Sheltonhunter3549

Rheumatoid arthritis (RA) is an autoimmune disease described by joint destruction, synovitis and pannus formation. The gut microbiota acts as an environmental factor that plays an important role in RA, but little research regarding the etiopathogenic mechanisms of the microbiome in RA has been carried out. We used an integrated approach of 16S rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass spectrometry-based metabolomics to analyze the structure and diversity of the intestinal flora and metabolites of the gut microbiota in RA patients compared with healthy subjects. In this study, α-diversity analysis of the gut microbiota showed that there was no significant difference between the healthy control (HC) and RA groups. However, β-diversity analysis showed that there was a significant difference between the two groups. Further analysis of alteration of the gut microbiota revealed that at the phylum level, the relative abundance of p_Bacteroidetes was significantly decreased in the RA group, while that of Verrucomicrobia and Proteobacteria was significantly increased in the RA group. At the genus level, Bacteroides, Faecalibacterium and some probiotics were decreased in the RA group, while 97 genera, including Lactobacillus, Streptococcus and Akkermansia, were increased in the RA group. Seventy-four differentially abundant metabolites were identified between the HC and RA groups, and we identified two potential biomarkers (9,12-octadecadiynoic acid and 10Z-nonadecenoic acid) in RA.UCEC is one of the three common malignant tumors of the female reproductive tract. According to reports, the cure rate of early UCEC can reach 95%. Therefore, the development of prognostic markers will help UCEC patients to find the disease earlier and develop treatment earlier. The ALDH family was first discovered to be the essential gene of the ethanol metabolism pathway in the body. Recent studies have shown that ALDH can participate in the regulation of cancer. In our research, we explored the expression of the ALDH family in 33 cancers. It was found that ALDH2 was abnormally expressed in UCEC. Besides, in vivo and in vitro experiments were conducted to explore the effect of ALDH2 expression on the proliferation of UCEC cell lines. Meanwhile, the change of its expression is not due to gene mutations, but is regulated by miR-135-3p. At the same time, the impact of ALDH2 changes on the survival of UCEC patients is deeply discussed. Finally, a nomogram for predicting survival was constructed, with a C-index of 0.798 and AUC of 0.764. This study suggests that ALDH2 may play a crucial role in UCEC progression and has the potential as a prognostic biomarker of UCEC.Racism is a threat to public health. Race is a sociopolitical construct that has been used for generations to create disparities in educational access, housing conditions, exposure to environmental contaminants, and access to health care. Nimodipine nmr Collectively, these disparities have a negative impact on the health of non-white Americans. The National Institutes of Health (NIH) funds biomedical research, including basic neuroscience research, aimed at understanding the mechanisms and consequences of health and disease in Americans. NIH has recently acknowledged its own structural racism, the disadvantage this perpetuates in the biomedical research enterprise, and has announced its commitment to eliminating these disparities. Here, we discuss different rates of disease in U.S. citizens from different racial backgrounds. We next describe ways in which the biomedical research enterprise (1) has contributed to health disparities and (2) can contribute to the solving this problem. Based on our own scientific expertise, we use neuroscience in general and mental health/addiction disorders more specifically as examples of a broader issue. The NIH, including its neuroscience-focused Institutes, and NIH-funded scientists, including neuroscientists, should prioritize research topics that reflect the health conditions that affect all Americans, not just white Americans.Over 80% of women with high-grade serous ovarian cancer develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we tested the hypothesis that expression of growth arrest-specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6-500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared to chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination. Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in homologous recombination-proficient and homologous recombination-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, homologous recombination-proficient high-grade serous ovarian cancer. Implications GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.Dysregulation of Notch signaling has been implicated in cellular transformation and tumorigenesis in a variety of cancers while potential roles of MIB1, an E3 ubiquitin ligase required for efficient Notch activation, remains to be investigated. We analyzed MIB1 expression levels in tumor samples and performed gain- and loss-of-function studies in cell lines to investigate potential roles of MIB1 in epithelial-to-mesenchymal transition (EMT), cell migration and cell survival. We found that overexpression of MIB1 is detected in a subset of lung squamous carcinoma and adenocarcinoma samples and negative correlation is observed between MIB1 expression and overall patient survival. Ectopic expression of MIB1 in A549 cells induces EMT and stimulates cell migration via a Notch-dependent pathway. Meanwhile, MIB1 stimulates the degradation of NRF2 in a Notch-independent manner and disrupts the antioxidant capacity of cells, rendering them more sensitive to inducers of ferroptosis. On the other hand, MIB1 knockout induces accumulation of NRF2 and resistance to ferroptosis. Collectively, these results indicate that MIB1 may function as a positive regulator of ferroptosis through targeted degradation of the master anti-oxidant transcription factor NRF2. Implications This study identifies a MIB1-induced proteasomal degradation pathway for NRF2 and reveals elevated ferroptosis sensitivity in MIB1-overexpressing cells which may provide novel insights into the treatment of MIB1-overexpressing cancers.High-risk Human papilloma viruses (HPVs), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin and upper aerodigestive tract. Previously, we identified ECD protein, the human homologue of the Drosophila ecdysoneless gene, as a novel HPV16 E6-interacting protein. Here, we show that ECD, through its C-terminal region, selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in cervical and Head & Neck Squamous Cell Carcinoma (HNSCC) cell lines as well as in tumor tissues. Using the TCGA dataset, we show that ECD mRNA overexpression predicts shorter survival in cervical and HNSCC patients. We demonstrate that ECD KD in cervical cancer cell lines led to impaired oncogenic behavior, and ECD co-overexpression with E7 immortalized primary human keratinocytes. RNAseq analyses of SiHa cells upon ECD knockdown led to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis-linked cellular genes, including splicing of components of mRNA splicing machinery itself. Taken together, our results support a novel role of ECD in viral and cellular mRNA splicing to support HPV-driven oncogenesis. Implications This study links ECD overexpression to poor prognosis and shorter survival in head & neck squamous cell carcinoma and cervical cancers and identifies a critical role of ECD in cervical oncogenesis through regulation of viral and cellular mRNA splicing.Stromal cells play a central role in promoting the progression of colorectal cancer. Here we analyze molecular changes within the epithelial and stromal compartments of dysplastic aberrant crypt foci (ACF) formed in the ascending colon, where rapidly developing interval cancers occur. We found strong activation of numerous neutrophil/monocyte chemokines, consistent with localized inflammation. The data also indicated a decrease in interferon signaling and cell-based immunity. The immune checkpoint and T cell exhaustion gene PDCD1 was one of the most significantly up-regulated genes, which was accompanied by a decrease in cytotoxic T cell effector gene expression. Additionally, CDKN2A expression was strongly up-regulated in the stroma and down-regulated in the epithelium, consistent with diverse changes in senescence-associated signaling on the two tissue compartments. Implications Decreased CD8 T cell infiltration, and increased T cell PD1 expression, occurs within proximal colon ACF in the context of a robust inflammatory response and potential stromal cell senescence, thus providing new insight into potential promotional drivers for cancers in the proximal colon.Close interactions between cancer cells and cancer associated fibroblasts (CAFs) have repeatedly been reported to support tumor progression. Yet, targeting CAFs has so far failed to show a real benefit in cancer treatment, as preclinical studies shown that such strategy can enhance tumor growth. Accordingly, recent paradigm-shifting data suggest that certain CAF subpopulations could also show tumor inhibitory capabilities. The present review aims to provide an in-depth description of the cellular heterogeneity of the CAF compartment in tumors. Through combining information from different cancer types, here we define 4 main CAF subpopulations that might cohabitate in any tumor microenvironment (TME). In addition, a model for the evolution of CAFs during tumor development is introduced. Moreover, the presence of tumor inhibitory CAFs in the TME as well as their molecular characteristics are extensively discussed. Finally, the potential cellular origins of these distinct CAF subpopulations are reviewed. To our knowledge, this is the first attempt at establishing a broad but comprehensive classification of CAF subpopulations. Altogether, the present manuscript aims to provide with the latest developments and innovative insights that could help refine therapeutic targeting of CAFs for cancer treatment.