Journal of Biomedical Research最新文献

This study aimed to evaluate the association of a healthy lifestyle pattern with mortality risk among patients with type 2 diabetes mellitus (T2DM). Data were derived from a prospective cohort enrolling 13,776 Chinese patients with T2DM. A healthy lifestyle pattern was constructed based on six lifestyle factors, including smoking, alcohol consumption, dietary habit, physical activity, sedentary time, and sleep duration. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. During a median follow-up of 9.0 years, 2,497 deaths were recorded. Compared to T2DM patients with the lifestyle pattern scoring 0-2, those scoring 5-6 had a 40% lower risk for all-cause mortality (HR = 0.60, 95% CI: 0.52-0.69), 33% lower risk for CVD mortality (HR = 0.67, 95% CI: 0.52-0.69), and 25% lower risk for cancer mortality (HR = 0.75, 95% CI: 0.58-0.97). In addition, we found that the association between the lifestyle pattern and all-cause mortality risk was stronger in females than in males ( P for interaction < 0.05). In conclusion, adherence to a healthy lifestyle pattern is associated with a decreased risk of all-cause, CVD, and cancer mortality, which has important implications for reducing premature mortality in patients with T2DM.

V-raf-leukemia viral oncogene 1 (RAF1), a serine/threonine protein kinase, is well established to play a crucial role in tumorigenesis and cell development. However, the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown. In this study, we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity (DIO) mice. Under normal chow diet feeding, overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight, fat mass, and impaired glucose tolerance. Conversely, Raf1 knockout in AgRP neurons protected against diet-induced obesity, reducing fat mass and improving glucose tolerance. Mechanistically, Raf1 activated the MAPK signaling pathway, culminating in the phosphorylation of cAMP response element-binding protein (CREB), which enhanced transcription of Agrp and Npy. Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis, highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance. Collectively, these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis, positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.

The present study assessed the efficacy and safety of thoracic radiotherapy (TRT) following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), focusing on the influence of different TRT timing strategies (consolidative vs. salvage) on survival rates. We retrospectively analyzed a total of 54 patients with ES-SCLC treated between January 2019 and July 2022. Patients receiving consolidative TRT (cTRT) within three months after completion of first-line treatment were compared with those receiving salvage TRT (sTRT) after disease progression. The primary endpoints were overall survival (OS), progression-free survival (PFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS); the secondary endpoint included safety. The cTRT group ( n = 41) showed significantly longer median OS (26.6 vs. 14.8 months, P = 0.048), PFS (12.9 vs. 3.5 months, P < 0.0001), and DMFS (10.7 vs. 3.4 months, P = 0.0044) than the sTRT group ( n = 13). Multivariate analysis revealed that cTRT was an independent, favorable prognostic factor. No significant differences in OS or LRFS were observed between high-dose (≥ 50 Gy) and low-dose (< 50 Gy) TRT. Hematologic and respiratory toxicities were the most frequently reported adverse events, with acceptable tolerability. In conclusion, cTRT after chemoimmunotherapy significantly improves survival outcomes for ES-SCLC patients, and low-dose TRT may be a suitable option.

Interferon-related genes are involved in antiviral responses, inflammation, and immunity, which are closely related to sepsis-associated acute respiratory distress syndrome (ARDS). We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS (MEARDS), the Molecular Epidemiology of Sepsis in the ICU (MESSI), and the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls. First, we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression (GReX). Second, we examined the association of the confirmed gene (interferon regulatory factor 1, IRF1) with ARDS risk and survival and conducted a mediation analysis. Through discovery and validation, we found that the GReX of IRF1 was associated with ARDS risk (odds ratio [OR _MEARDS] = 0.84, P = 0.008; OR _MESSI = 0.83, P = 0.034). Furthermore, individual-level measured IRF1 expression was associated with reduced ARDS risk (OR = 0.58, P = 8.67 × 10 ^-4), and improved overall survival in ARDS patients (hazard ratio [HR _28-day] = 0.49, P = 0.009) and sepsis patients (HR _28-day = 0.76, P = 0.008). Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex, including HLA-F, which mediated more than 70% of protective effects of IRF1 on ARDS. The findings were validated by in vitro biological experiments including time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate IRF1 in sepsis patients, thereby regulating HLA-F, may reduce the risk of ARDS and mortality, especially in severely ill patients.

Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in promoting BC-related bone metastasis. Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown reversed these effects. Notably, AMD3100, a specific CXCR4 antagonist, partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 bound to the CXCR4 promoter region (-230 to -326) and activated its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.

Clostridioides difficile ( C. difficile) is one of the major causes of nosocomial infections. Pregnant women, who are generally considered at low risk for C. difficile infection (CDI), have attracted attention because of an increasing number of reports. Oral vancomycin, the only first-line treatment for pregnant women infected with C. difficile, has been associated with increasing strain resistance, leading to decreased efficacy. Fecal microbiota transplantation (FMT) is recommended for severe, fulminant, and recurrent CDI; however, it is generally avoided in pregnant women because of safety concerns. We report a case of a pregnant woman with a primary ribotype 027 CDI who experienced a successful outcome with washed microbiota transplantation (WMT), an improved form of FMT, via enema. The specific strain of ribotype 027 is related to severe outcomes but has not previously been reported in pregnant women. The follow-up lasted for two years, during which the patient's diarrhea was fully alleviated without recurrence. The baby showed normal growth and development, and no adverse events were recorded for either. This case provides evidence for the efficacy and safety of WMT in pregnant women infected with C. difficile, indicating that WMT via enema may be a viable therapeutic strategy for this population for treating CDI.

Dent disease is a rare X-linked recessively inherited renal tubulopathy, caused by variants in the CLCN5 (Dent disease type 1, DD1) and OCRL (Dent disease type 2, DD2) genes, and characterized by low molecular weight proteinuria, hypercalciuria, microscopic hematuria, or nephrocalcinosis. In the current study, we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease, who were hospitalized at the Department of Nephrology, Children's Hospital of Nanjing Medical University between January 2014 and August 2023, aiming to assist in the early diagnosis and treatment of these patients. Among the 21 patients, 16 (76.19%) had CLCN5 variants, and five (23.81%) had OCRL variants, and four of the variants were novel. All patients presented with low molecular weight proteinuria, 14 (66.67%) of whom had nephrotic-range proteinuria. Eight patients underwent renal biopsies because of diagnostic uncertainty. We transfected the novel CLCN5 missense variant (p.G222R) and OCRL missense variant (p.I371T) plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells ( P < 0.05). Moreover, we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant, as assessed by the human androgen receptor gene assay. These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.

It is often challenging to diagnose acute myocardial infarction (AMI) in patients with elevated high-sensitivity cardiac troponin T (hs-cTnT) before a significant rise and/or fall of hs-cTnT can be observed. This study aimed to find an optimal cut-off to rule in AMI. A total of 76411 patients with elevated hs-cTnT were included. The predictive cut-off values for diagnosing ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were assessed by the area under the receiver operating characteristic curves (AUC). Among the patients, 50466 (66.0%) had non-cardiac diseases, 25945 (34.0%) had cardiac diseases, and 15502 (20.3%) had AMI, including 816 (1.1%) with STEMI and 14686 (19.2%) with NSTEMI. The median hs-cTnT level was 3788.0 ng/L in STEMI patients and 67.2 ng/L in NSTEMI patients. The optimal cut-off for diagnosing STEMI was 251.9 ng/L, with a sensitivity of 90.7%, specificity of 86.5%, and an AUC of 0.942; the optimal cut-off for diagnosing NSTEMI was 130.5 ng/L, with a sensitivity of 40.9%, specificity of 83.8%, and an AUC of 0.638. In patients with elevated hs-cTnT, optimizing the cut-off values for diagnosing STEMI and NSTEMI to 251.9 ng/L and 130.5 ng/L, respectively, demonstrated high accuracy in a large cohort of Chinese patients.

The OPTIMA-5 study demonstrated that a single bolus of half-dose recombinant staphylokinase (r-SAK) before primary percutaneous coronary intervention (PCI) significantly improved the patency of infarct related artery in patients with ST-elevation myocardial infarction (STEMI) expected to undergo PCI within 120 minutes. This study aimed to investigate the 1-year clinical outcome and the effect of the r-SAK antibody on a second r-SAK thrombolysis in OPTIMA-5 patients. The clinical outcome was major adverse cardiovascular events (MACE) within 360 days. Patients' r-SAK antibodies were determined on days 90 ± 7, 180 ± 7, and 360 ± 14 after thrombolysis, and in-vitro r-SAK antibody neutralization experiments were performed to explore an optimal interval for a second r-SAK thrombolysis. Results showed that the MACE incidence was numerically lower in r-SAK group compared with normal saline (NS) group (14.0% vs. 20.0%, HR 0.67, 95% CI: 0.34-1.32; log-rank P=0.245). The r-SAK antibody levels in r-SAK group decreased by time, but kept significantly higher than those in NS group on days 90 ± 7 (2.96 ± 0.68 vs. 0.22 ± 0.53, P<0.001), 180 ± 7 (2.19 ± 0.74 vs. 0.44 ± 0.65, P<0.001) and 360 ± 14 (1.73 ± 0.97 vs. 0.37 ± 0.71, P<0.001). The in-vitro r-SAK antibody neutralization experiments illustrated that the thrombolysis rate decreased exponentially as the antibody titer increased from 1.90 to 2.20 (67.80 ± 14.19% vs. 44.32 ± 21.54%, P< 0.0001). Therefore, for STEMI patients expected to undergo PCI within 120 minutes, a single bolus of half-dose r-SAK before primary PCI may reduce 1-year MACE risk. The r-SAK antibody lasts over 1 year, and a second r-SAK thrombolysis may not be indicated until 1 year after the first r-SAK thrombolysis if necessary.