Search

Abstract Background The long-term dynamic recurrence hazard of locally advanced gastric cancer (LAGC) in the clinical setting of adjuvant chemotherapy (ACT) remains unclear. Purpose This study aimed to investigate the dynamic recurrence risk of LAGC in patients who received ACT or not. Methods The study assessed data from patients with LAGC who underwent radical gastrectomy between January, 2010 and October, 2015. Inverse probability of treatment weighting (IPTW) was performed to reduce selection bias between the ACT and observational (OBS) groups. Conditional recurrence-free survival (cRFS) and restricted mean survival time (RMST) were used to assess the survival differences. Results In total, 1,661 LAGC patients were included (ACT group, n = 1,236 and OBS group, n = 425). The recurrence hazard gradually declined; in contrast, cRFS increased with RFS already accrued. Following IPTW adjustment, the cRFS rates were higher in the ACT group than those in the OBS group for patients at baseline or with accrued RFS of 1 and 2 years (p˂0.05). However, the cRFS rates of the ACT group were comparable with those of the OBS group for patients with accrued RFS of 3 or more years (p > 0.05). Likewise, the 5-year △RMST between the ACT and OBS groups demonstrated a similar trend. Moreover, the hematological metastasis rate of the ACT group was significantly lower than that of the OBS group for patients at baseline or with accrued RFS of 1 and 2 years, respectively (p˂0.05). Conclusions Although ACT could provide substantial benefits for patients with LAGC, the differences in recurrence hazard between the ACT and OBS groups may attenuate over time, which could help guide surveillance and alleviate patients’ anxiety. Further prospective large-scale studies are warranted.

Abstract Background Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. Methods The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein–protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. Results A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. Conclusions Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.

Gait disorders are a fundamental challenge in Parkinson’s disease (PD). The use of laser-light visual cues emitted from shoes has demonstrated effective in improving freezing of gait within less restrictive environments. However, the effectiveness of shoes-based laser-light cueing may vary among individuals with PD who have different types of impairments. We introduced an innovative laser-light visual shoes system capable of producing alternating visual cues for the left and right feet through one-side cueing at a time, while simultaneously recording foot inertial data and foot pressures. The effects of this visual cueing system on gait patterns were assessed in individuals with PD, both those with well-gait and those with worse-gait. Our device successfully quantified gait characteristics, including the asymmetry in the center of pressure trajectory, in individuals with PD. Furthermore, visual cueing prolonged stride times and increased the percentage of stance phase, while concurrently reducing stride length in PD individuals with well-gait. Conversely, in PD individuals with worse-gait, visual cueing resulted in a decreased freeze index and a reduction in the proportion of intervals prone to freezing episodes. The effects of visual cueing varied between PD individuals with well-gait and those with worse-gait. Visual cueing slowed down gait in the well-gait group while it appeared to mitigate freezing episodes in worse-gait group. Future researches, including enhancements to extend the projection distance of visual cues and clinical assessments conducted in real-world settings, will help establish the clinical utility of our proposed visual cueing system.

Summary: PRMT1 plays a vital role in breast tumorigenesis; however, the underlying molecular mechanisms remain incompletely understood. Herein, we show that PRMT1 plays a critical role in RNA alternative splicing, with a preference for exon inclusion. PRMT1 methylome profiling identifies that PRMT1 methylates the splicing factor SRSF1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and exon inclusion. In breast tumors, PRMT1 overexpression is associated with increased SRSF1 arginine methylation and aberrant exon inclusion, which are critical for breast cancer cell growth. In addition, we identify a selective PRMT1 inhibitor, iPRMT1, which potently inhibits PRMT1-mediated SRSF1 methylation, exon inclusion, and breast cancer cell growth. Combination treatment with iPRMT1 and inhibitors targeting SRSF1 phosphorylation exhibits an additive effect of suppressing breast cancer cell growth. In conclusion, our study dissects a mechanism underlying PRMT1-mediated RNA alternative splicing. Thus, PRMT1 has great potential as a therapeutic target in breast cancer treatment.

HNS-IV (Hexanitrostilbene-IV) is the main charge of the exploding foil initiators (EFI), and the microstructure of the HNS will directly affect its density, flowability, sensitivity, and stability. HNS microspheres were prepared using droplet microfluidics, and the particle size, morphology, specific surface area, thermal performance, and ignition threshold of the HNS microspheres were characterized and tested. The results shown that the prepared HNS microspheres have high sphericity, with an average particle size of 20.52 μm (coefficient of variation less than 0.2), and a specific surface area of 21.62 m2/g (6.87 m2/g higher than the raw material). Without changing the crystal structure and thermal stability of HNS-IV, this method significantly enhances the sensitivity of HNS-IV to short pulses and reduces the ignition threshold of the slapper detonator to below 1000 V. This will contribute to the miniaturization and low cost of EFI.

Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.

Abstract Background Neoplasms are a series of diseases affecting human health. Prognostic and tumor status–related markers for various tumors should be identified. Methods Based on 19,515 samples from multiple sources, for the first time, this study provided an overview of gene S-phase kinase associated protein 2 (SKP2) in pan-cancer. Differential SKP2 expression in multiple comparison groups was identified by the Kruskal–Wallis test and Wilcoxon rank-sum test. The prognosis significance of SKP2 in individuals with neoplasm was evaluated through univariate Cox regression analysis and Kaplan-Meier curves. The area under the curve was utilized to detect the accuracy of SKP2 in predicting cancer status. Spearman’s rank correlation coefficients were calculated in all correlation analyses. Gene set enrichment analysis was used to identify essential signaling pathways of SKP2 in human neoplasms. Results The study disclosed the upregulated SKP2 expression in 15 neoplasms and decreased SKP2 expression in three cancers (p 1, p

Abstract Background Centrosomal protein 55 (CEP55) plays a significant role in specific cancers. However, comprehensive research on CEP55 is lacking in pan-cancer. Methods In-house and multi-center samples (n = 15,823) were used to analyze CEP55 in 33 cancers. The variance of CEP55 expression levels among tumor and control groups was evaluated by the Wilcoxon rank-sum test and standardized mean difference (SMD). The clinical value of CEP55 in cancers was assessed using receiver operating characteristic (ROC) curves, Cox regression analysis, and Kaplan-Meier curves. The correlations between CEP55 expression and the immune microenvironment were explored using Spearman’s correlation coefficient. Results The data of clustered regularly interspaced short palindromic repeats confirmed that CEP55 was essential for the survival of cancer cells in multiple cancer types. Elevated CEP55 mRNA expression was observed in 20 cancers, including glioblastoma multiforme (p 0.95; p