalization as the best fitted model of the functional
divergence of SERPINB3 and B4 duplicates. [Gomes et al. 2014 Plos One].
The Human SERPIN repertoire and the evolution of 14q32.1 and 18q21.3 gene clusters
The human genome comprises two large clusters of serine protease inhibitor genes (SERPINs) originated by duplication events
that occurred at different moments of vertebrate evolution. The 14q32.1 cluster includes 11 members, all sharing a similar gene
structure to alpha-1-antitrypsin and the 18q21.3 cluster comprises 10 members, characterized by their homology to chicken
ovalbumin. Although the majority of these genes are widespread across mammalian species, some are restrained to certain
phylogenetic groups, making the repertoire of each species unique. In primates, events of gene duplication and divergence were
associated to the origin of SERPINA2 and SERPINB3. Evolutionary processes specific to the human lineage included the loss of
SERPINA13, an ancient gene only kept in primates, and the pseudogenization of SERPINB11, a gene under strong constrains in other
species. More recently in humans, natural selection acted in SERPINA2 and SERPINB11 favoring on one hand, a non-functional allele
carrying a 2 kb deletion and on the other, a resurrected gene linked to a novel non-inhibitory function. Considering a possible role
of SERPINs in inflammation and immunity, together with the perception of the impact of infectious diseases in the natural history
of human populations and other species, raised the hypothesis of an evolution driven by host-pathogens interactions. Overall,
gains and losses of genes seem to have had an important adaptive value in the long-term evolution of 14q32.1 and 18q21.3 clusters
with current implications in SERPIN activities and effects in human diseases. [Seixas 2015 In: Geiger M, Furtmüller M, Wahlmüller F,
Springer]
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Anavaj Sakuntabhai, Institut Pasteur, Paris, France - Genetic susceptibility in infectious diseases – dengue fever. Collaboration
under the funded the FP7 project Denfree. Co-supervision of a PhD student funded by FCT.
Martin Richards, University of Huddersfield, UK - Genetic diversity of European and East Asian populations. A co-supervised
PhD student presented thesis on January 2014, and we have still a co-supervised PhD student who will finish work by the end of
2015.
Viktor Cerny, Academy of Sciences of the Czech Republic, Prague - Genetic diversity of Arabian Peninsula and African
populations. The African GWAS study is part of the work of a PhD student funded by Marie Curie funded project Eurotast.
David Samuels, Vanderbilt University Medical Center, Nashville, TN, USA - Statistics applied to mtDNA clinical genetics
João Zilhão, University of Barcelona, Spain - Dating of archaeological samples from the Mediterranean Neolithic.
Victor Quesada, University of Oviedo, Spain - Evaluating the role of proteolysis in the male reproductive system through the
study of KLK and WFDC gene clusters. Collaboration under the funded the FCT project. Co-supervision of a PhD student funded
by FCT.
Dieter Jenne, Comprehensive Pneumology Center (CPC), Munich, Germany) - Study of the human genetic variation in the
context alpha-1-antitrypsin deficiency and its associated clinical manifestations.
Future Research
Functional assays in dengue fever candidate genes
Our results obtained in Cuba samples from dengue fever patients allowed us to identify the genes RXRA and OSBLP10, involved in
the African-ancestry protection previously identified by medical doctors in Cuba. We are writing this manuscript for publication, and
we are already performing in collaboration with Anavaj Sakuntabhai’s group at Pasteur, Paris, functional assays to further evaluate
the involvement of these genes in dengue fever. These genes have been identified previously as involved in infectious caused by
virus, and transcriptome data in dengue fever have indicated significant expression changes in pathways were these genes play
important roles. Ours is the first genomic identification performed so far. OSBPL10 gene is also being picked up by us in GWAS
analysis conducted in Thailand, when we apply ancestry-based methods, which is further confirmation of Cuban data.
Genome-wide screening in African Sahel
We will finish the Eurotast project, conducting to Petr Triska’s PhD. One of the main results of the thesis is related with the screening
of the Illumina chip for 2.5 million SNPs in 170 individuals from several Sahelian populations. Preliminary results testify that Sahel
was the main corridor for west-east migrations, and for migrations towards north and south, and is revealing interesting genetic
patterns in the nomadic Fulani. This geographical region was important for the emergence of certain phenotypes, such as malaria
susceptibility, food adaptations and potentially dengue infection resistance. Indeed, we are establishing a link between these
two works, as we are finding evidence of a long extended haplotype in the RXRA region in western Sahelian populations, which is
conferring the resistance to dengue fever in Cuba.
The effect of human ancestry in the susceptibility to Helicobacter pylori infection and gastric cancer
development
We will apply a population-based methodology to investigate the role played by host ancestry in the susceptibility to GC in general,
and to infection by Hp in particular. European and Asian populations have been covered by international consortia, which make
freely available whole genomes/exomes sequences (WGS/WES), transcriptomes, methylomes, and proteomes. We will extract and
process information from The Cancer Genome Atlas (data from Australia, Brazil, Canada, Germany, Poland, Russia, Ukraine, USA,
South Korea and Vietnam; 403 total). As African populations, so central in GC debate, have been overlooked in consortia, we will
obtain WES from Angolan and Mozambican GC patients (50 matched normal and tumour samples) and 50 healthy controls. We
will compare the normal tissue WGS/WES from TCGA and African patients with matched population controls, aiming to identify
signatures of genetic susceptibility in cases.
Association study for male infertility centred on KLK and WFDC clusters
We will complete the association study for male infertility centered in the gene families of KLK and WFDC. So far, we covered ¿94 kb
using a pooled high-throughput and paired-end sequencing strategy in a total of 222 individuals (cases and controls). We detected
several hundreds of rare and low frequency variants (<5%) differing in their frequencies between cases and controls, and between
cases and random populations with European ancestry (1000 Genomes). A fraction of those SNPs were already Sanger sequenced
to confirming the accuracy of our method and in a next step we will expand the screening of predicted deleterious variants to
larger sample of cases and controls. As a follow up of this study, we will perform a few experimental mass-spectrometry runs and
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other low-throughput proteomic assays in semen samples to specifically address the functional impact of identified KLK and WFDC
variants.
Searching for the missing heritability of COPD and Lung Cancer diseases among genes of proteolysis
We propose to carry out an in-depth study of the genetic diversity in a series of candidate genes with a greater focus in proteolysis,
in order to address their impact in different phenotypes of Chronic Obstructive Pulmonary Disease (COPD) and Lung Cancer (LC).
Specifically, we will to explore: 1) the existence of additional genetic modifiers of lung disease in alpha-1-antitrypsin deficiency cases;
2) the genetic variation that to some extent confers higher susceptibility to COPD/LC and to evaluate the biological significance of
those variants with predicted effects in lung physiology; and 3) the correlation between identified human genetic variability and the
microbiome of disease cases and controls. In this study, we will use different methodical approaches for the assessment of human
and microbiome genetic information and we will combine different experimental assays and statistical analysis to evaluate the
significance of our findings.
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Luísa Pereira (co-supervisor) and Verónica Fernandes (PhD student)PhD at the University of Leeds, UK; FCT grant
Luísa Pereira (supervisor), Pedro Soares (co-supervisor) and Petr Triska (PhD student)PhD in Biomedical Scientes at ICBAS; Marie
Curie funded project Eurotast
Luísa Pereira (supervisor), Pedro Soares (co-supervisor) and Andreia Brandão (PhD student)PhD in Biomedical Scientes at ICBAS;
FCT grant
Luísa Pereira (supervisor), Anavaj Sakuntabhai (co-supervisor) and Marisa Oliveira (PhD student)PhD in Biomedical Scientes at
ICBAS; FCT grant
Susana Seixas (supervisor), Victor Quesada (co-supervisor) and Patrícia Marques (PhD student)PhD in Biomedical Scientes at
ICBAS; FCT grant
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Pedro Soares (supervisor), Luísa Pereira (co-supervisor) and Marina Silva (Master student)Master in Biodiversity, Genetics and
Evolution at FCUP
Susana Seixas (supervisor) and Deolinda Silva (Master student)Master in Biochemistry; FCUP/ICBAS
Susana Seixas (supervisor), Sílvia Gomes (co-supervisor) and Catarina Monteiro (Master student)Master in Biochemistry at the
University of Aveiro
Invited Talks
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Luísa Pereira, Beatriz Sierra. Human genetics study in Cuba . 2nd annual DENFREE meeting. Belle Eglise, France. 15/10/2014.
Luísa Pereira. The influence of ancestry in complex diseases – the case study of dengue infection in Cuba.. From Gene to
Genious – 1st Annual Symposium of the Doctoral Program in Molecular and Cell Biology. Porto. 17/11/2014.
Luísa Pereira. Population genetics in infectious diseases.. 3rd Capita Selecta in Complex Disease Analysis Conference. Liége,
Belgium. 25/11/2014.
Oral Presentations
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Susana Seixas. Different evolutionary histories of genes of proteolysis with functions in reproduction and innate immunity. . II
AEICBAS Biomedical Congress. Porto. 26/04/2014.
2014
Genetic Dynamics of Cancer Cells
Objectives
The scientific question that drives our research is how genetic information is transferred between cancer cells, and how does that
transference impact on the heterogeneity, diversity and plasticity of cancer cells. We want to understand how do genetic mutations
arise in tumor cells and how do they spread in tumor cell subpopulations. We want to understand why do these tumor cell
subpopulations fluctuate over time, and how does this influence, and is influenced, by clinical events such as therapy and disease
progression. We address these questions in two research lines:
1- The study of canonical “vertical transmission” cell division-based models where genetic information is transmitted between
cancer cells and their progeny.
2- The study of extracellular vesicles called exosomes that are released by all cell types and that can transfer their cargo to various
recipient cells, as an example of “horizontal transmission” of genetic information.
We believe that our group deals with a fundamental and innovative question in the field of cancer biology, that may allow for a
better understanding of the dynamics of tumor progression as either the commonly accepted evolutionary competition between
differentially adapted tumor cells, or alternatively, as an exosomes-mediated cooperative process to form a unit of malignancy that
is able to invade, metastasize and relapse after treatment.
Main Achievements
We were awarded a research project by ADI aiming at the development of a liquid biopsy strategy for the molecular diagnosis and
disease monitoring of lung cancer. For this purpose a collaborative project was established with Hospital S. João and Hospital de
Gaia aiming at the prospective collection of plasma samples from lung cancer.
Fátima Carneiro was appointed coordinator of the national network of tumor banks.
Sónia Melo was awarded an FCT exploratory grant.
A funded collaborative project was established with the company Life Technologies aiming at the development and validation of IVD
tests in the field of molecular pathology.
Achievements in exosomes biology and cancer:
Reported for the first time the presence of genomic DNA in exosomes of serum of pancreatic ductal adenocarcinoma patients, with
implications in cancer prognosis, diagnosis and therapeutic intervention.¿
Described cell-independent miRNA biogenesis in exosomes from cancer cells and breast cancer patients, allowing exosomes
secreted by cancer cells to alter the transcriptome of neighbor and distant cells in the body.
Unraveled GPC1 positive exosomes as a biomarker for early detection of pancreatic cancer.
Reported IL1B is able to increase the expression/activation status of CREB and its target gene C/EBPß, which are mandatory for
gastric carcinoma cell survival. Our results support the hypothesis that the effect of chronic inflammation on gastric carcinogenesis,
as seen in the context of genetically susceptible individuals infected with Helicobacter pylori, includes modulation of signalling
pathways that regulate survival mechanisms in epithelial cells.
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Coordinator of the Multicenter project that envisages validating GPC1 on exosomes as a biomarker for early detection of
pancreatic cancer: Germany partners (Dresden, Heidelberg and Hamburg), one Austrian partner, one Danish partner, one UK
partner and one USA partner.
Partner in the OncoNetwork Global Consortium aiming at the development and validation of IVD tests in the field of molecular
pathology. Two Italian partners, one Swiss partner, one Dutch partner, one Japanese partner, one UK partner, one US partner,
one Irish partner, one Canadian partner, two French partners.
Future Research
Development of a liquid biopsy strategy for the molecular diagnosis and disease monitoring of lung cancer.
Show exosome-mediated transfer of genetic and proteomic information between subpopulations of cancer cells is one of the main
contributors to tumor heterogeneity.
Investigate how neoplastic cell mutations trigger immune response and what mechanisms neoplastic cells use to escape
immunosurveillance.
Unravel the cellular and molecular mechanisms by which genetic-driven drug resistance spreads in tumor cell populations.
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José Carlos Machado, Fátima Carneiro, Sónia Melo, José Luís Costa- Programa de Doutoramento em Medicina e Oncologia
Molecular (FMUP).
Programa de Doutoramento em Patologia e Genética Molecular (ICBAS).
Programa de Doutoramento em Biomedicina (FMUP).
Programa GABBA (ICBAS).
Programa de Doutoramento BiotechHealth (International Doctoral Programme in Molecular and Cellular Biotechnology Applied
to Health Sciences).
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José Carlos Machado, Fátima Carneiro, Sónia Melo, José Luís Costa- Programa de Doutoramento em Medicina e Oncologia
Molecular (FMUP).- Mestrado em Medicina e Oncologia Molecular (FMUP).
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Prizes
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Sónia Melo - The L’Oréal Portugal Medals of Honor for Women in Science 2014
Fátima Carneiro - Remissão endoscópica e histológica induzida pelo infliximab na colite ulcerosa moderada a grave – estudo
hérica”. Magro F., Lopes S, Lopes J, Rodrigues-Pinto E, Portela F, Silva M, Cotter J, João Moreira M, Lago P, Lopes C, Caetano
C, Peixe P, Chagas C, Carvalho L, Lopes S, Rosa B, Albuquerque A, Camila C, Afonso J, Geboes K, Carneiro F. - Best oral
communication in Semana Digestiva 2014
Carlos ResendeIL1B signaling leads to increased cell survival of gastric carcinoma cells”. Resende C, Regalo G, Durães C, Xiaogang
W, Figueiredo C, Machado JC - Best oral communication in the XXVII International Workshop on Helicobacter and Microbiota in
Inflammation and Cancer
2014
Objectives
The group “Glycobiology in Cancer” focus on the role that glycosylation plays in human cancer aiming at the understanding of
the molecular mechanisms controlling alterations of glycosylation that are important in the process of carcinogenesis and cancer
progression.
The research lines that the group is developing include:
1. Characterization of the molecular mechanisms underlying the glycan-mediated adhesion and infection of Helicobacter pylori
and the understanding of the importance of the host-pathogen crosstalk for the chronic infection of the gastric mucosa.
2. Evaluation of the role of glycans in cancer and pre-cancerous diseases addressing the molecular mechanisms controlling
glycosylation of key proteins involved in cancer development and progression.
3. Development of glycan-based strategies to improve diagnosis and treatment of cancer using innovative technologies for
identification of biomarkers with application in early cancer diagnosis and patient stratification.
The group applies a multidisciplinary approach combining molecular biology, cell biology, biochemistry, genomics, proteomics and
animal models for understanding and addressing key issues played by glycosylation in cancer.
Main Achievements
Characterization of glycan-mediated adhesion and infection of Helicobacter pylori and NHPH.
We have demonstrated that the glycan receptors expressed in the gastric mucosa are crucial for the adhesion and infection of
Helicobacter pylori and non-Helicobacter pylori Helicobacter spp. (Helicobacter. 2014 Aug;19(4):249-59. doi: 10.1111/hel.12125.
Epub 2014 Apr 2. PMID: 24689986.
We have identified the LacdiNAc specific adhesin (LabA)
We have identified the LacdiNAc specific adhesin (LabA), which mediates binding to LacdiNAc-motifs carried by MUC5AC gastric
mucins and promotes Helicobacter pylori adhesion to the human gastric mucosa. (J Infect Dis. 2014 Oct 15;210(8):1286-95. doi:
10.1093/infdis/jiu239. Epub 2014 Apr 21. PMID: 24755437).
Characterizations by AFM of the strength of binding between the Helicobacter pylori blood group antigenbinding adhesin (BabA)
We have applied atomic force microscopy measurements for characterizations of the strength of binding between the Helicobacter
pylori blood group antigen-binding adhesin (BabA) and its cognate glycan receptor Lewis b. (J R Soc Interface. 2014 Dec
6;11(101):20141040. doi: 10.1098/rsif.2014.1040).
O-glycoproteoma of circulating serum proteins in patients with gastric cancer.
We have characterized glycosylation changes in circulating serum proteins in patients with precursor lesions of gastric cancer.
Applying a glycoproteomic approach we have identified altered glycoproteins expressing the simple mucin-type carbohydrate
antigens T and STn in the serum of patients with gastritis, IM (complete and incomplete subtypes), gastric carcinoma and control
healthy individuals. (Gomes et al., J Proteome Res, 2013, Campos et al., Mol Cel. Proteomics, in press)
OXPHOS dysfunction has an impact in Integrin-ß1 glycosylation
We have demonstrated that OXPHOS dysfunction (by mutation of mitochondrial DNA) has an impact in the alteration of Integrin-ß1
glycosylation, in particular with higher levels of ß1,6 GlcNAc branched N-glycans. This integrin-ß1 N-glycosylation pattern was
correlated with higher levels of membrane-bound integrin-ß1 and also with increased binding to fibronectin, associated with
increased motility and migration properties (Nunes et al., Human molecular Genetics 2014).
Demonstration that sialylation affects a2ß1 integrin in pancreatic cancer cells
We demonstrated that in pancreatic cancer cells lines, the ST3Gal III transfected cells exhibited higher SLex and lower a2,6-sialic
acid content. These changes in the sialylation pattern affected a2ß1 integrin and E-cadherin, influencing the functional role of these
two glycoproteins and further supporting the role of these glycans as an underlying mechanism regulating pancreatic cancer cell
adhesion and invasion (Bassagañas et al., PLoS ONE 2014).
We have shown that ST3GAL4 leads to SLe(x) expression and induces c-Met activation as well as downstream
signaling pathways.
We have characterized the role of SLe(x) expression in gastric carcinoma cells. We have shown that the expression of ST3GAL4 leads
to SLe(x) expression and induces c-Met activation as well as downstream signaling pathways modulating an invasive phenotype in
gastric carcinoma cells. (Gomes et al., PLoS One. 2013)
We have demonstrated that Galectin-1 was overexpressed in the majority of canine malignant mammary
tumour (CMT) cells and stroma.
Its expression in malignant tumor cells was associated with smaller-sized tumours. Distant metastases presented a strong
intensity of galectin-1 and reduced galectin-3 expression, while the opposite was observed in circulating tumor cells. Interestingly
intravascular tumor cells presented galectin-3 up-regulation at the mRNA level. Double-labelling made it clear that galectin-3 and
galectin-1 expression did not overlap in normal-adjacent mammary and CMT cells. This might confer survival advantage to tumour
cells in different phases of tumour progression.
Role of sialylated glycans in various cancer models
We have demonstrated the role of other Sialylated glycans in various cancer models, including Sialyl-Tn (Ferreira et al., Mol Oncol.
2013; Lima et al., Br J Cancer. 2013).
Development and characterization of bioengineered surfaces for novel Helicobacter pylori treatment.
In collaboration with INEB we have contributed for the development and characterization of bioengineered surfaces that promote
specific protein-glycan mediated binding of the gastric pathogen Helicobacter pylori (Parreira et al., Acta Biomater., 2013) and
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developed.bacterial-binding chitosan microspheres for Helicobacter pylori capture and gastric infection treatment (Gonçalves et al.,
Acta Biomater., 2013).
Dysregulation of GnT-V-mediated branched N-glycans in intestinal T cells of IBD patients.
We found that patients with inflammatory bowel disease (a chronic immune-mediated disorder of the gastrointestinal tract with risk
to evolve to colorectal cancer) display a dysregulation of GnT-V-mediated branched N-glycans in intestinal T cells, which accompany
disease severity. Moreover, T lymphocytes from active IBD patients exhibited a reduction in MGAT5 gene transcription which
underlies the observed dysregulation of branched N-glycosylation in mucosal T cells. (Dias et al. Human Molecular Genetics 2014).
International Meeting on Glycosyltransferases: GLYCO-T 2014
The group Glycobiology in Cancer organized the International Meeting on Glycosyltransferases: GLYCO-T 2014, in Porto, Portugal.
The meeting received more than 200 participants from all over the World.
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We have established an European network in the context of an EU Marie Curie Training Network for the development of
identification of glycoprotein biomarkers in gastric cancer. - This network includes the participation of Prof. Pauline Rudd
(Dublin University); Dr Niclas Karlsson (Gotenburg University), and Dr. Daniel Kolarich (Max Planck Institute of Colloids and
Interfaces, Germany).
Faculty of Health Sciences of the University of Copenhagen - Ulla Mandel and Henrik Clausen - This collaboration has been
fundamental for characterization of carbohydrate antigens and glycosyltransferases using unique monoclonal antibodies. We
have been collaborating with this group for the characterization of the O-glycoproteome of gastric cells. A PhD student of the
group (Diana Campos) is doing a joint PhD thesis on this topic.
Umea University, Sweden – Thomas Borén. - This collaboration has contributed for the study of H.pylori adhesion to gastric
mucosa, developing binding assays, and evaluating the novel glycoengineering strategies for treatment of H.pylori infection .
Institut Pasteur, France - Eliette Touati. - This collaboration is essential for the study of Helicobacter pylori using animal models.
Naoyuki Taniguchi - Osaka University and RIKEN, Japan, and Jianguo Gu - Tohoku Pharmaceutical University, Japan - These
collaborations have been contributing to disclose the role of glycosylation modifications in the regulation of pivotal molecules
involved in gastric tumor development and progression.
The group has also collaborations with hospitals (Centro Hospitalar do Porto; Hospital S.João; IPO-Porto), - These include
collaborations with gastroenterologiests, pathologists, oncologists and surgeons that have been crucial for the translational
vision of the group´s projects.
Faculty of Veterinary Medicine, Ghent University, Belgium – Freddy Haesebrouck and Annemieke Smet. - This collaboration has
been contributing for the study of bacterium-host interactions of Non-H. pylori Helicobacters.
Future Research
The group is actively participating in the I3S Program on Cancer and on Host Interaction and Response.
The Glycobiology in Cancer group focus on the role that glycosylation plays in human cancer and pre-cancerous
conditions, aiming at the understanding of the molecular mechanisms controlling alterations of glycosylation
that are important in the process of carcinogenesis and cancer progression, envisioning potential clinical
applications.
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1 Characterization of the molecular mechanisms underlying the glycan-mediated adhesion of Helicobacter
pylori and the understanding of the importance of the host-pathogen crosstalk for the chronic infection.
This project has addressed how H. pylori modulates the host gastric mucosa glycophenotype and evaluated the impact of
this altered glycosylation profile on bacterial adhesion. We have demonstrated that H. pylori induces the expression of the
glycosyltransferase beta3GnT5 in human gastric cells, modulating the expression of the glycan Sialyl-Lewis X, the carbohydrate
ligand for the H. pylori SabA adhesin (Marcos et al, J Clin Invest 2008) and we have identified a novel H. pylori adhesin LabA,
which binds LacdiNAc-motifs carried by gastric mucins (Rossez et al.,2014).We have also demonstrated that the glycan receptors
expressed in the gastric mucosa are crucial for the adhesion and infection of Helicobacter pylori and non-Helicobacter pylori
Helicobacter spp. (Amorim et al., 2014). We further demonstrated that the more virulent H pylori strains induce the proteoglycan
Syndecan-4 expression in gastric epithelial cells (Magalhães et al, FEMS Immunol Med Microbiol. 2009).
1.1 These results have also been supported by additional studies performed by the group using wild type mice
(Gomes et al., PLoS One 2012) and genetically modified mouse models (Fut2-null mice) (Magalhães et al,
Glycobiology. 2009).
This line of research was reviewed in Magalhães et al, Expert Rev Proteomics, 2010, and in Pinho et al. Trends in Molecular Medicine,
2013. These achievements are presently providing the basis for the design of novel therapeutic strategies based on inhibition
of bacterial adhesion using carbohydrates (Parreira et al, Acta Biomater 2013, Gonçalves et al, Acta Biomater 2013; Patent US:
61642587).
1.2 We will continue the development of novel strategies for inhibition of H. pylori adhesion and infection.
This approach is being developed within an on-going collaboration with Dr. Cristina Martins from INEB. In this project we are
developing and testing chitosan microspheres modified with synthetic carbohydrates receptors for inhibition of H. pylori adhesion,
using cell line models expressing specific glycan receptors, gastric mucosa of genetically modified mice (previously published by our
group), and human gastric mucosa.
Following the in vitro observations that H. pylori is able to modulate the gastric glycophenotype by modulation of expression
of specific glycosyltransferases we will evaluate the glycosylation pathways,and the regulatory mechanisms underlying these
glycophenotypic changes, in the complex context of human H. pylori chronic infection, using well-characterized human gastric
biopsies.
1.3 We will address the role of the host transmembrane proteoglycan Syndecan-4
The role of the host transmembrane proteoglycan Syndecan-4, specifically induced by the more pathogenic H. pylori strains, in
H. pylori adhesion and assess Syndecan-4 involvement in the injection of bacterial virulence factors. We will establish cell line
models expressing different levels and mutated forms of Syndecan-4. These models will be used to evaluate the functional role of
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Syndecan-4 on H. pylori adhesion and on CagA injection, using well characterized H. pylori strains. Proximity Ligation Assays will be
used to visualize Syndecan-4 and beta1 integrin interplay upon infection. Finally, human gastric mucosa samples of non-infected and
H. pylori infected individuals will be used for validation of our in vitro observations.
2 The group will continue to evaluate the role of glycans in disease and particularly on the cancer and precancerous cell behaviour addressing the molecular mechanisms controlling glycosylation of key proteins.
Various specific research projects are going to be developed:
2.1 We will continue to analyse the role of E-cadherin glycosylation in gastric cancer cell behaviour.
We previously found a precise regulation of E-cadherin biological functions by the coordinated action of GnT-III and GnT-V-mediated
glycosylation in gastric cancer progression (Pinho et al. BBA 2013, Pinho et al. Trens Molecular Medicine 2013). We are currently
maping the structure-function relationship of E-cadherin N-glycans in a gastric cancer context envisioning potential clinical
applications. We are characterizing the different N-glycans structures attached to E-cadherin both at structural (by glycoproteomics
analysis) and at functional levels in a gastric cancer context. This site-specific E-cadherin glycosylation characterization has been
conducted by combining in vitro technical approaches, animal models and human clinical samples. Furthermore, the interplay
between E-cadherin N-glycosylation and O-mannosylation (a newly described type of glycosylation in E-cadherin) and its impact in
cancer development and progression is currently being assessed.
2.2 The group will continue to analyse the role that sialyltransferases play in the terminal glycosylation of
proteins important for the cancer cell behaviour.
We will use previously established gastric cell lines expressing sialyltransferases and displaying specific glycan phenotypes. Novel
glycoengineered cancer cell models will be used for the characterization of the role of glycosylation in cancer. We are using in vitro
and in vivo experiments to characterise the functional role of these glycans.
2.3 The group will continue to assess the role of glycosylation in the modulation of immune response in chronic
inflammation and inflammation-induced cancer.
Following our recent published results (Dias et al., Hum Mol Genet. 2014), we will continue to dissect the role of glycosylation in the
immune system network and its interface with cancer development, by addressing the impact of glycosylation modification on T
cells functions in Inflammatory Bowel Disease (a pre-malignant condition of colorectal cancer).
3 The group will continue to develop glycoproteomic strategies for identification of biomarkers that can be used
for cancer detection.
The group will perform glycoproteomic strategies for characterization of the glycoproteome of cancer patients both in tumour cells
and serum in order to detect novel targets that can be applied in cancer diagnosis tests. The following approaches will be used:
a) Development of Glycoengineered gastric cells for the characterization of O-glycosylation;b) Optimization of glycoprotein and
glycan separation, enrichment, and detection; c) Development of mass spectrometry methodologies for glycoproteins and glycans
identification and structural characterization of glycosylation; d)Validation of the identified glycoproteins bearing cancer-associated
carbohydrate antigens will be performed by complementary assays using clinical samples.
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Celso Reis, Hugo Osorio, Salomé Pinho, Fatima GartnerWorkshop on Cancer Research: biological and molecular basis Local:
IPATIMUP Instituição: IPATIMUP/ICBAS Âmbito: Curso de formação contínua
Celso Reis.Programa Doutoral de Medicina e Oncologia Molecular of the Medical Faculty of the University of Porto.
Celso Reis, Salome Pinho, Irina Amorim, Fátima Gartner Programa Doutoral em Patologia e Genetica Molecular do Instituto de
Ciencias Biomedicas Abel Salazar
Celso Reis, Salome Pinho, Ana Magalhães, Hugo Osório PhD program GABBA (Graduate program in areas of Basic and Applied
Biology) of the University of Porto
Celso Reis. Programa Doutoral em Biomedicina
Fátima Gärtner. Programa doutoral em Ciências Veterinárias
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Celso Reis, Medical Faculty of the University of Porto
Fátima GartnerMaster in Forensic Sciences, ICBAS, UP
Fátima Gartner, Celso Reis.Master in Oncology, ICBAS, UP
Invited Talks
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Celso A. Reis: . Role of glycosylation in cancer.. Meeting at the Imperial College London. Imperial College London, United
Kingdom. 13/12/2014.
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Celso A. Reis. Role of glycans in gastric cancer development and progression. . American Society for Glycobiology (SFG) &
Japanese Society of Carbohydrate Research (JSCR) 2014 Joint Annual Meeting.. Honolulu, HI, USA. 16/11/2014.
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Celso A. Reis: Glycosylation in gastric cancer: Biomarkers and potential targets. Institute Merieux Research Grant Meeting.
Annecy, France. 23/10/2014.
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Celso A. Reis: . Glycosylation in gastric cancer development and progression. RIKEN Seminar. RIKEN-Max Planck Joint Research
Center for Systems Chemical Biology. Tokyo, Japan. 13/11/2014.
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Celso A. Reis: . “Introdução à glicosilação no cancro. . Programa de Pós-graduação Instituto Nacional do Cancer-INCA. Rio de
Janeiro, Brasil . 24/02/2014.
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Salomé Pinho:. “Glycosylation in gastrointestinal disease: the role of branched N-glycans in the pathogenesis.”. RIKEN Seminar.
RIKEN-Max Planck Joint Research Center for Systems Chemical Biology. 14/11/2014.
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Salomé Pinho:. “Gastric Cancer: adding glycosylation to the equation” . Programa de Pós-graduação, Faculdade de Farmácia
da Universidade do Porto (FFUP) (“Conferências em Oncobiologia”). Faculdade de Farmácia da Universidade do Porto (FFUP)
(“Conferências em Oncobiologia”. 20/05/2014.
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Salomé Pinho: . “O papel da glicosilação no câncer. Implicações na função da E-caderina e na transição epitélio-mesenquimal” .
Programa de Pós-graduação Instituto Nacional do Cancer-INCA,. Rio de Janeiro, Brasil . 24/02/2014.
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Hugo Osório:. Proteomics: Principles and Applications. Cycle of Seminars in Omic Techniques for Biotechnology and
Bioengineering, . Centre of Biological Engineering Minho University, Braga,. 24/10/2014.
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Irina Amorim: Descrição macro e microscópica das lesões do aparelho digestivo e glândulas anexas dos carnívoros e
ruminantes. Uma só linguagem, um só diagnóstico. . Workshop em Patologia Veterinária. . UTAD, Vila Real.. 25/10/2014.
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Fátima Gärtner:. Descrição macro e microscópica das lesões da mama de cadela e gata. Uma só linguagem, um só diagnóstico. .
Workshop em Patologia Veterinária. UTAD, Vila Real.. 25/10/2014.
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Fátima Gärtner:. Sialylation dynamics in the microenvironment of mammary tumours – sialidase uncloaking. 9th International
Conference of Anticancer Research,. Sithonia, Halkidiki, Greece. 01/10/2014.
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Fátima Gartner. Can we replace the use of animals in experimental research? Are animals just biological machines? . IV LusoBrazilian Congress of Experimental Pathology,. Recife, Brazil,. 01/11/2014.
Oral Presentations
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Ana Magalhães. Modulation of the gastric mucosal glycosylation pathways by Helicobacter pylori chronic infection. GLYCO-T
2014 9th International Symposium on Glycosyltransferases, . Porto, Portugal. 18/06/2014.
Salomé Pinho:. “Regulation of T cell receptor by N-glycosylation: a novel molecular mechanism in Inflammatory Bowel Disease
pathogenesis.”. Glyco-T meeting 2014. . Porto, Portugal. 19/06/2014.
Amorim I:
. Authors: Amorim I, Freitas DP, Magalhães A, Faria F, Lopes C, Smet A, Haesebrouck F, Reis CA, Gartner F. Helicobacter
pylori and non-Helicobacter pylori Helicobacter spp. adhesion to canine gastric mucosa.. 11th International Workshop on
Pathogenesis and Host Responses of Helicobacters Infection,. Helsingor, Denmark. 02/07/2014.
Catarina Gomes
Authors: Catarina Gomes, Hugo Osório, Marta Teixeira Pinto, Diana Campos, Maria José Oliveira, Celso A. Reis.. “Expression
of ST3GAL4 leads to SLeX expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells”. . 9th
International Symposium on Glycosyltransferases - 18th-21st June 2014,. Porto, Portugal. 19/06/2014.
Prizes
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Celso Reis Nominated Member of the Scientific Advisory Board of the 23rd INTERNATIONAL SYMPOSIUM ON
GLYCOCONJUGATES
International Glycoconjugate Organization (IGO)
Celso Reis Member of the Organizing committee of the 11th jenner glycobiology and medicine symposium.
Nominated by The Royal Society of Medicine, UK
Irina Amorim was awarded with the Young Scientist Award - Best Oral Communication,
Scientific Comittee of 11th Workshop on Pathogenesis and Host Responses in Helicobacter Infections, Helsingor, Denmark.
2014
Population Genetics
Objectives
We aim at understanding the origin, evolution and consequences of genetic diversity, using a variety of model systems and
approaches under the perspective of population genetics theory.
The study of variants (and the development of tools for their identification), including the structural type, such as inversions, and
their interactions contributing to the etiology of, or the susceptibility to, genetic or infectious diseases is a main theme of research,
in order to develop efficient screenings and diagnostics, and to identify individuals at high risk of developing a disease, improving
genetic counselling and treatment, namely the research of neurodegenerative diseases, male infertility and pharmacogenetics.
The role of coding and non-coding sequences in gene expression regulation and the impact of structural genomic variation
on fertility and disease susceptibility, is investigated by two strategic approaches: an evo-devo line based on the evolutionary
comparison of specific genomic regions and their expression patterns in ontogeny, and genome wide methods.
Besides health an applied line of research is related to forensics and quality control issues through the development of methods,
techniques, and the design of exercises, recommendations and guidelines.
The research strategy described for humans is also applied to the history, conservation and management of domesticates and
laboratory animals, identification and diagnostic tools and food quality.
The Group is also devoted to the mathematical modelling of generalized kinship relations, automated DNA sequence analyses and to
the history, migration and substructure of metapopulations.
Main Achievements
Phylogeny of mitochondrial DNA of the Portuguese - an update and a revision
High quality data, complying with forensic standards, were obtained through double sequencing and complete mitogenomes of a
sample from mainland Portugal.
A typical Western European haplogroup composition was found, and a high level of diversity, with no signs of substructure.
A refinement of the previous haplogroup classification (namely inside H) made possible to enlarge haplogroup U phylogeny with 28
new U4 and U5 mitogenomes.
Linguistic and religious isolates in northeastern Portugal: new insights from Genetics
X chromosome markers from Mirandese speakers, and from the nearby Province of Zamora were genotyped.
The results showed that Miranda presented lower levels of diversity, in accordance with a linguistic isolation effect and detected the
Portuguese/Spanish political border as a barrier to gene flow between the two geographically close populations.
We have sequenced complete mtDNA genomes from crypto-Jewish descendants in the Bragança district and a high level of diversity
was found, with five haplogroups (HV0b, N1, T2b11, T2e and U2e) being putatively identified as Sephardic founding lineages.
Therefore these communities have managed to escape the expected inbreeding effects caused by centuries of religious repression
and have kept a significant proportion of the founder gene pool showing a surprising resistance to the erosion of genetic diversity in
the maternal lineages.
Genetic history of South American populations
We have studied 32 X chromosome indels in Colombia population samples and the results of admixture analysis show that the
high proportion of African ancestry in the North Pacific coast was primarily male driven. These men have joined to females with
higher Native American and European ancestry (likely resulting from a classic colonial asymmetric mating type: European male
x Amerindian female). This high proportion of male-mediated African contributions is atypical of colonial settings, suggesting
that the admixture occurred during a period when African people were no longer enslaved. In the remaining regions, the African
contribution was primarily female-mediated, whereas the European counterpart was primarily male driven and the Native American
ancestry contribution was not gender biased.
We have shown significant differences between Brazilian South Eastern and Northern populations that can be explained by
differences in the proportion of African and Native American Y chromosomes, as well as between admixed urban samples.
In a Bolivian sample set, we have typed each male individual simultaneously for the Y chromosome and a battery of autosomal
ancestry informative markers (AIMs). When comparing the ancestry of each individual assessed through his Y chromosome with
the one estimated using autosomal AIMs, (a) increased European ancestry in individuals with European Y chromosomes and (b)
higher Native American ancestry in the carriers of Native American Y-haplogroups were observed, disclosing the persistence of the
association between autosomal and Y-chromosomal markers, after centuries of European colonization.
Recombination patterns within large human chromosomal inversion rearrangements
Making use of publicly available population genotype data for the largest polymorphic inversion in the human genome
(8p23-inv), we reported recombination dissimilarity between inversion types, consistent across all populations analyzed, and
surpasses the effects of geographic structure. We also identified a short segment (350 kb, less than 10% of the whole inversion) in
the central region of the inversion where the genetic divergence between the two structural haplotypes is diminished. While
it is difficult to demonstrate it, this could be due to gene flow (possibly via double-crossing over events), which is consistent with
the higher recombination rates surrounding this segment. This study demonstrates for the first time that chromosomal inversions
influence the recombination landscape at a fine-scale, and highlights the role of these rearrangements as drivers of genome
evolution.
Species and strains genetic identification
Species identification in wildlife research: the case of red fox (Vulpes vulpes) identification in Tasmania.
We have demonstrated that the putatively fox-specific primers previously reported do not specifically hybridize to fox DNA, and we
have developed a new molecular method for the purpose, meeting forensic quality standards.
Mitochondrial single nucleotide polymorphisms (SNPs) to detect and identify Aspergillus fumigatus in clinical samples
Development of MLST@SNaP, a user-friendly software for simplification of multilocus sequence typing, classification and analyses of
microbial populations
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The typing of a set of 4 mtDNA SNPs proved to have diagnostic value in clinical samples from patients with questioned invasive aspergillosis.
Identification of grapevine (Vitis vinifera L.) varieties
A proposal of grapevine genotyping harmonization was outlined, aiming to meet the genetic identification forensic standards, using
microsatellites (or short tandem repeats, STRs) amenable to automation and high-throughput.
Molecular identification and genotyping of Pseudomonas aeruginosa
The combination of a colony-PCR strategy and the SnaPaer assay proved capable to simultaneously identify and genotype, in less
than 6 h, clinical P. aeruginosa samples.
Genetic determinants of male infertility
We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of
male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. We had previously
identified a novel 11p13 heterozygous deletion by high density SNP arrays in a patient with cryptorchidism and nonobstructive
azoospermia. We have confirmed it spans WT1, encompassing approximately 1 Mb and positioned the breakpoints within highly
homologous repetitive elements. We have also extended the mutational spectrum of WT1 mutations in male infertility by screening
Portuguese patients with non-obstructive azoospermia (NOA; n=194) and severe oligozoospermia (n=188).
Modifiers of repeat instability in Machado-Joseph disease (MJD/SCA3) transmissions
We searched for genetic modifiers of (CAG)n instability in 137 parent-child transmissions in Machado-Joseph disease (MJD/SCA3),
screening 768 SNPs from 93 of DNA replication and repair genes. We found a variant in ERCC6 (rs2228528) associated with an
expansion bias of MJD alleles. When using a gene-gene interaction model, the allele combination G-A (rs4140804-rs2972388) of
RPA3-CDK7 is also associated with MJD instability in a direction-dependent manner.
The variants in three transcription-coupled repair genes associated with the MJD mutation point therefore to distinct mechanisms
of (CAG)n instability.
Diversity in the androgen receptor CAG repeat has been shaped by a multistep mutational mechanism
In the most frequent Androgen Receptor lineage, (CAG)18 alleles have been generated by a multistep mutation mechanism, most
probably from longer alleles.
We have also identified the most powerful SNPs to tag AR lineages (rs7061037-rs12012620 and rs34191540-rs6625187-rs2768578 in
Europeans and Asians, respectively).
NAMPT and NAPRT1: novel polymorphisms, distribution of variants in normal tissues and tumors and
implications for treatment
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase domain containing 1 (NAPRT1) are the
main human NAD salvage enzymes. NAD availability is linked to pathologies such as cancer and neurodegeneration.
We have screened normal and tumor samples from different tissues and populations of origin for mutations in human NAMPT and
NAPRT1, and evaluated their potential pathogenicity. We have identified several novel polymorphisms and showed that NAPRT1
has a greater genetic diversity than NAMPT, where any alteration can have a greater functional impact. Some variants presented
different frequencies between normal and tumor samples that were most likely related to their population of origin. The novel
mutations described that affect protein structure or expression levels can be functionally relevant and should be considered in
a disease context. Particularly, mutations that decrease NAPRT1 expression can predict the usefulness of Nicotinic Acid in tumor
treatments with NAMPT inhibitors.
Greenlanders genetic makeup
Analysis of autosomal and X-chromosome data showed low levels of genetic diversity, along with an increased number of
X-chromosomal loci in linkage disequilibrium. Greenlanders are remarkably different from most populations, but closer to Inuit
groups from Alaska, and with low levels of European admixture.
A general approach to power calculation for relationship testing
A user friendly implementation for the computation of exclusion power of a set of markers and the distribution of likelihood ratios
of disputed family relationships was developed.
Interindividual variability and intraindividual stability of oral fungal microbiota over time.
A follow-up of healthy volunteers was carried out during ~30 weeks after the first sampling. The oral fungal community presented
a high interindividual variability, but the frequency and quantification of each fungal taxon was constant over the 30-week
observation period, showing a consistent intraindividual stability over time.
Mutation origin of Machado-Joseph disease in a Nigerian family
This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in
North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around
7000 years.
Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations.
Partial correction of a splicing mutation was achieved with a modified U1 snRNA that completely matches the splice donor site
suggesting that these molecules may have a therapeutic potential for some splicing mutations. Additionally, glucosamine treatment
resulted in an increase in the enzymatic activity, indicating a partial recovery of the correct folding of a protein encoded by another
splicing mutation.
A global analysis of Y-chromosomal haplotype diversity
We contributed to a worldwide collaborative effort, in which 19,630 Y-chromosomes were sampled from 129 different populations
in 51 countries and typed for 23 short-tandem repeat (STR) loci. A strong correlation was observed between the number of Y-STRs
included in a marker set and some of the forensic parameters under study; a weak but consistent trend toward smaller genetic
distances resulting from larger numbers of markers became apparent.
Quality control, quality assessment, proficiency testing and collaborative exercises
We have organized the Collaborative Exercises: “SPInDel - Taxonomic identification of forensic samples” and “Analysis of autosomal
ancestry- informative indels - AIM-Indels” and participated in the collaborative exercise on analysis and interpretation of autosomal
short tandem repeat (STR) mixture profiles of the Spanish and Portuguese-Speaking Group of the International Society for Forensic
Genetics (GHEP-ISFG)
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CISA – Centro de Investigação em Saúde de Angola (Miguel Brito, Chissengo Lucama Tchonhi) - Epidemiology of
hemoglobinopathies and erythrocyte enzymes in Bengo, Angola
International Society for Forensic Genetics (ISFG) - Leonor Gusmão; Member of the Executive Committee
Norwegian University of Life Sciences, IKBM, Aas, Norway (Thore Egeland) - Biostatistics and forensics
Department of Human Genetics, Washington University School of Medicine, St. Louis, Missouri, USA (Donald F. Conrad) Genetics of Male Infertility and Spermatogenesis Regulome (transcription and translation).NIH grant number: R01HD07864101A1 ; PIs: Conrad & Aston (Multi-PI); Project start and end date: 09/10/2014-05/31/2019; Project title: Genomics of
Spermatogenic Impairment; Project goal: The goal of this project is to characterize the genetic basis of human spermatogenic
impairment using genetic epidemiology.
Genetic Identification Laboratory and Research Group of Genetic Identification, Institute of Biology, School of Natural and
Exact Sciences (FCEN), University of Antioquia, Medellin, Antioquia, Colombia (Adriana Ibarra) - Genetics of South American
populations
Population and Conservation Genetics Group, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal / Laboratoire Évolution
& Diversité Biologique CNRS, Université Paul Sabatier, Toulouse, France (Lounès Chikhi) - Evolutionary patterns of human
chromosomal inversions and development of inferential statistical methods; candidate genes for speciation in non-human
primates.
Nocturnal Wildlife Research Pty Ltd, P.O. Box 2126, Wattletree Road RPO, East Malvern 3144, Australia (Clive Marks) - Wildlife
genetics
Human Genetics Center, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal (João Gonçalves) - Genetics of male
infertility
Division of Hygiene and Medical Microbiology (HMM), Innsbruck Medical University, Innsbruck, Austria (Michaela Lackner)
- Microbial genetics; detection and identification of Aspergillus fumigatus strains in clinical samples from patients with
questioned invasive aspergillosis
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University,Montreal, Canada
(Guy Rouleau) - Genetics of neurodegenerative diseases; modifiers of repeat instability and age-at-onset in MJD
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada (Christopher E. Pearson) - Genetics of
neurodegenerative diseases
Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China (Virginia Wong) - Genetics
of polyglutamine diseases
Institute of Electronics and Telematics Engineering of Aveiro, University of Aveiro, Portugal (Luisa Castro) - Bioinformatics
DNA Diagnostic Laboratory, Institute of Biology, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil (Elizeu Carvalho)
- Population genetics of South America
Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of
Copenhagen, Denmark (Niels Morling) - Population and forensic genetics
Instituto Nacional de Toxicología y Ciencias Forenses, Delegación de Canarias, La Cuesta, Tenerife, Spain (Juan J Sanchez) Population and forensic genetics
Academic Haematology, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (Denise
Syndercombe-Court) - Population and forensic genetics
DNA Forensic Laboratory, Argentinean Forensic Anthropology Team (EAAF), Córdoba, Argentina (Carlos Vullo)
Population genetics of South America
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany (João Teixeira). Genetics of Sephardic Jews
Institute of Cancer & Genetics, Cardiff University School of Medicine (David Cooper) - Compensatory mutations at the Human
Gene Mutation Database (HGMD)
Executive Committee of the Spanish and Portuguese Speaking Working Group of the International Society for Forensic Genetics
(GHEP-ISFG) (Cintia Alves) - Membership
Universitat Illes Balear, Majorca, Spain (Antonia Picornell) - Genetic characterization of a crypto-Jewish Majorcan population
(Chuetas)
Tunis-El Manar University,Tunis, Tunisia (Amel Ben Ammar El Gaaied ) - Genetic profiling of populations from Tunisia;
Y-chromosome markers
Genetics of Male Infertility (GeMInI) international consortium - We are part of an international consortium devoted to the
Genetics of Male Infertility (GeMInI) that has been funded by the NIH (R01HD078641-01A1) and gathered over 1000 DNA
samples from patients with severe spermatogenic failure.
Biocant and Center for Neuroscience and Cell Biology (Coimbra, Portugal) (Bruno Manadas); - Determination of ultrastructural
and protein profiles changes associated with Aspergillus species aging
Future Research
Native Americans ancestry
We will address in particular the admixture and genetic diversity distribution patterns of non-recombining lineages of Native
American ancestry in South American populations.
Species / strains identification
Molecular approaches to species identification using DNA will be continued. A special attention will be paid to
- European red fox (Vulpes vulpes) as an Australialian exotic predator.
- microbial identification by mini-sequencing
Compensatory evolution in disease-associated genes
We will continue the search on human disease-associated mutations that are compensated in non-human species by epistatic
interactions with a compensatory variant, and the basis of molecular compensation between amino acid variants.
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2014
Genetics of linguistic and religious isolates
We will pursue the research on the population genetics of Mirandese speakers and Portuguese Jewish descendants.
The genetic characterization of these populations will now include autosomal high-density SNP genetic profiles.
Chromosomal rearrangements and evolution
Under this topic, inversions will be addressed will special emphasis, namely those showing polymorphism.
Evolution of the beta-globin gene cluster
We plan to demonstrate the distinctive patterns of evolution of the delta-globin gene (HBD) in primates, in relation with the
ontogenic switches between loci of the beta cluster.
Development of software tools for single nucleotide polymorphism analysis of genomic diversity
Publicly available large genomic data, including complete genomes allow a myriad of large scale studies on human genetic variation.
However, the tools currently available are insufficient when the goal concerns some analyses of data sets encompassing more than
hundreds of base pairs and when considering haplotype sequences of single nucleotide polymorphisms (SNPs). We are developing
new and potent tool to deal with large data sets allowing the computation of a variety of summary statistics of population genetic
data, increasing the speed of data analysis.
Contribution of MJD class deubiquitinating proteins to the age-at-onset of Machado-Joseph disease
We intend to study the contribution of MJD class deubiquitinating proteins (ataxin-3 like and Josephin domain-containing proteins)
to the age-at-onset of Machado-Joseph disease.
Pharmacogenetics of a Portuguese Gypsy community
Characterization of a Portuguese Gypsy community at a Pharmacogenetics and Forensic Toxicology level through the study of a
panel of 10 polymorphisms in genes known to have pharmacogenetic implications, namely TPMT, CYP2C9, CYP2C19, NAT2 and
VKORC1
Molecular spectrum of Maple Syrup Urine disease and the pathogenic role of splicing variations
Contribution to the molecular spectrum of Maple Syrup Urine disease through the demonstration of the pathogenic role of
putative intronic and exonic splicing variations identified in BCKD complex’ genes using a minigene strategy.
Genetics of Male Infertility
In a follow up of our work on the analysis of copy number variation in male infertility (Lopes et al., PLoS Genet 9(3): e1003349) we
will analyse the genetic variation in exome sequences of patients with severe spermatogenic failure and in fertile controls.
We will also analyse potentially deleterious genetic variants (coding and non-coding) in another regulator of sexual development in
Portuguese patients with severe spermatogenic failure and in fertile controls (DMRT1 gene).
Genetic diversity of wild primates and rodents
We will investigate the genetic variation in the PRDM9 gene in wild lemurs, a candidate gene for hybrid incompatibility and
speciation.
A study on the mitochondrial and autosomal genetic diversity of North African wild gerbils (Meriones) is also under way.
Detection of recombination in Aspergillus fumigatus through single nucleotide polymorphisms typing
We aim to analyse single nucleotide polymorphisms (SNPs) in a set of environmental and clinical isolates of A. fumigatus in order to
detect signatures of recombination. A group of closely related Portuguese A. fumigatus isolates will be characterised by the mating
type and the genetic diversity of the intergenic regions, microsatellites and multilocus sequence typing (MLST) genes.
Development of single-tube PCR assay for detection of cyp51A and cyp51B triazole related polymorphisms in
Aspergillus fumigatus
The genetic variations associated with triazole resistance in Aspergillus fumigatus reside on mutations in cyp51 genes, including the
tandem repeats in the promoter region. Extensive sequencing analyses of cyp51 genes is regularly required and other molecular
alternative approaches do not allow the systematic screen of multiple mutations in large collections of isolates. Therefore, the
objective of this study is to develop a single-tube multiplex PCR assay that allows rapid detection of cyp51A and cyp51B mutations.
The strategy was based on testing 21 molecular markers associated to the most relevant polymorphic positions in cyp51 genes
Development of a molecular tool for genotyping Burkholderia cepacia and Burkholderia contaminans
Burkholderia contaminans (B. cepacia group K) was recently designated as clinically relevant phylotype, resolved after a MLST
approach combined with whole genome sequencing. We propose to optimize a simple and practical protocol for extensive
population analysis of Burkholderia cepacia and Burkholderia contaminans.
Therapeutic strategies for splicing mutations
We will continue to explore therapeutic strategies based on modified U1 snRNAs or chaperone treatments to rescue the activity of
encoded products of mutation that affect the normal RNA processing
Aging mechanisms in pathogenic Aspergilli
We aim to study the ultrastructural and molecular changes involved in aging of pathogenic species belonging to the Aspergillus
genera. Also, it is aimed to elucidate the pathogenic and virulence potential of aged conidia in embryonated chicken eggs,
providing information on the mechanisms controlling infection, allowing the identification of specific targets for antifungal agents
and enhancement of productivity and longevity of industrial fungi. These studies will also contribute to a better definition of the
patients’ isolation times and also the duration of the applied therapies
•
•
•
•
42
Amorim A - GABBA (Graduate Program in Areas of Basic and Applied Biology). UP
Amorim A - Programa de Pós-Graduação em Ecologia e Evolução (PPGEE), Universidade Estadual do Rio de Janeiro (UERJ), Brazil
Gusmão L - Programa de Pós-Graduação em Biociências, Universidade Estadual do Rio de Janeiro (UERJ), Brazil
Gusmão L - Programa de Pós-Graduação em Genética, Universidade Federal do Paraná (UFPR). Curitiba, Brazil
2014
•
•
•
Alvarez L, Alves C, Amorim A, Goios A, Gomes V, Gusmão L, Prata MJ, Pinto N, van Asch B, Pereira F, Oliveira M - MSc Forensic
Genetics. UP
Lopes AM,Martins S, Quental S - MSc Molecular and Cellular Biology UP
Gusmão L - Mestrado Profissional em Saúde, Medicina Laboratorial e Tecnologia Forense da Universidade do Estado do Rio de
Janeiro – UERJ, Brazil
Invited Talks
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ESSPlex Plus in Human Identification - IPATIMUP’s experience - Goios, A., Melo, F., Amorim, A., Alves, C
QIAGEN Investigator Forum. Dusseldorf, Germany. 03/04/2014. - Goios, A., Melo, F., Amorim, A., Alves, C
Modelling phylogenetic trees: a combinatorial approach - Soares I, Duarte R, Goios A, Amorim A, Oliveira AG
The 4th Combinatorics Day University of Aveiro. Aveiro, Portugal. 14/05/2014. - Soares I, Duarte R, Goios A, Amorim A, Oliveira
AG
Coding and non-coding DNA – boundaries on the move - Amorim A
Symposium on rare diseases II – Joining all stakeholders to discuss Human Genetic Diseases. Porto, Portugal. 17/01/2014. Amorim A
A origem das espécies - Amorim A
Cancro, Ciência e Cidade. Os Passos da Ciência nos Paços do Concelho. Porto, Portugal. 09/05/2014. - Amorim A
La herencia sefardí de La Raya: nuevos aportes desde la genética poblacional - Nogueiro I, Teixeira JC, Gusmão L, Alvarez L
Congreso Internacional “Zamora y La Raya: herencias sefardíes compartidas”. Vimioso and Carção (Portugal); Fermoselle and
Zamora (Spain) . 01/07/2014. - Nogueiro I, Teixeira JC, Gusmão L, Alvarez L
Origem e evolução fenotípica de novos genes - Azevedo L, Amorim A, Silva RM
II AEICBAS Biomedical Congress, Porto, Portugal . Porto, Portugal. 26/04/2014. - Azevedo L, Amorim A, Silva RM
Infertilidade masculina – um mosaico de doenças mendelianas por descobrir? . II AEICBAS Biomedical Congress. Porto, Portugal.
26/04/2014. - Lopes AM
Alquimia genética: aparecimento de novos genes de regiões ancestrais não codificantes.. Bioinformatics Seminar Series, IEETA,
University of Aveiro.. Aveiro, Portugal. 12/06/2014. - Azevedo L, Amorim A, Silva RM
Avaliação da diversidade genética da população colombiana mediante o estudo de marcadores genéticos do cromosoma
X. Ciclo de conferências mensais do curso de pós-graduação do Departamento de Patologia da UNIFESP. São Paulo, Brazil.
19/03/2014.
Gusmão L - Gusmão L
Marcadores de ancestría. Bases de datos y análisis poblacional. . Simposio Internacional de Genetica de Poblaciones Humanas.
Instituto de Investigações Inmunologicas. Universidade de Cartagena. Cartagena, Colombia. 28/03/2014. - Gusmão L
The X chromosome specific markers in Forensic Analysis. 4th International Conference on Forensic Genetics FORENSICA 2014.
Prague,Czech Republic. 21/05/2014. - Gusmão L
Importância da estratificação populacional em bases de dados de frequências de haplótipos de cromossoma Y de uso forense. .
Grupo Cientifico Latino-Americano de Trabajo sobre Identificación Humana. International Symposium on Human Identification.
Phoenix, Arizona, USA. Phoenix, Arizona, USA. 28/09/2014. - Gusmão L
Marcadores de Cromosoma Y en Genética Poblacional y forense. . Curso Iberoamericano de Genética Forense. Intepretación de
las Pruebas de ADN en la Identificación Humana. Monterey, Mexico. 24/11/2014. - Gusmão L
Evaluación de los resultados de STRs. Curso Iberoamericano de Genética Forense. Intepretación de las Pruebas de ADN en la
Identificación Humana. . Monterey, Mexico. . 24/11/2014. - Gusmão L
Valoración estadística de relaciones biológicas mediante STRs del cromosoma X y estudio y aplicación de indels en genética
forense y de poblaciones . VI curso internacional teórico-practico genetica de poblaciones y filiaciones biológicas. Medellín,
Colombia. 25/03/2014. - Gusmão L
Bioinformatics and new techniques (NGS) for Y chromosome and their forensic application. WORKSHOP pré-congresso XIX
JORNADAS DEL GHEP-ISFG. Quito, Ecuador. 10/09/2014. - Gusmão L
Análisis de marcadores del Cromossoma X . Curso Iberoamericano de Genética Forense. Intepretación de las Pruebas de ADN en
la Identificación Humana. . Monterey, Mexico. 24/11/2014. - Gusmão L
Oral Presentations
•
•
•
•
•
Goios, A., Marques, S., Rocha, A.M., Alves, C., Gusmão, L., Prata, M.J., Amorim, A. and Alvarez, L. Increasing phylogenetic
resolution of haplogroup U in Iberia through mtDNA complete sequencing. DNA in Forensics 2014. Brussels, Belgium.
16/05/2014.
Alvarez L. Linguistic and religious isolates in northeastern Portugal: new insights from genetics and demography. Seminário
internacional José Mattoso “Diálogos em torno da Interdisciplinaridade: para uma outra visão da Idade Média”. Lisbon,
Portugal. 20/11/2014.
Alves JM, Chikhi L, Amorim A, Lopes AM. Inversion polymorphism determines local recombination heterogeneity across human
populations. 16 th Portugaliae Genetica. Porto, Portugal. 21/03/2014.
C. Vullo, V. Gomes, C. Romanini, A. Oliveira, O. Rocabado, J. Gozi, A. Torres Balanza, A. Amorim, L. Gusmão
. Association between Y haplogroups and AIMs revealed intra-population substructure in Bolivian populations. DNA in Forensics
2014. Brussels, Belgium. 16/05/2014.
43
44
2014
2014
Post-Graduation
45
46
2014
2014
Post-Graduation Unit
Overview
IPATIMUP Post-Graduation Unit coordinates various activities of Post-graduation organised within the Institute.
GABBA Program: Module of Oncobiology 2014
The structure of the module: (24th March – 4th April) has a dual structure: lectures and seminars, and work on research projects.
The aims of the module: The Oncobiology module will have sessions to discuss biological/molecular mechanisms of cancer
development and progression. Sessions will include discussion of clinical cases followed by open discussions with the students about
the underlying etiological factors, the biological pathways and molecular mechanisms underlying pathological lesions. The sessions
will include: 1- Presentation of clinical cases (sporadic and hereditary); 2- Pathological aspects of the tumours; 3- Etiology and
molecular basis of the disease.
Teaching staff: Senior Researchers of IPATIMUP and Medical Faculty, and Post-docs.
The program of GABBA Program: Module of Oncobiology 2014
9.00-9.30 10.00-13.00 15.00-17:30 17.30-19.00 9.30-12.00 14.30-17.00 17.30-19.00 9.30-12.00 14.30-17.00 17.00-19.00 9.30-12.00 14.00-19.00 9.30-12.00 14.30-17.00 17.30-19.00 9.30-12.00 14.00-16.00 17:00-19.00 9.30-12.00 14.30-17.00 17.30-19.00 24 March:
Documents and structure of the module (Participants: R Seruca and Celso Reis)
Distribution of the projects (R Seruca and Celso Reis, with the collaboration of Raquel Almeida, Joana Paredes,
Paula Soares, Helena Vasconcelos).
Cancer genes: Beyond the classic dual division (Participant: M Sobrinho-Simões)
Projects preparation/discussion.
25 March:
Oncogenes and Tumor suppressor genes (Participants: Raquel Seruca)
Metabolism and cancer (Participants: Valdemar Máximo, Jorge Lima, M Sobrinho-Simões).
26 March:
Genomic dynamics of cancer cells (Participants: José Carlos Machado, José Luís Costa)
Tumor Growth and Immortalization (Participants: Paula Soares, João Vinagre, Ana Preto)
“Recent Advances in Gastric Cancer: From Etiopathogenesis to Treatment” (Comemoração dos 25 anos do
IPATIMUP).
27 March:
Infection and cancer: “the example of Helicobacter pylori and gastric carcinoma” (Participants: Céu Figueiredo,
Marina Leite e Cecília Durães)
28 March
Cell and tissue differentiation (Participants: Raquel Almeida, Leonor David, Rita Barros)
Cancer Stem Cells (Participant: Joana Paredes; Gabriela Almeida)
31 March
Role of glycosylation in cancer. (Participants: Celso Reis, Salomé Pinho, Ana Magalhães)
Proteomic applications in Cancer Research (Participants: Celso Reis, Hugo Osório)
1 April
Metastable phenotypes in Epithelial Cancer (Participants: Carla Oliveira, Joana Paredes)
Cancer Cell invasion (Participants: Raquel Seruca, Sérgia Velho, Fátima Carneiro)
Projects prepara
The workshop on Cancer Research 2014. This international Workshop is run at IPATIMUP and is recognized by
the University of Porto (Gives ECTS).
14h00-15h30 15h45-17h15 9h00-10h30m 10h45-12h15 14h30-16h30 13th May 2014 (Tuesday)
“Cancer genetics: oncogenes and tumour supressor genes” Raquel Seruca
“Tumor cell growth: proliferation, apoptosis and metabolism”. Paula Soares; Valdemar Máximo
14th May 2014 (Wednesday)
“Glycobiomarkers in cancer” Celso Reis; Hugo Osório
“Tumor Immunology” Maria José Oliveira
“Tumor cell invasion and metastasis. Genomics/Transcriptomics in Cancer Research”. Ana Sofia Ribeiro; Salomé
Pinho; Carla Oliveira
17h15-18h15 “Oncopathology-From tissue to genes and back to tissues” Manuel Sobrinho-Simões
15th May 2014 (Thursday)
9h00-10h30 “Cell and tissue differentiation”. Leonor David; Raquel Almeida
10h45-12h15 “Experimental models in vitro and in vivo in cancer research” Fátima Gartner, Marta T. Pinto
14h30-18h30 Practical sessions I
16th May 2014 (Friday):
9h00-10h00
Invited Seminar
10h15 - 13h15 Practical sessions II
15h00-16h00 Evaluation
47
2014
Ipatimup Seminars: 2014 (Wednesdays, 9h)
15 Jan 2014 22 Jan 2014 29 Jan 2014 5 Fev 2014 12 Fev 2014 19 Fev 2014 26 Fev 2014 12 Mar 2014 19 Mar 2014 26 Mar 2014 9 Abr 2014 30 Abr 2014 7 Mai 2014 14 Mai 2014 21 Mai 2014 28 Mai 2014 4 Jun 2014 11 Jun 2014 18 Jun 2014 2 Jul 2014 16 Jul 2014 17 Set 2014 24 Set 2014 8 Out 2014 15 Out 2014 22 Out 2014 29 Out 2014 5 Nov 2014 12 Nov 2014 19 Nov 2014 26 Nov 2014 3 Dez 2014 Cancer Drug Resistance (HV), Diana Sousa (HV)
Cancer Genetics (RS) Sérgia Velho (RS)
Expression Regulation in Cancer (CO)
Rui Ferreira (CF)
Cancer Genetics (RS) André Vieira (JP)
Differentiation in Cancer (RA) Lara Silva (LD)
Silvia Pereira (SS)
Cristina Santos (MJP)
Cancer Genetics (RS) Diana Martins (JP)
Cancer Biology (PS)
Cancer Genetics (RS)
Genetic Diversity (LP)
Patrícia Marques (SS)
Glycobiology in Cancer (CR) Sandra Carvalho (SP)
Cancer Genetics (RS) Marina Leite (CF)
Expression Regulation in Cancer (CO)
Population genetics (AA)
Cancer Genetics (RS)
Cancer Drug Resistance (HV)
Cancer Biology (PS)
Expression Regulation in Cancer (CO)10 Set 2014 Genetic Dynamics of Cancer Cells (JCM) José Luís Costa
Population Genetics (AA)
Cancer Genetics (RS) André Vieira (JP)
Glycobiology in Cancer (CR) Irina Amorim (FG)
Cancer Genetics (RS) Anabela Ferro
Genetic Diversity
Differentiation in Cancer (RA)
Population Genetics (AA)
Cancer Biology
Genetic Dynamics of Cancer Cells (JCM) Cecília Durães
Cancer Genetics (RS) Marina Leite (CF)
Differentiation in Cancer (RA)
Friday´s Journal Club (2014), 15:00h.
17 Jan 2014 24 Jan 2014 31 Jan 2014 7 Fev 2014 21 Fev 2014 7 Mar 2014 14 Mar 2014 2 Mai 2014 9 Mai 2014 16 Mai 2014 23 Mai 2014 30 Mai 2014 6 Jun 2014 13 Jun 2014 27 Jun 2014 11 Jul 2014 12 Set 2014 19 Set 2014 26 Set 2014 3 Out 2014 31 Out 2014 7 Nov 2014 14 Nov 2014 21 Nov 2014
5 Dez 2014 48
Cancer Biology
Population Genetics
Post-Doc Technical Seminar
Cancer Genetics
Ipatimup
WCR
Genetic Dynamics of Cancer cells
Expression Regulation and Cancer
Population Genetics
Genetic Diversity
Cancer Biology
Ipatimup
Population Genetics
Expression Regulation and Cancer
Genetic Dynamics of Cancer cells
Cancer Genetics
2014
Outreach Activities
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2014
2014
Science Diffusion
Overview
The Science Diffusion Unit aims to promote scientific culture, interacting whether with schools and with the community. Thus,
during 2014 the Science Diffusion Unit has developed/been involved in the following activities/projects:
1. “Laboratório Aberto”
2. “Porto de Crianças”
3. “Mostra UP”
4. “Ciência Viva no Verão”
5. IPATIMUP’s Day
6. “Noite dos Investigadores”
7. “Escola das Ciências da Vida e Saúde”
8. School meetings
9. “Traz um amigo também”
10. “Segunda há Ciência”
11. “Escola Científica”
12. “Auto Laboratório”
Highlights
Laboratório Aberto
In 2014 the objectives of the “Laboratório Aberto” have been met. The “Laboratório Aberto” has received 4579 students from
around the country that performed hands-on practical activities.
“Escola Científica”
This project aims twinning two laboratories in two schools, Esc. Sec. Cinfães and Esc. Sec. Aurélia de Sousa in collaboration /
scientific support IPATIMUP. This project is supported by the “Agência Ciência Viva”. Total Number of students:731.
“Auto Laboratório”
Funded project ON.2 / CCRN which is based experimental activities lead to schools, conducting activities in the context of the
classroom. To this end, via a vehicle moves schools without guaranteeing the quality of experimental teaching and reducing the
costs associated with the students. Total Number of students: 2698.
“Ciência Viva no Verão”
The project received two more students than last year (25 total) and there was also an increase in funding.
Porto de Crianças
In 2014, the protocol with the City Council of Porto, which was about to end, was maintained meeting the project objectives.
Four schools benefited from this project which contemplated 64 sessions in the classroom, with the participation of 92 students in
4th grade.
Quality Control
Laboratório Aberto
Laboratório Aberto
At the end of each visit, students and teachers filled out a satisfaction survey of the activities, with the following topics:
1. Satisfaction of the activities presented;
2. Appropriate scientific language;
3. Scientific rigor;
4. Would you return to “Laboratório Aberto”?
Nearly 100% of people have given maximum rating on the topics asked.
Activity Statistics
Visits to “Laboratório Aberto” in 2014 per month
Month
Students
Teachers
Total
Jan
618
61
679
Fev
566
54
620
Mar
549
50
599
Abr
458
51
509
Mai
772
79
851
Jun
160
18
178
Jul
115
18
133
Ago
0
0
0
Set
0
0
0
Out
561
44
605
Nov
434
38
472
Dez
346
31
377
TOTAL
4579
444
5023
51
2014
Visits to Laboratório Aberto in 2014 per district
Distrito
Aveiro
Braga
Guarda
Lisboa
Viana do Castelo
Porto
Viseu
TOTAL
Nº Alunos
301
147
57
68
51
3924
31
4579
Responsáveis
26
12
4
8
3
389
2
444
Total
327
159
61
76
54
4313
33
5023
“Auto Laboratorio” results in 2014 per month
Month
Students
Jan
51
Fev
361
Mar
564
Abr
190
Mai
498
Jun
0
Jul
0
Ago
0
Set
0
Out
271
Nov
472
Dez
291
“Auto Laboratorio” results in 2014 per district
Distrito
Aveiro
Braga
Porto
TOTAL
Nº Alunos
18
139
2541
2698
“Escola Científica” global results.
Escola
Localização
Escola Secundária /3 Prof. Dr. Flávio Pinto Resende
Cinfães
Escola Secundária Aurélia de Sousa
Porto
Total
Other Activities
interaction with the community
10ª Escola das Ciências da Vida e Saúde (4 students from 11º grade)
Segunda há Ciência: 5 Schools; 154 students
52
Nº de alunos
215
516
731
TOTAL
2698
2014
Public Awareness of Cancer
Overview
During 2014 the Public Awareness of Cancer Unit (PACU) developed an extensive activity focused on Cancer Prevention Education.
Besides expanding national and international collaborations, the PACU participated in several public events promoting new
strategies of cancer prevention. The results of the research work were presented in national and international meetings and
publications. Grant applications were prepared and submitted.
Highlights
Publications
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, et al. (2014). “Cancer – Educate to Prevent” – High-School Teachers, the New
Promoters of Cancer Prevention Education Campaigns. PLoS ONE 9(5): e96672. doi: 10.1371/journal.pone.0096672.
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, Santos-Silva F. (2014). “Cancer, educate to prevent” – Can high-school teachers
be the cornerstone of a new cancer prevention education?. Journal of Cancer Education 29:s1.
-Ribeiro N, Barros A, Almeida AM, Santos-Silva F. (2014). Happy: a cancer prevention mobile app supported by a qualitative study.
Revista de Saúde Pública, 48, special number, May 2014.
-Ribeiro N, Barros A, Almeida AM, Santos-Silva F. (2014). Happy: a cancer prevention smartphone app designed to promote behavior
change. Proceedings of the MobileMed 2014 conference. Prague, Czech Republic.
-Ribeiro N, Moreira L, Almeida AM, Santos-Silva F. (2014). Smartphones: Innovative Tools in Cancer Prevention. Encyclopedia of
E-Health and Telemedicine. (submitted).
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, Santos-Silva F (2014). An unexplored potential to reduce cancer burden of
future generations - improving the low levels of cancer literacy among adolescents. BMC Public Health. (submitted).
Oral Communications
-Santos-Silva F. (2014). Support networks for pancreatic cysts patients: an European perspective. Patient Forum on Cystic Tumours
of the Pancreas. Royal Free Hospital. London, UK.
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, Lamas S, Santos-Silva F. (2014). “Cancer, educate to prevent” – Can high-school
teachers be the cornerstone of a new cancer prevention education?. International Cancer Education Conference: Building Global
Bridges. Florida, USA.
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, Santos-Silva F. (2014) “Communicating” Cancer – A new model for cancer
prevention education mediated by teachers. SciCom PT - 2º Congresso Nacional de Comunicação de Ciência. Porto, Portugal.
-Barros A, Santos H, Moreira L, Santos-Silva F. (2014). “Cancer, Educate to Prevent–Presentation of a study of Primary Prevention”.
VII Congresso Português de Sociologia. Universidade de Évora. Évora, Portugal.
-Santos-Silva F, Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L (2014) “Cancer Prevention Education - Bringing Teachers to a
Brave New World”. Fourth International Conference on Health, Wellness and Society. University of British Columbia, Vancouver,
Canada.
-Ribeiro N, Barros A, Almeida AM, Santos-Silva F. (2014). Happy: a cancer prevention smartphone app. Conference on Mobile and
Information Technologies in Medicine MobileMed. Prague, Czech Republic.
-Ribeiro N, Barros A, Almeida AM, Santos-Silva F. (2014). “HAPPY: a Cancer Prevention Mobile App supported by a Qualitative Study”.
2nd IPLeiria International Health Congress: Challenges & Innovation in Health. IPLeiria School of Health Sciences. Leiria, Portugal.
Posters
-Barros A, Moreira L, Santos H, Hollingsworth MA, Santos-Silva F. (2014). The Cancer - Educate to Prevent program: Schools as
beacons of cancer prevention education programs in vulnerable populations. Seventh AACR Conference: The Science of Cancer
Health Disparities in Ethnic Minorities and the Medically Underserved. Texas, USA.
-Barros A, Moreira L, Santos H, Ribeiro N, Carvalho L, Lamas S, Santos-Silva F. (2014) Cancer Prevention Education: Building the
Future Through School Community. 4th I3S Meeting. Póvoa de Varzim, Portugal.
-Ribeiro N, Almeida AM, Santos-Silva F. (2014). HAPPY: prevenção de cancro no smartphone. SciCom PT - 2º Congresso Nacional de
Comunicação de Ciência. Porto, Portugal.
-Ribeiro N, Almeida AM, Santos-Silva F. (2014). HAPPY: Health Awareness and Prevention Personalized for You. 4th I3S Meeting.
Póvoa de Varzim, Portugal.
Grants Preparation
-“HYPE – Healthy Youth through Prevention Education” grant submitted to Gulbenkian Programme for Innovation in Health.
(Awarded).
-“Development of an innovative education model for a nutrition savvy population” grant submitted to the Public Health Initiatives
Program – EEA Grants Portugal.
Other Activities
Other Activities
-Design and production management of the book “Cancro Ponto e Vírgula”edited by IPATIMUP and Calouste Gulbenkian Foundation.
-Coordination of the communication strategy of the European COST ACTION BM1204 - An integrated European platform for
pancreas cancer research: from basic science to clinical and public health interventions.
-Management of the Website EUPancreas (www.eupancreas.com).
-Participation on the PAPERPAC study, focused on surveys and questionnaires to patients with pancreatic cystic tumours.
-Peer review of abstracts for the International Cancer Education Conference 2014: Building Global Bridges, Providing Quality Cancer
Education – Florida, USA.
-National Jury for Biomedical area of “Concurso Jovens Investigadores - 2014”.
-International Jury: Member of Scientific Review Committee (SRC) of Intel ISEF 2015.
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2014
Ipatimup
Diagnostics
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2014
2014
Overview
In 2014, IPATIMUP Diagnostics maintained the high quality standards successfully achieved in the previous years through CAP
accreditation, after CAP self-inspection held in Februrary 2014. Also, the ISO 9001:2008 certification was maintained through the
renovation audit held in March 2014.
Other goals for 2014, such as maintaining the unit as a professional training center, maintaining the number of tests from the
previous year, achieving better client satisfaction with our services and participating in research projects with health institutions and
pharmaceutical companies, and inclusion in international networks, were totally accomplished.
Highlights
•
•
•
•
•
CAP accreditation and ISO 9001:2008 certification was successfully maintained by IPATIMUP Diagnostics;
Participation in international networks – maintained for EUROFORGEN
Overall client satisfaction was maintained relatively to the previous year;
Training increased in 1 trainee in relation to the previous year. IPATIMUP has maintained its position as a professional training
centre through its nomination by the Portuguese Physician’s Association (Ordem dos Médicos) as a reference centre in
molecular pathology of the Anatomical Pathology internship;
Participation in research projects with health institutions and pharmaceutical companies, as well as the establishment of
specific national and international service contracts with hospitals and other health institutions, increased and diversified in
2014.
Activity Statistics
EXAMS
LAP
Total
Histology
6003
Cytology (includes 2852 cases of FNA cytology)
10936
Molecular Pathology
965
Consultations
219
Telepathology
5421
LDG
Total
4727
Tumour mutation screening
2267
Genetic Diagnosis
2460
286
LPIG
Total
Genetic Characterizations (including lineage markers)
76
Parentage investigations (individuals) and genetic profile
comparisons (sample/individual)
23544
210
CONSULTATIONS - TOTAL - 219
Algeria
2 Belgium
9 Brazil
7 Croatia
1
Czech Republic
1 England
14 France
17 Germany
1
Greece
9 Holland
4 Ireland
4 Israel
1
Malta
2 Monaco
1 Mozambique
5 Norway
2
4 Turkey
1
Portugal
112 Spain
22 Switzerland
Quality Control
1. INTERNAL QUALITY CONTROL
A) LAP
In 2014 the “turn-around time” (TAT) was the following:
•
Histological Exams: 28.60% of reports are sent in 2 working days.
•
Cytological Exams: 86.10% of reports are sent in 2 working days.
•
Screening cytologies: 93.00% of reports are sent in 7 working days.
57
2014
The main results for the Gynecological Cytology quality control analysis were:
2011
2012
2013
2014
Total cases
6977
6862
7108
6982
Reviewed cases
1281
1349
1391
297
2011
2012
2013
2014
1204
(93.99%)
1245
(92.3%)
1326
(95.3%)
296
(99.6%)
77
(6.01%)
104
(7.7%)
65
(4.7%)
1
(0,3%)
Concordance between pathologist and
cytotechnician
Discordance between pathologist and
cytotechnician
The percentage of the total amount of unsatisfactory cases for analysis was 1.40% (1.69% in 2013, 1.43% in 2012, 0.85% in 2011,
0.59% in 2010).
ASCUS/ACG were diagnosed in 260 cases with a ASCUS/Lesion reason of 1.8 (2.61 in 2013, 1.84 in 2012, 2.23 in 2011 and 2.57 in
2010).
B) LDG
The diagnostic genetics laboratory has an internal quality control system that includes proficiency testing.
Internal proficiency testing is performed twice a year using samples that represent diseases not covered in the external quality
control exercises. In 2014 we accomplished a 100% concordance rate in the internal quality control exercise.
C) LPIG
The main features comprising internal quality control are measured according to PR.QUA.10. The main finding concerns the overall
turn-around time (Tat), where better results were obtained for 2014 relatively to 2013, especially for exams with limit samples):
Type of exam
Tat
2011
2012
2013
2014
1
Exams with simple
reference samples
10 working days
80,75%
82,26%
87.34%
88.6%
2
Exams with complex
reference samples
20 working days
62,75%
100%
100%
100%
3
Exams with limit samples
30 working days
87,50%
96,43%
83.33%*
100%
All the other quality control measures are within the goals established as acceptable.
2. EXTERNAL QUALITY CONTROL
During 2014 Ipatimup Diagnostics has participated in the following proficiency tests and quality assurance programs: CHPVA, CYK,
EGFR-A, GHEP-ISFG, HER2, ISH2, KIT-A, KRAS-A, KRAS-EQA, MGL-A, MK, MSI-A, EGFR-B, CHPV - B, KRAS-B, KIT-B, EGFR-EQA, MGL-B,
MSI-B, NGC, PAP-M, PARF (A, B e C), PIP and PM2. As a result, 1513 unique parameters were evaluated with approval in all tests.
Other Activities
TRAINING
In total, there were 24 people who underwent training at IPATIMUP Diagnostics during 2013, according to the following table:
NAME
58
START DATE
END DATE
Helena Sofia Teixeira Rodrigues Martins
Portugal
COUNTRY
07-05-2014
31-08-2014
Mariana da Costa Dias
Portugal
04-08-2014
31-12-2014
Elisabete Cruz da Silva
Portugal
24-02-2014
13-03-2014
Monique Batista da Costa Lemos
Brazil
03-11-2014
31-12-2014
Maria Teresa Rocha e Pinho Pereira
Portugal
01-09-2014
31-12-2014
Bozidar Kovacevic
Serbia
01-02-2014
31-03-2014
Roberto Nicolau Pestana Silva
Portugal
02-01-2014
31-01-2014
Gemma Mateu Esquerda
Spain
01-10-2014
30-11-2014
Luiza
Brazil
02-06-2014
30-06-2014
Sofia Raquel Fernandes Salta
Portugal
10-02-2014
11-03-2014
NAME
COUNTRY
2014
START DATE
END DATE
Santiago Ortiz Fernández
Portugal
02-05-2014
30-06-2014
Susana Cláudia Pinto Moutinho
Portugal
12-03-2014
08-04-2014
Luís Eugénio de Albuquerque Carreiras Mascarenhas de Lemos
Portugal
01-05-2014
30-05-2014
Leandro Aurélio Liporoni Martins
Brazil
01-04-2014
30-05-2014
Raquel Patrícia Morgado Teixeira da Silva
Portugal
10-04-2014
29-08-2014
Jennifer Lima da Costa
Portugal
17-06-2014
20-06-2014
Hélder Manuel Casal Cardoso
Portugal
02-07-2014
01-01-2015
Luciana Kaeser
Portugal
18-08-2014
17-10-2014
Catuxa Celeiro Muñoz
Spain
06-10-2014
14-11-2014
Tânia Patrícia Amorim Fernandes
Portugal
10-09-2014
31-12-2014
Daniela Ferreira Rodrigues
Portugal
17-11-2014
12-12-2014
Raquel Margarida Gomes Martins
Portugal
13-02-2014
18-02-2014
Tiffany dos Santos Pinho
Portugal
24-11-2014
06-02-2015
JUAN JOSE
Spain
21-11-2014
28-11-2014
PUBLICATIONS
1.
Melo F, Amorim A, Alves C (2014) Comparative performance between ‘‘next generation’’ multiplex systems and the new
European Standard Set of STR markers in the Portuguese Population, Forensic Sci. Int. Genet. 8(1):137-142. doi: 10.1016/j.
fsigen.2013.08.015
2. M. Crespillo, P.A. Barrio, J.A. Luque, C. Alves, M. Aler, F. Alessandrini, L. Andrade, R.M. Barretto, et al. (2014) GHEP-ISFG
collaborative exercise on mixture profiles of autosomal STRs (GHEP-MIX01, GHEP-MIX02 and GHEP-MIX03): Results and
evaluation, Forensic Sci Int Genet 10:64–72. doi: 10.1016/j.fsigen.2014.01.009.
3. Josephine Purps, Sabine Siegert, Sascha Willuweit, Marion Nagy, Cíntia Alves, Renato Salazar, Sheila M.T. Angustia, et al. (2014)
A global analysis of Y-chromosomal haplotype diversity for 23 STR loci. Forensic Sci Int Genet. 2014 12: 12-23. doi: 10.1016/j.
fsigen.2014.04.008.
4. Lyra J, Vinagre J, Batista R, Pinto V, Prazeres H, Rodrigues F, Eloy C, Sobrinho-Simões M, Soares P. “mTOR activation in
medullary thyroid carcinoma with RAS mutation.” Eur Journal of Endocrinology. 2014;171(5):633-40
5. Nakazawa T, Cameselle-Teijeiro J, Vinagre J, Soares P, Rousseau E, Eloy C, Sobrinho-Simões M. “C-cell-derived calcitonin-free
neuroendocrine carcinoma of the thyroid: the diagnostic importance of CGRP immunoreactivity.” International Journal of
Surgical Pathology. 2014 22(6):530-5
6. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, SalgadoC, Eloy C, Castro P, Prazeres H,
Lima J, Amaro T, Lobo C, Martins MJ, Moura M, Cavaco B, Leite V, Cameselle-Teijeiro JM, Carrilho F, Carvalheiro M, Máximo
V, Sobrinho-Simões M, Soares P. “TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid
carcinomas.” J Clin Endocrinol Metab. 2014;99(5):E754-65
7. Cameselle-Teijeiro J, Ladra MJ, Abdulkader I, Eloy C, Soares P, Barreiro F, Sobrinho-Simões M, Beiras-Iglesias A. “Increased
lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease).” Virchows Arch. 2014 Sep;465(3):359-64.
8. Eloy C, Cameselle-Teijeiro JM, Rousseau E, Sobrinho-Simões M. “Small cell tumors of the thyroid gland: a review.” International
Journal of Surgical Pathology. 2014 ;22(3):197-201
9. Rossi ED, Gerhard R, Cirnes L, Machado JC, Schmitt F. Detection of Common and Less Frequent EGFR Mutations in Cytological
Samples of Lung Cancer. Acta Cytol 58:275-80, 2014.
10. Vissers LE, Bonetti M, Paardekooper Overman J, Nillesen WM, Frints SG, de Ligt J, Zampino G, Justino A, Machado JC, Schepens
M, Brunner HG, Veltman JA, Scheffer H, Gros P, Costa JL, Tartaglia M, van der Burgt I, Yntema HG, den Hertog J. Heterozygous
germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur J Hum Genet 23:31724, 2015.
11. Amorim T, Wyon M, Maia J, Machado JC, Marques F, Metsios GS, Flouris AD, Koutedakis Y. Prevalence of Low Bone Mineral
Density in Female Dancers. Sports Med (in press).
PROJECTS
•
•
•
•
•
Project with Sanofi Pasteur MSD – Epidemiological study for evaluation of anogenital condilomas in a population that undergoes
dermatology and/or DST counselling in Portugal.
Project with Politécnico Viseu – Prevalence and relationship of Helicobacter pylori with other microorganisms from the oral
flora.
QREN Projects:
Anti-EGFR – Development of a diagnostic solution for mutations associated with colorectal carcinoma for commercialization.
DoIt – Optimization of an algorithm for therapy decision in metastatic colorectal carcinoma.
MuSa – Detection of mutations and epigenetic alterations in blood circulating tumoral DNA.
FCT Project – Portuguese study on Familial Dilated Cardiomyopathy.
Projects with Life Technologie - Lung Fusion transcripts – RNA Ion Ampliseq Cancer Panel, a partnership with “OncoNetwork Fusions”, Life technologies
59
60
2014
2014
Innovation
&
Translation
61
62
2014
2014
Ipatimup Innovation
Overview
The Innovation Unit’s mission is to create value from the commercial exploitation of intellectual property (I.P.) and from stimulating
the creation and growth of spin-off companies based at IPATIMUP. Through consulting and coaching, the Innovation Unit helped
researchers achieve the different steps in the innovation cycle of services and products derived from their core research activities.
In 2014, the Innovation Unit undertook four main lines of action: 1) Registration of I.P. and Licensing to established companies; 2)
Application to Innovation funding programs/awards; 3) Launching of new spin-off companies; 4) Direct presentation of projects to
Venture Capitals and investors.
Highlights
Portfolio of innovation projects
The Innovation unit took a pro-active role in prospecting knowledge and research that can constitute the basis for innovative
products or services which have highly differentiated, cutting-edge, science-based character and, most importantly, a potential
market that is economically interesting. In 2014 the portfolio of projects/technology/materials supported by the Innovation Unit
encompasses 16 projects and includes: formulations of nanobiomaterials for eradication of Helicobacter pylori, microvesicle-based
biomarkers of multidrug resistance, new cell models for HCV replication, bacterial-derived fungicide, chiken-egg in vivo assays, in
vitro assays to determine potential antitumor effects, genomic bioinformatics services, informatics algorithm to quantify protein
expression, proprietary hybridomas to produce diagnostic and therapy selection antibodies, serum biomarkers associated with
gastric cancer and it’s precursor lesions, ultrasensitive assay of bladder cancer biomarkers in urine, multiplex system for human
identification and digital cytology for oral cancer, PNA FISH probes for Helicobacter pylori, Therapeutic Glycans, Gastric cancer
prognostic biomarkers for selections of stage I-II patients eligible for adjuvant chemotherapy.
The Innovation unit undertook several types of actions, established in a case by case basis, in order to take each of the
above mentioned projects further in the innovation cycle aiming to obtaining economic revenue from promotion of their
commercialization.
1. Registration of IP and Licensing
In terms of patent submission, overall, in 2014 the Innovation Unit made a total of 5 new IP registrations in which IPATIMUP is
applicant, with entitled ownership. These corresponded to 4 provisional patent applications and 1 international stage application.
In 2014 a total of 9 proposals were sent to companies offering a license to commercialize Helicobacter pylori microspheres that have
been developed by IPATIMUP researchers and we received a proposal for licencing PNA FISH probes for Helicobacter pylori. As a
result, one licensing agreement was accomplished with Chromoperformance, a spin-off company from University of Minho.
2. Application to Innovation funding programs/awards
In 2014 the Innovation Unit promoted 9 applications to innovation funding projects, programs or awards. One or more applications
were sent to the following calls: “Concurso InovPortugal”; Portugal Venture’s Call for Entrepreneurship; “Building Global Innovators;
“BES Inovação”, “ANJE - Jovem Empreendedor”, “Arrisca C”. Overall 3 applications achieved funding, 1 project was awarded an
honorable mention and 1 project reached the final stage of Buiding Global Innovators.
3. Launching of new spin-off companies
In 2014 the Innovation Unit helped promoters launch 2 new spin-off companies. Glyco4clinics will provide glycan-based therapeutics
for inflammatory bowel diseases and VitaControl will commercialize a point-of-care IVD kit for Leshmaniosis embodying research
performed at IBMC. Knowledge-transfer agreement is being negotiated so that IPATIMUP and IBMC, respectively can benefit from
royalties over sales provided by these spin-offs.
4. Direct presentation to Investors and Venture Capitals
As a means to attract investment to our portfolio of projects, the Innovation Unit directly contacted investors and venture capitals
(VCs). Projects were presented to 8 Investors/Venture Capitals and 2 VCs asked for board meetings. In 2014 one investment of about
199.000,00€ was formalized and was started. The Innovation Unit will be attributed a percentage of this investment in the form of
medical-device certification consultancy services.
Activity Statistics
censing Sucssess rate
Projects/Prizes:
Applications Submitted
IP: Licencing Proposals IP: Licencing Agreements IP Licensing Sucssess rate
Projects/Prizes:
Applications Submitted
Projects/Prizes:
Applications already
Evaluated
Projects/Prizes:
Applications still under
evaluation
Projects/Prizes:
Applications Approved
Projects/Prizes: Success
rate
Column1
IP: New applications
2012
6
0
0
0%
2
2
0
0
0%
2013
6
14
2
14%
18
16
2
4
25%
2014
5
9
1
11%
9
9
0
3
33%
Projects/Prizes:
Applications already
Evaluated
Projects/Prizes:
Applications still under
evaluation
Projects/Prizes:
Applications Approved
Projects/Prizes: Success
rate
Spin-Offs: New
Companies
Venture Capital
Investments
Venture Capital: Success
rate
0
0%
Presentations to Venture Venture Capital: Board
Capitals:
meetings
0%
2
2
0
0
0%
0
0
14%
18
16
2
4
25%
2
10
4
0
0%
11%
9
9
0
3
33%
2
8
2
1
13%
63
2014
Other Activities
1. Technical work (agreements, application forms, business plans, etc.)
In the setting of the above mentioned activities, the Innovation Unit performed a body of technical work, which could be
summarized in: IP sharing agreements (2); IP registries (5); Innovation Award Applications (9); Company Business Plans (2); Pitch
Presentations (5); Licencing Proposals (10); Licencing agreements (1) and VC Investment Plans (1).
2. Aside from technical work, the innovation Unit has:
Negotiated preferential access to UPTEC for spin-offs
Established relationships with the UP Innovation Ecosystem (interlocution with UPIN, mentoring at UPTEC)
Integrated cooperative networks: POP; HCP sub-cluster; ANJE
Planned an I3S Knowledge Transfer Platform
Hosted visits from other Innovation experts
Contributed to create and maintain connections between IPATIMUP and several spin-off companies: Expertus; Bioinf2bio;
TargeTalent; Biomode (now Chromoperformance); Glyco4Clinics, Vitacontrol.
Main challenges for 2015:
Extract H2020 funding available for SMEs through the Fast track for Innovation instrument (3 potential applications),
Help new spin-offs structure their companies and generate earnings,
Integrate the new spin-offs in Cooperative Networks: P-Bio; HCP, other,
Extract funding from the Portugal 2020 Program, the new QREN, through projects co-promoted between the Spin-off Companies
and IPATIMUP (4 potential applications),
Partner with a VC fund ( Negotiations are undergoing with Hovione ventures)
Increase maturation of some technologies to potentiate chances of licencing deals,
Increase direct contact with Venture Capitals and Investors to fund proof-of-concept projects,
Keep launching new spin-offs that can mature and reach eligibility standards to apply for Portugal 2020 in co-promotion with
IPATIMUP.
64
2014
Ipatimup Translational Research
Overview
The Ipatimup Translational Research Unit (TRU) is at the interface between the Health Care Industry, academic research teams and
clinicians, potentiating the Institutes’ scientific knowledge as a means of delivering innovative clinical and translational research
in cancer. By generating added value partnerships with pharmaceutical and biotechnology companies, in convergence with the
emergent drug R&D pharma model and framed in the new pharmacotherapeutic paradigm (stratification), this unit has been setting
up Ipatimup as a partner in research and co-development of breakthrough projects, thereby contributing to accelerate proof of
concept.
If between February 2012 (the date of inception of the unit) and the beginning of 2013 the TRU was fully dedicated to the process
of its own implementation and especially to the establishment of formal contacts with Global R&D company departments in the
Pharma and Biotech, the years of 2013 and 2014 showed the outcome of the efforts exerted in the former years. After its first
protocol/contracted research signed early in 2013, the TRU has contracted a total of four Projects with Big Pharma companies
(Investigator-initiated Research Contracts Agreements) and one with a Portuguese Biotech; these projects were followed/managed
by TRU during all 2014. This follow-on working system includes the supervision of the work-in-progress within the research groups,
through follow-up meetings, in order to ensure the accomplishment of the contracted milestones, the reporting schedule agreed
with the companies and to warrant the tranche payments.
In 2014, and framed in the validated strategy defined by the TRU, the unit has prepared and submitted 8 new projects to Pharma
Industry, four of them through specific web-portals, but having previous work and close discussion with the company counterparts.
The companies engaged in these submissions were Roche, Merck (GOI program), Bayer and Astrazeneca.
Additional important interactions to discuss potential projects also took place during 2014. The TRU specifically organized face-toface meetings with international scientific teams from Bayer, GlaxoSmithKline, Pfizer, GSK, Abbvie and Janssen, and with companies
that were not included yet in the unit’s company portfolio, such as Gilead. It is important to highlight the frequent meetings that
occurred with Bristol-Myers Squibb, with whom TRU is planning a protocol for the stimulation and awareness for the research in
Imuno-Oncology, but also envisioning the evaluation of a project proposal with a BMS in-market drug for an off-label indication. This
submission process already started. TRU was also invited by BMS to participate in the Imuno-Oncology Forum which took place in
Porto by June 2014.
As a result of an intense and productive negotiation period, TRU signed in 2014 a new contracted research agreement (Investigatorinitiated Research Contract) with Abbvie, a pharmaceutical company where innovation is the cornerstone of their business. Abbvie
is known by its ability to discover and reach all corners of the globe with important strategic investments in innovative projects.
This was a very interesting period of negotiation that is considered as an exemplar model of translational research partnership and
business development between Ipatimup, hospital, clinicians, local pharma and international R&D headquarters. This particular
partnership is expected to have a significant impact in the area of biomarker discovery and validation in Inflammatory Bowel Disease
(IBD), and lead to a worldwide press release by the company throughout the most known pharma press channels.
Of note, these contracts/projects as a whole, not only allowed the recruitment of human resources for research, but most
importantly, they represent about 30% of the total budget for research contracted at Ipatimup in 2013 and 2014.
In 2014, Ipatimup was awarded by APIFARMA (Associação Portuguesa de Indústrias Farmacêuticas) as “Best Research Partner” of
the pharma industry, a prize that that was attributed in the context of the celebration of the 75 years of APIFARMA. This award
was also endorsed to IMM and to AIBILI, two research institutes with an extensive track record in partnerships with pharma and
in clinical trials. The endorsement of such award to Ipatimup, three years after the newly adopted strategy of pharma industry
approach, was the best recognition of the efforts made by the TRU and had a public impact in the research-pharma environment in
Portugal, being highlighted in a special edition of Diário Económico dedicated to Pharma Industry.
2014 was also the year of registration, expertise profiling and diffusion of IPATIMUP in the IMI (The Innovative Medicines Initiative)
networking database. This action is of outstanding importance for IPATIMUP since IMI is the Europe’s largest public-private initiative
aiming to speed up the development of better and safer medicines for patients. IMI supports collaborative research projects and
builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. The registration of
Ipatimup, together with its detailed identification and areas of expertise, is an important step to facilitate the procurement of other
partners for comprehensive translational research projects, but especially an important strategic way of gaining visibility to other
translational players and European stakeholders involved in academia-pharma projects. In this context, TRU also participated in an
IMI event in Portugal, were an important contact was established with the Chair of the IMI Scientific Committee.
Having in mind the close conceptual connection between Translational Research and Personalized Medicine, and being IPATIMUP
identified by FCT as an Institute that best represents the developments in translation research and also the growing dedication
to personalized research, the TRU, through its leading element, was invited to represent FCT in the “Agenda of the Coordination
& Support Action (CSA) PerMed workshop: Personalized Medicine 2020 and beyond – Preparing Europe for leading the global
way”, held in Berlin. The Coordination & Support Action (CSA) PerMed is a multidisciplinar and transeuropean working group
that was initiated to step up coordination efforts between European key stakeholders to allow synergies and avoid duplication or
competition, to ensure maximum transparency and openness, preparing Europe for leading the global way. The ultimate goals of the
CSA PerMed are 1) to complement existing activities by identifying and promoting promising research topics; 2) to develop strategic
research and innovation agendas in Europe and beyond, and 3) to bring forward the implementation of Personalized Medicine for
the benefit of society.
In a global environment of budget cuts, including investment in scientific research, industry/academia R&D cooperative strategies
are not only crucial to leverage resources and expertise within companies, but also contribute to broaden the spectrum of
funding sources to academic environment. Sensing this, several academic centers in Portugal invited the TRU during 2014 in
order to discuss the implemented strategy and business model followed at Ipatimup in terms of translational research and
partnerships with Industry. Among these, seminars were proffered at University of Algarve, University of Lisbon, GABBA Program
(Bioentrepreneurship module), Hovione MIT-Portugal Symposium (poster) and at the 60th International Pharmaceutical SF World
Congress with a talk entitled “The New Era of Translational Science: Recent Advances in Therapeutics and Biomarkers”.
Among others, some relevant presences were: EACR that was held in Munique, ASPIC Congress and Novartis Congress – Innovation,
Delivering the Promise.
Overall Appreciation and Directions
During the third year, the TRU maintained its strategic roadmap, actively connecting IPATIMUP with world class pharma partners
among industries, and managing innovative translational research projects with them. TRU also participated in several events
65
2014
focused on translational research and industry-related scientific forum. Most importantly, TRU generated new contracted research
agreements for joint R&D projects between IPATIMUP researchers and big pharma. With the experience, recognition and visibility
gained in the last 3 years of activities, the year of 2015 is expected to be the year to tackle the European Translational Projects,
through the application to IMI and Horizon2020 calls.
Highlights
Invited Talks or Presentations
o Invited talk on 60th International Pharmaceutical SF World Congress with a talk entitled “The New Era of Translational Science:
Recent Advances in Therapeutics and Biomarkers”.
o Several seminars entitled “How can I Translate Research into Business”, held at several Portuguese Universities.
o Presentation entitled “Fueling innovation across biomedical industry: The challenging footsteps to Translate Science in the new
era of Personalized Medicine” at Hovione MIT-Portugal Symposium.
External Diffusion Activities
o Set up of project discussion meetings with Portuguese and International Big Pharma/Biotech companies such as, Hoffman- La
Roche, Abbvie, Bristol-Myers Squibb, Pfizer, Astrazeneca, Bayer, GSK and Janssen.
IPATIMUP-Industry Projects Management & Contracted Research Performance
o Management of 4 running contracted research projects
o Eight new projects submitted.
o Four new Projects ongoing and in advanced negotiations or under appreciation with the following companies: Astrazeneca and
Bayer.
o Signature of Investigator-initiated Research Contracts Agreements with one world-level Pharma Company (Abbvie).
Other Activities
Integration Stategy in the I3S
o In 2014 and envisioning the integration in the I3S, the TRU team (as part of the Ipatimup Innovation & Translation Research
Platform) intensified the meetings started late in 2013 with the INEB’s and IBMC’s technology transfer offices in order to standardize
procedures, and especially to discuss and build a prototype structure model (iTTECH) for I3S. Such prototype will be based on
the following supports: a) IP Register & Licensing; b) Innovation Awards and Capital Ventures; c) Spin-off launch and support; d)
Contracted Research and e) European Calls and International Networks. The actual expertise from the personnel already working at
their own Institutions will be dynamically and efficiently spread by these 5 areas of intervention.
66
2014
Internal Services
67
68
2014
2014
Animal Model Facility
Overview
Ipatimup’s Animal Experimentation Unit is working at the CIM-FMUP Animal House under an established protocol. Our Animal
Unit occupies three rooms, one for breeding and stock of an immunodeficient mouse strain (N: NIH(s) II-nu/nu), other used for
maintenance and procedures involving tumor xenograft research and the third, a bigger room to maintain the conventional strains.
We have two animal handlers working each one with the animals accordingly to their microbiological status. Animal maintenance
areas are kept under controlled conditions of light and humidity. Conventional mice strains allocated in the Animal Facility were
received by our Researchers under collaboration with external groups/Institutions. These include wild-type strains and transgenic
models. All mice strains are maintained and expanded to fulfill researcher projects needs. At our Institution all in vivo studies, are
regulated by the European and National Law that standardize the use of animals in research. The 3Rs (that is the replacement,
refinement and reduction of the use of animals in research) are implicit in the Directive 2010/63/EU of the European Parliament
and of the Council of 22nd September 2010 on the protection of animals used for scientific purposes, as well as in the National
Regulation published In 2013 (Diário da República, 1.ª série — N.º 151 — 7 de agosto de 2013). Any researcher planning to use
animals in their project research has to submit the project draft to the ethics committee. All research protocols are made under
direct supervision. In terms of personnel IPATIMUP’s Animal Experimentation Unit includes a Veterinarian doctor (Director), a
Research technician (Responsible technician/Coordinator) and two Animal handlers. All personnel are certified by DGAV (Direção
Geral de Alimentação e Veterinária), the National Regulator Entity under National and European Legislation.
Highlights
Tumor biology research – tumorigenesis, invasion, metastization and response to stimuli
Tumor biology research – tumorigenesis, invasion, metastization and response to stimuli and anticancer drugs
NIH(s) II-nu/nu mice are breeded in our Unit in SPF-like conditions. Breeding is maintained in a reasonable level in order to maintain
(1) an outbred colony of genetically-variable composition mice, (2) allowing the periodic replacement of active reproductive couples
and (3) improve the reproduction level when there is the need to perform experiments. During the year 2014 we started 12 in vivo
assays – 9 were internal and 3 were performed in collaboration with two external Institutions. In terms of type of experiment, 3
were tumorigenesis assays and 9 were tumorigenesis and metastization assays. In some cases, response to specific therapies was
also tested. In all of these cases the invasive procedures (examples: inoculation of tumor cells, surgery) or not invasive (examples:
monitorization of animal health status, anthropometric parameters registry), were done under the directives that regulate the
use and care of laboratory animals and were performed by the Coordinator or its Director aided by a well-trained Animal Handler
or by the certified researcher. Number of animals, period of experiments and procedures will be presented in the point “Activity
statistics”.
Conventional strains - maintenance and expansion of transgenic and/or knockout mice
Conventional strains - maintenance and expansion of transgenic and/or knockout mice
In 2014 we had to spread out and maintain 16 colonies of wild-type and transgenic models. All the manipulations performed were
done by the personnel from the Facility accompanied by the certified researchers, under coordinated supervision. To consider that
the work with these models implies a routine based follow-up of the colonies by genotyping, crossings and back-crossings of defined
genotyped mice as well as collection of samples from the desired genetically modified animals. Number of cages maintained per
month will be presented in the point “Activity statistics”.
Activity Statistics
TABLE 1 : N: Breeding and Research NIH(s) II-nu/nu mice cages maintained per month - year 2014
N (Breeding)
jan-14
11
828
N (Research)
677
Active couples
fev-14
12
587
411
mar-14
14
733
294
abr-14
18
837
298
mai-14
13
862
323
jun-14
12
828
463
jul-14
19
755
483
ago-14
15
877
121
set-14
19
988
111
out-14
18
1008
283
nov-14
26
1060
407
dez-14
32*
1306*
657
Total
209
10669
4528
* December 2014 includes 7 active couples and 160 cages/month from breeding Balb/c strain
TABLE 2 : Number of NIH(s) II-nu/nu mice used in research, duration
and procedures according to Internal /External Research Groups - year
2014
Internal
External
Conventional
*
Total
Na
117
40
Nb
82
12
Nc
759
300
Nd
73
20
Nf
9
3
157
94
1059
86
12
a) N, number of animals (includes animals used in internal controls, n=14)
b) N, number of necropsies
c) N, total number of maintenance days
d) N, Number of surgical procedures (primary tumours removal/heterotransplantation
procedures/orthotopic inoculations)
f) N, number of assays
TABLE 4: Conventional strains cages - WT and transgenic- maintained per month - year 2014
Research Group
Glicobiology in Cancer
Cancer Biology
Differentiation and
Cancer
Cancer Genetics
TOTAL
jan-14
1501
1603
fev-14
1008
1176
mar-14
1445
1302
abr-14
1543
1259
mai-14
1403
1311
jun-14
1532
1288
jul-14
1981
1256
ago-14
2034
1265
set-14
1827
1300
out-14
1336
1235
nov-14
914
778
dez-14
947
712
TOTAL
17471
14485
764
109
3977
526
84
2794
449
106
3302
187
104
3093
226
124
3064
265
136
3221
571
186
3994
625
376
4300
653
616
4396
667
799
4037
609
595
2896
672
426
2757
6214
3661
41831
69
2014
Cell Lines Bank
Overview
IPATIMUP’s Cell Line Bank (BLC) main goal is the maintenance of stocks of parental cell lines characterized for their genetic identity
and microbiological status, in particular infection by bacteria of the genus Mycoplasma. BLC is composed by a collection of cell lines,
mostly from tumors of various histological topographies and represent an unquestionable heritage of the Institute. BLC cell lines
were commercially obtained, established at the Institute or provided by external Institutions under scientific collaboration.
Highlights
BLC Tasks
The main task in the year 2014 was the maintenance of cell lines frozen stocks. This is a continuous task and new cell lines are
always arriving to fulfill researchers and research needs. In 2014, services provided by the Unit were maintained in a reasonable
level. These include (1) provision of parental cell lines genotypically identified and tested for contaminants (specifically bacteria of
the genus Mycoplasma), provided in frozen aliquots or in culture and (2) Mycoplasma testing to cell samples donated by internal
research groups and (3) support in acquisition of new commercially available cell lines. Tasks (2) and (3) are kept into a minimum
due reduction of staff. BLC Technician also gave support in any case of cell culture problems, recommendations for the use of
consumables (for example, FBS testing control and acquisition) and any other question considered relevant for the improvement of
in vitro quality performance. Table 1 summarizes the 2014 BLC activity in terms of the exposed services.
Quality Control
Quality Control
IPATIMUP’s BLC Technician performs an internal control for microbiological status, specifically in the case of Mycoplasma
infection, using a commercial kit based on high specific PCR techniques. All the controls, positive, negative and internal (to test the
performance of the reaction itself) are included. We also microscopically check all the BLC cell lines in culture and perform bacterial
and fungal examinations when there is the suspicion of other possible infections. The genetic identification of our cell lines is made
by IPATIMUP’s Diagnostic Service, which is accredited by CAP.
Activity Statistics
Table 1: Services executed by IPATIMUP's Cell Line Bank - year 2014
N*
Cell Lines
requests
Gastric
26
colorectal
14
Breast
1
Lymphoblasts
Others
Total
Mycoplasma tests
Acquisitions
N**
N
1
NA
2
3
47
NA
NA
10
1
* N, number of requested frozen vials
** N, number of requested cell lines in culture (T25 flask)
Acquisitions refers to support that is given in ordering new cell lines
Other Activities
Continuous testing of new cell culture media and reagents in order to obtain the best results in terms of cost-effectiveness.
70
2014
In vivo CAM Assays
Overview
The chick embryo is a well-known animal model extensively used in cancer studies. The chick embryo presents several advantages
to mammalian models: it is naturally immunoincompetent, simple to manipulate, inexpensive, it involves short experimental
times and there is no need for official authorization from animal experimentation committees (as long as experiments end before
hatching). The CAM is an extraembryonic membrane, connected to the embryonic circulation and highly vascularised. It provides a
perfect environment to grow mammalian grafts and therefore evaluate features such as tumour mass formation, tumour induced
angiogenesis, cell migration, intravasion, extravasion and metastization. The 3Rs (that is the replacement, refinement and reduction
of the use of animals in research) are implicit in the Directive 2010/63/EU of the European Parliament and of the Council of 22nd
September 2010 and on the Portuguese law Decreto lei 113/2013, on the protection of animals used for scientific purposes. The use
of the chick embryo as an animal model meets this directive given that it will allow validation of in vitro results without resorting
to rodent animal models or, at least, by refining experimental conditions in order to reduce the number of mice used in a given
experiment.
IPATIMUP’s “In vivo CAM assays Unit” is functioning as an internal IPATIMUP’s service unit since June 2012. In 2013 and 2014,
several collaborative works were performed based on the established knowledge (please see “activities” and “highlights”). Also, the
innovative and business potential of CAM assays continued to be developed (please see “other activities).
Highlights
“Classically and alternatively activated macrophages differently modulate gastric cancer cell invasion, motility
and angiogenesis.” BMC Cancer, Submitted - AP Cardoso, ML Pinto, MT Pinto, AT Pinto, C Monteiro, MI Oliveira,
S Santos, R Seruca, A Mantovani, M Mareel, MA Barbosa and MJ Oliveira
Since MMP activity is important in terms of angiogenesis, and the fact that conditioned medium from IL-10-treated macrophages
was able to stimulate the number of new vessels in the chick embryo CAM assay, we inoculated AGS cells with CM from IL-10treated macrophages (AGS+CM(IL-10-mac)) with Galardin, always using a control condition in the same egg without the inhibitor
. The presence of Galardin resulted in a significant decrease in the angiogenic stimulus provided by soluble factors produced by
this macrophage population. These results indicate that MMPs are required for the support of cancer cell invasion provided by all
macrophage populations and, for the stimulation of angiogenesis by IL-10-treated macrophages.
We used the CAM assay to evaluate the Angiogenic response of gastric AGS cell suspended in conditioned medium (CM) from
different populations of macrophages namely, M0, M1 and M2. AGS cells subjected to CMM0 and CMM1 had a reduced angiogenic
response while cells with CMM2 presented a significant increased angiogenic response
Quantification of the angiogenic potential by CAM assays of MCF7 3D mono and co-cultures. In collaboration
with Marta Estrada and Catarina Brito (IBET)
In order to study the impact of stroma on tumour progression, MCF7 cells were encapsulated as tumour aggregates alone
or together with human dermal Fibroblasts (HDF). After 15 days in culture, tumour aggregates presented several phenotypic
alterations, such as loss of aggregate roundness, increased aggregate size and aggregate leakage from the capsules. To analyse if
the observed phenotypic alterations were related with tumour progression into more advanced stages of the disease, CAM assays
were performed at IPATIMUP with the aim to quantify the angiogenic potential (CAM assays) of both mono and co-cultures in
two different time-points: day 2 (early time point) and day 15 (late time point). The results obtained demonstrated that there is a
significant difference between mono and co-cultures at day 15 of culture, although the significance disappears when compared with
the early time point.
These assays allowed us to demonstrate that the presence of HDF in this co-culture system contributed to the increased capacity of
tumour cells to stimulate angiogenesis.
Activity Statistics
Summary of (technical) activities
During 2014, about 700 eggs were manipulated, 560 were inoculated in the framework of 10 research projects. These projects were
from Ipatimup’ research groups: Cancer Genetics, Expression Regulation and Cancer, Differentiation and Cancer and Glycobiology
and Cancer; but also external to Ipatimup, from the following research institutes: IBET, Lisbon; CNC, Coimbra, CIIMAR Porto and
INEB, Porto.
Nr of inoculated eggs
300
250
200
150
100
50
0
Ipatimup
INEB
Others
71
2014
Nr of research projects
7
6
5
4
3
2
1
0
Ipatimup
INEB
Others
Other Activities
Ipatimups’s spin off – “Expertus, CAM assays
The Ipatimups’s spin off - Expertus, CAM assays” created in 2013 – consolidated its activities. The start-up project was one of
five finalists, to the contest “Jovem Empreendedor BGI - Building Global Innovators”, ISCTE-IUL MIT venture competition (May to
November 2013). Other applications for business development and research funding were done to “2014 Entrepreneurs Award
of the Everis Foundatio “ . In the frame work of “Projectos Estágio 3Is” a research trainee (with a MSc in Oncobiology and PhD
student) was recruited to work in the project.
Funding applications
- Marta Teixeira Pinto applied to a FCT post doc fellowship (SFRH/BPD/99494/2014) which was not granted.
- Marta Teixeira Pinto applied to a FCT funding as a PI with the project “Bcl3, a novel therapeutic target to inhibit cancer
metastases. Developing human xenograft drug screening platforms” (PTDC/BBB-ECT/1346/2014).
- As responsible for the CAM assays Unit, Marta Teixeira Pinto was invited as a consultant in the following projects:
(Ipatimup) PI: Sérgia Velho - “Deconstructing stromal-epithelial interactions in colorectal cancer: understanding the parts to
fight the whole” - to evaluate the angiogenic potential induced by cancer-associated fibroblasts isolated from different stages of
colorectal cancer development
(Ipatimup) PI: Helena Pópulo - “Changing melanoma cell metabolism to change melanoma therapy” - to evaluate the angiogenic
and tumorigenic responses of melanoma cancer cell lines subjected Dichloroacetate (DCA) treatment alone or in combination with
mTOR or BRAF inhibition.
(Ipatimup) PI: Fatima Gartner - “Bringing ruthenium from bench to clinical trials with a view to breast cancer therapy” - to use CAM
assays to evaluate the angiogenic and invasive responses of breast cancer cell lines subjected selected compounds.
(Ipatimup and INESC) Carla Oliveira and Susana Silva - “Endoscope based on photonic crystal fibers using Raman spectroscopy” - to
generate solid tumours derived from highly tumorigenic gastric cancer cell lines developed by Dr. Oliveira’s group.
(Ipatimup) PI: Manuela Oliveira - “Chronological aging in pathogenic Aspergillus species” - used to study of the virulence and
pathogenicity of different Aspergillus species.
72
2014
Proteomics
Overview
The IPATIMUP Proteomics Unit offers to the scientific community analysis of protein samples from solutions, bands or protein spots
from 1D or 2D SDS PAGE gels.
The following proteomics approaches were performed in 2014:
1. Mass Analysis of Intact Proteins, Peptides and Metabolites by mass spectrometry.
2. Protein identification and characterization by Peptide Mass Fingerprint - PMF (MALDI-TOF).
3. Protein identification and characterization by PMF following peptide sequencing/fragmentation (MALDI-TOF/TOF, PMF+MS/MS).
4. Protein Post-Translational Modifications (PTMs) characterization by mass spectrometry.
5. Protein separation by 1D or 2D gel electrophoresis.
In addition, a novel activity, microorganism characterization by mass spectrometry, started to be implemented.
The provided services included: protein separation; enzymatic digestion and peptide extraction of isolated proteins from 1D or
2D SDS-PAGE gels or purified proteins in solution; peptide analysis by mass spectrometry (MALDI-TOF) with the option of peptide
sequencing (MALDI-TOF/TOF); protein identification using UniProt and/or NCBI protein sequence databases; data analysis; and
delivery of a report with the identified protein(s). “Personalized” specific analysis were also performed, including: analysis of amino
acids sequences, gene identification, determination of protein molecular weight and isoelectric point, search for relevant proteins,
characterization of protein PTMs and enzymatic characterization studies.
In 2014, the annual financial balance was positive by 5 562.75 euros. In addition, the IPATIMUP proteomics unit has participated in
5 research projects and 5 scientific publications. It was included as a RNEM node, the Portuguese Mass Spectrometry Network, in
the FCT’s Research Infrastructures Roadmap, category 1. In 2015, novel proteomics approaches are planned to be available for the
scientific community, namely liquid chromatography mass spectrometry (LC-MS).
Highlights
IPATIMUP Proteomics Unit – Highlights 2014
The IPATIMUP Proteomics Unit developed its activity in 2014, similarly to the previous years, by performing research-based
activities and providing services to the inside and outside scientific community.
The annual financial balance was positive by 5 562.75 euros. The overall income in 2014 was 72 651.93 euros (external analyses
services 25 189.97 euros, internal services 9 647.25 euros, and 37 814.71 euros from QREN financing). The overall cost was 67
089.18 euros (Wages 30 430.59, Productivity Prizes 12 173.93, Current Expenses 10 079.42, Missions 2 322.24 and Maintenance 12
082.90 euros).
These results were the outcome of the following approaches which started in 2013: 1) progressive replacement of the collaboration
prices by the standard costs of the analyses; 2) increase in the number and variety of the analyses performed; 3) promotion
of networking activities with research groups developing projects from different scientific backgrounds and participation in
multidisciplinary studies; and 4) stimulation of scientific collaborations leading to the publication of scientific papers, submission of
research projects and patent applications.
Analyses Performed
- The IPATIMUP Proteomics Unit has performed a total of 53 independent analysis divided by the following activities:
Molecular weight determination of protein and peptides: 284
Protein identification by Peptide Mass Fingerprint (PMF): 166
Protein identification by PMF and MS/MS peptide sequencing / characterization of Protein post-translational modifications: 293
Protein separation by 1D and 2D gel electrophoresis: 14
Microorganism characterization by mass spectrometry (implementation in progress)
Proteomic analyses were performed to the following institutions:
IPATIMUP: Cancer Biology, Cancer Drug Resistance, Cancer Genetics, Expression Regulation in Cancer, Glycobiology in Cancer, and
Population Genetics research groups.
IBMC.INEB
CIIMAR
University of Porto: FMUP, FFUP and ICBAS
University of Minho
University of Coimbra / CNC
Participation in the following research projects:
1. Gastric GlycoExplorer, EU Grant 316929, FP7-PEOPLE-2012-ITN; PI: Celso Reis
2. Zinc-finger nuclease-glycoengineered SimpleCell lines for characterization of the O-glycoproteome of cancer cells, PTDC/BBB-
73
2014
EBI/0786/2012; PI: Celso Reis
3. Glycomic approach to unravel the role of glyco structures in gastric carcinogenesis, Merieux Research Grant; PI: Celso Reis
4. Unraveling a new Helicobacter pylori virulence factor involved in tight junction dysfunction, PTDC/BIA MIC/116890/2010; PI: Céu
Figueiredo
5. Mucin MUC16 - CA125 cancer biomarker – biological functions and development of new biomarker assays, PTDC/SAUONC/117216/2010; PI: Leonor David
Publications
1. Branquinho R, Sousa C, Lopes J, Pintado ME, Peixe LV, Osório H (2014)
Differentiation of Bacillus pumilus and Bacillus safensis using MALDI-TOF-MS.
PLoS One 9, e110127.
2. Branquinho R, Sousa C, Osório H, Meirinhos-Soares L, Lopes J, Carriço JA, Busse HJ, Abdulmawjood A, Klein G, Kämpfer P, Pintado
ME, Peixe LV (2014)
Bacillus invictae sp. nov., isolated from a health product.
Int J Syst Evol Microbiol. 64, 3867-3876.
3. Maia LF, Magalhães R, Freitas J, Taipa R, Pires MM, Osório H, Dias D, Pessegueiro H, Correia M, Coelho T (2014)
CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings.
J Neurol Neurosurg Psychiatry 86, 159-167.
4. Martins JC, Campos A, Osório H, da Fonseca R, Vasconcelos V (2014)
Proteomic Profiling of Cytosolic Glutathione Transferases from Three Bivalve Species: Corbicula fluminea, Mytilus galloprovincialis
and Anodonta cygnea.
Int J Mol Sci 15, 1887-1900.
5. Sousa R, Osório H, Duque L, Ribeiro H, Cruz A, Abreu I (2014)
Sensitization and identification of Plantago lanceolata pollen allergens using an immunoproteomic approach.
J Investig Allergol Clin Immunol. 24, 177-183.
Other Activities
Participation in pre-graduated, graduated and training programs:
GABBA graduated PhD program from the University of Porto
“Análise In silico de Genomas, Transcriptomas e Proteomas”, Mestrado de Biologia Celular e Molecular, FCUP
IV Workshop on Cancer Research
UCOs integrated at FMUP (DPO)
Cycle of Seminars in Omic Techniques for Biotechnology and Bioengineering, Minho University
Networking
Ipatimup Proteomics Unit is a node from RNEM, the Portuguese Mass Spectrometry Network. RNEM was recently recommended for
inclusion in the FCT’s Research Infrastructures Roadmap in category 1 (ref. ROTEIRO/0028/2013).
Member of ProCura, the Portuguese Proteomics Association.
Submitted Projects to the FCT Call (2014)
Ipatimup - Hugo Osorio, PI – 174 216 euros, Celso Reis, Catarina Gomes and Valdemar Máximo will develop proteomics approaches
in some tasks of their projects.
Ipatimup has also been involved as a participant in 3 other submitted projects with budget allocated for Proteomics analysis: IPO 33 520 euros, FFUP – 36 000 euros and UM - 24 000 euros.
74
2014
Sequencing Service
Overview
Ipatimup’s sequencing service was initiated in 2006 to serve investigators and technicians who develop their work there. The
sequencing service performs the sequencing reaction of plasmids and PCR products and automated analysis of genotyping and
sequencing products by capillary electrophoresis for internal and external requests. The sequencing service is also in charge of the
acquisition and distribution (only at an internal level) of some consumables.
Highlights
Extra 4-capillary sequencer
An extra 4-capillary sequencer previously exclusive to Parentage testing and Genetic Identification Unit (LPIG) was added to the
service which increased the capacity of the service.
Stability of sequencing service
Current economic conditions are not favorable but internal and external requests have maintained the numbers of 2013.
Next Generation Sequencing (NGS)
Although not fully functional, NGS integrated the service by the end of 2014. We have received many internal and external requests
about the functioning of the service which shows us that scientific community is interested and receptive.
Activity Statistics
9.000
8.000
7.000
6.000
5.000
4.000
3.000
2.000
1.000
0
Internal
External
Other Activities
Other activities of sequencing service
The sequencing service also has the responsibility of the following:
1. Monitoring and management of liquid nitrogen levels and material stored in dewars;
2. Real-time PCRs schedule management and equipment maintenance;
3. QIAxcel equipment maintenance;
4. Software and equipment training for new users upon request.
75
76
2014
2014
Core Services
77
2014
Informatics
Overview
Our main goal is to give access to the Institute Researchers all necessary tools available to register, promote and
publish their work.
Our Unit it’s divided in 2 areas, the Networking and the Information System.
The networking staff is responsible for the maintenance and configuration of all informatics infrastructure and gives helpdesk
support for all informatics equipment.
In other hand the Information System staff is responsible for the creation and maintenance of all web applications mainly created in
the Outsystems Platform and Oracle Application Express.
Our department is expected to perform some operations in the telephone network, like create new telephone extensions, unlock
telephone for external calling and resolution of other minor problems.
Highlights
RNBT Central [Development]
The RNBT CENTRAL application enables the query and visualization of data from the National Tumor Bank Network.
The National Network Tumor Bank application is a database with samples taken at each of the participating institutions in the
network.
The developed application allows on the one hand the registration, consultation and the request for viewing and use of data by
external users as well as the maintenance of data
by each one of the participating institutions.
RNBT Local [Development]
The RNBT Local application allows the management of harvests of an institution.
This application is a database with samples taken by the institution.
The developed application allows the registration and maintenance of each of the samples taken.
Person Admission Module [Development]
On PhD Student Admission Workflow, when the Organization Unit is not child of research category, the user should specify the
account instead of projects.
Project Financing (Project Module) [Development]
Create an interface where given a Year, is possible to generate an excel with all projects
The excel file has also the project total Lifetime, total budget, lifetime per year and budget per year.
Absence Notification Module [Development]
In case the mission has some expense of a project for which funding requires to do a scientific report , it not allows submit expenses
while not attach their scientific report.
Scientific Data Module [Development]
We create a second level of characterization of cases.
Who Is In Manager Module [Development]
We have created a module to be able to create custom visitor cards.
Stock Manager Module [Development]
Add tab “Reagents - Check Barcode”.
Automatic change to this tab when scanner reads a barcode.
When Material Safety Data Sheet (MSDS) exist, show pdf file content on page.
Site [Development]
We changed the site face to the 25 years of IPATIMUP .
One page has been created for the sale of the book “Cancro Ponto e Vírgula”.
Permissions Module [Development]
All users who manage the person manager module can grant or revoke any permission Information System .
Event Registration Manager Module [Development]
In registrations:
We added an email icon to send email to remind who has not paid yet.
We include PayPal as payment method.
We changed “export to excel” to have Dynamic Columns and we added all options of the registration.
We added a filter for search panel to filter by paid, unpaid and all.
-In Abstracts
We added the field of session. This field is used to indicate at which session the abstract should be contemplated .
Requisition Module [Development]
We put a minimum limit for the amount of the requisition , to project accounts that its funding has this specification.
[Networking]
Our department performs all software maintenance, like upgrading versions or changing licenses. When needed we install specific
software on the computers of the Institution or in the personal laptops, if there is a valid license to perform this task.
We replaced the old machines that were still working with Windows XP with new ones. We installed the Windows 7 operating
system because the XP support has ended.
78
2014
We replaced the old Symantec Antivirus with a new solution. Afterwards we implemented this new anti-virus application on all
workstations.
The support for Symantec Messaging Gateway, SPAM filter, also ended in this year and so we had to replace it with another solution,
but this new one is open source and has been performing well since August.
The construction of I3S building and IPATIMUP building rehabilitation led to some changes in resource allocation. We made some
changes on the network infrastructure and in the telephone network. We had to reallocate several computers and change/create
several telephone extensions.
We did maintenance of Linux, windows and VMware servers.
This year we put on production a new storage solution that will be our primary storage, since it has a large capacity.
Activity Statistics
Tickets Created
Solved Avg delay (days)
Informatics > Computer
88
88
30,3
Informatics > Computer > Hardware
31
29
26,5
Informatics > Computer > Software
113
113
16,0
Informatics > Internet
18
19
5,4
Informatics > Printer
153
153
0,6
41
40
19,6
444
442
14,9
Informatics > Site
Informatics [Networking]
Programs’ Office
Overview
During the year 2014, the office announced to the researchers of i3S hundreds of funding opportunities such as projects, awards,
fellowships and job positions; it supported the submission of around 120 research project proposals (40% to national funding
programs of which 25% to FCT (mostly in collaborative projects and different ERA-Net) and 60% to international agencies with 30%
to European Commission programs, the majority to H2020) and also supported other scientific research related programs, which
are included in the regular activities of the institutes, such as licensing projects that involve animal experimentation, by the National
Authority DGAV.
Like in previous years, the responsible for the office attended information sessions about research funding programs such as Horizon
2020 (European Commission’s Research & Development Funding Program) among others. The programs’ office also had a relevant
role in the coordination of the relations between the 3 institutes, concerning the i3S Seminars and other information and diffusion
activities.
79
2014
Risk Management System
Overview
Ipatimup have the OSHAS 18001:2007 certification in Occupational Health and Safety Management Systems since 2012.
The Ipatimup undertakes to develop a systematic approach whose objective is to minimize the various professional risk factors for
their colaborators, risks to users and all stakeholders through:
• Comply with the rules of safety and health at work in force;
• Implement a continuous process of identifying, assessing and monitoring risks;
• Promote and ensure a safe and healthy workplace for all facility users;
• Promote training activities so that all employees are involved in the area of safety and health;
• Review and improve the system of health and safety;
• Provide this policy to the general public.
Highlights
TRAINING
- Induction Training in Health, Safety & Security, monthly;
- “BasicLife Support” Training, Oct 2014;
- “Chemical Spill Containment Kits” Training, Out 2014;
- Practical training in the use of extinguishers and reels, July 2014
- “Internal Security Plan”, Manuel Carvalho, March 2014
- “Internal Security Plan”, Manuel Carvalho, June 2014
- “Internal Security Plan”, Manuel Carvalho, July 2014
- “Security in the perspective of cleaning activities” training,May 2014
- “How to take care the spinal column on a daily basis”, Training in ergonomics, May 2014
The contents of training are available for consultation on the IPATIMUP intranet in the Risk Management System area.
INTERNAL AUDITS
In 2014 a total of two internal audits were performed in Ipatimup by Always the Best (Oct 2014) and Medilogics (Dec 2014).
The reports resulting from audits are available in in the IPATIMUP intranet, in the Risk Management System documents.
SIMULACRUM 2014
At 11.07.2014 was performed the simulacrum and were involved:
- All the Ipatimup collaborators, Porto Firefighters, Public Security Police & Nacional Medical Emergency (INEM);
The simulacrum reports are available in in the Ipatimup intranet, in the Risk Management System documents (PSI tab).
PERIODIC MEETINGS
As part of the risk management system several working groups met periodically throughout the year to discuss and analyze issues of
health and safety and their risks and propose corrective and /or preventive actions.
The working groups are constituted by:
- Comission Risk;
- Local Safety Contacts with Filipa Valente;
RMS DOCUMENTAL DATABASE
In order to maintain the OSHAS 18001:2007 certification the Risk Management System produced and updated several documents in
2014 like
- Ipatimup Risk Assessment 2014;
- System Review Acta 2014;
- Ipatimup Health & Safety Plan for 2014;
- Action Planning / 2014;
- Analysis reports related to the 2014 submitted accident/incident reports;
- Periodic checklists completing/development;
- MIRR 2014 fill and submission;
- Regulation of streets and park parking Ipatimup Rules;
- Internal Security Plan;
- Waste Management Plan;
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2014
- Work Accidents - Analysis and Participation Circuit Doc;
- Risk Management System Procedures;
- Cell Culture Rooms Safety Rules;
- Risk Assessment Document;
Activity Statistics
Risk Assessment
% of proposed measures
2014
97,70%
2013
2012
89,30%
86
Nº implemented measures
92
75
81,50%
88
Nº proposed measures
103
92
2012
2013
2014
Secretary General
Overview
The General Secretary carries out the general administrative tasks of IPATIMUP:
- Treasury and accounting;
- Projects management, comprising all the tasks of financial reporting and providing assistance to the Principal Investigators in
administrative and legal related issues;
- Human Resources management;
- Organization of events;
- Control of purchase orders and Contratação Pública;
- Validation of contracts with general suppliers;
- Updating data on the information system
Highlights
General highlights
A controlling table for infrastructural expenditure has been monthly updated .
The management software developed in-house has been improved following specific needs.
The accounting is made in accordance with the SNC – Standard Accounting System, using a certified software (SAGE).
All assets are labelled.
All requisitions of goods and services and equipment maintenance are administratively verified.
The General Secretary supports the maintenance and renewal of the IPATIMUP’s library.
The administrative services receives and instructs all requests for human resources movements - entries, renewals or voluntary
trainings - through workflows created for this purpose.
The General Secretary takes charge of all organization tasks related to international meetings and seminars.
There are specific workflows for control of accidents, for monitoring of occupational health and for updating a database of
applicable laws.
Slides Digitalization Service
Overview
The Slides Digitalization Service (SDL) converts histological and cytological glass slides into high-quality and high-resolution digital
images. The SDL provides also the storage those images and its visualization.
Highlights
During 2014 2000 digitalization of histological slides were executed. The total amount of online slides reach 10.000 by the end of the
year.
The SDS supported again the practical work of two disciplines on Porto Medical Faculty and started supporting two more on
Coimbra Medical Faculty, paving the way to the replacement of the optical microscopy by the digital microscopy.
The SDS also supported all Anatomic Pathology Interdepartemental Meetings held monthly, organized by CHSJ.
81
2014
Technical Body
Overview
The Technical Body is an infrastructural service responsible for the management of the Ipatimup’s common
research resources crossing the different areas and research groups:
- Equipment maintenance;
- Planning and monitoring the use of those equipments by the different researchers;
- Establishing procedures and good work practices;
- Proposing technical solutions to problems related with the laboratories space and equipment management;
- Keeping work records;
- Training (for new colaborators and for users of specific equipments/facilities);
- Management/Maintenance of the equipment acquisition workflow;
- Management/Maintenance of the incident/acident participation workflow;
- Management of solid and liquid GIII and IV residues;
- Management os the reagents (aquisition, reception and discard) workflow;
- Management of maintenance contracts related with the equipments and infrastruture;
- Management/Maintenance of the Helpdesk Tickets system and devices database;
- Management /Maintenance of the Material Safety Data Sheet (MSDS) Database;
Highlights
TRAINING
- Integration Training, monthly
- “Containment Kits chemical spills”, Oct 2014
- “Security in the perspective of cleaning activities”, May 2014
- “Internal Security Plan”, March 2014
- “Ultracentrifuge: usage rules, procedure and care maintenance”, 2014
COMMON WORKING ROOMS MAINTENANCE
Tecnhical Supervisor is responsible for daily maintenance of several rooms ( eg. Cell culture rooms 1 and 2, Pré PCR room,
Advanced microscopy room, Dark room, HPLC and Image acquisition room, Centrifuges and incubators room,
-80ºC and 4ºC Cold rooms) permanently ensuring that:
- equipments are in good operating conditions;
- the correct use of the facilities and equipments;
- colaborators receive specific training;
- control the users access to the specific rooms/lab. areas;
- logbooks maintenance;
- equipments Standart Operating Procedures (SOP) needs identification & development;
- Safety Rules development;
- risks identification in equipments & facilities with signage;
- space management of -80ºC freezers, 4ºC rooms, cell culture, pré-PCR and biosafety level 2 rooms and warehouse;
Quality Control
QUALITY/SAFETY CONTROL
Preventive Maintenance/Verification Contracts establishedfor the laboratorial equipments:
- Microtome, Thermo Electron Corporation Shandon Finesse 325, S/N: FI50850603
- Cooling plate Kunz CP-4, S/N: 2006-1262
- Histologic Bath Kunz Hir-3, S/N: 2006-2041
- Centrifuge SHANDON Cytospin 3, S/N: MA170403R
- Genetic Analyser Applied Biosystems, 3130-4, S/N: 19336-040
- Genetic Analyser 310, Applied Biosystems, S/N: 1205-017
- Real Time PCR Applied Biosystems, 7500, S/N: 275012980
- Autoclave AJC, S/N: 100 - Dishwasher MIELE, S/N: 16/18332096
- Dishwasher MIELE, S/N: 16/18332095
- Drying Incubator Memmert 800, Int. Ref.: 120008/1996
- Sterilizer Machine MIELE, Int. Ref.: 1200048/1997 94
- Laminar Flux Cabinets; Biosafety Cabinets;
- Hottes
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Preventive Maintenance/Verification Contracts establishedfor the insfrastructural equipments:
- Elevator;
- AVAC equipments;
- Plague control units;
- Personal hygiene units;
Preventive Maintenance/Verification Contracts establishedfor the insfrastructural services:
- Collection and treatment of waste (Types III and IV);
- Gas cylinders;
- Emergency units (Automatic system of fire detection);
- Extinguisher;
- Garden;
Activity Statistics (tables only)
Tickets System
Training
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Checklists
Other Activities
RISK MANAGEMENT SYSTEM (RMS)
Technical body was fully involved in the Risk Management Project, namely Filipa Valente as member of risk comission
and responsible for health and safety at IPATIMUP and Ana M. Rocha also as member of the risk comission.
In the aim of this project Filipa Valente produced several Safety Rules/SOP’s for equipments and rooms with specific
requirements;
- 2014 IPATIMUP risk evaluation table;
- Health, Safety and Security Training;
- New Checklists development for verification of equipments/facilities and improvement of the Checklists already existent;
- Maintenance of the RMS Database (documentation feeding);
- Elaboration of meetings oficial records (p.e. commission risk);
- Coordination of the accident/incident reports submitted;
- Elaboration of the Technical Supervisor reports related to the accident/incident reports submitted;
- Participation, as the Institute responsible for Safety and Hygiene, in all the audits in the scope of OSHAS
18001:2007 certification since 2013;
Other Activities
- Maintenance of the 2013 Pricelist for the most used consumables in IPATIMUP (by F. Valente);
- Elaboration of specifications/requisits necessary during equipment acquisitions processes;
- Coordination/management of the research groups workspace changes/transferences during the I3S works & Risks evaluation;
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Annexes
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2014
Recent PhD’s
1. Verónica Cristina Neves da Nova Fernandes
17-01-2014, Faculty of Biological Sciences, University of Leeds, UK
High-resolution characterization of genetic markers in the Arabian Peninsula and Near East
Supervisores: Martin B. Richards and Luísa Pereira
2. Cristiana Tavares Branco da Cunha
10-10-2014, FMUP
Deconstruction CD44 - Engineering 3 D matrices to elucidate CD44 modulation in gastric malignancy
Supervisora: Raquel Seruca
3. Lara Patrícia Marcos da Silva
06-11-2014, FMUP
Mucin MUC16- CA125 cancer biomarker: biological functions and development of new biomarker assays
Supervisora: Leonor David
4. Vânia Raquel Gomes Camilo
10-11-2014, FMUP
Sox2 modulation in the establishment of CDX2-dependent intestinal metaplasia
Supervisora: Raquel Almeida
5. João Miguel Fernandes Alves
15-12-2014, ICBAS
Understanding the impact of chromosomal inversion on the evolution of the human genome
Supervisor: António Amorim
6. Bárbara Beatriz Pinheiro Ribeiro de Sousa
15-12-2014, ICBAS
Underlying the role of P-cadherin in cancer metabolism
Supervisora: Joana Paredes
7. Irina Ferraz Amorim
16-12-2014, ICBAS
Canine gastric pathology. Helicobacter spp. Infection in dogs - an epidemiological and molecular study
Supervisores: Fátima Gartner e Celso Reis
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2014
Research Projects
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O Nemátode-Da-Madeira-Do-Pinheiro (NMP), Bursaphelenchus Xyliophilus [IMAR]
Genetics of populations of Jewish origin [Ipatimup]
Development of tools for automatic comparison of biological sequences [Ipatimup]
Galectins as modulators of tumor progression:Establishement of anti-cancer action of bioactive fragments from pectin by
inhibiting galectin - 3 [Ipatimup]
The involvement of CDH1 in CG angiogenesis [Ipatimup]
Approaching basal-like breast carcinomas to target therapy. A project combining the reinforcement of logistic facilities with
translational research [Ipatimup]
Banco de Tumores - Amostras Congeladas [Ipatimup]
Alterações metabólicas e cancro: GRIM-19 um gene do metabolismo celular e um gene supressor tumoral, que poderá ser um
target terapêutico interssante [Merck]
Cooperação Portugal/França Programa Pessoa 2011-2012 [FCT]
Study of mTOR pathway in GISTs [Novartis Farma]
Genetic and chronological characterisation of the European settlement by modern humans in the Upper Palaeolithic [FCT]
Effect of radio-and chemotherapy on cancer cell invasion: the role of macrophages [FCT]
GRIM-19, a novel protein involved in cell apoptosis: structure-function characterization [FCT]
Helicobacter pylori diversity in pathogenesis, antibiotic resistance, and evasion from natural and vaccine-induced immune
responses (HELDIVPAT) [FCT]
Tumour spectrum in hereditary Diffuse Gastric Cancer [FCT]
New E-cadherin RNAs: the dark side of a tumour suppressor gene [FCT]
E-cadherin Post-Translational Modifications by N-glycosylation: a potencial new mechanism of E-cadherin deregulation in
cancer [FCT]
Conhecer a doença: Os doentes em primeiro lugar [FCG]
An approach to thyroid cancer targeted-therapy using transgenic zebrafish as a model [Ipatimup]
Biomarcadores para avaliação de efectividade terapêutica no carcinoma colorectal [ADI - IDEIA]
Sorting out the genetics of neuroendocrine tumours [Ipatimup]
Aging genes in model and non-model organisms a comparative approach [Ipatimup]
Telepathological Assessment of histopathological and cytological techniques [UE]
A European Initial Training Network on the History, Archaeology, and New Genetics of the Trans-Atlantic Slave Trade [UE]
Glycomic Approach to unravel the role of Glycostructures in Gastric Carcinogenesis [Institut Mérieux]
Functional, molecular and pharmacological studies of p53 family proteins: from yeast to human cells [FCT]
Mouse models of intestinal metaplasia - exploring pathways from the TGF-beta superfamily [Ipatimup]
Regulation of the glycomucinome in cancer and pre-neoplastic lesions [Ipatimup]
Consolidação e expansão do Banco de DNA e RNA acoplado ao Banco de Tecidos e Tumores do H.S. João [Ipatimup]
Benign and malignant apocrine lesions of the Breast [Ipatimup]
Dengue research framework for resisting epidemics in Europe [UE]
The role of sialylation in modulating galectin-3 functions in the metastatic process [FCT]
HERICA - Histological and Endoscopic Evaluation of Remission induced by Infliximab in moderately to severely active ulcerative
Colitis Patients [GEDII]
Unravelling a new Helicobacter pylori virulence factor involved in tight junction dysfunction [FCT]
Adhesion, Differentiation and Invasion: different processes, common cadherin players [FCT]
Helicobacter pylori genetic variation: An opportunity to identify individuals at increased risk for disease [FCT]
Mapeamento de genes de susceptibilidade para tumores familiares da tireóide [FCT]
PYLORICIDAL - Engineered biomaterials with Helicobacter PYLORI bacteriCIDAL effect [FCT]
Expression of Mesothelin in gastric cancer: its relevance in tumor differentiation and in prognosis (Mesothelin) [Ipatimup]
TUMORTAG - Tumor-targeted nanoparticles for early diagnosis of gastric cancer [FCT]
Modulation of CDX2 expression in gastric intestinal metaplasia using na siRNA delivery system in vivo [SPG]
Irradiation and atherosclerotic disease - epidemiologic and biologic evaluation of a cohort irradiated in childhood for tinea
capitis treatment [Ipatimup]
Identification of genetic markers for prediction of the clinical course and development of complications in Portuguese Crohn’s
Disease patients. [GEDII]
Mucin MUC16 - CA125 cancer biomarker - biological functions and development of new biomarker assays [FCT]
Phylogeography and population structure of the powdery mildew fungus, Erysiphe necator, from diverse Vitis vinifera cultivars
grown in Portugal [Reitoria UP]
Signalling pathoway in luminal B Breast Cancer [Ipatimup]
Projecto financiado pelo Ciência Viva Escola Científica Ciência Viva [Ciência Viva]
Differentiation in cancer with emphasis on glycoproteome alterations [ON]
Auto Laboratório [ON]
Molecular mechanisms underlying cancer cell invasion in two cancer disease models, gastric and breast [ON]
Microenvironment, metabolism and cancer [ON]
Reforço e consolidação da capacidade infraestrutural do Ipatimup para o sistema regional de inovação. [ON]
2014
53.
54.
55.
56.
Estudo da via AKT-mtor em carcinomas das glândulas salivares [Novartis Farma]
Alternative oncogenic signalling pathways in medullary thyroid cancer [UIT]
The Metabolic Requirements of Epithelial of Mesenchymal Transition [Ipatimup]
Investigação do papel funcional da osteopontina e de suas variantes de splicing alternativo nos tumores papilares da tireóide
[Ipatimup]
57. Sodium/Iodide symporter restoration in thyroid tumors: A role for MTOR inhibitors in overcoming therapy resistance?
[Ipatimup]
58. Glycosylation of the T cell receptor: a new mechanism underlying IBD pathogenesis Icuplications for therapy stratification
[GEDII]
59. Determing the CCAAT/enhancer binding protein ß (C/EBPß) partnership profile in gastric carcinogenesis [Ipatimup]
60. Project support by FCG - Financial Fee [FCG]
61. Glicosilação e cancro: da glicómia funcional à aplicação clínica [Convénio FCT/CAPES 2013/2014]
62. Portuguese study of familial dilated cardiomyopathies [FCT]
63. Initial Training Network - Systems Glycobiology of Gastric Cancer. [FP7]
64. CONtaminant-driven GENEtic ERosion: consequences on the viability of Amphibia populations [FCT]
65. Evaluating the role of proteolysis in the male reproductive system through the study of KLK (19q13.4) and WFDC (20q.13) gene
clusters [FCT]
66. Zinc-finger nuclease-glycoengineered SimpleCell lines for characterization of the O-glycoproteome of cancer cells. [FCT]
67. Genetic history and population structure in Southeast Asia [FCT]
68. Mutant E-Cadherin and Novel Interactors in Cancer (MECANIC). The role of mutant E-cadherin-integrin-ECM crosstalk in gastric
cancer [FCT]
69. Insulin Growth Factor and PI3K pathway ROLe in Luminal Breast Cancer survival [FCT]
70. Combining siRNA and AAV therapy approaches to target human basal-like breast cancer: from vector development to antitumor efficacy evaluation [FCT]
71. Linguistic and religious isolates in northeastern Portugal: new insights from Genetic and Demography [FCT]
72. Mesenchymal stem cells in inflammatory bowel disease: therapeutic strategy versus cancer induction [Ipatimup]
73. Implementation of a biological material bank of thyroid tumours: clinicopathological and molecular characterization.
[Ipatimup]
74. Sistema Informação da Rede Nacional de Banco de Tumores [Ipatimup]
75. Using NGS to uncover structural and regulatory variation in Gastric Cancer [Coimbra Genomics]
76. Glycosylation of cellular receptors in Cancer. [Industry]
77. T cell receptor N-glycosylation as a new mechanism underlying Inflammatory Bowel Disease pathogenesis. Implications for
therapy. [FCT]
78. Contributos para o reforço da capacidade do Ipatimup enquanto actor do sistema regional de inovação: actualização
tecnológica em sequenciação e acesso a técnicas de citometria. [ON]
79. MuSA-Deteção de mutações e alterações epigenéticas em ADN tumoral circulante em sangue [ADI - IDEIA]
80. Programa Incentivo FCT [FCT]
81. Fellowship para apoio ao Internato de Anatomia Patológica no Cantro Hospitalar de S.João. (CHSJ) [FCG]
82. Improving gastric cancer patient stratification towards personalised therapy [FCT]
83. Modifiers of Machado-Joseph disease: study of ataxin-3 like and josephin domain containing proteins [FCT]
84. Epithelial stromal crosstalk as a major driver of colorectal cancer development and progression: an aproach to identify its
master regulations. [FCT]
85. Carcinoma Basocelular da cabeça e pescoço: caracterização do perfil genético e identificação de factores de risco na
população de Trás-os-Montes e Alto Douro [Ipatimup]
86. Estudo CISAE [GEDII]
87. Estudo Acertive [GEDII]
88. SwetMic-Helicobacter pylori entrapment using sweet microsponges: a new alternative for gastric infection treatment [FCT]
89. Caracterização da ancestralidade genética da-Amazônia Maranhense: avaliação populacional e forense [Ipatimup]
90. Educação para a Prevenção do Cancro. Desenvolvimento e implementação de modelos educativos inovadores” [Ipatimup]
91. Acções de colaboração com instituições norte-americanas [FLAD]
92. Urease de helicobacter pylori: propriedades não relacionadas com a actividade enzimática que potencialmente contribuem
para gastrite e cancro gástrico [CAPES]
93. Dasatinib as an option to breat P-cadherin-overexpressing poor prognosis breast cancer [Laço]
94. Identification of a potential new prognostic biomarker to select IBD patients that fail standard therapy. [Abbvie]
95. The functional role of exosomes in tumor hetesogeneity and cancer all plasticity. [FCT]
96. Epidemiologia das hemoglobinopatias: variabilidade genética da hemoglobina e de enzimas eritrocitárias na Província do
Bengo, Angola [FCG]
97. Cytological training at European Standard through telepathology. [UE]
98. HYPE - Healthy Youth through Prevention Education [FCG]
99. Understanding the interactions between P-glycoprotein and microRNAs in the transfer of drug resistance by extracellular
vesicles [Ipatimup]
100. Characterization of glycoproteins as biomarkers of cancer [Ipatimup]
101. Atenção integrada ao doente oncológico no Hospital Central de Maputo - Reforço da capacidade institucional [FCG]
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2014
SCIENTIFIC PAPERS
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Vullo C, Gomes V, Romanini C, Oliveira AM, Rocabado O, Aquino J, Amorim A, Gusmão L. Association between Y haplogroups
and autosomal AIMs reveals intra-population substructure in Bolivian populations. International journal of legal medicine;
Epub ahead of print. 2014. [Epub ahead of print] DOI: 10.1007/s00414-014-1025-x PMID: 24878616 IF=2,597
Ibarra A, Freire-Aradas A, Martínez M, Fondevila M, Burgos G, Camacho M, Ostos H, Suarez Z, Carracedo A, Santos S, Gusmão
L. Comparison of the genetic background of different Colombian populations using the SNPforID 52plex identification panel.
International journal of legal medicine; 128: 19-25. 2014. [Article] DOI: 10.1007/s00414-013-0858-z PMID: 23665814 IF=2,597
Baldaque-Silva F, Marques M, Lopes J, Carneiro F, Vieth M, Macedo G. Crypt dysplasia on Barrett’s oesophagus. Gut; 63: 528-9.
2014. [Letter] DOI: 10.1136/gutjnl-2013-305278 PMID: 23812321 IF=13,319
Beca F, Santos R, Vieira D, Zeferino L, Dufloth R, Schmitt F. Primary relapse site pattern in women with triple-negative breast
cancer. Pathology, research and practice; 210: 571-5. 2014. [Article] DOI: 10.1016/j.prp.2014.05.011 PMID: 24939141 IF=1,562
Almeida D, Gerhard R, Leitão D, Davilla C, Damasceno M, Schmitt F. Topoisomerase II-alfa gene as a predictive marker of
response to anthracyclines in breast cancer. Pathology, research and practice; 210: 675-9. 2014. [Article] DOI: 10.1016/j.
prp.2014.06.017 PMID: 25042383 IF=1,562
Ferreira V, Reis CA, Perez S, Rauter AP, Videira PA. Meeting report on EMBO workshop: glycobiology and glycochemistry,
applications to human health and disease. Glycobiology; 24: 782-3. 2014. [Editorial Material] DOI: 10.1093/glycob/cwu070
PMID: 25028393 IF=3,747
Beca F, Andre R, Martins DS, Bilhim T, Martins D, Schmitt F. p-mTOR expression is associated with better prognosis in luminal
breast carcinoma. Journal of clinical pathology; 67: 961-7. 2014. [Article] DOI: 10.1136/jclinpath-2014-202320 PMID: 25053543
IF=2,551
Albuquerque A, Rios E, Carneiro F, Macedo G. Evaluation of clinico-pathological features and Helicobacter pylori infection in
gastric inflammatory fibroid polyps. Virchows Archiv : an international journal of pathology; 465: 643-7. 2014. [Article] DOI:
10.1007/s00428-014-1659-6 PMID: 25257403 IF=2,56
Cameselle-Teijeiro J, Ladra MJ, Abdulkader I, Eloy C, Soares P, Barreiro F, Sobrinho-Simões M, Beiras-Iglesias A. Increased
lymphangiogenesis in Riedel thyroiditis (Immunoglobulin G4-related thyroid disease). Virchows Archiv : an international journal
of pathology; 465: 359-64. 2014. [Article] DOI: 10.1007/s00428-014-1626-2 PMID: 25011997 IF=2,56
Boaventura P, Pereira D, Mendes A, Teixeira-Gomes J, Sobrinho-Simões M, Soares P. Thyroid and parathyroid tumours in
patients submitted to X-ray scalp epilation during the tinea capitis eradication campaign in the North of Portugal (1950-1963).
Virchows Archiv : an international journal of pathology; 465: 445-52. 2014. [Article] DOI: 10.1007/s00428-014-1644-0 PMID:
25146169 IF=2,56
Vinagre J, Pinto V, Celestino R, Reis M, Pópulo H, Boaventura P, Melo M, Catarino T, Lima J, Lopes JM, Máximo V, SobrinhoSimões M, Soares P. Telomerase promoter mutations in cancer: an emerging molecular biomarker?. Virchows Archiv : an
international journal of pathology; 465: 119-33. 2014. [Review] DOI: 10.1007/s00428-014-1608-4 PMID: 25048572 IF=2,56
Rossi ED, Bizzarro T, Fadda G, Larocca LM, Schmitt F. Is morphology alone able to predict BRAF-mutated malignancies on
thyroid FNAC?. Virchows Archiv : an international journal of pathology; 465: 247-8. 2014. [Letter] DOI: 10.1007/s00428-0141607-5 PMID: 24928715 IF=2,56
Gündisch S, Slotta-Huspenina J, Verderio P, Ciniselli CM, Pizzamiglio S, Schott C, Drecoll E, Viertler C, Zatloukal K, Kap M,
Riegman P, Esposito I, Specht K, Babaryka G, Asslaber M, Bodó K, den Bakker M, den Hollander J, Fend F, Neumann J, Reu S,
Perren A, Langer R, Lugli A, Becker I, Richter T, Kayser G, May AM, Carneiro F, Lopes JM, Sobin L, Höfler H, Becker KF. Evaluation
of colon cancer histomorphology: a comparison between formalin and PAXgene tissue fixation by an international ring trial.
Virchows Archiv : an international journal of pathology; 465: 509-19. 2014. [Article] DOI: 10.1007/s00428-014-1624-4 PMID:
25085759 IF=2,56
Rito M, Schmitt F, Pinto AE, André S. Fibromatosis-like metaplastic carcinoma of the breast has a claudin-low
immunohistochemical phenotype. Virchows Archiv : an international journal of pathology; 465: 185-91. 2014. [Article] DOI:
10.1007/s00428-014-1603-9 PMID: 24903673 IF=2,56
Soares P, Celestino R, Melo M, Fonseca E, Sobrinho-Simões M. Prognostic biomarkers in thyroid cancer. Virchows Archiv : an
international journal of pathology; 464: 333-46. 2014. [Review] DOI: 10.1007/s00428-013-1521-2 PMID: 24487783 IF=2,56
Durães C, Almeida GM, Seruca R, Oliveira C, Carneiro F. Biomarkers for gastric cancer: prognostic, predictive or targets of
therapy?. Virchows Archiv : an international journal of pathology; 464: 367-78. 2014. [Review] DOI: 10.1007/s00428-013-1533-y
PMID: 24487788 IF=2,56
Santos S, Oliveira M, Amorim A, van Asch B. A forensic perspective on the genetic identification of grapevine (Vitis vinifera
L.) varieties using STR markers. Electrophoresis; 35: 3201-7. 2014. [Review] DOI: 10.1002/elps.201400107 PMID: 25146979
IF=3,161
Campanella NC, Celestino R, Pestana A, Scapulatempo-Neto C, de Oliveira AT, Brito MJ, Gouveia A, Lopes JM, Guimarães DP,
Soares P, Reis RM. Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs). European journal of
human genetics : EJHG; Epub ahead of print. 2014. [Epub ahead of print] DOI: 10.1038/ejhg.2014.195 PMID: 25248398 IF=4,225
Nogueiro I, Teixeira J, Amorim A, Gusmão L, Alvarez L. Reply to letter from Felice L. Bedford and Doron Yacobi. European
journal of human genetics : EJHG; Epub ahead of print. 2014. [Epub ahead of print] DOI: 10.1038/ejhg.2014.232 PMID:
25370035 IF=4,225
Nogueiro I, Teixeira J, Amorim A, Gusmão L, Alvarez L. Echoes from Sepharad: signatures on the maternal gene pool of
crypto-Jewish descendants. European journal of human genetics : EJHG; Epub ahead of print. 2014. [Epub ahead of print] DOI:
10.1038/ejhg.2014.140 PMID: 25074462 IF=4,225
Bordeira-Carriço R, Ferreira D, Mateus DD, Pinheiro H, Pêgo AP, Santos MA, Oliveira C. Rescue of wild-type E-cadherin
expression from nonsense-mutated cancer cells by a suppressor-tRNA. European journal of human genetics : EJHG; 22: 108592. 2014. [Article] DOI: 10.1038/ejhg.2013.292 PMID: 24424122 IF=4,225
Sanches JM, Figueiredo J, Fonseca M, Durães C, Melo S, Esménio S, Seruca R. Quantification of mutant E-cadherin using
bioimaging analysis of in situ fluorescence microscopy. A new approach to CDH1 missense variants. European journal of human
genetics : EJHG; Epub ahead of print. 2014. [Epub ahead of print] DOI: 10.1038/ejhg.2014.240 PMID: 25388006 IF=4,225
Campanella NC, Berardinelli GN, Scapulatempo-Neto C, Viana D, Palmero EI, Pereira R, Reis RM. Optimization of a pentaplex
panel for MSI analysis without control DNA in a Brazilian population: correlation with ancestry markers. European journal of
human genetics : EJHG; 22: 875-80. 2014. [Article] DOI: 10.1038/ejhg.2013.256 PMID: 24193342 IF=4,225
2014
24. Nunes JB, Peixoto J, Soares P, Maximo V, Carvalho S, Pinho SS, Vieira AF, Paredes J, Rego AC, Ferreira IL, Gomez-Lazaro M,
Sobrinho-Simoes M, Singh KK, Lima J. OXPHOS dysfunction regulates integrin-ß1 modifications and enhances cell motility
and migration. Human molecular genetics; Epub ahead of print. 2014. [Epub ahead of print] DOI: 10.1093/hmg/ddu612 PMID:
25504047 IF=6,677
25. Dias AM, Dourado J, Lago P, Cabral J, Marcos-Pinto R, Salgueiro P, Almeida CR, Carvalho S, Fonseca S, Lima M, Vilanova M,
Dinis-Ribeiro M, Reis CA, Pinho SS. Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in
ulcerative colitis. Human molecular genetics; 23: 2416-27. 2014. [Article] DOI: 10.1093/hmg/ddt632 PMID: 24334766 IF=6,677
26. Simões-Correia J, Silva DI, Melo S, Figueiredo J, Caldeira J, Pinto MT, Girão H, Pereira P, Seruca R. DNAJB4 molecular chaperone
distinguishes WT from mutant E-cadherin, determining their fate in vitro and in vivo. Human molecular genetics; 23: 2094-105.
2014. [Article] DOI: 10.1093/hmg/ddt602 PMID: 24293545 IF=6,677
27. Melo CA, Melo SA. MicroRNA biogenesis: dicing assay. Methods in molecular biology (Clifton, N.J.); 1182: 219-26. 2014. DOI:
10.1007/978-1-4939-1062-5_20 PMID: 25055915
28. Parreira P, Fátima Duarte M, Reis CA, Martins MC. Helicobacter pylori infection: A brief overview on alternative natural
treatments to conventional therapy. Critical reviews in microbiology; Epub ahead of print. 2014. [Epub ahead of print] DOI:
10.3109/1040841X.2014.892055 PMID: 24606042 IF=6,087
29. Peña L, Gama A, Goldschmidt MH, Abadie J, Benazzi C, Castagnaro M, Díez L, Gärtner F, Hellmén E, Kiupel M, Millán Y, Miller
MA, Nguyen F, Poli A, Sarli G, Zappulli V, Mulas JM. Canine Mammary Tumors: A Review and Consensus of Standard Guidelines
on Epithelial and Myoepithelial Phenotype Markers, HER2, and Hormone Receptor Assessment Using Immunohistochemistry.
Veterinary pathology; 51: 127-45. 2014. [Article] DOI: 10.1177/0300985813509388 PMID: 24227007 IF=2,038
30. Amorim I, Freitas DP, Magalhães A, Faria F, Lopes C, Faustino AM, Smet A, Haesebrouck F, Reis CA, Gärtner F. A comparison
of Helicobacter pylori and non-Helicobacter pylori Helicobacter spp. Binding to Canine Gastric Mucosa with Defined Gastric
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diabetic foot ulcer on lower extremity amputation and mortality risk. Journal of diabetes and its complications; 28: 632-8.
2014. [Article] DOI: 10.1016/j.jdiacomp.2014.04.011 PMID: 24877985 IF=1,925
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Advances in Anatomic Pathology
American Journal of Cancer Therapy and Pharmacology
Annales de Génétique
Annals of Human Genetics
Computational Biology and Bioinformatics
Current Diagnostic Pathology
Dataset Papers in Biology
Dataset Papers in Oncology
Endocrine Pathology
Endocrine Related Cancer
European Journal of Cancer Prevention
Forensic Science International. Genetics
Frontiers in Genetics
Frontiers in Genomic Assay Technology
Helicobacter
Histopathology
International Journal of Medical Students
International Journal of Surgical Pathology
ISRN Genomics
Journal of Clinical Pathology
Journal of Integrated OMICS
Journal of Pathology
Open Pathology Journal
Pathology, Research and Practice
Patologia
PloS one
Research in Cancer and Tumor
Seminars in Diagnostic Pathology
The Open Forensic Science Jounal
The Scientific World Journal
Ultrastructural Pathology
Virchows Archiv : an International Journal of Pathology
World Journal of Biological Chemistry
World Journal of Clinical Infectious Diseases
World Journal of Gastroenterology
2014
2014
Relatório das actividades comemorativas dos 25 anos
Instituto de Patologia
e Imunologia Molecular
da Universidade do Porto
Relatório das actividades
comemorativas dos 25 anos
1
99
2014
Instituto de Patologia
e Imunologia Molecular
da Universidade do Porto
Relatório das actividades
comemorativas dos 25 anos
2
3
Ancorado no sucesso científico e financeiro do
decidiu assinalar este ano de transição com
XII European Congress of Pathology, o Ipatimup
uma programação regular dirigida ao grande
nasceu no final de 1989. Em 2014, ao completar
público e à comunidade científica em que
25 anos, o Instituto orgulha-se da sua produção
está inserido. Decidiu também avançar com
científica, dos seus doutoramentos e pós-douto-
a produção de uma escultura comemorativa
ramentos, dos prémios, das patentes e dos protó-
do 25º aniversário da autoria do escultor
tipos, das iniciativas de difusão científica e de
Zulmiro de Carvalho, e com a publicação de
prevenção do cancro, do elevadíssimo número
um livro com a história do Instituto. Estas
e da qualidade dos exames de diagnóstico que
iniciativas, sublinhe-se, só foram possíveis
realiza para todo o mundo e do seu património
com o apoio das EMPRESAS AMIGAS, a
edificado.
quem muito agradecemos.
O ano de 2014 foi verdadeiramente extraordi-
Na organização da programação, e com
nário: não só completámos 25 anos de existência,
o objectivo de reforçar o reconhecimento
como iniciámos um novo capítulo da nossa
público e chegar a toda a comunidade,
história com a materialização do Consórcio
contámos com a colaboração das principais
Instituto de Inovação e Investigação em Saúde
instituições da cidade do Porto, a quem
da Universidade do Porto. Tratando-se de um
também queremos agradecer.
marco histórico, mas também do início de um
Na sua globalidade, a comemoração dos 25
novo rumo estratégico, a Direcção do Ipatimup
anos do Ipatimup foi alvo de grandes reportagens, nomeadamente no EXPRESSO, no JN,
na Antena1 e em vários canais de televisão.
4
100
5
2014
Eventos Permanentes
MAR - DEZ 2014
Eventos
Permanentes
MAR - DEZ 2014
Olhares com memória
Exposição fotográfica itinerante (em
paredes de luz) sobre o património
edificado e humano do IPATIMUP
ao longo dos 25 anos de existência.
Acompanhou os vários eventos comemorativos durante o ano de 2014.
Ipatimup no Facebook: O Ipatimup
inaugurou, no início de Março, a sua
página oficial no Facebook com o
objectivo de criar uma relação de
maior proximidade com o público.
Nesta página encontrará tudo sobre
as actividades das comemorações dos
25 anos, muito do trabalho que produzimos no instituto, os acontecimentos
que consideramos mais relevantes e
ainda muitas fotografias e vídeos.
Campanha de Outdoors: o Ipatimup
conquistou a cidade, ajudando a
conhecer melhor a sua missão, as suas
descobertas, o seu funcionamento e
os serviços que oferece. O quotidiano
das praças e ruas portuenses esteve
povoado por informação e desafios. Será que conhece, de facto, o
Ipatimup?
O que é o Ipatimup? Um filme que
deu a conhecer o que 25 figuras
públicas da ciência, da cultura e da
política da cidade do Porto e do País
pensam sobre o Ipatimup. Quisemos
conhecer-nos melhor através do olhar
dos outros.
saiba mais em
www.ipatimup.pt/25anos
Ipatimup trocado por miúdos: O
trabalho de investigação realizado no
Ipatimup explicado pelo olhar imaginativo e inocente das crianças. Este
vídeo, de que nos orgulhamos particularmente, acompanhou grande parte
das iniciativas que realizámos em
2014.
Até onde se estendem as raízes e os
frutos do Ipatimup? Utilizando um
mapa interactivo, pudemos e continuamos a poder localizar actuais e
antigos colaboradores do Ipatimup
espalhados pelo Mundo, conhecer
os seus cargos actuais e saber de
que forma o Ipatimup moldou o seu
percurso.
6
7
Eventos Permanentes
MAR - DEZ 2014
Ipatimup
MAR - DEZ 2014
MARÇO
O CANCRO
PREVINE-SE, OS
DOENTES CURAM-SE:
Ciclo de conferências
sobre prevenção
e diagnóstico
precoce do cancro
· Jantar de Abertura das Comemorações dos 25 anos do Ipatimup, na
Casa da Música. Juntámos todos os
nossos amigos ao som da Orquestra
Sinfónica do Porto e distribuímos o
livro que editámos.
· 16th Portugaliae Genetica. Tema:
«Evolution at interacting levels:
from molecules to populations». Na
sequência das 15 edições anteriores,
a 16th Portugaliae Genetica reuniu
mais de cem especialistas nacionais e
estrangeiros.
Quatro sessões sobre os avanços nas estratégias
de prevenção e diagnóstico precoce de alguns dos
cancros mais frequentes:
—
Advances in Gastric Cancer: From Etiopathogenesis
to Diagnosis and Therapy Selection
Comissário: Prof. Fátima Carneiro
26 de Março, às 17:00, Auditório do Ipatimup
—
Diabetes e Cancro: O Valor da Prevenção
Comissário: Prof. Manuel Sobrinho Simões
01 Abril, às 18:00, Auditório do Ipatimup
As quatro sessões foram
muito concorridas, esgotando
os 139 lugares do auditório.
—
Ocular Tumours:
From Genetics to Treatment
Comissário: Prof. José Manuel Lopes
05 Junho, às 9:00, Auditório do Ipatimup
—
Translation Research on Cancer
and Precancerous Lesions
of the Gastrointestinal Tract
Comissário: Prof. José Carlos Machado
Auditório do Ipatimup
8
9
101
Ipatimup
MAR - DEZ 2014
2014
Ipatimup
MAR - DEZ 2014
ABRIL
MAIO
· Online Docs
[IN VIVO] Prevenir o Cancro:
A série de documentários científicos
[IN VIVO] Prevenir o Cancro apresenta de forma acessível e com utilidade para todos, orientações fundamentais para a prevenção dos
cancros mais comuns. Estes vídeos,
que têm sido repetidamente classificados como tendo uma qualidade
excepcional, foram apresentados em
vários momentos das comemorações dos 25 anos e serviram de mote
a conversas informais entre especialistas, associações de doentes oncológicos e público em geral. http://www.
Ipatimup.pt/invivo/
· Cancro, Ciência e Cidade: Os Passos
da Ciência nos Paços de Concelho:
Uma exposição dedicada à apresentação das actividades do Ipatimup,
constituída por vários tipos de material expositivo com uma vocação
pedagógica. A «ocupação» da Câmara
Municipal incluiu também filmes e
actividades interactivas que garantiram uma verdadeira aproximação
da Ciência à população. A partir da
história do Ipatimup e das descobertas dos seus investigadores,
partilhámos conhecimento sobre a
prevenção e o diagnóstico precoce de
diferentes tipos de cancro e as características genéticas e hábitos da população portuguesa. Esta iniciativa, que
teve lugar nos Paços do Concelho da
Câmara Municipal do Porto e foi inaugurada pelo Presidente da autarquia, teve como objectivo principal
aumentar a literacia de jovens e menos
jovens nos problemas do cancro,
procurando induzir comportamentos
que melhorem a sua prevenção e diagnóstico precoce. O vídeo da inauguração pode ver-se em: http://www.
youtube.com/watch?v=tx2Bt-vZhHA
· Laboratório Aberto: Em Abril, 35 Mil
Em seis anos de vida, o Laboratório
Aberto foi utilizado por milhares de
crianças de escolas do ensino básico
e secundário. Distinguimos o nosso
visitante 35 mil com um programa
surpresa.
Foi notícia no Diário de Notícias e no
Jornal de Notícias, no JPN, no site de
notícias da Câmara Municipal do Porto
e no Porto Canal. A reportagem no
Porto Canal: http://portocanal.sapo.
pt/noticia/23776
…
10
11
Ipatimup
MAR - DEZ 2014
Ipatimup
MAR - DEZ 2014
MAIO
Foi notícia na Antena1, no site JustNews, no site de notícias da autarquia,
na televisão da Universidade do Porto,
na Rádio Nova e investigadores do
Ipatimup estiveram todos os dias em
directo no PortoCanal.
A exposição foi visitada ao longo de
oito dias por mais de duas mil pessoas.
· No último dia da exposição na autarquia teve lugar um Peddy-Paper pela
luta contra o cancro da mama.
Inscreveram-se 40 pessoas.
· DIA DA TIREÓIDE:
No Dia Internacional da Tireóide
o Ipatimup organizou uma sessão
pública de informação e divulgação
das doenças da tireóide, suas causas
e formas de as diagnosticar e tratar.
Foi também possível realizar testes
de TSH e ecografia tiroideia gratuitos.
Esta iniciativa foi aberta a toda a
comunidade e contou com a participação do Grupo de Estudos da
Tireóide da Sociedade Portuguesa de
Endocrinologia, Diabetes e Metabolismo e da Associação de Doentes da
Tireóide.
Foi notícia no jornal Público, JPN, na
Rádio Nova, no site Just News, no
Portal da Saúde, no site Pontos de
Vista e no site NewsFarma.
Inscreveram-se 150 pessoas para
fazerem os rastreios e, para além
destas, estiveram presentes mais 150
para as conferências, que esgotaram a
lotação do auditório.
12
102
Venha conhecer
as instituições e
associações que lutam
no seu dia-a-dia por
esta causa!
Junte-se a nós!
Prevenção
Rastreio
Diagnóstico
Tratamento
Investigação
Aconselhamento
Qualidade de Vida
Peddy-Paper
CAMINHE
PELA LUTA
CONTRA
O CANCRO
DA MAMA!
12 MAIO · 9:30
PONTO DE PARTIDA:
CÂMARA MUNICIPAL DO PORTO
Inscrições:
[email protected]
(equipas até 3 pessoas)
Inserido nas Comemorações dos 25 anos do Ipatimup
Exposição Os Passos da Ciência nos Paços do Concelho
(Câmara Municipal do Porto)
JUNHO
· GLYCO-T 2014:
9TH INTERNATIONAL SYMPOSIUM
ON GLYCOSYLTRANSFERASES
Depois de Toronto, Estocolmo, Le
Touquet, Tsukuba, Atlanta,Tóquio
e Hannover, o Porto, e muito
especificamente o Ipatimup, acolheu
a reunião deste ano. O simpósio
realizou-se nas instalações da
Fundação Eng. António de Almeida.
Participaram mais de 200 investigadores nacionais e estrangeiros.
13
Ipatimup
MAR - DEZ 2014
Ipatimup
MAR - DEZ 2014
JULHO
SETEMBRO
· ANCESTRALIDADE
E MULTICULTURALISMO:
Ancestralidade e multiculturalismo: O
estudo da ancestralidade das populações humanas é um tema chave
do Ipatimup e esteve em debate
entre Ana Gerschenfeld (jornalista
de ciência do Público e autora do
blog “Os meus genes e eu”) e Luísa
Pereira (investigadora do Ipatimup).
Seguiu-se uma visita guiada à Sinagoga Kadoorie Mekor Haim, a maior
da Península Ibérica, onde se fez
uma contextualização histórica da
influência judaica em Portugal.
Foi notícia na Rádio Nova, no JPN, no
site Norte em Rede, no site Ciência 2.0
e no site CulturaNorte.
Participaram na visita e no debate
cerca de 100 pessoas.
· COMER COM SUCESSO:
Comer Com Sucesso: Uma palestra sobre
alimentação saudável, e como isso pode
ajudar a prevenir o cancro, com o nutricionista Pedro Graça, seguida de show
cooking, com o Chefe Hélio Loureiro. 2
Foi manchete no JN, e notícia no site
da CCDR-Norte, no JPN, no site Ciência
Hoje, no site JustNews no site PortugalNews e na Rádio Nova.
Participaram nas actividades cerca de 50
pessoas.
· Arranque no Ipatimup da 18.ª edição
do Ciência Viva em Férias. Convidámos ex-alunos de várias gerações
que passaram pelos laboratórios do
Ipatimup e também alunos e familiares que desenvolveram actividades
connosco neste Verão.
Foi notícia na Agência Lusa, no Porto
Canal, no site Viva Porto, na Rádio
Nova e no Jornal de Notícias.
· Apresentação do livro da Prof. Maria de
Sousa “Meu dito, meu escrito” - «Futuros
e Desafios na Ciência: Ouvir os novos
com ouvidos cansados. Ou um encontro
de velhos e novos sangues para a continuidade da estrutura de um país científico». Ouvimos investigadores entre os
30 e os 40 anos falarem sobre o futuro
da investigação científica em Portugal
e sobre o que esperam vir a ser as suas
vidas como investigadores nos próximos
20 anos. Destacamos também a participação do ex-reitor da Universidade
do Porto, Prof. Marques dos Santos, que
falou da sua experiência de gerir interesses e ambições de centros de investigação dentro e fora das Faculdades; de
Nuno Azevedo, que discutiu o problema
da filantropia nos dias de hoje (uma
modificação do paradigma tradicional
da caridade nas sociedades cristãs), e de
Luís Portela, que partilhou a sua experiência na investigação biomédica e aplicação clínica na indústria farmacêutica.
Foi notícia na Antena1, no Porto canal,
no JPN e na TVU. A reportagem na TVU:
https://www.youtube.com/watch?v=tp2gS1TZjXo
A audiência esgotou a lotação do auditório.
14
15
Ipatimup
MAR - DEZ 2014
Ipatimup
MAR - DEZ 2014
OUTUBRO
NOVEMBRO
· XVI CONFERÊNCIA DO EQUINÓCIO:
Saberes Permitidos, Saberes Proibidos: O Ipatimup organiza todos
os anos, desde 1997, graças ao entusiasmo do Prof. Rui Mota Cardoso,
um dia de reflexão interdisciplinar
que designa por Conferências do
Equinócio. Estas conferências prosseguem o objectivo de pensar transversalmente a Medicina, a Ciência
e a Investigação, promovendo o
estudo e a discussão multi e interdisciplinar destes temas. A Conferência
do Equinócio de 2014 foi programada
e organizada pelo Prof. João Lobo
Antunes.
Foi notícia no Diário de Notícias, no
site da Universidade do Porto, na
Rádio Nova, no site do Primeiro de
Janeiro, no site Ciência 2.0, no site
Norteemrede, no site da NewsFarma.
Tanto as sessões da manhã e da tarde
no Ipatimup, como a sessão nocturna
na Fundação de Serralves, esgotaram
a lotação dos respectivos auditórios.
IPATIMUP – 2 DIAS ABERTOS:
Durante dois dias, o Ipatimup abriu
as suas portas à comunidade, permitindo espreitar o dia-a-dia de um
instituto científico, assim como o
funcionamento dos seus laboratórios de investigação e de diagnóstico. O primeiro dia foi mais dedicado
à comunidade escolar e o segundo
(um sábado) à população em geral. A
iniciativa contou com a participação
da Junta de freguesia de Paranhos.
Foi notícia na Agência Lusa, no
Expresso, na RTP, no DN, na TVI,
na Rádio Nova, no site A Página da
Educação, no site Porto24, no Portal
de Informação Português de Oncologia Pediátrica, no PortoCanal e no
JPN. A reportagem no Jornal das 8
da TVI: https://www.youtube.com/
watch?v=-O2IfLJGZAc
Estiveram presentes cerca de 500
pessoas no primeiro dia, entre alunos e
professores. E também cerca de cinco
centenas de pessoas no segundo dia.
· Workshop do Prof. Andrew Schally,
Prémio Nobel da Medicina, que esteve
no Ipatimup a debater o problema
dos antagonistas e agonistas de
hormonas hipotalâmicas no tratamento de cancro e de outras patologias. Na sequência da visita assinou-se
um protocolo de colaboração entre o
laboratório que dirige na Universidade
de Miami e o Ipatimup.
16
2014
…
17
103
Ipatimup
MAR - DEZ 2014
Ipatimup
MAR - DEZ 2014
NOVEMBRO
· BIODEGRADÁVEIS: A Companhia de Teatro Visões Úteis, numa
co-produção com o Teatro Nacional
São João e em colaboração com o
Ipatimup e o 3B’s, apresentou a peça
de teatro Biodegradáveis, centrada
nos efeitos da passagem do tempo
sobre os corpos e as estratégias que
vão sendo encontradas - e inventadas
- para superar os limites da biologia
humana.
Foi notícia na agência Lusa, no
Público, na Visão, no JPN, no jornal A
Bola e no site da RTP
2014
NOVEMBRO
· 1º CONGRESSO INTERNACIONAL
DA ASPIC Associação Portuguesa de
Investigação em Cancro – Com uma
forte ligação ao Ipatimup (por a sua
sede funcionar nas nossas instalações
e pela presidente da Direcção, Prof.
Leonor David, ser investigadora sénior
do Ipatimup), este primeiro congresso
da recém-criada ASPIC envolveu
especialistas internacionais de elevadíssima qualidade e reuniu mais de
250 investigadores em cancro portugueses e estrangeiros. Os investigadores do Ipatimup compareceram em
peso e foram distinguidos com um
prémio da European Association for
Cancer Research (EACR) e selecionados para várias apresentações orais.
Foi notícia na Agência Lusa, na Rádio
Renascença, no site da RTP, no site
Ciência 2.0, no jornal Destak, no site
da TVI24, no Diário Digital, no site do
PortoCanal e no site Just News.
· FÓRUM DO FUTURO:
Fórum do Futuro: O Cancro: O Pelouro
da Cultura da Câmara Municipal do
Porto (CMP), em colaboração com
a Universidade do Porto, a Casa da
Música e a Fundação de Serralves,
apresentou um programa de debates
e actividades paralelas que reuniu,
durante uma semana, investigadores
e criadores nacionais e internacionais com o objectivo de questionar os
desafios que o futuro nos coloca. A
CMP escolheu o Ipatimup para desenvolver um dia dedicado ao Cancro e
aos grandes desafios que esta doença
nos coloca e o Instituto convidou o
Prémio Nobel da Química em 2004, o
cirurgião Aaron Ciechanover, e participou activamente na sessão realizada
no Rivoli: https://www.youtube.com/
watch?v=hz7im-VgHl0
Foi notícia no jornal Público, no site da
RTP e no Notícias ao Minuto.
· O Ipatimup e todos os seus profissionais homenageados pelo Rotary
Club Porto Portucale Novas Gerações,
clube Rotário da cidade do Porto.
18
19
Ipatimup
MAR - DEZ 2014
DEZEMBRO
DEZEMBRO
· 57ª VOLTA A PARANHOS: o Ipatimup
associou-se à organização da 57ª
Volta a Paranhos, a prova de estrada
mais antiga e mais popular do Norte e
habitualmente organizada pelo Sport
Comércio e Salgueiros/Câmara Municipal Porto/PORTO LAZER. O objetivo do Ipatimup com esta parceria
foi promover a atividade física e um
estilo de vida saudável, dinamizando
também a interação entre os investigadores e a população. O Instituto
participou com uma equipa composta
por mais de três dezenas de pessoas,
entre investigadores e demais funcionários, disponibilizou as suas instalações para toda a logística necessária e
deu o tiro de partida.
Foi notícia no Jornal I, no Porto Canal,
no Sapo Desporto, no site da RTP e no
Record.
Na prova de 10km inscreveram-se
2500 pessoas. No total, incluindo a
Caminhada Pais e Filhos de 3,5km,
participaram três mil pessoas.
· O Ipatimup organizou o primeiro
Curso de Patologia Molecular para
internos e especialistas de Anatomia
Patológica (12 e 13 de Dezembro).
Participaram, num curso que se
realizou pela primeira vez em Portugal,
60 médicos.
· O Ipatimup foi homenageado
pela APIFARMA com a distinção de
«Parceiro de Excelência em Investigação». Este reconhecimento público
aconteceu durante a cerimónia de
celebração dos 75 anos da Associação
Portuguesa da Indústria Farmacêutica.
20
104
Ipatimup
MAR - DEZ 2014
· Inauguração do marco do escultor
Zulmiro de Carvalho e implantação da
Cápsula do Tempo na sapata da escultura. Na cápsula, que será aberta daqui
a 25 anos, foram colocados o livro dos
25 anos, o programa das actividades
do aniversário, os depoimentos de 25
personalidades e de 25 «anónimos»
sobre o que pensam hoje, sobre como
será encarado o cancro daqui a três
décadas. No fundo, são depoimentos
para memória futura, constituindo
uma voz comum de expectativas
que servirão de inspiração às novas
gerações de cientistas. Colocámos
também na Cápsula do Tempo o vídeo
das crianças – Ipatimup trocado por
miúdos – que foi protagonizado pelos
filhos de investigadores, técnicos e
administrativos do Ipatimup e de que
tanto nos orgulhamos. Vai ter graça,
para eles, verem daqui a 25 anos como
eram em 2014.
21
2014
As comemorações dos 25 Anos do Ipatimup
terminam oficialmente em 31 de Dezembro, mas vão
ser prolongadas com a exposição interactiva «Cancro
ponto e vírgula», que irá realizar-se de 26 a 31 de
Janeiro de 2015, na Fundação Calouste Gulbenkian.
O objectivo fundamental da exposição é aumentar
a literacia dos alunos em relação aos problemas
da Saúde e do Cancro e, deste modo, estimular a
prevenção e o diagnóstico precoce. Para além da
exposição pedagógica, que terá como guias os especialistas do Ipatimup, cada dia será dedicado a um
ou dois dos cancros mais comuns – do colon-recto,
estômago, tireoide, pele, colo do útero e mama –
num ambiente de contacto informal. Serão também
projectados filmes sobre estes tipos de cancro e a
melhor forma de os prevenir, abertos a uma conversa
e discussão em grupo com especialistas do Ipatimup.
A exposição pedagógica, os vídeos e restante material expositivo continuarão, em 2015, a «viajar» pelo
País, estando já assegurada a realização da «Semana
do Ipatimup» no Museu do Dragão (F.C. Porto) e nas
sedes de algumas ONGs.
22
O nosso especial agradecimento vai para as empresas,
entidades e personalidades amigas que tornaram possível a
comemoração destes 25 anos:
Amorim Investimentos e Participações, SGPS, SA
Arsopi, Indústrias Metalúrgicas Arlindo S. Pinho, S.A.
Astrazeneca – Produtos Farmacêuticos, Lda
Banco Carregosa
Banco Espírito Santo, SA
Banco BPI, SA
Banco Santander Totta, SA
Bayer Portugal, SA
BIAL- Portela & Ca., SA
Câmara Municipal do Porto
Casa das Artes
Fundação Calouste Gulbenkian
Fundação Casa da Música
Fundação GlaxoSmithKline para as Ciências da Saúde
Fundação Manuel António da Mota
Janssen-Cilag Farmacêutica, Lda
Rosalina Machado
Santa Casa da Misericórdia do Porto
Sonae SGPS
Unicer Bebidas de Portugal, SGPS, SA
Ainda uma palavra de reconhecimento para todos
os colaboradores do Ipatimup por tudo o que fizeram ao longo deste
percurso de construção do que o Ipatimup representa hoje.
23
Rua Dr. Roberto Frias s/n
4200-465 Porto
Portugal
www.ipatimup.pt
105

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