Mapping Conformational Changes in the Saliva Proteome Potentially Associated with Oral Cancer Aggressiveness.

Diverse proteomics-based strategies have been applied to saliva to quantitatively identify diagnostic and prognostic targets for oral cancer. Considering that these targets may be regulated by events that do not imply variation in protein abundance levels, we hypothesized that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed limited proteolysis-mass spectrometry in saliva samples to explore structural alterations, comparing the proteome of healthy control and oral squamous cell carcinoma (OSCC) patients with and without lymph node metastasis. Thirty-six proteins with potential structural rearrangements were associated with clinical patient features including transketolase and its interacting partners. Moreover, N-glycosylated peptides contribute to structural rearrangements of potential diagnostic and prognostic markers. Altogether, this approach utilizes saliva proteins to search for targets for diagnosing and prognosing oral cancer and can guide the discovery of potential regulated sites beyond protein-level abundance.

Exploring the Potential of Structure-Based Deep Learning Approaches for T cell Receptor Design.

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively unexplored. A relevant application is the design of T cell receptors (TCRs). Given the crucial role of T cells in mediating immune responses, redirecting these cells to tumor or infected target cells through the engineering of TCRs has shown promising results in treating diseases, especially cancer. However, the computational design of TCR interactions presents challenges for current physics-based methods, particularly due to the unique natural characteristics of these interfaces, such as low affinity and cross-reactivity. For this reason, in this study, we explored the potential of two structure-based deep learning protein design methods, ProteinMPNN and ESM-IF, in designing fixed-backbone TCRs for binding target antigenic peptides presented by the MHC through different design scenarios. To evaluate TCR designs, we employed a comprehensive set of sequence- and structure-based metrics, highlighting the benefits of these methods in comparison to classical physics-based design methods and identifying deficiencies for improvement.

Gene expression profile of renal cell carcinoma clear cell type

PURPOSE: The determination of prognosis in patients with renal cell carcinoma (RCC) is based, classically, on stage and histopathological aspects. The metastatic disease develops in one third of patients after surgery, even in localized tumors. There are few options for treating those patients, and even the new target designed drugs have shown low rates of success in controlling disease progression. Few studies used high throughput genomic analysis in renal cell carcinoma for determination of prognosis. This study is focused on the identification of gene expression signatures in tissues of low-risk, high-risk and metastatic RCC clear cell type (RCC-CCT). MATERIALS AND METHODS: We analyzed the expression of approximately 55,000 distinct transcripts using the Whole Genome microarray platform hybridized with RNA extracted from 19 patients submitted to surgery to treat RCC-CCT with different clinical outcomes. They were divided into three groups (1) low risk, characterized by pT1, Fuhrman grade 1 or 2, no microvascular invasion RCC; (2) high risk, pT2-3, Fuhrman grade 3 or 4 with, necrosis and microvascular invasion present and (3) metastatic RCC-CCT. Normal renal tissue was used as control. RESULTS: After comparison of differentially expressed genes among low-risk, high-risk and metastatic groups, we identified a group of common genes characterizing metastatic disease. Among them Interleukin-8 and Heat shock protein 70 were over-expressed in metastasis and validated by real-time polymerase chain reaction. CONCLUSION: These findings can be used as a starting point to generate molecular markers of RCC-CCT as well as a target for the development of innovative therapies.

Combined 17 alpha-hydroxylase/17, 20-lyase deficiency due to a homozygous 25 BP duplication (NT 4157-4181) at exon 5 in the CYP17 resulting in a premature stop codon predicted by molecular modeling / Deficiência combinada de 17 alfa-hidroxilase/17, 20 liase devido a duplicação de 25 PB (NT 4157-4181) no éxon 5 do CYP17 resultando em parada prematura de leitura predita por modelagem molecular

Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia characterized by the coexistence of hypertension, caused by the hyperproduction of mineralocorticoid precursors and DSD in males and sexual infantilism in females, due to impaired production of sex hormones. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we described a novel CYP17 mutation in two Brazilian sisters with primary amenorrhea, 46,XY karyotype, high basal levels of progesterone (3.4-4.9 ng/mL) and hypokalemic hypertension born to consanguineous parents. After PCR and automatic sequencing of CYP17 coding region, 25 bp duplication at exon 5 was found in the patients. This duplication started at codon 318 resulting in a premature stop codon at position 320 resulting in an ineffective and truncated protein and in accordance with the molecular modeling of P450c17. Therefore we expanded the repertoire of CYP17 mutations describing the largest duplication found in this gene in both sisters, with a clinical phenotype of combined 17alpha-hydroxylase/17,20-lyase deficiency and emphasizes the importance of the P450c 17 molecular modeling to predict the functional effect of these mutations.

A deficiência combinada de 17 alfa-hidroxilase/17,20 liase é uma doença rara, de herança autossômica recessiva, causa de hiperplasia adrenal congênita caracterizada pela presença de hipertensão resultante do acúmulo de precursores mineralocorticóides, distúrbio da diferenciação sexual em homens e infantilismo sexual em mulheres devido à falha na produção de esteróides sexuais. Várias mutações no gene CYP17 resultando em deficiência de 17 alfa-hidroxilase/17,20-liase têm sido descritas. No presente estudo, descrevemos uma nova mutação no CYP17 em duas irmãs, nascidas de pais consangüíneos, com quadro de amenorréia primária, cariótipo 46,XY, dosagens basais elevadas de progesterona (3,4-4,9 ng/mL) e hipertensão hipocalêmica. Após PCR e seqüenciamento automático da região codificadora do CYP17, uma duplicação de 25 pb no exon 5 foi identificada nas pacientes. Esta duplicação inicia-se no códon 318 resultando em parada prematura de leitura no códon 320 gerando uma proteína truncada e inativa conforme predito pela modelagem molecular do P450c17. Com este achado, ampliamos o repertório de mutações do CYP17 descrevendo a maior duplicação descrita até então neste gene em duas irmãs com fenótipo de deficiência combinada de 17 alfa-hidroxilase/17,20-liase e enfatizamos a importância da modelagem molecular do P450c 17 em predizer o efeito funcional destas mutações.

Angioplastia renal transluminal percutânea no tratamento da hipertensäo renovascular / Percutaneous Transluminal Renal Angioplasty for Treatment of Renovascular Hypertension

Objetivo - Avaliar o efeito da angioplastia renal transluminal percutânea (ARTP) no tratamento da hipertensäo renovascular. Métodos - Foram avaliados 23 pacientes com estenose da artéria renal e hipertensäo arterial submetidos à tentativa de ARTP. Onze indivíduos eram do sexo masculino e 12 do feminino com idades que variaram de 10 a 78 anos (45,8 ñ 17,41). Vinte Lesöes eram ateroscleróticas, 7 por displasia fibromuscular e 1 por arterite de Takayasu. Em 3 casos a dilataçäo foi bilateral e em 2 foi repetida por reestenose. Dois pacientes apresentavam insuficiencia renal aguda por estenose crítica das artérias renais. Resultados - Obteve-se sucesso técnico em 21 dos 25 procedimentos. Após 20 dilataçöes satisfatórias seguiu-se o sucesso clínico em 17(100// das lesöes por displasia fibromuscular e 77// das ateroscleróticas). A reduçäo da pressäo arterial diastólica após a ARTP foi estatisticamente significante (p<0,001). Nos dois casos de insuficiência renal aguda houve normalizaçäo da funçäo renal com a angioplastia. Ocorreram 2 complicaçöes e nenhum óbito foi relacionado ao procedimento. Conclusäo - O método foi eficaz e seguro no tratamento da hipertensäo renovascular no acompanhamento a curto prazo. Foi possível reverter a insuficiência renal aguda com a ARTP em 2 pacientes

Purpose - To analyze the effect of percutaneous transluminal renal angioplasty (PTRA) in renovascular hypertension. Methods - Twenty-three patients with renal artery stenosis and arterial hypertension underwent PTRA. There were 11 male an 12 female, 19 to 78 years old (45.8±17.41). In 20 lesions the diagnosis was atherosclerosis, in 7 fibromuscular dysplasia and in 1 Takayasu artheritis. Three patients underwent bilateral dilatation and 2 patients repeated the procedure due to reestenosis. Two patients presented with acute renal failure and severe bilateral renal artery stenosis. Results - There were 21 technical success in 25 procedures. After 20 satisfatory dilatations, clinical success followed in 17 (100% of cases of fibromascular dysplasia cases and 77% of atherosclerosis. The fall in diastolic arterial pressure after PTRA was statistical significant (p<0.001). In two cases acute renal failure the renal function became normal after angioplasty. There were 2 complications and no death attributed to PTRA. Conclusion - The method was effective and safe in the management of renovascular hypertension during the short-term follow-up. It was possible in two cases of acute renal failure to normalize renal function

Angioplastia coronária em octogenários. Resultados imediatos e complicações / Coronary angioplasty in octogenarians. Results and complications

Objetivo: Analisar os resultados e complicações das angioplastias coronárias em octogenários. Métodos: Num estudo retrospectivo de 4.552 procedimentos realizados no período de outubro de 1988 a abril de 1997, foram encontrados 88 procedimentos em octogenários (1,9por cento), correspondendo a 109 lesões (balão 88, stents 17 e rotablator 4); 45 eram do sexo masculino (51,1por cento). Clinicamente havia 16 pacientes com angina estável (18,2por cento), 55, com angina instável (62,5por cento); 17, com infarto do miocárdio (19,3por cento), 3 dos quais com choque cardiogênico (3,4por cento). A artéria descendente anterior foi abordada 51 vezes com 56 lesões (51,4por cento); coronária direita, 31 em 35 lesões (32,1por cento); circunflexa, 12 em 14 lesões (12,8por cento); ponte de safena, 3 (2,8por cento); tronco de coronária esquerda, 1 (0,9por cento). Havia 9 ((8,3por cento) lesões do tipo A (AHA/ACC); 74 (67,9por cento), do tipo B e 26 (23,8por cento), do tipo C. Resultados: O sucesso total foi alcançado em 74 procedimentos (84,1por cento); 56, por balão (84,8por cento); 15, por stent (88,2por cento) e 3, por rotablator (75por cento). Houve insucesso em 14 casos (15,9por cento) devido ao fato de: o guia não ter ultrapassado a lesão em 5 casos; o cateter balão não ter dilatado a lesão em 4 casos,; ter havido oclusão aguda e subaguda em 7 casos (7,9por cento), sendo 3 (3,4por cento) encaminhados à cirurgia de urgência com 2 casos de sucesso e 1 óbito, havendo ainda 1 implante de stent com sucesso, 2 dilatações por balão (1 com sucesso) e 1 óbito. O total de óbitos no estudo foi 4(4,5por cento). Conclusão: Concluímos que tanto os índices de sucesso como o de óbitos são semelhantes aos da literatura, quando avaliado igual período de tempo. Tendo em vista a elevada idade e o estudo foi bom para o período de estudo, sendo esse um tratamento que pode ser utilizado nesse grupo de pacientes de alto risco