RESUMO
Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Microbiota , Derrame Pleural Maligno , Derrame Pleural , Humanos , RNA Ribossômico 16S/genética , Derrame Pleural Maligno/diagnóstico , Mesotelioma/diagnóstico , Mesotelioma/patologia , Biomarcadores , Derrame Pleural/diagnóstico , Prognóstico , Microbiota/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/complicaçõesRESUMO
Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.
Assuntos
Dieta , Resistência à Doença , Suscetibilidade a Doenças , Exposição Ambiental , Interações entre Hospedeiro e Microrganismos , Microbiota , Obesidade/etiologia , Ração Animal , Animais , Dieta/efeitos adversos , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético , Microbioma Gastrointestinal , Camundongos , Fatores de Tempo , Aumento de PesoRESUMO
Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized. Here we delineate the role of mitotic kinases in receptor trafficking during asymmetric division. Targeted perturbations reveal that Cyclin-dependent Kinase 1 (CDK1) and Aurora Kinase promote storage of Fibroblast Growth Factor Receptors (FGFRs) by suppressing endosomal degradation and recycling pathways. As cells progress through metaphase, loss of CDK1 activity permits differential degradation and targeted recycling of stored receptors, leading to asymmetric induction. Mitotic receptor storage, as delineated in this study, may facilitate rapid reestablishment of signaling competence in nascent daughter cells. However, mutations that limit or enhance the release of stored signaling components could alter daughter cell fate or behavior thereby promoting oncogenesis.
Assuntos
Aurora Quinases/fisiologia , Proteína Quinase CDC2/fisiologia , Mitose/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Animais Geneticamente Modificados , Aurora Quinases/genética , Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/metabolismo , Ciona intestinalis/embriologia , Ciona intestinalis/genética , Embrião não Mamífero , Mitose/genética , Transporte Proteico/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/genética , Distribuição Tecidual/genéticaRESUMO
Laboratory mouse studies are paramount for understanding basic biological phenomena but also have limitations. These include conflicting results caused by divergent microbiota and limited translational research value. To address both shortcomings, we transferred C57BL/6 embryos into wild mice, creating "wildlings." These mice have a natural microbiota and pathogens at all body sites and the tractable genetics of C57BL/6 mice. The bacterial microbiome, mycobiome, and virome of wildlings affect the immune landscape of multiple organs. Their gut microbiota outcompete laboratory microbiota and demonstrate resilience to environmental challenges. Wildlings, but not conventional laboratory mice, phenocopied human immune responses in two preclinical studies. A combined natural microbiota- and pathogen-based model may enhance the reproducibility of biomedical studies and increase the bench-to-bedside safety and success of immunological studies.
