RESUMO
A growing body of evidence indicates an important role of miRNAs in cancer; however, there is no definitive, convenient-to-use list of cancer-related miRNAs or miRNA genes that may serve as a reference for analyses of miRNAs in cancer. To this end, we created a list of 165 cancer-related miRNA genes called the Cancer miRNA Census (CMC). The list is based on a score, built on various types of functional and genetic evidence for the role of particular miRNAs in cancer, e.g. miRNA-cancer associations reported in databases, associations of miRNAs with cancer hallmarks, or signals of positive selection of genetic alterations in cancer. The presence of well-recognized cancer-related miRNA genes, such as MIR21, MIR155, MIR15A, MIR17 or MIRLET7s, at the top of the CMC ranking directly confirms the accuracy and robustness of the list. Additionally, to verify and indicate the reliability of CMC, we performed a validation of criteria used to build CMC, comparison of CMC with various cancer data (publications and databases), and enrichment analyses of biological pathways and processes such as Gene Ontology or DisGeNET. All validation steps showed a strong association of CMC with cancer/cancer-related processes confirming its usefulness as a reference list of miRNA genes associated with cancer.
Assuntos
Bases de Dados de Ácidos Nucleicos , MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética , Reprodutibilidade dos TestesAssuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Leucemia Prolinfocítica de Células T/terapia , Leucemia Prolinfocítica de Células T/mortalidade , Leucemia Prolinfocítica de Células T/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do TratamentoRESUMO
Recent research indicates that gut microbiota may be vital in the advancement of melanoma. In this study, we found that melanoma patients exhibited a distinct gut mycobiota structure compared with healthy participants. Candida albicans, Candida dubliniensis, and Neurospora crassa were more abundant in samples from patients with melanoma, whereas Saccharomyces cerevisiae and Debaryomyces hansenii were less abundant. During anti-PD-1 treatment, the relative amount of Malassezia restricta and C. albicans increased. A higher level of Saccharomyces paradoxus was associated with a positive response to anti-PD-1 treatment, whereas a higher level of Tetrapisispora blattae was associated with a lack of clinical benefits. High levels of M. restricta and C. albicans, elevated serum lactate dehydrogenase, and being overweight were linked to increased risk of melanoma progression and poorer response to anti-PD-1 treatment. Thus, this study has revealed melanoma-associated mycobiome dysbiosis, characterized by altered fungal composition and fungi species associated with a higher risk of melanoma progression, identifying a role for the gut mycobiome in melanoma progression.
Assuntos
Microbioma Gastrointestinal , Melanoma , Micobioma , Humanos , Fungos/fisiologia , Disbiose/microbiologia , Melanoma/tratamento farmacológico , Saccharomyces cerevisiaeRESUMO
Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger pyroptosis-like cell death and IL-1α release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1α and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1α as a potential novel component driving the pulmonary immunothromobosis in COVID-19.
RESUMO
A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.
Assuntos
Biomarcadores , Imageamento por Ressonância Magnética , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Biomarcadores/análise , Biomarcadores/metabolismo , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Imagem de Tensor de Difusão/métodos , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Idoso de 80 Anos ou mais , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Medula Espinal/metabolismoRESUMO
As operaçöes de aneurismas do arco aórtico dependem do tempo de parada circulatória hipotérmica total (PCH). Diversas técnicas têm sido propostas para melhorar a proteçäo do cérebro e estender o tempo seguro de isquemia (45 minutos em hipotermia profunda). A proteçäo cerebral durante duas horas de parada circulatória hipotérmica foi estudada em 23 suínos, divididos em quatro grupos. Nos grupos de controle, 8 animais foram submetidos a anestesia (Grupo 1) e a circulaçäo extracorpórea (Grupo 2). Os outros dois grupos foram à PCH associada à perfusäo cerebral anterógrada a 28 graus Celsius (Grupo 3) e a PCH associada a perfusäo retrógrada do cérebro a 28 graus Celsius (Grupo 4). A proteçäo cerebral foi avaliada pelo estudo histológico e pelo metabolismo celular cerebral estudado pela espectroscopia por ressonância nuclear magnética (RNM). Durante a PCH associada à perfusäo cerebral anterógrada a 28 graus Celsius, o metabolismo cerebral manteve-se normal durante todo o experimento e houve preservaçäo das estruturas cerebrais no estudo histológico. Na PCH com a perfusäo cerebral retrógrada a 28 graus Celsius, o pH intracelular, a fosfocreatina (Pcr) e o trifosfato de adenosina (ATP) diminuíram durante o período de parada circulatória e näo retornaram aos seus níveis normais durante a reperfusäo, permanecendo o cérebro em grave acidose intracelular. Concluímos que, durante duas horas de PCH, a perfusäo anterógrada a 28 graus Celsius proporcionou uma adequada proteçäo ao cérebro. A PCH associada à perfusäo retrógrada em hipotermia moderada a 28 graus Celsius näo porporcionou proteçäo cerebral, no estudo metabólico e histológico.