Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45.208
Filtrar
1.
Adv Exp Med Biol ; 1287: 169-181, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034032

RESUMO

The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.


Assuntos
Progressão da Doença , Neoplasias/patologia , Receptores Notch , Transdução de Sinais , Genes Supressores de Tumor , Humanos , Neoplasias/genética , Oncogenes , Receptores Notch/metabolismo
2.
Hum Genomics ; 14(1): 35, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008459

RESUMO

Precision medicine aims to empower clinicians to predict the most appropriate course of action for patients with complex diseases like cancer, diabetes, cardiomyopathy, and COVID-19. With a progressive interpretation of the clinical, molecular, and genomic factors at play in diseases, more effective and personalized medical treatments are anticipated for many disorders. Understanding patient's metabolomics and genetic make-up in conjunction with clinical data will significantly lead to determining predisposition, diagnostic, prognostic, and predictive biomarkers and paths ultimately providing optimal and personalized care for diverse, and targeted chronic and acute diseases. In clinical settings, we need to timely model clinical and multi-omics data to find statistical patterns across millions of features to identify underlying biologic pathways, modifiable risk factors, and actionable information that support early detection and prevention of complex disorders, and development of new therapies for better patient care. It is important to calculate quantitative phenotype measurements, evaluate variants in unique genes and interpret using ACMG guidelines, find frequency of pathogenic and likely pathogenic variants without disease indicators, and observe autosomal recessive carriers with a phenotype manifestation in metabolome. Next, ensuring security to reconcile noise, we need to build and train machine-learning prognostic models to meaningfully process multisource heterogeneous data to identify high-risk rare variants and make medically relevant predictions. The goal, today, is to facilitate implementation of mainstream precision medicine to improve the traditional symptom-driven practice of medicine, and allow earlier interventions using predictive diagnostics and tailoring better-personalized treatments. We strongly recommend automated implementation of cutting-edge technologies, utilizing machine learning (ML) and artificial intelligence (AI) approaches for the multimodal data aggregation, multifactor examination, development of knowledgebase of clinical predictors for decision support, and best strategies for dealing with relevant ethical issues.


Assuntos
Infecções por Coronavirus/genética , Diabetes Mellitus/genética , Neoplasias/genética , Pneumonia Viral/genética , Medicina de Precisão/tendências , Cardiomiopatias , Infecções por Coronavirus/epidemiologia , Análise de Dados , Diabetes Mellitus/epidemiologia , Genômica/tendências , Humanos , Metabolômica/tendências , Neoplasias/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Proteômica/tendências
3.
Nat Commun ; 11(1): 4965, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009371

RESUMO

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.


Assuntos
Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , DNA Tumoral Circulante/genética , Intervalo Livre de Doença , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Medicina de Precisão , Resultado do Tratamento , Adulto Jovem
4.
Yi Chuan ; 42(9): 817-831, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952117

RESUMO

Enhancers are a type of cis-acting DNA elements that enhance transcriptional activity of target genes. However, the uncertainty in the orientation and distance between enhancers and target genes could post significant difficulties in identifying the target genes and the regulatory mechanisms of the enhancers. Numerous studies have shown that the mutations and/or abnormalities in the functions of enhancers are associated with development of diseases. A few studies have reported that enhancers could activate cancer development or drug resistance by promoting the expression of target genes. At present, enhancers involved in carcinogenesis and drug resistance have not been fully identified, and the underlying mechanism are still largely unknown. This paper summarizes the main methods used in identifying and characterizing enhancers and analyzing the regulatory mechanism at the genome-wide level. It further reviews the recent research progress of enhancers in cancer diagnosis, treatment, and the underlying mechanism during carcinogenesis, thereby providing a reference for the screening of these enhancers involved in carcinogenesis and drug resistance and exploring their regulatory mechanisms of target genes. It also provides a new perspective for improving the diagnosis of cancer and insights for formulating cancer therapeutic strategies.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias , Carcinogênese , Humanos , Neoplasias/genética
5.
Adv Exp Med Biol ; 1255: 109-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949394

RESUMO

Cancer is one of the leading causes of death worldwide and well known for its complexity. Cancer cells within the same tumor or from different tumors are highly heterogeneous. Furthermore, stromal and immune cells within tumor microenvironment interact with cancer cells to play important roles in how tumors progress and respond to different treatments. Recent advances in single cell technologies, especially massively parallel single cell sequencing, have made it possible to analyze cancer cells and cells in its tumor microenvironment in parallel with unprecedented high resolution. In this chapter, we will review recent developments in single cell sequencing technologies and their applications in cancer research. We will also explain how insights generated from single cell sequencing can be used to develop novel diagnostic and therapeutic approaches to conquer cancer.


Assuntos
Neoplasias/diagnóstico , Neoplasias/terapia , Análise de Sequência , Análise de Célula Única , Humanos , Neoplasias/genética , Microambiente Tumoral
6.
Adv Exp Med Biol ; 1255: 123-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949395

RESUMO

Hypermethylation can downregulate many tumor suppressor gene expressions. Aplasia Ras homologue member I (ARHI, DIRAS3) is one of the maternally imprinted tumor suppressors in the RAS superfamily. This chapter overviewed the importance of ARHI methylation and expression phenomes in various types of cancers, although the exact mechanisms remain unclear. As an imprinted gene, aberrant DNA methylation of the paternal allele of ARHI was identified as a primary inhibitor of ARHI expression. The role of methylation in the CpG islands of the ARHI promoter region vary among ovarian cancers, breast cancers, hepatocellular carcinoma, colon cancers, pancreatic cancer osteosarcoma, glial tumors, follicular thyroid carcinoma, or lung cancers. The methylation of ARHI provides a new insight to understand molecular mechanisms of tumorigenesis and progression of cancers.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Neoplasias/genética , Regiões Promotoras Genéticas , Proteínas rho de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos
7.
Adv Exp Med Biol ; 1255: 175-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949400

RESUMO

Personalized medicine has been driven by improvements in genomic sequencing and analysis. For several diseases, in particular cancers, it has for nearly a decade been standard clinical practice to analyze the genome and expression of the genes of patients. The results are reflected directly in the treatment plan for the patient, in targeted medical inventions. This specialized mode of diagnostics has been restricted to account for averaged trends in the tumor. The approach sharply contrasts our knowledge on heterogeneity within tumors. Several studies further describe how treatment against one tumor subclone in some cases merely serves to provide space and support for uncontrolled growth of more aggressive subclones. In this chapter, we describe current possibilities for implementation of single cell sequencing of malignomas in clinic, as well as discuss hands-on practical advice for single cell routine diagnostics that allows for full delineation of tumor clonality.


Assuntos
Neoplasias/diagnóstico , Neoplasias/genética , Medicina de Precisão , Análise de Sequência , Análise de Célula Única , Humanos , Neoplasias/patologia
8.
Adv Exp Med Biol ; 1268: 53-114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918214

RESUMO

Increasing scientific evidence supports the link between vitamin D and cancer risk. The active metabolite 1,25(OH)2D exerts its activity by binding to the vitamin D receptor (VDR), an intracellular receptor that mediates transcriptional activation and repression of target genes. The binding of 1,25(OH)2D to VDR is able to regulate hundreds of different genes. VDR is active in virtually all tissues including the colon, breast, lung, ovary, bone, kidney, parathyroid gland, pancreatic b-cells, monocytes, T lymphocytes, melanocytes, keratinocytes, and also cancer cells.The relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies.We have carried out a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies considering ethnicity as a key factor for heterogeneity.Up to December 2018, we identified 176 independent studies with data to assess the risk of breast, prostate, colorectal, skin (melanoma and non-melanoma skin cancer), lung, ovarian, kidney, bladder, gallbladder, esophageal, thyroid, head and neck, liver and pancreatic cancer, oral squamous cell carcinoma, non-Hodgkin lymphoma, multiple myeloma and sarcoma.Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1, Apa1, Cdx2), breast (Fok1, Bsm1, Taq1, Apa1, CdX2), colorectal (Fok1, Bsm1, Taq1, Apa1), and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites.Conflicting data have been reported for most malignancies, and at present, it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that other factors such as ethnicity, phenotype, 25(OH)D plasma levels, and UV radiation exposure play a role as confounding factors and introduce heterogeneity.To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with assessment of vitamin D status and stratified by ethnicity.


Assuntos
Neoplasias/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Humanos , Neoplasias/sangue , Vitamina D/sangue
9.
Nat Commun ; 11(1): 4374, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873787

RESUMO

Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.


Assuntos
Amplificação de Genes , Genômica/métodos , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico/métodos , Análise Citogenética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
10.
Nat Commun ; 11(1): 4370, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873792

RESUMO

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sítio Alostérico/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/genética , Simulação de Acoplamento Molecular , Mutação , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/ultraestrutura , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
11.
Nat Commun ; 11(1): 4676, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938922

RESUMO

Translation efficiency varies considerably between different mRNAs, thereby impacting protein expression. Translation of the stress response master-regulator ATF4 increases upon stress, but the molecular mechanisms are not well understood. We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress by promoting translation reinitiation in the ATF4 5'UTR. We find DENR and MCTS1 are only needed for reinitiation after upstream Open Reading Frames (uORFs) containing certain penultimate codons, perhaps because DENR•MCTS1 are needed to evict only certain tRNAs from post-termination 40S ribosomes. This provides a model for how DENR and MCTS1 promote translation reinitiation. Cancer cells, which are exposed to many stresses, require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Furthermore, additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner.


Assuntos
Fator 4 Ativador da Transcrição/genética , Fatores de Iniciação em Eucariotos/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Regiões 5' não Traduzidas , Fator 4 Ativador da Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Códon , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/genética , Regulação da Expressão Gênica , Células HeLa , Humanos , Neoplasias/genética , Proteínas Oncogênicas/genética , Oncogenes , Fases de Leitura Aberta , RNA Mensageiro , RNA de Transferência/genética , RNA de Transferência/metabolismo , Subunidades Ribossômicas Menores de Eucariotos/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo , Ribossomos/genética
12.
Nat Commun ; 11(1): 4455, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901005

RESUMO

Dysregulated alternative splicing (AS) driving carcinogenetic mitosis remains poorly understood. Here, we demonstrate that cancer metastasis-associated antigen 1 (MTA1), a well-known oncogenic chromatin modifier, broadly interacts and co-expresses with RBPs across cancers, contributing to cancerous mitosis-related AS. Using developed fCLIP-seq technology, we show that MTA1 binds abundant transcripts, preferentially at splicing-responsible motifs, influencing the abundance and AS pattern of target transcripts. MTA1 regulates the mRNA level and guides the AS of a series of mitosis regulators. MTA1 deletion abrogated the dynamic AS switches of variants for ATRX and MYBL2 at mitotic stage, which are relevant to mitosis-related tumorigenesis. MTA1 dysfunction causes defective mitotic arrest, leads to aberrant chromosome segregation, and results in chromosomal instability (CIN), eventually contributing to tumorigenesis. Currently, little is known about the RNA splicing during mitosis; here, we uncover that MTA1 binds transcripts and orchestrates dynamic splicing of mitosis regulators in tumorigenesis.


Assuntos
Carcinogênese/genética , Carcinogênese/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , Mitose/fisiologia , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Processamento Alternativo , Animais , Sítios de Ligação/genética , Montagem e Desmontagem da Cromatina/genética , Instabilidade Cromossômica , Feminino , Células HCT116 , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Mitose/genética , Neoplasias/genética , Neoplasias/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Transativadores/antagonistas & inibidores , Transativadores/genética
13.
Nat Commun ; 11(1): 4469, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901013

RESUMO

Dissecting tumor heterogeneity is a key to understanding the complex mechanisms underlying drug resistance in cancers. The rich literature of pioneering studies on tumor heterogeneity analysis spurred a recent community-wide benchmark study that compares diverse modeling algorithms. Here we present FastClone, a top-performing algorithm in accuracy in this benchmark. FastClone improves over existing methods by allowing the deconvolution of subclones that have independent copy number variation events within the same chromosome regions. We characterize the behavior of FastClone in identifying subclones using stage III colon cancer primary tumor samples as well as simulated data. It achieves approximately 100-fold acceleration in computation for both simulated and patient data. The efficacy of FastClone will allow its application to large-scale data and clinical data, and facilitate personalized medicine in cancers.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Neoplasias/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Biologia Computacional/métodos , Simulação por Computador , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Genéticos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Filogenia , Medicina de Precisão , Análise de Sequência de DNA
14.
Anticancer Res ; 40(10): 5399-5404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988859

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate whether idarubicin (IDR) induces oxidative DNA damage in the presence of copper (II). MATERIALS AND METHODS: DNA damage was evaluated by pBR322 plasmid DNA cleavage. The formation of oxidative stress markers [O2 •- and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] was analysed. RESULTS: IDR induced DNA damage and O2 •- and 8-OHdG generation in the presence of copper (II). CONCLUSION: IDR induced oxidative DNA damage in the presence of copper (II). Since it has been reported that the concentration of copper in the serum of cancer patients is higher than that in healthy groups, IDR-induced oxidative DNA damage in the presence of copper (II) may play an important role in anticancer therapeutic strategies.


Assuntos
Antraciclinas/farmacologia , Idarubicina/farmacologia , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antraciclinas/química , Cobre/química , Dano ao DNA/efeitos dos fármacos , Humanos , Idarubicina/química , Neoplasias/genética , Neoplasias/patologia , Espécies Reativas de Oxigênio/química , Superóxido Dismutase/genética
15.
Medicine (Baltimore) ; 99(35): e21989, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871949

RESUMO

BACKGROUND: Bipolar disorder (BD), a common kind of mood disorder with frequent recurrence, high rates of additional comorbid conditions and poor compliance, has an unclear pathogenesis. The Gene Expression Omnibus (GEO) database is a gene expression database created and maintained by the National Center for Biotechnology Information. Researchers can download expression data online for bioinformatics analysis, especially for cancer research. However, there is little research on the use of such bioinformatics analysis methodologies for mental illness by downloading differential expression data from the GEO database. METHODS: Publicly available data were downloaded from the GEO database (GSE12649, GSE5388 and GSE5389), and differentially expressed genes (DEGs) were extracted by using the online tool GEO2R. A Venn diagram was used to screen out common DEGs between postmortem brain tissues and normal tissues. Functional annotation and pathway enrichment analysis of DEGs were performed by using Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Furthermore, a protein-protein interaction network was constructed to identify hub genes. RESULTS: A total of 289 DEGs were found, among which 5 of 10 hub genes [HSP90AA1, HSP90AB 1, UBE2N, UBE3A, and CUL1] were identified as susceptibility genes whose expression was downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that variations in these 5 hub genes were obviously enriched in protein folding, protein polyubiquitination, apoptotic process, protein binding, the ubiquitin-mediated proteolysis pathway, and protein processing in the endoplasmic reticulum pathway. These findings strongly suggested that HSP90AA1, UBE3A, and CUL 1, which had large areas under the curve in receiver operator curves (P < .05), were potential diagnostic markers for BD. CONCLUSION: Although there are 3 hub genes [HSP90AA1, UBE3A, and CUL 1] that are tightly correlated with the occurrence of BD, mainly based on routine bioinformatics methods for cancer-related disease, the feasibility of applying this single GEO bioinformatics approach for mental illness is questionable, given the significant differences between mental illness and cancer-related diseases.


Assuntos
Transtorno Bipolar/genética , Proteínas Culina/genética , Mineração de Dados/métodos , Proteínas de Choque Térmico HSP90/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Mapas de Interação de Proteínas , Adulto Jovem
16.
Nature ; 585(7824): 277-282, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879489

RESUMO

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo
17.
Anticancer Res ; 40(10): 5489-5496, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988871

RESUMO

BACKGROUND/AIM: Cytokine-induced killer (CIK) cells are a heterogenous population of immune cells showing promising applications in immunotherapeutic cancer treatment. Neuropilin (NRP) proteins have been proven to play an important role in cancer development and prognosis. In this study, CIK cells were tested for expression of NRPs, transmembrane proteins playing a role in the proliferation and survival of cancer cells. MATERIALS AND METHODS: CIK cells were analyzed at different time points via flow cytometry and quantitative real-time polymerase chain reaction for neuropilin expression. RESULTS: Phenotyping results showed CIK cells having developed properly, and low levels of NRP2 were detected. On the other hand, no NRP1 expression was found. Two cancer cell lines were tested by flow cytometry: A549 cells expressed NRP1 and NRP2; U251-MG cells expressed high amounts of NRP2. CIK cell showed low levels of NRP2 expression on day 14. CONCLUSION: The presence of NRP2, but not NRP1, was shown for CIK cells. Recognizing NRP2 in CIK cells might help to improve CIK cell cytotoxicity.


Assuntos
Imunoterapia , Neoplasias/genética , Neuropilina-1/genética , Neuropilina-2/genética , Células A549 , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias/imunologia , Neuropilinas/genética , Prognóstico
18.
Nat Commun ; 11(1): 4534, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913330

RESUMO

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proliferação de Células/genética , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Neoplasias/genética , Estruturas R-Loop/genética , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Montagem e Desmontagem da Cromatina , Dano ao DNA , Instabilidade Genômica , Humanos , Neoplasias/patologia , Transcrição Genética
19.
Medicine (Baltimore) ; 99(36): e22003, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899047

RESUMO

OBJECTIVE: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the melanocortin 4 receptor (MC4R), gene which are associated with risk of obesity. Since obesity is an established risk factor of cancer, several studies have examined the association between SNPs near the MC4R gene and cancer risk, but the findings are inconsistent. The present study aimed to perform a meta-analysis to clarify the association between SNPs near MC4R and cancer risk. METHODS: The PubMed and Embase databases were searched for potentially eligible publications. All studies that evaluated the association between MC4R rs17782313 SNP (or its proxy rs12970134) and cancer risk were included. The pooled odds ratios with 95% confidence intervals (CIs) were calculated using the random-effects model. And subgroup analysis by cancer type (colorectal cancer, endometrial cancer and breast cancer) was conducted for further investigate the association. RESULTS: A total of 6 eligible studies (6517 cases and 16,886 controls) were included in the present meta-analysis. The results indicated that MC4R rs17782313 SNP was moderately associated with cancer risk (odds ratio = 1.12, 95% CI = 1.01-1.24). However, the subgroup analysis between different cancer types shows that rs17782313 is only associated with colorectal cancer but not the endometrial cancer and breast cancer. Risk factor in colorectal cancer was both significantly associated with rs17782313 with and without adjustment for body mass index; while the risk factor of the endometrial cancer and breast cancer were both not associated with the rs17782313 with and without adjustment for body mass index. There was no publication bias for the association between MC4R rs17782313 and cancer risk. CONCLUSION: The present meta-analysis confirmed the moderate association between MC4R rs17782313 and cancer risk.


Assuntos
Neoplasias/genética , Receptor Tipo 4 de Melanocortina/genética , Humanos , Polimorfismo de Nucleotídeo Único
20.
BMC Bioinformatics ; 21(1): 377, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883200

RESUMO

BACKGROUND: A large number of experimental studies show that the mutation and regulation of long non-coding RNAs (lncRNAs) are associated with various human diseases. Accurate prediction of lncRNA-disease associations can provide a new perspective for the diagnosis and treatment of diseases. The main function of many lncRNAs is still unclear and using traditional experiments to detect lncRNA-disease associations is time-consuming. RESULTS: In this paper, we develop a novel and effective method for the prediction of lncRNA-disease associations using network feature similarity and gradient boosting (LDNFSGB). In LDNFSGB, we first construct a comprehensive feature vector to effectively extract the global and local information of lncRNAs and diseases through considering the disease semantic similarity (DISSS), the lncRNA function similarity (LNCFS), the lncRNA Gaussian interaction profile kernel similarity (LNCGS), the disease Gaussian interaction profile kernel similarity (DISGS), and the lncRNA-disease interaction (LNCDIS). Particularly, two methods are used to calculate the DISSS (LNCFS) for considering the local and global information of disease semantics (lncRNA functions) respectively. An autoencoder is then used to reduce the dimensionality of the feature vector to obtain the optimal feature parameter from the original feature set. Furthermore, we employ the gradient boosting algorithm to obtain the lncRNA-disease association prediction. CONCLUSIONS: In this study, hold-out, leave-one-out cross-validation, and ten-fold cross-validation methods are implemented on three publicly available datasets to evaluate the performance of LDNFSGB. Extensive experiments show that LDNFSGB dramatically outperforms other state-of-the-art methods. The case studies on six diseases, including cancers and non-cancers, further demonstrate the effectiveness of our method in real-world applications.


Assuntos
Algoritmos , Neoplasias/patologia , RNA Longo não Codificante/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Área Sob a Curva , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Neoplasias/genética , RNA Longo não Codificante/genética , Curva ROC
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA