PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients

OBJECTIVES: The phosphatidylinositol 3-kinase/AKT axis is an important cell-signaling pathway that mediates cell proliferation and survival, two biological processes that regulate malignant cell growth. The phosphatidylinositol 3-kinase CA gene encodes the p110α subunit of the phosphatidylinositol 3-kinase protein. There are phosphatidylinositol 3-kinase CA mutations in several types of human tumors, and they are frequently observed in breast cancer. However, these mutations have not been investigated in Brazilian breast cancer patients. METHODS: PCR-SSCP and direct DNA sequencing were performed to identify phosphatidylinositol 3-kinaseCA exon 9 and exon 20 mutations in 86 patients with sporadic breast cancer. The relationships between PIK3CA mutations and patient clinicopathological characteristics and survival were analyzed. The presence of the TP53 mutation was also examined. RESULTS: Twenty-three (27%) of the 86 primary breast tumors contained PIK3CA mutations. In exons 9 and 20, we identified the hotspot mutations E542K, E545K, and H1047R, and we identified two new missense mutations (I1022V and L1028S) and one nonsense (R992X) mutation. Phosphatidylinositol 3-kinase CA exon 20 mutations were associated with poor overall survival and TP53 gene mutations. CONCLUSIONS: Phosphatidylinositol 3-kinase CA mutations are common in tumors in Brazilian breast cancer patients, and phosphatidylinositol 3-kinase CA and TP53 mutations are not mutually exclusive. Phosphatidylinositol 3-kinase CA exon 20 mutations are associated with poor survival, and they may be useful biomarkers for identifying breast cancer patients with aggressive tumors and for predicting the response to treatment with PI3K pathway inhibitors

PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients

OBJECTIVES: The phosphatidylinositol 3-kinase/AKT axis is an important cell-signaling pathway that mediates cell proliferation and survival, two biological processes that regulate malignant cell growth. The phosphatidylinositol 3-kinase CA gene encodes the p110 alpha subunit of the phosphatidylinositol 3-kinase protein. There are phosphatidylinositol 3-kinase CA mutations in several types of human tumors, and they are frequently observed in breast cancer. However, these mutations have not been investigated in Brazilian breast cancer patients. METHODS: PCR-SSCP and direct DNA sequencing were performed to identify phosphatidylinositol 3-kinaseCA exon 9 and exon 20 mutations in 86 patients with sporadic breast cancer. The relationships between PIK3CA mutations and patient clinicopathological characteristics and survival were analyzed. The presence of the TP53 mutation was also examined. RESULTS: Twenty-three (27%) of the 86 primary breast tumors contained PIK3CA mutations. In exons 9 and 20, we identified the hotspot mutations E542K, E545K, and H1047R, and we identified two new missense mutations (I1022V and L1028S) and one nonsense (R992X) mutation. Phosphatidylinositol 3-kinase CA exon 20 mutations were associated with poor overall survival and TP53 gene mutations. CONCLUSIONS: Phosphatidylinositol 3-kinase CA mutations are common in tumors in Brazilian breast cancer patients, and phosphatidylinositol 3-kinase CA and TP53 mutations are not mutually exclusive. Phosphatidylinositol 3-kinase CA exon 20 mutations are associated with poor survival, and they may be useful biomarkers for identifying breast cancer patients with aggressive tumors and for predicting the response to treatment with PI3K pathway inhibitors.Departamento de Ciencia e Tecnologia-Ministerio da Saude/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [577587/2008-0 DECIT/CNPq]Departamento de Ciencia e TecnologiaMinisterio da Saude/Conselho Nacional de Desenvolvimento Cientifico e TecnologicoCNPq grantCNPq grant [305408/2009-7

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness

Pharmacogenomic Profile and Adverse Drug Reactions in a Prospective Therapeutic Cohort of Chagas Disease Patients Treated with Benznidazole

Chagas disease remains a major social and public health problem in Latin America. Benznidazole (BZN) is the main drug with activity against Trypanosoma cruzi. Due to the high number of adverse drug reactions (ADRs), BZN is underprescribed. The goal of this study was to evaluate the genetic and transcriptional basis of BZN adverse reactions. Methods: A prospective cohort with 102 Chagas disease patients who underwent BZN treatment was established to identify ADRs and understand their genetic basis. The patients were classified into two groups: those with at least one ADR (n = 73), and those without ADRs (n = 29). Genomic analyses were performed comparing single nucleotide polymorphisms between groups. Transcriptome data were obtained comparing groups before and after treatment, and signaling pathways related to the main ADRs were evaluated. Results: A total of 73 subjects (71.5%) experienced ADRs. Dermatological symptoms were most frequent (45.1%). One region of chromosome 16, at the gene LOC102724084 (rs1518601, rs11861761, and rs34091595), was associated with ADRs (p = 5.652 × 10−8). Transcriptomic data revealed three significantly enriched signaling pathways related to BZN ADRs. Conclusions: These data suggest that part of adverse BZN reactions might be genetically determined and may facilitate patient risk stratification prior to starting BZN treatment

Low-cost ultrasensitive flexible carbon fiber-based biosensor for the detection of SARS-CoV-2 in human saliva

The ongoing COVID-19 pandemic continues to have a significant impact on our daily lives, necessitating the rapid development of early diagnostic tools to mitigate the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. In this context, biosensor technology has emerged as a highly promising strategy to address the challenges of low sensitivity, specificity, and high cost associated with clinical diagnosis. In this study, we present a novel and cost-effective approach for the rapid detection of SARS-CoV-2 using miniaturized flexible carbon fiber (FCF) electrodes that are modified with immunoglobulin G (IgG). Our strategy take advantage of on the antigen-antibody interaction (IgG-SARS-CoV-2) and leverages the surface chemistry characteristics of FCF to achieve signal amplification. Under standard conditions, we achieved a remarkable detection limit of 0.16 pg mmL−1 for the SARS-CoV-2 RBD protein. Additionally, when analyzing human saliva samples, our biosensing approach demonstrated good agreement with RT-PCR results, specifically for patients who tested positive for SARS-CoV-2. The sensitivity, selectivity, and accuracy of our approach were approximately 93.3%

ALTERAÇÕES TRANSCRICIONAIS PRECOCEMENTE ENVOLVIDAS NA PROGRESSÃO DE PACIENTES PARA DOENÇA ARTICULAR CRÔNICA PÓS-CHIKUNGUNYA

Introdução/Objetivo: Infecções pelo vírus Chikungunya (CHIKV) podem frequentemente resultar no desenvolvimento de Doença Articular Inflamatória Crônica pós-Chikungunya (pCHIKV-CIJD). Essa condição gera impactos na qualidade de vida dos pacientes e nos gastos com a saúde pública. Neste estudo, visamos identificar mecanismos moleculares precocemente envolvidos na evolução para pCHIKV-CIJD. Método: Pacientes em fase aguda de chikungunya foram incluidos em uma coorte prospectiva e tiveram o seguimento de 90 dias. Aqueles pacientes que permaneceram com sinais clínicos de artrite e exame de imagem alterado foram considerados pCHIKV-CIJD. O RNA foi obtido do sangue total dos pacientes e foi realizado o sequenciamento de RNA total e small RNA. Foram realizadas análises de genes e microRNAs diferencialmente expressos, enriquencimento de vias, análise de módulos de coexpressão e interactoma. Resultados: Comparando os pacientes que evoluíram para pCHIKV-CIJD com aqueles que não evoluíram, nós identificamos assinaturas moleculares precocemente associadas a cronificação nas fases aguda e subaguda da doença. Essas moléculas foram principalmente associadas a alterações na regulação da resposta imune. Dentre elas, o gene LIFR, que codifica para um receptor celular envolvido em um aumento de transcrição de IL-6, encontra-se sub-expresso em pacientes pCHIKV-CIJD. LIFR foi previamente validado como um alvo de miR-98-5p, que encontra-se superexpresso nesses pacientes. Pacientes que evoluíram para doença crônica também apresentaram redução dos níveis de transcritos de importantes mediadores imunológicos como interleucinas e seus receptores, como IL-6 e IL-6R; genes associados ao recrutamento de células imunes e resposta adaptativa, como CCR2; e genes que codificam diferentes subunidades do complexo proteossoma. Além disso, esses pacientes apresentaram redução dos níveis de MMP8, LFT e DDIT4. Esses genes já foram descritos como alterados em outros tipos de artrite como osteoartrite e artrite reumatóide e parecem também ser relevantes para o desenvolvimento de pCHIKV-CIJD. Conclusão: Juntos, nossos achados adicionam conhecimento acerca dos mecanismos moleculares precocemente envolvidos na cronificação e destacam potenciais alvos para novos estudos. Entender esses mecanismos é crucial para o desenvolvimento de terapias efetivas e intervenções para os pacientes acometidos, podendo mitigar os efeitos da doença e reduzir os impactos causados

Declining antibody levels to Trypanosoma cruzi correlate with polymerase chain reaction positivity and electrocardiographic changes in a retrospective cohort of untreated Brazilian blood donors.

BackgroundAlthough infection with Trypanosoma cruzi is thought to be lifelong, less than half of those infected develop cardiomyopathy, suggesting greater parasite control or even clearance. Antibody levels appear to correlate with T. cruzi (antigen) load. We test the association between a downwards antibody trajectory, PCR positivity and ECG alterations in untreated individuals with Chagas disease.Methodology/principal findingsThis is a retrospective cohort of T. cruzi seropositive blood donors. Paired blood samples (index donation and follow-up) were tested using the VITROS Immunodiagnostic Products Anti-T.cruzi (Chagas) assay (Ortho Clinical Diagnostics, Raritan NJ) and PCR performed on the follow-up sample. A 12-lead resting ECG was performed. Significant antibody decline was defined as a reduction of > 1 signal-to-cutoff (S/CO) unit on the VITROS assay. Follow-up S/CO of Conclusions/significanceLow and falling antibody levels define a phenotype of possible spontaneous parasite clearance

Shotgun metagenomic sequencing of the first case of monkeypox virus in Brazil, 2022

Monkeypox virus (MPXV), a zoonotic virus endemic to the African continent, has been reported in 33 non-endemic countries since May 2022. We report an almost complete genome of the first confirmed case of MPXV in Brazil. Shotgun metagenomic sequencing was completed in 18 hours, from DNA extraction to consensus sequence generation