Identification of VPS34-PI(3)P-FEN1-mediated DNA repair pathway as a potential drug target to overcome chemoresistance.

Intrinsic or acquired chemoresistance represents a major obstacle in cancer treatment. Multiple mechanisms can contribute to cancer cells' resistance to chemotherapy. Among them, an aberrantly strengthened DNA repair mechanism is responsible for a large proportion of drug resistance to alkylating agents and radiation therapy. In cancer cells, damping overactivated DNA repair system can overcome survival advantages conferred by chromosomal translocations or mutations and lead to cytostatic effects or cytotoxic. Therefore, selectively targeting DNA repair system in cancer cells holds promise for overcoming chemoresistance. In this study, we revealed that the endonuclease Flap Endonuclease 1 (FEN1), essential for DNA replication and repair, directly interacts with phosphatidylinositol 3-phosphate [PI(3)P], and FEN1-R378 is the primary PI(3)P-binding site. PI(3)P-binding deficient FEN1 mutant (FEN1-R378A) cells exhibited abnormal chromosomal structures and were hypersensitized to DNA damage. The PI(3)P-mediated FEN1 functionality was essential for repairing DNA damages caused by multiple mechanisms. Furthermore, VPS34, the major PI(3)P synthesizing enzyme, was negatively associated with patients' survival in various cancer types, and VPS34 inhibitors significantly sensitized chemoresistant cancer cells to genotoxic agents. These findings open up an avenue for counteracting chemoresistance by targeting VPS34-PI(3)P-mediated DNA repair pathway, and call for assessing the efficacy of this strategy in patients suffering from chemoresistance-mediated cancer recurrence in clinical trials.

Association of stress hyperglycemia with clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention: a cohort study.

BACKGROUND: In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI). METHODS: Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality. RESULTS: Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2. CONCLUSIONS: Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.

Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients.

BACKGROUND: Stress hyperglycemia ratio (SHR), associated with adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI), has several definitions. This study aims to assess the prognostic value of SHR, derived from hemoglobin A1c (HbA1c) or glycated albumin (GA), to mortality. METHODS: The study comprised 1,643 STEMI patients who underwent percutaneous coronary intervention (PCI) in two centers. SHR1 was calculated using fasting blood glucose (FBG)/GA, while SHR2 was calculated using the formula FBG/(1.59*HbA1c-2.59). The primary endpoints were in-hospital death and all-cause mortality, with a median follow-up duration of 1.56 years. RESULTS: Higher SHR1 and SHR2 values are associated with increased risks of in-hospital death and all-cause mortality. Each standard deviation increase in SHR1 corresponded to a 39% and 22% escalation in in-hospital death and all-cause mortality, respectively. The respective increases for SHR2 were 51% and 26%. Further examinations validated these relationships as linear. Additionally, the areas under the curve (AUC) for in-hospital death were not significantly different between SHR1 and SHR2 (p > 0.05). Incorporating SHR1 or SHR2 into the base model significantly improved the discrimination and risk reclassification for in-hospital and all-cause mortality. A subgroup analysis revealed that the effects of SHR1 and SHR2 were more pronounced in patients with hypercholesteremia. CONCLUSION: SHR1 and SHR2 have emerged as robust and independent prognostic markers for STEMI patients undergoing PCI. The SHR calculation based on either HbA1c or GA can provide additional predictive value for mortality beyond traditional risk factors, helping to identify high-risk STEMI patients.

Association of systemic immune inflammatory index with all-cause and cause-specific mortality among individuals with type 2 diabetes.

BACKGROUND: The evidence regarding the association between the systemic immune inflammatory index (SII) and mortality among individuals with diabetes is limited. This study aims to evaluate the associations between SII and all-cause and cause-specific mortality among individuals with diabetes. METHODS: The study included 8,668 participants with diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 with follow-up until 31 December 2019. The calculation of SII in this study was performed using the following formula: the neutrophil-to-lymphocyte ratio multiplied by the platelet count (10^9 cells/µL). RESULTS: The study documented 2,463 deaths over 68,542 person-years, including 853 deaths from CVD and 424 from cancer. An increase in SII was significantly associated with higher all-cause and CVD mortality risk after multivariate adjustment. For each standard deviation increment in natural log transformed SII (lnSII), all-cause mortality increased by 17%, and CVD mortality increased by 34% (both P < 0.001). Additionally, the association between SII and all-cause mortality was U-shaped, with the inflection point at 6.02. The association between SII and CVD mortality was non-linear and J-shaped, where the risk increased significantly when lnSII exceeded 6.22. Furthermore, the association between SII and CVD mortality was attenuated in female and hyperlipidemia patients. CONCLUSION: In this study, we observed a significant positive association between the SII and both all-cause and CVD mortality in patients with diabetes. Additionally, it was discovered that this association exhibited a non-linear pattern. These findings suggest that maintaining SII within an optimal range may play a critical role in mitigating the risk of mortality.

Safety evaluation of bempedoic acid: A pharmacovigilance analysis using FDA adverse event reporting system data.

BACKGROUND: Bempedoic acid exhibits promising potential in hyperlipidemia therapy and preventing cardiovascular events. However, investigations into its adverse drug reactions remain scant. This study seeks to utilize data mining techniques with the FDA Adverse Event Reporting System (FAERS) database to assess adverse drug events (ADEs) linked to bempedoic acid. METHODS: Based on the drug's market release timeline, we extracted data from the FAERS database covering the fourth quarter of 2020 through the fourth quarter of 2023 for disproportionality analysis. RESULTS: This study gathered a total of 5,797,543 adverse event case reports, of which 735 were linked to bempedoic acid. These reports covered 19 System Organ Classes (SOCs) and 22 Preferred Terms (PTs). Predominantly, the musculoskeletal and nervous systems were implicated in these adverse events. By conducting PT-level screening, various signals for ADEs were detected, including myalgia (ROR 30.33, PRR 28.51, IC 4.83, EBGM 28.47), arthralgia (n = 34, ROR 6.34, PRR 6.09, IC 2.61, EBGM 6.09), tendon disorders (ROR 99.57, PRR 98.75, IC 6.62, EBGM 98.28), and dizziness (ROR 3.18, PRR 3.13, IC 1.65, EBGM 3.13). Particularly noteworthy was the hypertensive crisis (ROR 28.63, PRR 28.51, IC 4.83, EBGM 28.47), which exhibited a robust signal strength, an observation previously unreported in clinical studies and drug labeling. CONCLUSION: While our results are largely consistent with the drug's specifications, several new adverse reaction signals, such as hypertensive crisis, have not been previously documented. Therefore, further investigations are necessary to assess these unlabeled adverse reactions, offering crucial support for the clinical utilization of bempedoic acid.

Association of kidney disease index with all-cause and cardiovascular mortality among individuals with hypertension.

BACKGROUND: This study aimed to investigate the association between a novel kidney disease index (KDI), which combines information from both estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR), and all-cause and cardiovascular disease (CVD) mortality among individuals with hypertension. METHODS: We analyzed data from 19 988 adults with hypertension who participated in the National Health and Nutrition Examination Survey from 1999 to 2018. Mortality outcomes were determined by linking to National Death Index records through December 31, 2019. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for all-cause and CVD mortality. RESULTS: Baseline KDI levels were positively associated with glucose, insulin resistance, hemoglobin A1c, triglycerides, and C-reactive protein (p value for trend <.05). During a follow-up period of 179 859 person-years, a total of 5069 deaths were documented, including 1741 from cardiovascular causes. After multivariable adjustment, each standard deviation increment in KDI level was associated with a 27% increased risk of all-cause mortality and a 31% increased risk of cardiovascular deaths (both p < .05). Further analysis showed a J-shaped association between KDI and mortality, with the risk increasing dramatically when KDI exceeded 0.27. CONCLUSION: Elevated KDI levels were significantly associated with increased mortality from all causes and CVD among individuals with hypertension. We recommend routine testing of eGFR and uACR in hypertensive patients, and using KDI as a tool to identify individuals who are most likely to benefit from preventive therapies.

External validation of the SWEDEHEART score for predicting in-hospital major bleeding among East Asian patients with acute myocardial infarction.

Background: Risk scores for predicting in-hospital major bleeding in patients with acute myocardial infarction (AMI) are rare. The Swedish web-system for the enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART) score (SS), consisting of five common clinical variables, is a novel model for predicting in-hospital major bleeding. External validation of SS has not yet been completed. Methods and results: A retrospective study recruiting consecutive East Asian patients diagnosed with AMI was conducted in the Second Affiliated Hospital, Zhejiang University. The primary endpoint was the ability of SS to predict in-hospital major bleeding, which was defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding. To validate SS, the discrimination and calibration were assessed in the overall population and several subgroups. The receiver operating characteristic (ROC) curves and the areas under ROC curves (AUCs) were calculated for discrimination. The calibration of SS was evaluated with the unreliability U test. A total of 2,841 patients diagnosed with AMI during hospitalization were included, and 1.94% (55) of them experienced in-hospital major bleeding events. The AUC of SS for the whole population was only 0.60 [95% confidence interval (CI), 0.52-0.67], without an acceptable calibration (p = 0.001). Meanwhile, the highest AUC (0.72; 95% CI, 0.61-0.82) of SS for the primary endpoint was found in the diabetes subgroup, with an acceptable calibration (p = 0.87). Conclusion: This external validation study showed that SS failed to exhibit sufficient accuracy in predicting in-hospital major bleeding among East Asian patients with AMI despite demonstrating acceptable performance in the diabetic subgroup of patients. Studies to uncover optimal prediction tools for in-hospital major bleeding risk in AMI are urgently warranted.

Effect of corticosteroids on atrial fibrillation after catheter ablation: a meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to explore the effect of corticosteroids on atrial fibrillation (AF) following catheter ablation. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for published articles describing the effect of corticosteroids in preventing AF recurrence after catheter ablation. Data on study and patient were extracted. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by use of a random-effect model, and P values of <0.05 were considered significant. RESULTS: Two randomized controlled trials (RCTs) and three cohort studies involving 846 patients were included in this meta-analysis. Within one month of catheter ablation, corticosteroid use was associated with a declined risk of recurrence of AF in RCT (RR 0.57, 95% CI 0.39 to 0.85, P=0.005), but without significant effect in cohort studies (RR 1.01, 95% CI 0.79 to 1.30, P=0.94). After three months of catheter ablation, corticosteroids did not have a significant effect in the prevention of late recurrence of AF in either RCT (RR 0.78, 95% CI 0.38 to 1.59, P=0.49) or cohort studies (RR 0.96, 95% CI 0.70 to 1.31, P=0.78). CONCLUSIONS: Our meta-analysis suggested that periprocedural administration of corticosteroids of catheter ablation was associated with reduction of early but not late recurrence of AF.

Cell cycle and pluripotency: Convergence on octamer­binding transcription factor 4 (Review).

Embryonic stem cells (ESCs) have unlimited expansion potential and the ability to differentiate into all somatic cell types for regenerative medicine and disease model studies. Octamer­binding transcription factor 4 (OCT4), encoded by the POU domain, class 5, transcription factor 1 gene, is a transcription factor vital for maintaining ESC pluripotency and somatic reprogramming. Many studies have established that the cell cycle of ESCs is featured with an abbreviated G1 phase and a prolonged S phase. Changes in cell cycle dynamics are intimately associated with the state of ESC pluripotency, and manipulating cell­cycle regulators could enable a controlled differentiation of ESCs. The present review focused primarily on the emerging roles of OCT4 in coordinating the cell cycle progression, the maintenance of pluripotency and the glycolytic metabolism in ESCs.