Objective: Cardiovascular disease (CVD) is the leading cause of mortality in patients with end-stage renal disease (ESRD) undergoing maintenance dialysis. To further clarify this critical relationship, we conducted a prospective study to evaluate the prognostic significance of calcification in different segments of the thoracic aorta for all-cause mortality in this patient population.
Methods: This prospective study enrolled stable adult patients who were undergoing maintenance hemodialysis (MHD) at our center between July 2019 and December 2020 and who had available chest X-rays or computed tomography (CT) scans. Thoracic aortic calcification (TAC) was assessed via chest CT or X-ray imaging. Cox proportional hazards models and Kaplan‒Meier curves were used to describe the risk factors for mortality.
Results: At a mean follow-up of 3.95 years, 18 of 62 patients had died. Cox proportional hazards regression models demonstrated that elevated systolic blood pressure (HR 1.029), aortic arch calcification (AAC) (HR 1.104), and descending thoracic aortic calcification (DTAC) (HR 1.066) were independent risk factors for all-cause mortality in patients with MHD (all P < 0.05). Additionally, the presence of severe DTAC or severe AAC emerged as an independent risk factor for death in this patient population (log-rank test, P < 0.05).
Conclusion: AAC and DTAC are important predictors of all-cause mortality among patients undergoing maintenance hemodialysis.
Objective: Fluid management in patients with septic shock and coexisting heart failure is a critical challenge, as it requires balancing resuscitation and the risk of fluid overload. This study investigated the potential of the fluid accumulation index (FAI), which is measured serially during the initial 72 h of intensive care unit (ICU) care, to provide dynamic prognostic information to guide fluid management in this high-risk population.
Methods: Restricted cubic spline (RCS) analysis was used to explore the relationships between FAI levels at different time points within 72 h of ICU admission and ICU mortality. Associations were quantified via multivariate Cox proportional hazards models. Subgroup analyses and Kaplan‒Meier survival curves were used to evaluate the consistency of associations and differences in survival between groups.
Results: A total of 643 patients with septic shock and concurrent heart failure were included, among whom 127 died. The RCS revealed a significant nonlinear relationship between FAI levels at various time points and ICU mortality. The optimal FAI cutoff values decreased over time: the cumulative values were 0.87 at 24 h, 0.59 at 48 h, and 0.56 at 72 h. The cutoff values for specific intervals were 0.27 for the 24-48 h period (2-24 h-FAI) and 0.12 for the 48-72 h period (3-24 h-FAI). In the fully adjusted model, FAI values exceeding these time-specific thresholds were significantly associated with increased ICU mortality (24 h-FAI > 0.87, HR = 1.96, P = 0.0251; 2-24 h-FAI > 0.27, HR = 2.07, P = 0.0051; 48 h-FAI > 0.59, HR = 2.50, P = 0.0005; 3-24 h-FAI > 0.12, HR = 2.05, P = 0.0091; 72 h-FAI > 0.56, HR = 2.97, P < 0.0001). These associations remained consistent across most predefined subgroups.
Conclusion: FAI serves as a dynamic and independent prognostic marker for critically ill patients with septic shock and heart failure during the first 72 h of ICU admission. A key finding was the time-dependent decline in the optimal FAI cutoff values (0.87 at 24 h vs. 0.12 for the 3-24 h period). This temporal decline supports a shift in fluid management strategy from an initial liberal approach toward a conservative strategy after the first 24 h, which may mitigate mortality risk.
Objective: To investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the bacterial profile of lower respiratory tract infections (LRTIs) and the prevalence of major drug-resistant bacteria in Hubei Province, China, by comparing five-year periods before (2015-2019) and after (2020-2024) the pandemic.
Methods: A retrospective analysis was conducted on microbial culture and antimicrobial susceptibility test results from sputum and bronchoalveolar lavage fluid (BALF) samples obtained from patients with LRTIs. Pathogen distribution and the prevalence of key drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), cefotaxime/ceftriaxone-resistant Enterobacterales, carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPAE), carbapenem-resistant Acinetobacter baumannii (CRABA), ampicillin-resistant Haemophilus influenzae (ARHI), and penicillin/erythromycin-resistant Streptococcus pneumoniae (PRSP/ERSP), were compared between the two periods.
Results: The overall number of bacterial isolates significantly increased during the post-pandemic period. Gram-negative bacteria remained dominant, although their relative composition shifted. The detection rates of common community-acquired pathogens (Haemophilus influenzae, Streptococcus pneumoniae) decreased sharply during the strict control phase (2020-2022) but rebounded from 2023 to 2024. The overall prevalence of most key drug-resistant bacteria followed a decreasing trend. Notably, the detection rates of MRSA and cefotaxime/ceftriaxone-resistant Enterobacterales decreased most markedly (> 15%). The prevalence of CRE and CRABA followed a "decrease-then-increase" trend, while carbapenem-resistant Klebsiella pneumoniae detection rates remained higher than the 2015 baseline, and carbapenem-resistant Escherichia coli prevalence was on par with the 2015 level in 2024. Although the detection rate of CRABA tended to decrease, it remained above 60%. In contrast, the detection rate of the ERSP was consistently high (> 90%), whereas that of the ARHI exhibited a continuous upward trend (increasing by more than 30%).
Conclusion: The COVID-19 pandemic significantly altered the bacterial ecology and resistance patterns of LRTIs. While stringent public health measures initially suppressed the transmission of some resistant pathogens, they may have facilitated the subsequent emergence and spread of more formidable drug-resistant bacteria. Continuous surveillance and reinforced infection control measures are crucial in the post-pandemic era.
Objective: This study aimed to investigate the associations of the triglyceride-glucose (TyG) index with kidney function decline, cardiovascular disease (CVD) events, and all-cause mortality across different glucose tolerance statuses.
Methods: We analyzed 8,434 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. The primary outcomes were kidney function decline, CVD events, and all-cause mortality. Associations between the TyG index and outcomes were evaluated using binary logistic regression models.
Results: During a 5-year follow-up, 150 participants (1.80%) developed kidney function decline, 357 (4.30%) experienced CVD events, and 335 (4.00%) died from all causes. An elevated TyG index was associated with increased risks of kidney function decline, nonfatal CVD events, and all-cause mortality in the overall population and among participants with diabetes (quartile 4 [Q4] vs. quartile 1 [Q1]: hazard ratio [HR] [95% confidence interval, P-value] = 4.97 [1.41-31.71, P = 0.034], 4.63 [1.25-30.19, P = 0.047], and 4.54 [1.70-15.88, P = 0.007], respectively). These associations were not statistically significant in participants with normal glucose tolerance or prediabetes. Notably, an elevated TyG index was significantly associated with increased risk of fatal CVD events in the overall population and across all glucose tolerance subgroups, with the strongest association observed in participants with prediabetes rather than diabetes.
Conclusions: The TyG index is significantly associated with the risks of kidney function decline, CVD events, and all-cause mortality, and these associations differ by glucose tolerance status.
Objective: Huaier, a traditional Chinese medicine (TCM) approved by the National Medical Products Administration (NMPA) of China for cancer therapy, demonstrates broad antitumor activity. However, its potential to overcome resistance to gefitinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in non-small cell lung cancer (NSCLC) and the underlying mechanisms remain unclear. This study aimed to determine whether Huaier aqueous extract enhances the efficacy of gefitinib against resistant NSCLC and to elucidate the molecular basis of this effect.
Methods: Cell proliferation was evaluated using the Cell Counting Kit-8 and colony formation assays. Apoptosis, reactive oxygen species (ROS), and lipid ROS were measured using flow cytometry, and mitochondrial morphology was examined using transmission electron microscopy. RNA sequencing and integrated bioinformatics analyses of GEO datasets were performed to identify ferroptosis-related genes, which were validated by qPCR and Western blotting. The in vivo efficacy was assessed using a PC-9GR xenograft model.
Results: Huaier aqueous extract significantly enhanced the sensitivity of gefitinib-resistant NSCLC cells to gefitinib in vitro, and suppressed tumor growth in vivo. Mechanistically, the combined treatment activated the ferroptosis pathway, accompanied by the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Pharmacological inhibition of ferroptosis or ACSL4 partially attenuated the antitumor effect, confirming their key roles in mediating the synergistic activity of Huaier aqueous extract and gefitinib.
Conclusions: Huaier aqueous extract reversed gefitinib resistance in NSCLC cells by promoting ACSL4-dependent ferroptosis, thereby providing a promising therapeutic strategy for improving EGFR-TKI efficacy.
Objective: To investigate the inhibitory effects of mitofusin 2 (MFN2) on hepatic stellate cell (HSC) activation and liver fibrosis progression in nonalcoholic fatty liver disease (NAFLD) through the inhibition of β-catenin nuclear translocation.
Methods: In vitro, primary mouse HSCs were treated with palmitic acid (PA), and MFN2 expression was modulated using lentiviral overexpression or knockdown. Fibrotic markers and β-catenin localization were analyzed via Western blot, cellular fractionation, and immunofluorescence. In vivo, liver fibrosis was induced in C57BL/6 J mice using a high-fat diet (HFD) combined with CCl₄ injections. MFN2 was systemically overexpressed or silenced via AAV2 vectors delivered through tail vein injection. Liver tissues were examined histologically and biochemically for fibrosis progression.
Results: PA treatment markedly downregulated MFN2 and upregulated fibrotic markers in HSCs. Overexpression of MFN2 strongly suppressed HSC activation, reduced α-SMA and N-cadherin levels, and significantly inhibited β-catenin nuclear accumulation. Conversely, MFN2 knockdown exacerbated fibrotic responses and promoted β-catenin translocation. In mice, MFN2 overexpression substantially attenuated collagen deposition and improved liver histology, while MFN2 silencing significantly aggravated fibrosis and enhanced β-catenin signaling.
Conclusion: MFN2 inhibits HSC activation and liver fibrosis by suppressing β-catenin nuclear translocation, making it a promising therapeutic target for NAFLD-related fibrosis and associated complications, such as hepatocellular carcinoma.
Osteoarthritis (OA) is a prevalent degenerative and inflammatory disease posing a significant financial and medical burden on patients and society. Lactic acid, the terminal metabolite of glycolysis, is recognized as a pivotal signaling molecule governing diverse physiological and pathological processes, particularly in cancer and inflammatory diseases. Emerging evidence suggests that metabolic disorders are closely associated with OA, which may provide a metabolic lens for further exploring its mechanisms. Glycolytic reprogramming is now recognized as a hallmark of OA, leading to the pronounced accumulation of lactic acid within the joint microenvironment. This review synthesizes current evidence to elucidate the role of lactic acid in OA pathogenesis. We summarize the mechanism of glycolytic reprogramming in chondrocytes and macrophages under pathological conditions. Furthermore, we demonstrate that lactic acid exacerbates cartilage degeneration while simultaneously promoting inflammation resolution. These dual roles are mediated by extracellular acidification, HCAR1, and lactylation. Given that duality, we suggest that redirecting lactate flux presents considerable potential as a therapeutic approach for the prevention and management of OA.
Yes-associated protein-1 (YAP1) is an oncogenic effector of the Hippo signaling pathway, activated in several cancer types, and has been extensively studied in cancer progression and therapy. A large number of studies have established the importance of YAP1 in promoting cell-autonomous functions, including uncontrolled growth, sustained proliferative signaling, drug resistance, and metastasis, across multiple cancer types. Therapeutic targeting of YAP1 to combat incurable neoplasms has been the focus of intense investigations. Solid tumors exhibit an organ-like morphology that comprises malignant cells, nonmalignant cells such as fibroblasts, endothelial cells, and immune cells, and non-cellular components, including the extracellular matrix and exosomal vesicles. Tumor progression is accompanied by persistent, reciprocal interactions between malignant cells and other cell types in the tumor microenvironment (TME). Ample evidence indicates the functional importance of YAP1 in nonmalignant components of the TME, which fuel cancer progression. In this review, we provide a comprehensive overview of the functional significance of YAP1 and its downstream signaling pathways across different compartments of the TME, which orchestrate cancer growth, stemness, drug resistance, and metastasis. In particular, this review focuses on understanding the mechanisms by which YAP1 drives distinct cell types in the TME, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and exosome-derived factors, to fuel tumor progression. Furthermore, we summarize the progress in the development of recent YAP1 inhibitors, their mechanisms of action in Hippo-YAP1-dependent cancers, and their combination benefits with existing treatment strategies.
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