Translational research : the journal of laboratory and clinical medicine
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The current study performed bioinformatics and in vitro and in vivo experiments to explore the effects of ADAM8 on the malignant behaviors and immunotherapeutic efficacy of renal clear cell carcinoma (ccRCC) Cells. The modular genes most associated with immune cells were screened. Then, prognostic risk models were constructed by univariate COX analysis, LASSO regression analysis and multivariate COX analysis, and their diagnostic value was determined. ⋯ Furthermore, ABI3, ADAM8, APOL3, MX2, CCDC69 and STAC3 might play important roles in treatment concerning CTLA4 inhibitors or PD-1 inhibitors or combined inhibitors. Finally, we confirmed that ADAM8 could promote the proliferation, migration and invasion of ccRCC cells through in vitro experiments, and further found that in in vivo experiments, ADAM8 knockdown could inhibit tumor formation in ccRCC cells, improve the therapeutic effect of anti-PD1, and prolong the survival of mice. Our study highlighted the alleviative role of silencing ADAM8 in ccRCC patients.
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Diabetic lipo-toxicity is a fundamental pathophysiologic mechanism in DM and is now increasingly recognized a key determinant of DKD. Targeting lipid metabolic disorders is an important therapeutic strategy for the treatment of DM and its complications, including DKD. This study aimed to explore the molecular mechanism of lipid metabolic regulation in kidney, especially renal PTECs, and elucidate the role of lipid metabolic related molecule lipin-1 in diabetic lipid-related kidney damage. ⋯ Interestingly, lipin-1 deficiency might be a pathogenic driver of DKD-to-CKD transition, which could further accelerate the imbalance of renal lipid homeostasis, the dysfunction of mitochondrial and energy metabolism in PTECs. Mechanistically, lipin-1 deficiency resulted in aggravated PTECs injury to tubulointerstitial fibrosis in DKD by downregulating FAO via inhibiting PGC-1α/PPARα mediated Cpt1α/HNF4α signaling and upregulating SREBPs to promote fat synthesis. This study provided new insights into the role of lipin-1 as a regulator for maintaining lipid homeostasis in the kidney, especially PTECs, and its deficiency led to the progression of DKD.
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Epstein-Barr virus (EBV) related- nasopharyngeal carcinoma (NPC) is a squamous carcinoma of the nasopharyngeal mucosal lining. Endemic areas (EA) are east and Southeast Asia, were NPC was recorded with higher incidence and longer estimated survival than in non-endemic area (NEA) such as Europe, We analyzed the gene expression and microenvironment properties of NPC in both areas to identify molecular subtypes and assess biological and clinical correlates that might explain the differences in incidence and outcome between EA- and NEA-NPCs. Six EA-NPC transcriptomic datasets, including tumor and normal samples, were integrated in a meta-analysis to identify molecular subtypes using a ConsensusClusterPlus bioinformatic approach. ⋯ In the NEA cohort, Cl1, Cl2 and Cl3 were represented, while perineural-interaction/EBV-exhaustion was almost absent. The immune/biological characterization and treatment-response prediction analyses of NEA-NPC partially replicated the EA-NPC results. Well characterized EA- and NEA-NPC retrospective and prospective cohorts are needed to validate the obtained results and can help designing future clinical studies.
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Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) that poses a serious risk as it can lead to end-stage renal disease (ESRD). DKD is linked to changes in the diversity, composition, and functionality of the microbiota present in the gastrointestinal tract. The interplay between the gut microbiota and the host organism is primarily facilitated by metabolites generated by microbial metabolic processes from both dietary substrates and endogenous host compounds. ⋯ We will discuss in detail the primary and gut-derived metabolites in DKD, and the mechanisms of the metabolites involved in DKD progression. Further, we will address the importance of metabolomics in helping identify potential DKD markers. Furthermore, the possible therapeutic interventions and research gaps will be highlighted.
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Lynch syndrome, an autosomal dominant hereditary disease arising from mutations in mismatch repair genes, is linked to the development of multiple tumor types, notably colorectal cancer, endometrial carcinoma and upper urinary tract urothelial carcinoma. In this study, we present the case of a young patient diagnosed with upper urinary tract urothelial carcinoma, notable for a familial history of diverse malignancies. By employing genetic analysis, we verified the presence of Lynch syndrome within the family and detected novel variants, MSH2 p. ⋯ Significantly, we found that the MSH2 p. A604D variant and TSC2 p. C738Y variant synergistically enhance the promotion of urothelial carcinoma.