INFECÇÃO POR CHLAMYDIA TRACHOMATIS E NEISSERIA GONORRHOEAE EM UTENTES DE UMA CONSULTA DE DOENÇAS DE TRANSMISSÃO SEXUAL - ANÁLISE DE DEZ ANOS

Background: Reports indicating incidence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections have been increasing. Objectives: To determine the prevalence of CT and NG infected individuals attending a Sexually Transmitted Disease (STD) clinic in a University Hospital. Methods: A cross-sectional study was conducted on attendees of the STD clinic throughout a 10 year period. Diagnoses of CT and NG infections were enabled upon nucleic acid amplification analysis (PCR). Results: In our study population there was a male predomi- nance (83.3%). Overall prevalence of CT and NG infection was 1.6% and 0.8%, respectively. A prevalence of 3% of chlamydia infection was recorded when routine screening was implemented. More so, 53% of individuals displayed asymptomatic infection, 78% of which had chlamydia infection and 22% had gonococcal infection (p<0.05). Routine screening of STD attendees has resulted in the diagnosis and treatment of an average of 13.7 asymptomatic individuals. Conclusion: Unlike gonococcal infection we found an increase of chlamydia infection prevalence when routine screening was implemented. Screening of STD attendees for CT provided the opportunity to identify and treat asymptomatic Chlamydia infections. Systematic screening of STD attendees of both genders for CT should be offered.KEYWORDS – Chlamydia Infections; Chlamydia trachomatis; Gonorrhea; Neisseria gonorrhoeae; Ambulatory Care Facilities.Introdução: Estudos recentes têm apontado para um aumento da incidência de infecções por Chlamydia trachomatis (CT) e Neisseria gonorrhoeae (NG). Objetivos: Determinar a prevalência de infecção por CT e NG em utentes de uma consulta de Doenças de Transmissão Sexual (DST) num Hospital Universitário. Métodos: Foi realizado um estudo transversal nos utentes de uma clínica de DTS ao longo de um período de 10 anos. Os diagnósticos foram efectuados recorrendo a análise de amplificação de ácidos nucleicos (PCR). Resultados: Na população estudada houve um predomínio do sexo masculino (83,3%). A prevalência global da infecção por CT e NG foi de 1,6% e 0,8%, respectivamente, e após implementação do rastreio a todos os utentes observados, a prevalência de infecção por CT subiu para 3%. Adicionalmente, 53% dos utentes assintomáticos foram diagnosticados como portares da infecção, 78% com infecção por CT e 22% com infecção por NG (p <0,05). O rastreio sistemático resultou no diagnóstico e no tratamento de uma média de 13,7 indivíduos assintomáticos. Conclusão: Contrariamente ao observado na infecção por NG, os autores encontraram um aumento da prevalência da infecção por CT, após implementação do rastreio sistemático de todos os utentes da consulta. A triagem para a infecção por CT possibilitou a identificação e tratamento das infecções assintomáticas por este microorganismo. Os autores sugerem o rastreio sistemático de todos os utentes das consultas de STD para a infecção por CT.PALAVRAS-CHAVE – Chlamydia Trachomatis; Neisseria gonorrhoeae; Infecções por Clamídia; Gonorreia

How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

The significance of RET in thyroid cancer comes from solid evidence that, when inherited, an RET activating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. The RET gene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature of RET point mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs

INFECÇÃO CUTÂNEA POR MYCOBACTERIUM HAEMOPHILUM EM DOENTE IMUNODEPRIMIDO

Mycobacterium haemophilum skin infection is a rare disease with a difficult diagnosis and a challenging treatment. We report the case of a patient on chronic corticotherapy for myositis with nodules on the lower limbs in which Mycobacterium haemophilum was identified by PCR technique. This case emphasizes the need for a high index of suspicion for the diagnosis. In fact, this infection can currently be underdiagnosed due to the special requirements for culture. It should be considered in patients with chronic granulomatous processes in combination with negative my- cobacteriological examination.KEYWORDS – Mycobacterium haemophilum; Immunocompromised host; Mycobacterium infections; Skin diseases, bacterial.A infecção cutânea por Mycobacterium haemophilum é uma patologia rara, de difícil diagnóstico e cujo tratamento constitui um desafio. Descreve-se o caso de um doente sob corticoterapia crónica no contexto de miosite com nódulos dos membros inferiores, nos quais foi detectada uma estirpe de Mycobacterium haemophilum pela téc- nica de PCR. Este caso enfatiza a necessidade de um alto nível de suspeição clínica para o diagnóstico. De facto, esta infecção pode actualmente estar sub-diagnosticada devido aos requisitos especiais de cultura. Deve ser considerada em doentes com processos granulomatosos crónicos em associação a exame cultural persistentemente negativo.PALAVRAS-CHAVE – Mycobacterium haemophilum; Micobactéria atípica; Imunossupressão

Severe interstitial pneumonia due to murine typhus in a patient returning from Bali

Murine typhus has been increasingly reported as a cause of fever in returning travelers from Southeast Asia. We report a case of a previously healthy traveler returning from Bali with an non-specific febrile illness which quickly progressed to a severe form of interstitial pneumonia. After a careful epidemiological evaluation and laboratory analysis, murine typhus was diagnosed.info:eu-repo/semantics/publishedVersio

Genetic Alterations in Poorly Differentiated and Undifferentiated Thyroid Carcinomas

Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC)

TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.Fundação para a Ciência e a Tecnologia; Norte 2020 – Programa Operacional Regional do Norte project: (“Advancing cancer research: from basic knowledgment to application” - grant: NORTE-01-0145-FEDER-000029); Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education: (I3S)

TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas

Context: 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.We acknowledge GENZYME for funding our work through a research project. This study was supported by the Portuguese Foundation for Science and Technology through PhD Grant SFRH/BD/81940/2011 (to J.V.); PhD Grant SFRH/BD/87887/2012 (to C.T.); PhD Grant SFRH/BD/79135/2011 (to A.A.); and the Scientific Investigation Project PIC/IC/83037/2007. Further funding was obtained from the project “Microenvironment, Metabolism and Cancer,” partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the European Regional Development Fund. The work of J.M.C.-T. was supported by Grant PI12/00749-FEDER from the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness (Madrid, Spain). The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an associate laboratory of the Portuguese Ministry of Science, Technology, and Higher Education, which is partially supported by the Foundation for Science and Technology

Frequency of TERT promoter mutations in human cancers

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.We thank to Mrs Mafalda Rocha for the excellent technical support in the sequencing work. This work was partially supported by the Portuguese Science and Technology Foundation (FCT) through BPD (SFRH/BPD/85249/2012 to H. P.), PhD (SFRH/BD/81940/2011 to J.V. and SFRH/BD/79135/2011 to A. A.) and BI grants, and the grant through the Program Ciencia 2008 (J.L.) and the project (PIC/IC/83037/2007). Further funding was obtained from the project 'Microenvironment, metabolism and cancer' partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referencia Estrategico Nacional (QREN), and through the Fundo Europeu de Desenvolvimento Regional (FEDER). IPATIMUP is an associate laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by the FCT

TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas

Funding: This study was supported by the Portuguese Foundation for Science and Technology through PhD Grant SFRH/BD/81940/ 2011 (to J.V.); PhD Grant SFRH/BD/87887/2012 (to C.T.); PhD Grant SFRH/BD/79135/2011 (to A.A.); and the Scientific Investigation Project PIC/IC/83037/2007. Further funding was obtained from the project “Microenvironment, Metabolism and Cancer,” partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the European Regional Development Fund. The work of J.M.C.-T. was supported by Grant PI12/00749-FEDER from the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness (Madrid, Spain). The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an associate laboratory of the Portuguese Ministry of Science, Technology, and Higher Education, which is partially supported by the Foundation for Science and Technology.Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives:Weaimed 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.publishersversionpublishe

Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations

<p>Abstract</p> <p>Background</p> <p>Thyroid carcinomas show a high prevalence of mutations in the oncogene BRAF which are inversely associated with RAS or RET/PTC oncogenic activation. The possibility of using inhibitors on the BRAF pathway as became an interesting therapeutic approach. In thyroid cancer cells the target molecules, implicated on the cellular effects, mediated by inhibition of BRAF are not well established. In order to fill this lack of knowledge we studied the proliferation and survival pathways and associated molecules induced by BRAF inhibition in thyroid carcinoma cell lines harbouring distinct genetic backgrounds.</p> <p>Methods</p> <p>Suppression of BRAF pathway in thyroid cancer cell lines (8505C, TPC1 and C643) was achieved using RNA interference (RNAi) for BRAF and the kinase inhibitor, sorafenib. Proliferation analysis was performed by BrdU incorporation and apoptosis was accessed by TUNEL assay. Levels of protein expression were analysed by western-blot.</p> <p>Results</p> <p>Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAF^V600Emutation. In BRAF^V600Emutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27^Kip1. Specific inhibition of BRAF by RNAi in cells with BRAF^V600Emutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAF^V600Emutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2.</p> <p>Conclusion</p> <p>Our results in thyroid cancer cells, namely those harbouring BRAF^V600Emutation showed that BRAF signalling pathway provides important proliferation signals. We have shown that in thyroid cancer cells sorafenib induces apoptosis by affecting Mcl-1 and Bcl-2 in BRAF^V600Emutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly those refractory to conventional treatment and harbouring BRAF mutations.</p