Mutational profile of driver genes in Brazilian melanomas

Mutation testing of the key genes involved in melanoma oncogenesis is now mandatory for the application of targeted therapeutics. However, knowledge of the mutational profile of melanoma remains largely unknown in Brazil. PURPOSE Mutation testing of the key genes involved in melanoma oncogenesis is now mandatory for the application of targeted therapeutics. However, knowledge of the mutational profile of melanoma remains largely unknown in Brazil. PATIENTS AND METHODS In this study, we assessed the mutation status of melanoma driver genes BRAF, NRAS, TERT, KIT, and PDGFRA in a cohort of 459 patients attended at Barretos Cancer Hospital between 2001 and 2012. We used polymerase chain reaction followed by Sanger sequencing to analyze the hot spot mutations of BRAF exon 15 (V600E), NRAS (codons 12/13 and 61), TERT (promoter region), KIT (exons 9, 11, 13, and 17), and PDGFRA (exons 12, 14, and 18) in tumors. The mutational profile was investigated for associations with demographic, histopathologic, and clinical features of the disease. RESULTS The nodular subtype was most frequent (38.9%) followed by the superficial spreading subtype (34.4%). The most frequent tumor location was in the limbs (50.0%). The mutation rates were 34.3% for TERT and 34.1% for BRAF followed by NRAS (7.9%), KIT (6.2%), and PDGFRA (2.9%). The BRAF (P = .014) and TERT (P = .006) mutations were associated with younger patients and with different anatomic locations, particularly in the trunk, for the superficial spreading and nodular subtypes, respectively (P = .0001 for both). PDGFRA mutations were associated with black skin color (P = .023) and TERT promoter mutations with an absence of ulceration (P = .037) and lower levels of lactate dehydrogenase. There was no association between patient survival rates and mutational status. CONCLUSION The similar mutational profile we observe in melanomas in Brazil compared with other populations will help to guide precision medicine in this country.CAPES -Coordenação de Aperfeiçoamento de Pessoal de Nível Superior(2012/04194-1

HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance

<p>Abstract</p> <p>Background</p> <p>Many epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by <it>M. leprae</it>. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population.</p> <p>Methods</p> <p>One hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers(One Lambda^®, CA, USA).</p> <p>Results</p> <p>There was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy <it>per se </it>(7.3% <it>vs</it>. 3.2%, <it>P </it>= 0.01, OR = 2.52, CI = 1.26–5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% <it>vs</it>. 20.9%, <it>P </it>= 0.0424, OR = 1.61, CI = 1.09–2.39) was higher in patients, and HLA-DQA1*02 (3.0% <it>vs</it>. 7.5%, <it>P </it>= 0.0392, OR = 0.39, CI = 0.16 – 0.95) and HLA-DQA1*04 (4.0% <it>vs</it>. 9.1%, <it>P </it>= 0.0314, OR = 0.42, CI = 0.19 – 0.93) frequencies lower, <it>P</it>-values were not significant after the Bonferroni's correction. Furthermore, HLA-DRB1*1601 (9.0% <it>vs</it>. 1.8%; <it>P </it>= 0.0016; OR = 5.81; CI = 2.05–16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% <it>vs</it>. 1.2%; <it>P </it>= 0.0037; OR = 12.00; CI = 1.51 – 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection.</p> <p>Conclusion</p> <p>These data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy <it>per se</it>, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.</p

Seguimento clínico de dois pacientes brasileiros com MODY-glicoquinase (MODY2) e descrição de uma nova mutação

Mutations in the glucokinase gene (GCK) account for many cases of monogenic diabetes featuring maturity-onset diabetes of the young type 2 (MODY2). The clinical pattern of this form of hyperglycemia is rather stable, with a slight elevation in blood glucose, which is usually not progressive. Patients rarely require pharmacological interventions and microvascular complications related to diabetes are unusual. We describe the clinical follow-up of two cases of MODY2 with two different mutations in GCK gene, one in exon 7, p.Glu265Lys (c.793 G> A), which has been previously described, and a novel one, in exon 2, p.Ser69Stop (c. 206C> G). The clinical course of both cases shows similarity in metabolic control of this form of diabetes over the years. Arq Bras Endocrinol Metab. 2012;56(8):490-5Mutações no gene da glicoquinase (GCK) são determinantes de uma forma de diabetes monogênico denominada de MODY2 (maturity-onset diabetes of the young, tipo 2). O padrão clínico dessa forma de distúrbio glicêmico é bastante estável, com hiperglicemia leve, geralmente não progressiva. Intervenções farmacológicas raramente são necessárias e complicações crônicas secundárias ao diabetes são infrequentes. Descrevemos o acompanhamento clínico de dois casos de MODY2 com duas mutações diferentes, uma no éxon 7, p.Glu265Lys (c.793 G>A) já descrita anteriormente, e outra inédita no éxon 2 p.Ser69Stop (c. 206C>G). A evolução clínica de ambos os casos demonstra uma semelhança no padrão metabólico dessa forma de diabetes ao longo dos anos. Arq Bras Endocrinol Metab. 2012;56(8):490-5Faculdade de Medicina da Universidade de São Paulo Hospital das Clínicas Instituto da CriançaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Laboratório de Endocrinologia Molecular e TranslacionalUNIFESP-EPM Centro de DiabetesUNIFESP, EPM, Laboratório de Endocrinologia Molecular e TranslacionalUNIFESP, EPM Centro de DiabetesSciEL

Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) remain first line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan CL patients at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of PD-L1 and IDO1 proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared to non-infected lesional CD68+ monocytes / macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host directed therapy target in leishmaniasis

Copy number signatures and mutational processes in ovarian carcinoma.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.NIHR, Ovarian Cancer Action, Cancer Research UK Cambridge Centre, Cambridge Experimental Cancer Medicine Centr

Estudos da comissão especial de direito médico da OAB Tocantins: reflexões e perspectivas

- Divulgação dos SUMÁRIOS das obras recentemente incorporadas ao acervo da Biblioteca Ministro Oscar Saraiva do STJ. Em respeito à Lei de Direitos Autorais, não disponibilizamos a obra na íntegra.- Localização na estante: 347.56:614.25(81) E82c- Felippe Abu-Jamra Corrêa é o coordenador da obra

"Bomba hormonal": os riscos da contracepção de emergência na perspectiva dos balconistas de farmácias no Rio de Janeiro, Brasil

Resumo: A pesquisa objetivou conhecer a perspectiva dos balconistas de farmácias sobre a contracepção de emergência na Região Metropolitana do Rio de Janeiro, Brasil. O material empírico advém de pesquisa socioantropológica com vinte entrevistas semiestruturadas com balconistas dos sexos feminino (8) e masculino (12). Os entrevistados apresentam concepções negativas sobre a contracepção de emergência, enfatizando os riscos que ela pode provocar à saúde. O medicamento é considerado uma "bomba hormonal" que pode causar danos aos órgãos reprodutivos femininos e outros sistemas do corpo. Eles destacam os riscos do uso "descontrolado" ou "indiscriminado", especialmente por adolescentes e mulheres jovens. Por ser considerado "perigoso" aos corpos femininos, eles atribuem a responsabilidade de orientação e aconselhamento sobre o uso do método aos médicos ginecologistas e não aos farmacêuticos. Discute-se a necessidade de ampliação do debate público sobre contracepção de emergência no Brasil, incluindo-se os farmacêuticos e balconistas de farmácia, além dos profissionais de saúde e educadores