Quantitative proteomic analysis of sperm in unexplained recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss (RPL) refers to two or more spontaneous abortions that occur consecutively with the same spouse. RPL severely affects human reproduction health, and causes extreme physical and mental suffering to patients and their families. METHODS: We used isobaric tags for relative and absolute quantitation (iTRAQ), which was coupled with liquid chromatography mass spectrometry (LC-MS) proteomic analysis, in order to identify differentially expressed proteins. Moreover, we used western blot to analyze differentially expressed proteins. RESULTS: Of the 2350 non-redundant proteins identified, 38 proteins were significantly altered and were identified as potential biomarkers for RPL. The protein-protein interaction network constructed using GeneMANIA revealed that 35.55% displayed similar co-expression, 30.87% were predicted, and 20.95% had physical interaction characteristics. Based on Gene ontology classification and KEGG pathway enrichment analyses, the majority of these differentially expressed proteins were found to be related to biological regulation, metabolic and cellular processes, protein binding and different enzymes activities, as well as disorder of fat and glucose metabolic pathways. It is noteworthy that three metabolism related biomarkers (HK1, ACLY, and FASN) were further confirmed through western blot analysis. CONCLUSIONS: These results suggest that these differentially expressed proteins may be used as biomarkers for RPL, and related signaling pathways may play crucial roles in male induced RPL.

SETBP1 mutation determines sensitivity to immune checkpoint inhibitors in melanoma and NSCLC.

SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents (i.e., anti-CTLA-4, anti-PD-1/PD-L1, or combination therapy). Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81, P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group (42.9% vs. 29.1%, P = 0.016). The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.