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Background CFLAR L , also known as c-FLIP L , is a critical anti-apoptotic protein that inhibits activation of caspase 8 in mammalian cells. Previous studies have shown that arginine 122 of CFLAR L can be mono-methylated. However, the precise role of arginine methyltransferase of CFLAR L remains unknown. PRMT5 and PRMT1, which are important members of the PRMT family, catalyze the transfer of methyl groups to the arginine of substrate proteins. PRMT5 can monomethylate or symmetrically dimethylate arginine residues, while PRMT1 can monomethylate or asymmetrically dimethylate arginine residues. Methods Lung cancer cells were cultured following the standard protocol and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the protein interaction was assayed by co-immunoprecipitation (Co-IP) or GST pull-down assay. CFLAR L ubiquitination level was evaluated by proteasomal inhibitor treatment combined with HA-Ub transfection and WB assay. PRMT1 and PRMT5 genes were knocked down by siRNA technique. Results We show that PRMT5 up-regulated the protein levels of CFLAR L by decreasing the ubiquitination and increasing its protein level. Additionally, PRMT1 down-regulated the protein level of CFLAR L by increasing the ubiquitination and degradation. The overexpression of PRMT5 can inhibit the interaction between CFLAR L and ITCH, which has been identified as an E3 ubiquitin ligase of CFLAR L , while overexpressed PRMT1 enhances the interaction between CFLAR L and ITCH. Furthermore, we verified that dead mutations of PRMT5 or PRMT1 have the same effects on CFLAR L as the wild-type ones have, suggesting it is the physical interaction between CFLAR and PRMT1/5 that regulates CFLAR L degradation other than its enzymatic activity. Finally, we showed that PRMT5 and PRMT1 could suppress or facilitate apoptosis induced by doxorubicin or pemetrexed by affecting CFLAR L in NSCLC cells. Conclusions PRMT5 and PRMT1 mediate the distinct effects on CFLAR L degradation by regulating the binding of E3 ligase ITCH in NSCLC cells. This study identifies a cell death mechanism that is fine-tuned by PRMT1/5 that modulate CFLAR L degradation in human NSCLC cells.

Chronic kidney disease (CKD) is a condition influenced by both genetic and environmental factors and has been a focus of extensive research. Utilizing Mendelian randomization, researchers have begun to untangle the complex causal relationships underlying CKD. This review delves into the advances and challenges in the application of MR in the field of nephrology, shifting from a mere summary of its principles and limitations to a more nuanced exploration of its contributions to our understanding of CKD. Key findings from recent studies have been pivotal in reshaping our comprehension of CKD. Notably, evidence indicates that elevated testosterone levels may impair renal function, while higher sex hormone-binding globulin (SHBG) levels appear to be protective, predominantly in men. Surprisingly, variations in plasma glucose and glycated hemoglobin levels seem unaffected by genetically induced changes in the estimated glomerular filtration rate (eGFR), suggesting an independent pathway for renal function impairment. Furthermore, lifestyle factors such as physical activity and socioeconomic status emerge as significant influencers of CKD risk and kidney health. The relationship between sleep duration and CKD is nuanced; short sleep duration is linked to increased risk, while long sleep duration does not exhibit a clear causal effect. Additionally, lifestyle factors, including diet, exercise, and mental wellness activities, play a crucial role in kidney health. New insights also reveal a substantial causal connection between both central and general obesity and CKD onset, while no significant links were found between genetically modified LDL cholesterol or triglyceride levels and kidney function. This review not only presents the recent achievements of MR in CKD research but also illuminates the path forwards, underscoring critical unanswered questions and proposing future research directions in this dynamic field.

Background GMEB1 was originally identified via its interaction with GMEB2, which binds to the promoter region of the tyrosine aminotransferase ( TAT ) gene and modulates transactivation of the glucocorticoid receptor gene. In the cytosol, GMEB1 interacts with and inhibits CASP8, but the molecular mechanism is currently unknown. Methods Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of GMEB1/USP40/CFLAR L complex by WB, GST Pull-Down Assay, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. A549 cells overexpressing green fluorescent protein and GMEB1 shRNA were used for tumor xenograft using female athymic nu/nu 4-week-old mice. Results We found GMEB1 interacted with CFLAR L (also known as c-FLIP L ) in the cytosol and promoted its stability. USP40 targeted CFLAR L for K48-linked de-ubiquitination. GMEB1 promoted the binding of USP40 to CFLAR L . USP40 knockdown did not increase CFLAR L protein level despite GMEB1 overexpression, suggesting GMEB1 promotes CFLAR L stability via USP40. Additionally, GMEB1 inhibited the activation of pro-caspase 8 and apoptosis in non-small cell lung cancer (NSCLC) cell via CFLAR L stabilization. Also, GMEB1 inhibited the formation of DISC upon TRAIL activation. CFLAR L enhanced the binding of GMEB1 and CASP8. Downregulation of GMEB1 inhibited A549 xenograft tumor growth in vivo. Conclusions Our findings show the de-ubiquitinase USP40 regulates the ubiquitination and degradation of CFLAR L ; and GMEB1 acts as a bridge protein for USP40 and CFLAR L . Mechanistically, we found GMEB1 inhibits the activation of CASP8 by modulating ubiquitination and degradation of CFLAR L . These findings suggest a novel strategy to induce apoptosis through CFLAR L targeting in human NSCLC cells.

Background Bromodomain-containing protein (BRD) play a pivotal role in the development and progression of malignant tumours. This study aims to identify prognostic genes linked to BRD-related genes (BRDRGs) in patients with triple-negative breast cancer (TNBC) and to construct a novel prognostic model. Methods Data from TCGA-TNBC, GSE135565, and GSE161529 were retrieved from public databases. GSE161529 was used to identify key cell types. The BRDRGs score in TCGA-TNBC was calculated using single-sample Gene Set Enrichment Analysis (ssGSEA). Differential expression analysis was performed to identify differentially expressed genes (DEGs): DEGs1 in key cells, DEGs2 between tumours and controls and DEGs3 in high and low BRDRGs score subgroups in TCGA-TNBC. Differentially expressed BRDRGs (DE-BRDRGs) were determined by overlapping DEGs1, DEGs2 and DEGs3. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and protein-protein interaction (PPI) network analysis were conducted to investigate active pathways and molecular interactions. Prognostic genes were selected through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses to construct a risk model and calculate risk scores. TNBC samples from TCGA-TNBC were classified into high and low-risk groups based on the median risk score. Additionally, correlations with clinical characteristics, Gene Set Enrichment Analysis (GSEA), immune analysis, and pseudotime analysis were performed. Results A total of 120 DE-BRDRGs were identified by overlapping 605 DEGs1 from four key cell types, 10,776 DEGs2, and 4,497 DEGs3. GO analysis revealed enriched terms such as ‘apoptotic process,’ ‘immune response,’ and ‘regulation of the cell cycle,’ while 56 KEGG pathways, including the ‘MAPK signaling pathway,’ were associated with DE-BRDRGs. A risk model comprising six prognostic genes (KRT6A, PGF, ABCA1, EDNRB, CTSD and GJA4) was constructed. A nomogram based on independent prognostic factors was also developed. Immune cell abundance was significantly higher in high-risk group. In both risk groups, TP53 exhibited the highest mutation frequency. The expression of KRT6A, ABCA1, EDNRB, and CTSD went decreased progressively in pseudotime. Conclusion A novel prognostic model for TNBC associated with BRDRGs was developed and validated, providing fresh insights into the relationship between BRD and TNBC.

ObjectiveUncommon and particularly deadly, pulmonary sarcomatoid carcinoma (PSC) is an aggressive type of lung cancer. This research aimed to create a risk categorisation and nomogram to forecast the overall survival (OS) of patients with PSC.MethodsTo develop the model, 899 patients with PSC were taken from the Surveillance, Epidemiology, and End Results database from the USA. We also used an exterior verification sample of 34 individuals with PSC from Fujian Provincial Hospital in China. The Cox regression hazards model and stepwise regression analysis were done to screen factors in developing a nomogram. The nomogram’s ability to discriminate was measured employing the area under a time-dependent receiver operating characteristic curve (AUC), the concordance index (C-index) and the calibration curve. Decision curve analysis (DCA) and integrated discrimination improvement (IDI) were used to evaluate the nomogram to the tumour–node–metastasis categorisation developed by the American Joint Committee on Cancer (AJCC-TNM), eighth edition, and an additional sample confirmed the nomogram’s accuracy. We further developed a risk assessment system based on nomogram scores.ResultsSix independent variables, age, sex, primary tumour site, pathological group, tumour–node–metastasis (TNM) clinical stage and therapeutic technique, were chosen to form the nomogram’s basis. The nomogram indicated good discriminative ability with the C-index (0.763 in the training cohort and 0.746 in the external validation cohort) and time-dependent AUC. Calibration plots demonstrated high congruence between the prediction model and real-world evidence in both the validation and training cohorts. Nomogram outperformed the AJCC-TNM eighth edition classification in both DCA and IDI. Patients were classified into subgroups according to their risk ratings, and significant differences in OS were observed between them (p<0.001).ConclusionWe conducted a survival analysis and nomogram for PSC. This developed nomogram holds potential to serve as an efficient tool for clinicians in prognostic modelling.

This study developed a machine learning model for predicting the presence of tertiary lymphoid structures (TLSs) and treatment response to neoadjuvant therapy (NAT) in triple-negative breast cancer (TNBC). This multicenter study retrospectively included 697 patients, including the training cohort ( n  = 137), the TLS validation cohort ( n  = 63) and the NAT response validation cohorts ( n  = 560). Five machine learning models were developed to predict the presence of TLSs, and the XGBoost model, which exhibited the best performance, was selected as the radiomics-based TLS (rTLS) predictive model. The rTLS predictive model demonstrated robust predictive performance, including across various patient subgroups. Prognostic analysis showed that the rTLS predictive score was significantly correlated with disease-free survival (DFS) in TNBC receiving NAT, and was identified as a strong independent prognostic factor. Pathomic features further explained the pathological heterogeneity of TNBC with different responses to NAT. Overall, the rTLS predictive model, which accurately predicted the presence of TLSs and treatment response to NAT in TNBC, held promise for future clinical application in formulating personalized strategies for TNBC, ultimately improving prognosis, aiding in individualized patient treatment.

Background Studies suggest that obesity may exacerbate the clinical symptoms of chronic obstructive pulmonary disease (COPD), and early screening is critical for improving treatment outcomes. This study aims to investigate the correlation between a novel metabolic indicator, the Body Roundness Index (BRI), and the risk of COPD. Methods Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2003–2016, we employed multivariate logistic regression models to assess the association between BRI and COPD. Stratified subgroup analyses, smooth curve fitting, and threshold effect analyses were conducted for further exploration. Results Among 35,356 participants included in the study, 3,018 were diagnosed with COPD. Logistic regression revealed that elevated BRI levels were significantly associated with an increased risk of COPD after adjusting for confounding factors ( P -value < 0.001). Subgroup analyses indicated that this association was more pronounced in Mexican Americans, individuals with education beyond high school, and those with diabetes ( P -value < 0.05). Smooth curve fitting identified a threshold effect for BRI, with a significant inflection point at 4.57 ( P  = 0.048) based on threshold effect analysis. Conclusion This study suggests that BRI is associated with COPD risk and may serve as a potential predictor, though causality cannot be inferred due to the cross-sectional design. Longitudinal studies are warranted to confirm this relationship.

In order to diagnose a respiratory disease in a pig farm, the lungs, spleen, and lymph nodes of three dead pigs were collected for pathogen detection by PCR and isolation on the basis of preliminary clinical diagnosis. The virus isolate was identified by gene sequence analysis and Immunoperoxidase monolayer assay (IPMA). The bacterial isolate was identified by biochemical tests, 16S rDNA sequence analysis, and species- and serotype-specific PCR, and the pathogenicity was analyzed. Porcine circovirus type 2a (PCV2a) genotype from the lungs, spleen, and lymph nodes and Pasteurella (P.) multocida capsular serotypes D from the lungs were found. The PCV2a isolates could specifically bound the anti-PCV2-Cap polyclonal antibody. The 16S rDNA sequence of P. multocida isolates had 99.9% identity with that of the strain from cattle, and the isolate was highly pathogenic to mice. The results showed that the co-infection of PCV2a and P. Multocida capsular serotypes D should be responsible for the disease. The uncommon PCV2a is still prevalent in some pig farms besides the dominant PCV2d genotype. This study could provide important etiological information for effective control and treatment of the disease in pig farms.

Background The aim of this study was to characterize an optimal strategy in managing thoracic esophageal perforation, focusing on the differential diagnosis and treatment of patients with contained versus noncontained perforations and on the importance of the time interval between injury and repair and how that affects the outcome of a primary repair. Methods A retrospective study was conducted. A strict definition of contained or noncontained perforation was based on a combination of esophagography, chest CT scan, and endoscopy as well as monitoring systemic symptoms. Management options for our cohort included conservative therapy, primary repair and debridement, esophagectomy, and mesh-covered stents. Patients were stratified into two groups according to the time interval after injury: ≤48-h group and >48-h group. Results Between January 1997 and January 2013, a total of 66 consecutive patients (47 males and 19 females, mean age = 49.1 ± 16.2 years) were treated for thoracic esophageal perforation. Perforation was confirmed by esophagography in 51 patients and by endoscopy in 15 patients. Eighteen patients were assigned to the contained perforation group. All these patients were successfully cured without surgery. The noncontained group included 48 patients; its mortality rate was 7.7 % (3/39) with surgery and 55.6 % (5/9) with stent placement. Compared with the contained group, the noncontained group had a significantly longer length of stay (LOS) (16 ± 3.2 vs. 26.3 ± 18.7 days; p  < 0.05) and a higher mortality rate (0 vs. 22.9 %, p  < 0.05). In the two time-interval groups, patient characteristics, including age, gender, and comorbidities, etiologic cause, length and location of the perforation, and the incidence of using tissue buttress were similar ( p  > 0.05). The incidence of postoperative leak was significantly higher in >48-h group (0 in ≤48-h group vs. 37.5 % in >48-h group; p  < 0.01). In addition, the >48-h group had a significantly longer LOS (18.0 ± 9.1 days in ≤48-h group vs. 31.5 ± 18.6 days in >48-h group; p  < 0.01). The two deaths occurred in the >48-h group (0 in ≤48-h group vs. 12.5 % in >48-h group; p  > 0.05) due to postoperative leaks. Conclusions Contained or noncontained perforation should be rigorously differentiated. Then, for a contained perforation, conservative therapy coupled with repeated imaging is reasonable treatment. For a noncontained perforation, a primary repair can be safely performed within 48 h after injury. After that, a primary repair is still reasonable but is associated with an increased risk of postoperative leaks.

CFLAR , also known as c-FLIP , is a critical anti-apoptotic protein that inhibits activation of caspase 8 in mammalian cells. Previous studies have shown that arginine 122 of CFLAR can be mono-methylated. However, the precise role of arginine methyltransferase of CFLAR remains unknown. PRMT5 and PRMT1, which are important members of the PRMT family, catalyze the transfer of methyl groups to the arginine of substrate proteins. PRMT5 can monomethylate or symmetrically dimethylate arginine residues, while PRMT1 can monomethylate or asymmetrically dimethylate arginine residues. Lung cancer cells were cultured following the standard protocol and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the protein interaction was assayed by co-immunoprecipitation (Co-IP) or GST pull-down assay. CFLAR ubiquitination level was evaluated by proteasomal inhibitor treatment combined with HA-Ub transfection and WB assay. PRMT1 and PRMT5 genes were knocked down by siRNA technique. We show that PRMT5 up-regulated the protein levels of CFLAR by decreasing the ubiquitination and increasing its protein level. Additionally, PRMT1 down-regulated the protein level of CFLAR by increasing the ubiquitination and degradation. The overexpression of PRMT5 can inhibit the interaction between CFLAR and ITCH, which has been identified as an E3 ubiquitin ligase of CFLAR , while overexpressed PRMT1 enhances the interaction between CFLAR and ITCH. Furthermore, we verified that dead mutations of PRMT5 or PRMT1 have the same effects on CFLAR as the wild-type ones have, suggesting it is the physical interaction between CFLAR and PRMT1/5 that regulates CFLAR degradation other than its enzymatic activity. Finally, we showed that PRMT5 and PRMT1 could suppress or facilitate apoptosis induced by doxorubicin or pemetrexed by affecting CFLAR in NSCLC cells. PRMT5 and PRMT1 mediate the distinct effects on CFLAR degradation by regulating the binding of E3 ligase ITCH in NSCLC cells. This study identifies a cell death mechanism that is fine-tuned by PRMT1/5 that modulate CFLAR degradation in human NSCLC cells.