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1.
BMC Cancer ; 22(1): 767, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35836204

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.


Assuntos
Neoplasias de Cabeça e Pescoço , Inibidores de Checkpoint Imunológico , Albuminas/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Hemoglobinas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
2.
BMC Bioinformatics ; 22(1): 298, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082707

RESUMO

BACKGROUND: RNA-Seq is a well-established technology extensively used for transcriptome profiling, allowing the analysis of coding and non-coding RNA molecules. However, this technology produces a vast amount of data requiring sophisticated computational approaches for their analysis than other traditional technologies such as Real-Time PCR or microarrays, strongly discouraging non-expert users. For this reason, dozens of pipelines have been deployed for the analysis of RNA-Seq data. Although interesting, these present several limitations and their usage require a technical background, which may be uncommon in small research laboratories. Therefore, the application of these technologies in such contexts is still limited and causes a clear bottleneck in knowledge advancement. RESULTS: Motivated by these considerations, we have developed RNAdetector, a new free cross-platform and user-friendly RNA-Seq data analysis software that can be used locally or in cloud environments through an easy-to-use Graphical User Interface allowing the analysis of coding and non-coding RNAs from RNA-Seq datasets of any sequenced biological species. CONCLUSIONS: RNAdetector is a new software that fills an essential gap between the needs of biomedical and research labs to process RNA-Seq data and their common lack of technical background in performing such analysis, which usually relies on outsourcing such steps to third party bioinformatics facilities or using expensive commercial software.


Assuntos
Computação em Nuvem , Análise de Dados , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , RNA-Seq , Análise de Sequência de RNA , Software
3.
Commun Biol ; 4(1): 1179, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635782

RESUMO

AKT-phosphorylated IWS1 promotes Histone H3K36 trimethylation and alternative RNA splicing of target genes, including the U2AF65 splicing factor-encoding U2AF2. The predominant U2AF2 transcript, upon IWS1 phosphorylation block, lacks the RS-domain-encoding exon 2, and encodes a protein which fails to bind Prp19. Here we show that although both U2AF65 isoforms bind intronless mRNAs containing cytoplasmic accumulation region elements (CAR-E), only the RS domain-containing U2AF65 recruits Prp19 and promotes their nuclear export. The loading of U2AF65 to CAR-Elements was RS domain-independent, but RNA PolII-dependent. Virus- or poly(I:C)-induced type I IFNs are encoded by genes targeted by the pathway. IWS1 phosphorylation-deficient cells therefore, express reduced levels of IFNα1/IFNß1 proteins, and exhibit enhanced sensitivity to infection by multiple cytolytic viruses. Enhanced sensitivity of IWS1-deficient cells to Vesicular Stomatitis Virus and Reovirus resulted in enhanced apoptotic cell death via caspase activation. Inhibition of this pathway may therefore sensitize cancer cells to oncolytic viruses.

4.
Nat Commun ; 12(1): 4624, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330897

RESUMO

AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.


Assuntos
Adenocarcinoma de Pulmão/genética , Ciclo Celular/genética , Proliferação de Células/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas de Ligação a RNA/genética , Fator de Processamento U2AF/genética , Fatores de Transcrição/genética , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Animais , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mutação , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Fator de Processamento U2AF/metabolismo , Fatores de Transcrição/metabolismo
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