ESS - APCT - Anatomia Patológica, Citológica e Tanatológica
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- Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient micePublication . Gomes Pereira, Sandra Isabel; Rodrigues, Pedro Nuno; Appelberg, Rui; Gomes, Maria SaloméMycobacterium avium is an opportunistic infectious agent in immunocompromised patients, living inside macrophage phagosomes. As for other mycobacterial species, iron availability is a critical factor for M. avium survival and multiplication. Indeed, an association between host secondary iron overload and increased susceptibility to these mycobacteria is generally acknowledged. However, studies on the impact of primary iron overload on M. avium infection have not been performed. In this work, we used animal models of primary iron overload that mimic the human disease hereditary hemochromatosis. This pathology is characterized by increased serum transferrin saturation with iron deposition in parenchymal cells, mainly in the liver, and is most often associated with mutations in the gene encoding the molecule HFE. In this paper, we demonstrate that mice of two genetically determined primary iron overload phenotypes, Hfe(-/-) and beta 2m(-/-), show an increased susceptibility to experimental infection with M. avium and that during infection these animals accumulate iron inside granuloma macrophages. beta 2m(-/-) mice were found to be more susceptible than Hfe(-/-) mice, but depleting Hfe(-/-) mice of CD8(+) cells had no effect on resistance to infection. Overall, our results suggest that serum iron, rather than total liver iron, levels have a considerable impact on susceptibility to M. avium infection.
- Caraterização de tumores sólidos numa amostra pediátrica do Instituto Português de Oncologia do Porto Francisco Gentil, EPEPublication . Santos, Ana; Serra, Carla; Mota, Marlene; Sousa, Manuela; Mendes, CarlosCaracterizar uma amostra pediátrica com TS quanto à sua frequência, óbito, sexo e idade ao diagnóstico. Estudar o possível envolvimento da MO ao diagnóstico, recorrendo a dados qualitativos de mielogramas. Estudo observacional descritivo transversal, dos registos dos dados de pacientes pediátricos com TS (n=148), diagnosticados entre 2000-2008. O TS mais frequente foi o Neuroblastoma (NB=37,2%), e os com maior registo de óbitos foram Rabdomiossarcoma (RMS=30,4%) e Família Tumores Ewing (FTE=28,0%). Nas raparigas os Tumor Wilms (TW=68,0%) e Osteossarcoma (58,3%) foram mais frequentes, enquanto nos rapazes foram os Retinoblastoma (75,0%), RMS (65,2%) e NB (61,8%). O NB manifestou-se, em 30,9% dos casos, até aos 12 meses de idade, o TW, em 32,0% dos casos, até aos 2 anos, e o RMS, em 69,6% dos casos, entre os 1-10 anos. A maioria dos pacientes com FTE (80,0%), NB (74,6%) e RMS (73,9%) realizaram mielograma ao diagnóstico. Observando os resultados qualitativos do mielograma, os tumores onde poderá ter ocorrido invasão da MO foram o NB e RMS. Na frequência dos TS verificou-se que seguem o descrito na literatura, excepto a FTE que surge em segundo lugar conjuntamente com o TW, sendo o NB mais frequente. Nos óbitos, o tumor com maior registo, RMS, não corresponde ao com maior gravidade (NB) descrito na investigação. Para estes resultados pode ter contribuído o número reduzido da amostra. Relativamente ao sexo, o NB e o RMS são mais frequentes nos rapazes, enquanto o TW é mais frequente nas raparigas, como descrito na literatura. Doentes com NB, TW e RMS apresentaram idades ao diagnóstico que indicam um melhor prognóstico. O NB, RMS e FTE, em alguns casos, disseminam-se para a MO, podendo ser esta a explicação para os resultados obtidos quanto à realização ou não de mielograma. Dos resultados obtidos nos mielogramas, verifica-se que poderá ter ocorrido invasão medular nos NB e RMS. Propõe-se continuar este estudo com amostra, por TS, mais representativa e com dados dos hemogramas e biópsias ósseas.
- S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) AggregationPublication . Botelho, Hugo; S. Leal, Sónia; Cardoso, Isabel; Yanamandra, Kiran; Morozova-Roche, Ludmilla A.; Fritz, Günter; Gomes, Cláudio M.S100A6 is a small EF-hand calcium- and zinc-binding protein involved in the regulation of cell proliferation and cytoskeletal dynamics. It is overexpressed in neurodegenerative disorders and a proposed marker for Amyotrophic Lateral Sclerosis (ALS). Following recent reports of amyloid formation by S100 proteins, we investigated the aggregation properties of S100A6. Computational analysis using aggregation predictors Waltz and Zyggregator revealed increased propensity within S100A6 helices HI and HIV. Subsequent analysis of Thioflavin-T binding kinetics under acidic conditions elicited a very fast process with no lag phase and extensive formation of aggregates and stacked fibrils as observed by electron microscopy. Ca2+ exerted an inhibitory effect on the aggregation kinetics, which could be reverted upon chelation. An FT-IR investigation of the early conformational changes occurring under these conditions showed that Ca2+ promotes anti-parallel β-sheet conformations that repress fibrillation. At pH 7, Ca2+ rendered the fibril formation kinetics slower: time-resolved imaging showed that fibril formation is highly suppressed, with aggregates forming instead. In the absence of metals an extensive network of fibrils is formed. S100A6 oligomers, but not fibrils, were found to be cytotoxic, decreasing cell viability by up to 40%. This effect was not observed when the aggregates were formed in the presence of Ca2+. Interestingly, native S1006 seeds SOD1 aggregation, shortening its nucleation process. This suggests a cross-talk between these two proteins involved in ALS. Overall, these results put forward novel roles for S100 proteins, whose metal-modulated aggregation propensity may be a key aspect in their physiology and function.
- Deregulated expression of selected histone methylases and demethylases in prostate carcinomaPublication . Quintela Vieira, Ana Filipa; Costa-Pinheiro, Pedro; Ramalho-Carvalho, João; Menezes, Francisco Duarte; Antunes, Luis; Carneiro, Isa; Oliveira, Jorge; Henrique, Rui; Jeronimo, CarmenProstate cancer (PCa), a leading cause of cancer-related morbidity and mortality, arises through the acquisition of genetic and epigenetic alterations. Deregulation of histone methyltransferases (HMTs) or demethylases (HDMs) has been associated with PCa development and progression. However, the precise influence of altered HMTs or HDMs expression and respective histone marks in PCa onset and progression remains largely unknown. To clarify the role of HMTs and HDMs in prostate carcinogenesis, expression levels of 37 HMTs and 20 HDMs were assessed in normal prostate and PCa tissue samples by RT-qPCR. SMYD3, SUV39H2, PRMT6, KDM5A, and KDM6A were upregulated, whereas KMT2A-E (MLL1-5) and KDM4B were downregulated in PCa, compared with normal prostate tissues. Remarkably, PRMT6 was the histone modifier that best discriminated normal from tumorous tissue samples. Interestingly, EZH2 and SMYD3 expression levels significantly correlated with less differentiated and more aggressive tumors. Remarkably, SMYD3 expression levels were of independent prognostic value for the prediction of disease-specific survival of PCa patients with clinically localized disease submitted to radical prostatectomy. We concluded that expression profiling of HMTs and HDMs, especially SMYD3, might be of clinical usefulness for the assessment of PCa patients and assist in pre-therapeutic decision-making.
- Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processingPublication . Sousa, Elsa Joana; Pinho dos Santos Graça, Maria Inês; Baptista, Tiago; Quintela Vieira, Ana Filipa; Palmeira, Carlos; Henrique, Rui; Jeronimo, CarmenProstate cancer (PCa) is one of the most incident malignancies worldwide. Although efficient therapy is available for early-stage PCa, treatment of advanced disease is mainly ineffective and remains a clinical challenge. microRNA (miRNA) dysregulation is associated with PCa development and progression. In fact, several studies have reported a widespread downregulation of miRNAs in PCa, which highlights the importance of studying compounds capable of restoring the global miRNA expression. The main aim of this study was to define the usefulness of enoxacin as an anti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in a TRBP-mediated manner. Using a panel of five PCa cell lines, we observed that all of them were wild type for the TARBP2 gene and expressed TRBP protein. Furthermore, primary prostate carcinomas displayed normal levels of TRBP protein. Remarkably, enoxacin was able to decrease cell viability, induce apoptosis, cause cell cycle arrest, and inhibit the invasiveness of cell lines. Enoxacin was also effective in restoring the global expression of miRNAs. This study is the first to show that PCa cells are highly responsive to the anti-tumoral effects of enoxacin. Therefore, enoxacin constitutes a promising therapeutic agent for PCa.
- Anti-neoplastic properties of hydralazine in prostate cancerPublication . Pinho dos Santos Graça, Maria Inês; Sousa, Elsa Joana; Costa-Pinheiro, Pedro; Quintela Vieira, Ana Filipa; Torres-Ferreira, Jorge; Martins, Maria Gabriela; Henrique, Rui; Jeronimo, CarmenProstate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.
- TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomasPublication . Melo, Miguel; Gaspar Da Rocha, Adriana; Vinagre, João; Batista, Rui; Peixoto, Joana; Tavares, Catarina; Celestino, Ricardo; Almeida, Ana; Salgado, Catarina; Eloy, Catarina; Castro, Patrícia; Prazeres, Hugo; Lima, Jorge; Amaro, Teresina; Lobo, Cláudia; Martins, Maria João; Moura, Margarida; Cavaco, Branca; Leite, Valeriano; Cameselle-Teijeiro, José; Carrilho, Francisco; Carvalheiro, Manuela; Maximo, Valdemar; Sobrinho-Simões, Manuel; Soares, PaulaContext: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.
- Telomerase promoter mutations in cancer: an emerging molecular biomarker?Publication . Vinagre, João; Pinto, Vasco; Celestino, Ricardo; Reis, Marta; Populo, H; Boaventura, Paula; Melo, Miguel; Catarino, T.; Lima, Jorge; Lopes, José Manuel; Maximo, Valdemar; Sobrinho-Simões, Manuel; Soares, PaulaCell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the “alternative mechanism of telomere lengthening” (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and non-neoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.
- Sound exposure of garage rock bands musiciansPublication . Almeida, João; Silva, Daniel; Carmo, Paulo; Neves, Paula; Rodrigues, Matilde A.Previous studies have been shown that musicians are exposed to high sound levels in the course of rehearsals and performances (Rodrigues et al .,2014), which can be the source of hearing damages (Jansen et al ., 2009). However, other musical groups can also be exposed to high sound levels, as is the case of the garage rock bands musicians. This particular group of musicians, due to the style of the music played, can be exposed to dangerous sound levels. This situation can be even worse if considered the conditions of the rooms where the rehearsals and performances are being done. In fact, in most of cases, rock musicians play in rooms with small dimensions and with poor acoustic conditions. Despite the importance of this issue, few studies analyzed this issue, particularly integrating two important issues, the sound exposure and to hearing damages.
- Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs)Publication . Campanella, Natália C; Celestino, Ricardo; Pestana, Ana; Scapulatempo-Neto, C; Oliveira, Antonio Talvane de; Brito, Maria josé; Gouveia, António; Lopes, José Manuel; Guimarães, Denise Peixoto; Reis, Rui; Soares, PaulaSomatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene, mainly at positions c.-124 and c.-146 bp, are frequent in several human cancers; yet its presence in gastrointestinal stromal tumor (GIST) has not been reported to date. Herein, we searched for the presence and clinicopathological association of TERT promoter mutations in genomic DNA from 130 bona fide GISTs. We found TERT promoter mutations in 3.8% (5/130) of GISTs. The c.-124C>T mutation was the most common event, present in 2.3% (3/130), and the c.-146C>T mutation in 1.5% (2/130) of GISTs. No significant association was observed between TERT promoter mutation and patient's clinicopathological features. The present study establishes the low frequency (4%) of TERT promoter mutations in GISTs. Further studies are required to confirm our findings and to elucidate the hypothetical biological and clinical impact of TERT promoter mutation in GIST pathogenesis.