Competência emocional nos fisioterapeutas da rncci – estudo descritivo

Torna-se fundamental conhecer a componente emocional daqueles que prestam cuidados directos aos utentes (Vilela, 2006; Agostinho, Arruda, 2010). Parte-se do construto de Competência Emocional (CE), (Bisquerra, 2002; Veiga Branco, 2004a, b) baseado no conceito teórico inicial de Inteligência Emocional (Salovey & Mayer, 1990), para compreender como os Fisioterapeutas da RNCCI vivenciam emoções em contexto laboral (Gard, 2000). Reconhecer a frequência dos comportamentos enquanto variáveis do perfil de CE dos Fisioterapeutas da RNCCI. Metodologia: Estudo quantitativo de carácter descritivo e exploratório, numa amostra de 58 Fisioterapeutas da RNCCI. Foi aplicada a Escala Veiga de Competência Emocional (EVCE), (Veiga Branco, 2004) para aceder ao perfil de CE através das cinco capacidades do construto. As respostas indicaram a frequência temporal das vivências, variando entre 1=”Nunca” e 7=”Sempre” e foram submetidas à análise de consistência interna (α) e estudo descritivo (SPSS 17). A amostra revelou que “por norma” (x= 4,19) vivencia comportamentos de CE. Vive “por norma” a Autoconsciência (x=4,11; =0,48; α=0,69), a Empatia (x=4,83; =0,64; α=0,79) e a Gestão de Emoções em Grupos (x=4,58; =0,70; α=0,87) e vive “pouco frequentemente” a Gestão de Emoções (x=3,83; =0,70; α=0,81) e a Automotivação (x=3,60; =0,56; α=0,81)

Competência emocional nos fisioterapeutas da rede nacional de cuidados continuados integrados

O presente estudo foi delineado com a finalidade de elaborar uma imagem diagnóstica de perfil em Competência Emocional (CE) – conceito aqui assumido como objeto de estudo - dos Fisioterapeutas da Rede Nacional de Cuidados Continuados Integrados, para projetar uma eventual intervenção formativa nesta comunidade. Os Objetivos concentraram-se em reconhecer, num primeiro momento cronológico, os comportamentos e atitudes que identificam as cinco capacidades da C.E. (Autoconsciência, Gestão de Emoções, Automotivação, Empatia e Gestão de Emoções em Grupos) destes profissionais, para, num segundo momento, se aceder aos comportamentos ou atitudes considerados mais perturbadores, e portanto, aos pontos críticos de intervenção, comprovando assim a pertinência – ou não - para uma formação nesta área de desenvolvimento humano, aqui assumida como a Educação Emocional. Para aceder a estes objetivos, foi levado a cabo um estudo exploratório, quantitativo e correlacional, tendo como amostra respondente 58 Fisioterapeutas da RNCCI - concretamente nas Unidades de Internamento – sendo 49 do género feminino e 9 do género masculino e com idades compreendidas maioritariamente dos 21 aos 30 anos. Os dados recolhidos a partir das respostas da amostra ao instrumento de recolha de dados – Escala Veiga de C.E. (EVCE) (Veiga-Branco, 2005, 2007), aplicado via on line através do Google Docs - foram submetidos a diferentes procedimentos estatísticos: inicialmente através de estatística descritiva, seguida de estudos correlacionais com respetiva significância estatística, obtendo assim quais as capacidades que expressam o perfil atitudinal e comportamental da C.E. Os resultados das correlações entre as capacidades e a Competência Emocional são positivas e muito fortes, no entanto, neste perfil a amostra revela um perfil diferente do apresentado em construto teórico. O facto de os Fisioterapeutas expressarem que só “Por Norma”, vivem as capacidades de Gestão de Emoções, Gestão de Emoções em Grupos e de Automotivação, revelam necessidade de intervenção de Educação Emocional nestas destrezas, como forma promotora da sua C.E..The present study was designed with the aim of developing a diagnostic imaging profile in Emotional Competence (EC) – a concept adopted here as an object of study – the National Network of Physiotherapists of Continuous Care, to design a possible training in this community. Objectives focused on recognizing, at first chronological, behaviors and attitudes that identify five capabilities of EC (Self-Awarness, Emotions Management, Self Motivation, Empathy and Emotions Management Groups) of these professionals, for, second, if access behaviors or attitudes considered more disturbing, and therefore the critical points of intervention, thus proving the relevance – or not – for training in this area of human development, here assumed to Emotional Education. To reach these goals, it was carries out an exploratory study, quantitative and correlational, and a sample of 58 RNCCI Physiotherapists respondents – specifically in Inpatient Units – which 49 females and 9 males and aged mostly from 21 at age 30. The data collected from the responses of the sample to the instrument for data collection – Escala Veiga de Competência Emocional (EVCE) (Veiga-Branco, 2005, 2007) on line through Google Docs – were subjected to different statistical procedures: initially through descriptive statistics, followed by correlational studies with respective statistical significance, thereby obtaining what capabilities express attitudinal and behavioral profile of EC. The results of the correlations between the capabilities and Emotional Competence are positive and very strong, however, in this profile the sample reveals a different profile presented in the theoretical construct. The fact that Physiotherapists only express “By Norma”, living skills Management Emotions, Emotions Management Groups and Self Motivation, reveal the need for intervention of Emotional Education in these skills as a way of promoting their EC

Competência emocional (CE) nos fisioterapeutas da rede nacional de cuidados continuados integrados (RNCCI)

Os cuidados de saúde revelam a necessidade de se ser competente na área que diz respeito aos conceitos do que, atualmente, se considera CE dentro da atividade profissional. Verifica-se a importância de conhecer a componente emocional daqueles que prestam cuidados diretos aos utentes (Vilela, 2006; Agostinho e Arruda, 2010), nomeadamente de como os Fisioterapeutas das Unidades de Internamento da RNCCI vivenciam emoções, reconhecendo de que forma consideram que a sua CE se correlaciona com as cinco capacidades que a integram – Autoconsciência, Gestão de Emoções, Automotivação, Empatia e Gestão de Emoções em Grupos. Para o efeito, foi desenvolvido um estudo transversal, quantitativo, analítico e exploratório, com recurso a amostra de 58 Fisioterapeutas da RNCCI, 49 do género feminino e 9 do género masculino e com idades compreendidas maioritariamente dos 21 aos 30 anos. Foi aplicada a Escala Veiga de Competência Emocional (EVCE), (Veiga Branco, 2004) para traçar o perfil de CE através das cinco capacidades do construto e foi determinado o coeficiente de correlação r de Pearson, permitindo conhecer a existência ou não de correlação entre as cinco capacidades, quer entre si, quer com a CE. Os resultados do tratamento dos dados com recurso ao SPSS 20.0 revelaram que todas as correlações entre as capacidades e a Competência Emocional são positivas e, extremamente, fortes. O estudo revelou que a CE dos Fisioterapeutas tem correlação mais forte com as capacidades de Empatia (r=,811), de Automotivação (r=,809) e de Autoconsciência (r=,804), seguida da Gestão de Emoções (r=,795) e da Gestão de Relacionamentos em Grupos (r=,734)

Translating biology into clinic: new insights on prognostic and predictive biomarkers for urothelial bladder carcinoma

Tese de doutoramento em Ciências da SaúdeUrothelial bladder carcinoma (UBC) represents a significant health problem, as a consequence of its heterogeneous natural history and clinical behavior. Most morbidity and mortality associated with UBC is caused by the muscle-invasive (MI) form of the disease, which represents about 20-30% of all newly diagnosed cases. Moreover, an important proportion of high risk non-muscle invasive (NMI) tumours relapse after transurethral resection and progress to MI disease. Despite radical cystectomy, half of the patients with MI tumours develop metastases. Although perioperative and palliative systemic chemotherapy is recommended for locally-advanced or metastatic UBC, survival benefits are impaired in a significant proportion of patients due to inherent or acquired chemoresistance. Currently, prognostication of patients with MI-UBC is severely hampered by the insufficiency of standard clinicopathological risk factors in accurately predicting individual treatment outcomes. This major drawback can potentially be overcome if biomarkers of tumour aggressiveness and response to chemotherapy are routinely evaluated and included in the pathology reports. Current research efforts are directed into the elaboration of nomograms that can combine well-established clinicopathological parameters with novel putative biomarkers. In this line of investigation, we aimed to characterize a phenotype of bladder cancer aggressiveness in a human series of UBC by studying the clinical and prognostic significance of a panel of distinct biomarkers that, although poorly explored in UBC setting, were described as being involved in tumour angiogenesis and lymphangiogenesis, invasion and metastasis, energy metabolism reprogramming and tumour microenvironment. Moreover, we intended to validate potential therapeutic targets in in vitro assays. Angiogenesis, lymphangiogenesis and lymphovascular invasion (LI) occurrence was assessed with the use of immunohistochemical markers, namely the blood endothelial cell marker CD31, the lymphatic endothelial cell marker D2-40, the lymphangiogenic vascular endothelial growth factor (VEGF)-C and its receptor VEGFR-3. The specific staining of blood and lymphatic endothelium significantly contributed to an accurate evaluation of LI occurrence, and to a specific distinction between blood vessel invasion (BVI) and lymphatic vessel invasion (LVI). A correlation among high blood vessel density (BVD), high lymphatic vessel density (LVD), tumour progression and LI occurrence was found. BVI by malignant emboli assessed by CD31 staining, and LVI by isolated malignant cells assessed by D2-40 staining, significantly impaired overall survival, and BVI was identified as an independent prognostic factor. When included in a model of bladder cancer aggressiveness combining classical clinicopathological parameters with biomarkers, BVI and LVI contributed to separate between low and high aggressiveness groups. VEGF-C overexpression was correlated with an aggressive phenotype characterized by increased tumour stage, loss of differentiation, high BVD and LVD counts, and characterized by increased tumour stage, loss of differentiation, high BVD and LVD counts, and In the scenario of invasion and metastasis, we evaluated the immunoexpression of the endoglycosidase heparanase and of the metastasis suppressor RKIP (Raf kinase inhibitor protein). Heparanase was upregulated in the malignant urothelium, and exhibited a heterogeneous pattern, with the invasion front of the tumours being more intensely stained than the tumour’s core, supporting its role in the disassembly of the extracellular matrix as an invasion-promoter mechanism. An opposite pattern was found when evaluating RKIP immunoexpression. This metastasis-supressor biomarker was homogeneously expressed in normal urothelium and in tumour sections with a favourable clinico-pathological profile. Heterogeneous expression, with the tumour centre being more intensely stained than the invasion front, associated with LI occurrence. Low RKIP expression significantly impaired prognosis, remaining as an independent prognostic factor for disease-free survival. Thus, RKIP loss emerges as a novel biomarker of UBC aggressiveness, and additional studies are necessary to validate our results and to further explore therapeutic strategies that can potentially restore RKIP functionality as a suppressor of bladder cancer metastases. Reprogramming cellular energetics and modeling the tumour microenvironment are inherent traits of malignancy. Among the plethora of biomarkers associated with this hallmark of cancer, we investigated the immunoexpression of CD147, monocarboxylate transporters (MCTs), CD44 and carbonic anhydrase (CA) IX. We observed that MCT1 and MCT4 were overexpressed in malignant urothelial cells, associating with an unfavourable clinicopathological profile. MCT1 expression correlated with poor prognosis. Significant associations were found between the pattern of expression of CD147, MCT1 and MCT4, supporting the role of CD147 as a chaperone for MCTs. CD147 upregulation clearly associated with UBC aggressiveness and poor prognosis, lowering significantly disease-free and overall survival rates. When included in a scoring system of UBC aggressiveness, CD147 overexpression allowed an accurate discrimination of bladder cancer patients’ prognosis. There was a substantial concordance among CD44 and MCTs expressions, and CD44 and CD147, which suggests an interactive scenario where CD44, MCTs and CD147 cooperate in regulating the acidic microenvironment. Moreover, CD44 expression was also associated with UBC aggressiveness. CAIX exhibited a heterogeneous pattern of expression, being stronger at the hypoxic core of MI tumours or at the luminal face of papillary lesions, were its expression was predominant. CAIX expression correlated with MCT4, CD147 and CD44 expressions, supporting hypoxia as a trigger mechanism of the glycolytic phenotype. Importantly, the CD147/MCT1 double-positive profile associated with unfavourable clinico-pathological parameters and poor prognosis, and discriminated a poor-prognosis group within patients who received platinum-based chemotherapy. These interesting results led us to further investigate CD147 as a potential biomarker of aggressiveness and cisplatin resistance in UBC cell lines. CD147 specific downregulation was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our findings shed light into the putative role of CD147 and its interactions in determining progression and resistance to cisplatin-based chemotherapy in UBC setting, unraveling possibilities for target therapeutic intervention that urge to be investigated. In summary, the results herein reported represent our contribution to a better understanding on biological parameters that seem to influence bladder cancer aggressiveness and chemoresistance, and should be further explored as potential prognosis/theranostics biomarkers and/or therapeutic targets.O carcinoma urotelial da bexiga (CUB) representa um importante problema de saúde pública, em resultado da heterogeneidade associada à sua histogénese e comportamento clínico. A morbilidade e mortalidade associadas ao CUB são principalmente causadas pela variante músculo-invasora (MI), que representa cerca de 20-30% de todos os casos diagnosticados. Adicionalmente, uma proporção significativa de tumores não-músculo invasivos (NMI) de alto risco recidiva após a ressecção transuretral e progride para formas invasoras. Apesar de submetidos a cistectomia radical, metade dos doentes com tumores MI desenvolvem metástases. Em casos de CUBs localmente avançados ou disseminados, são recomendados esquemas de quimioterapia sistémica peri-operatória e paliativa. No entanto, potenciais benefícios em termos de sobrevivência são francamente diminuídos numa proporção significativa de doentes que apresentam quimio-resistência intrínseca ou adquirida. Atualmente, o prognóstico de doentes com CUBs MI é gravemente prejudicado pela dificuldade que os fatores de risco clínico-patológicos clássicos apresentam em prever, com precisão e por indivíduo, resultados dos tratamentos. Este grande entrave poderá ser potencialmente superado se biomarcadores de agressividade tumoral e resposta à quimioterapia forem rotineiramente avaliados e incluídos nos relatórios de patologia. Os esforços de pesquisa atuais são, cada vez mais, direcionados para a elaboração de nomogramas que combinem parâmetros clínicos padrão com possíveis biomarcadores. Nesta linha de investigação, o projeto descrito nesta tese teve como objetivo principal caracterizar um fenótipo de agressividade do CUB numa série de tumores, estudando o significado clínico e prognóstico de um painel de biomarcadores distintos que, apesar de pouco explorados no âmbito dos CUBs, foram já descritos como mediadores da angiogénese e linfangiogénese tumorais, invasão e metastização, e remodelação do metabolismo energético e do microambiente tumoral. Adicionalmente, pretendeu-se validar potenciais alvos terapêuticos em ensaios in vitro. A ocorrência de angiogénese, linfangiogénese e invasão linfovascular (IL) foi avaliada através de marcação imuno-histoquímica, recorrendo a anticorpos anti- CD31 (marcador de células endoteliais sanguíneas), D2-40 (marcador de células endoteliais linfáticas), VEGF-C (fator linfangiogénico, vascular endotelial growth factor C) e VEGFR-3 (recetor de VEGF-C). A marcação específica dos endotélios sanguíneo e linfático contribuiu significativamente para uma avaliação precisa da ocorrência de IL, e para uma distinção específica entre invasão vascular sanguínea (IVS) e invasão vascular linfática (IVL). Foram encontradas correlações entre densidade vascular sanguínea (DVS) e densidade vascular linfática (DVL) elevadas, progressão tumoral e ocorrência de IL. A ocorrência de IVS por êmbolos de células malignas identificada pela marcação específica com CD31, assim como a ocorrência de IVL por células malignas isoladas identificada pela marcação específica com D2-40, diminuíram significativamente a sobrevivência global. A ocorrência de IVS foi identificada como um fator independente de prognóstico. Quando incluídas num modelo de agressividade do CUB que combinou parâmetros clínico-patológicos clássicos com biomarcadores, a ocorrência de IVS e IVL contribuiu para a distinção entre grupos de baixa e elevada agressividade. O aumento de expressão de VEGF-C associou-se a um fenótipo de agressividade tumoral caracterizado pelo incremento do estádio patológico, perda de diferenciação, contagens de DVS e DVL elevadas, e ocorrência de IVS e IVL. O VEGFR-3 foi expresso, de forma monótona e consistente, pelo urotélio maligno. Tais resultados suportam a necessidade de estabelecer um método reprodutível de avaliação da ocorrência de IL que possa ser incorporado na prática clínica. Destaca-se o potencial papel deste processo biológico na seleção de doentes que poderão beneficiar de tratamentos adjuvantes. Os níveis de p-mTOR (phospho–mammalian target of rapamycin), bem como a possível associação com a ocorrência de angiogénese e linfangiogénese, foram igualmente estudados, na tentativa de clarificar o papel da via mTOR como mediadora de neovascularização no CUB. Foram selecionadas secções tumorais com representação de mucosa não-tumoral adjacente. Observou-se imunoexpressão nas células em guarda-chuva do urotélio não-tumoral, em todas as camadas celulares do urotélio de tumores NMI (de maior intensidade nas células superficiais), e em spots de células nas lesões MI. A expressão do p-mTOR diminuiu com o aumento do estádio tumoral, mas os poucos tumores pT3/pT4 positivos associaram-se a piores prognósticos. Por outro lado, a ocorrência de angiogénese ficou comprometida nos tumores pT3/pT4 negativos. Será necessário realizar estudos adicionais direcionados aos restantes membros desta via de sinalização, na tentativa de clarificar os resultados agora obtidos. Com o objetivo de explorar os fenómenos de invasão e metastização no CUB, avaliou-se a imunoexpressão da endoglicosidase heparanase e do supressor de metástases RKIP (Raf kinase inhibitor protein). Observaram-se níveis aumentados de heparanase no urotélio maligno, que exibiu um padrão heterogéneo, onde a frente de invasão tumoral se encontrava mais intensamente marcada do que o centro dos tumores, o que suporta o papel desta enzima na degradação da matriz extracelular, um mecanismo promotor de invasão. Em relação à proteína RKIP, foi encontrado um padrão de expressão oposto. Este biomarcador supressor de metástases foi homogeneamente expresso no urotélio normal e em secções tumorais caracterizadas por um perfil clínico-patológico favorável. Uma expressão heterogénea, com o centro do tumor mais intensamente marcado do que a frente de invasão, associou-se à ocorrência de IL. A diminuição da expressão de RKIP associou-se significativamente a um prognóstico desfavorável, mantendo-se como um fator independente de prognóstico relativamente à sobrevivência livre de doença. Assim, a perda de expressão de RKIP surge como um novo biomarcador de agressividade do CUB. Estudos adicionais são necessários para validar os resultados aqui apresentados e explorar estratégias terapêuticas que possam potencialmente restaurar a funcionalidade desta proteína como um supressor de metástases no carcinoma da bexiga. A reprogramação do metabolismo energético e a modelação do microambiente tumoral são características inerentes ao fenótipo de malignidade. Entre a diversidade de biomarcadores associados a tais fenómenos, foi estudada a imunoexpressão de CD147, de transportadores de monocarboxilatos (monocarboxylate transporters, MCTs), de CD44 e de anidrase carbónica (carbonic anhydrase, CA) IX. Verificou-se o aumento da expressão de MCT1 e MCT4 nas células uroteliais malignas. Os tumores negativos apresentaram perfis clínico-patológicos favoráveis. A expressão de MCT1 associou-se a um prognóstico desfavorável. Foram encontradas associações significativas entre o padrão de expressão de CD147, MCT1 e MCT4, o que fundamenta o papel da proteína CD147 como chaperone dos MCTs. O aumento da expressão de CD147 associou-se claramente a um fenótipo de agressividade tumoral e a um prognóstico adverso, reduzindo significativamente as taxas de sobrevivência livre de doença e sobrevivência global. Quando incluída num sistema de discriminação de agressividade tumoral, a expressão de CD147 permitiu distinguir, com rigor, o prognóstico dos doentes com CUB. Verificou-se uma concordância significativa entre a expressão de CD44 e MCTs, e entre a expressão de CD44 e CD147, o que sugere um cenário interativo onde CD44, MCTs e CD147 cooperaram na regulação do microambiente tumoral. Além disso, a expressão de CD44 associou-se igualmente com a agressividade do CUB. A enzima CAIX exibiu um padrão de expressão heterogénea, sendo a marcação mais forte no centro hipóxico dos tumores MI ou na face luminal das lesões papilares, onde a sua expressão se revelou predominante. A expressão de CAIX associou-se com a expressão de MCT4, CD147 e CD44, o que sugere a ocorrência de hipoxia como um mecanismo promotor do fenótipo glicolítico. De salientar que o perfil duplamente-positivo CD147/MCT1 associou-se a parâmetros clínico-patológicos desfavoráveis e a um pior prognóstico, e discriminou um subgrupo de doentes com prognóstico adverso entre um grupo tratado com quimioterapia à base de compostos de platina. Tais resultados encorajaram à realização de estudos adicionais em linhas celulares de CUB, na tentativa de clarificar a função da proteína CD147 como um potencial biomarcador de agressividade tumoral e resistência à cisplatina. O silenciamento específico da CD147 foi acompanhado por uma diminuição da expressão de MCT1 e MCT4 e, notoriamente, por um aumento na quimio-sensibilidade à cisplatina. Estes estudos demonstram o papel provável da CD147 e suas interações na determinação da progressão tumoral e resistência à quimioterapia baseada em cisplatina em doentes com CUB, revelando possibilidades de intervenção terapêutica dirigida que devem ser exploradas num futuro próximo. Em resumo, os resultados descritos nesta tese representam o tributo para uma melhor compreensão sobre parâmetros biológicos que parecem influenciar a agressividade do carcinoma urothelial da bexiga, bem como a resistência à quimioterapia, e que devem ser investigados como potenciais biomarcadores de prognóstico e previsão de resposta à terapêutica, bem como alvos terapêuticos

In vivo anticancer activity of AZD3965: a systematic review

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords “AZD3965 in vivo” as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01- 0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). J.A. received a fellowship from FCT, ref. SFRH/BPD/116784/2016

Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumour aggressiveness

Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.This study was supported by the Life and Health Sciences Research Institute (ICVS) from the School of Health Sciences of the University of Minho. JA received a postdoctoral fellowship from ICVS (reference ICVS-SSRL: ON.2 SR&TD Integrated Program, NORTE-07-0124-FEDER-000017).info:eu-repo/semantics/publishedVersio

Immunoexpression profile of hypoxia-inducible factor (HIF) targets in potentially malignant and malignant oral lesions: a pilot study

Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated.  Objectives: This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers’ immunoexpression, clinicopathological features, and prognostic parameters. Methodology: OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. Results: CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. Conclusion: OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis

Glucose metabolism reprogramming in bladder cancer: hexokinase 2 (HK2) as prognostic biomarker and target for bladder cancer therapy

Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in “in vitro” and “in vivo” preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell’s viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance.The work presented herein was performed at the Life and Health Sciences Research Institute (ICVS), University of Minho. Financial support was provided by the Scientific Microscopy Platform of ICVS, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122), by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020, and by the projects NORTE 01-0145-FEDER-000039 and NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). J.A. was supported by FCT (fellowship ref. SFRH/BPD/116784/2016). C.G. was supported by Programme NORTE 2020 [CTTI-117/21-ICVS(1)] and FCT (contract ref. 2021.02600.CEECIND). D.F. was supported by “Liga Portuguesa contra o Cancro—Núcleo Regional do Norte” (fellowship ref. LPCC-NRN).info:eu-repo/semantics/publishedVersio

Prognostic value of Monocarboxylate Transporter 1 overexpression in cancer: a systematic review

Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords “cancer”, “Monocarboxylate transporter 1”, “SLC16A1” and “prognosis”. Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter’s overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01- 0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). A.S., M.C.C. and J.A. received fellowships from FCT, references 2022.11018.BD (A.S.), 2022.10233.BD (M.C.C.) and SFRH/BPD/116784/2016 (J.A.)