A preliminary study of sirtuin-1 on angiotensin II-induced senescence and inflammation in abdominal aortic aneurysms.

Objective: Recent evidence suggests the involvement of senescence and inflammation in abdominal aortic aneurysm (AAA). Considering the role of sirtuin-1 (SIRT1) in delaying senescence, we aimed to preliminarily investigate the potential mechanism underlying the effects of SIRT1 in senescence and inflammation during AAA. Material and Methods: A cell AAA model was established using angiotensin II (Ang II) as the inducer, which was applied to treat human aortic vascular smooth muscle cells (HASMCs). The senescence and cell cycle of treated HASMCs were evaluated based on senescence-associated (SA)-b-galactosidase (b-gal) assay and flow cytometry, respectively. The levels of inflammatory cytokines and proteins related to senescence-associated secretory phenotype (SASP), along with nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinases (MAPK) pathways, as well as SIRT1, were gauged. The correlation between SIRT1 and NF-kB and MAPK pathway-related proteins was further estimated. Results: In Ang II-treated HASMCs, reduced SIRT1 and B-cell lymphoma-2 levels yet increased levels of SASP-related proteins P16 and P21, inflammatory cytokines, as well as Bax and caspases were all visible. In the meantime, Ang II exposure enhanced the number of b-gal-positive HASMCs and promoted cell cycle arrest. SIRT1 was also repressed following Ang II treatment and negatively correlated with NF-kB and MAPK pathway-related proteins (P < 0.05). Furthermore, the overexpression of SIRT1 diminished the levels of SASP-related proteins and reduced the phosphorylation of extracellular regulated kinase 1/2 and P65 in Ang II-treated HASMCs (P < 0.05). Conclusion: Taken together, our results indicate that SIRT1 overexpression attenuates the inflammatory and senescent responses of HASMCs in the Ang II-induced AAA cell model. This finding suggests that SIRT1 can be a highly promising target for clinical treatment of AAA.

Estimation of Physiologic Ability and Surgical Stress scoring system for predicting complications following abdominal surgery: A meta-analysis spanning 2004 to 2022.

BACKGROUND: Postoperative complications remain a paramount concern for surgeons and healthcare practitioners. AIM: To present a comprehensive analysis of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) scoring system's efficacy in predicting postoperative complications following abdominal surgery. METHODS: A systematic search of published studies was conducted, yielding 17 studies with pertinent data. Parameters such as preoperative risk score (PRS), surgical stress score (SSS), comprehensive risk score (CRS), postoperative complications, postoperative mortality, and other clinical data were collected for meta-analysis. Forest plots were employed for continuous and binary variables, with χ2 tests assessing heterogeneity (P value). RESULTS: Patients experiencing complications after abdominal surgery exhibited significantly higher E-PASS scores compared to those without complications [mean difference and 95% confidence interval (CI) of PRS: 0.10 (0.05-0.15); SSS: 0.04 (0.001-0.08); CRS: 0.19 (0.07-0.31)]. Following the exclusion of low-quality studies, results remained valid with no discernible heterogeneity. Subgroup analysis indicated that variations in sample size and age may contribute to heterogeneity in CRS analysis. Binary variable meta-analysis demonstrated a correlation between high CRS and increased postoperative complication rates [odds ratio (OR) (95%CI): 3.01 (1.83-4.95)], with a significant association observed between high CRS and postoperative mortality [OR (95%CI): 15.49 (3.75-64.01)]. CONCLUSION: In summary, postoperative complications in abdominal surgery, as assessed by the E-PASS scoring system, are consistently linked to elevated PRS, SSS, and CRS scores. High CRS scores emerge as risk factors for heightened morbidity and mortality. This study establishes the accuracy of the E-PASS scoring system in predicting postoperative morbidity and mortality in abdominal surgery, underscoring its potential for widespread adoption in effective risk assessment.

Diagnostic plasma small extracellular vesicles miRNA signatures for pancreatic cancer using machine learning methods.

BACKGROUND: Identifying biomarkers may lead to easier detection and a better understanding of pathogenesis of pancreatic ductal adenocarcinoma (PDAC). METHODS: Plasma small extracellular vesicles (sEV) from 106 participants, including 20 healthy controls (HC), 12 chronic pancreatitis (CP) patients, 12 benign pancreatic tumour (BPT) patients, and 58 PDAC patients, were profiled for microRNA (miRNA) sequencing. Three machine learning methods were applied to establish and evaluate the diagnostic model. RESULTS: The plasma sEV miRNA diagnostic signature (d-signature) selected using the three machine learning methods could distinguish PDAC patients from non-PDAC individuals, HC, and benign pancreatic disease (BPD, CP plus BPT) both in training and validation cohort. Combining the d-signature with carbohydrate antigen 19-9 (CA19-9) performed better than with each model alone. Plasma sEV miR-664a-3p was selected by all methods and used to predict PDAC diagnosis with high accuracy combined with CA19-9. Plasma sEV miR-664a-3p was significantly positively associated with the presence of vascular invasion, lower surgery ratio, and poor differentiation. MiR-664a-3p was mainly distributed in the PDAC cancer stroma, including fibers and vessels, and was accompanied by VEGFA expression. Overexpression of miR-664a-3p could promote the epithelial-mesenchymal transition (EMT) and angiogenesis. CONCLUSION: In conclusion, our study demonstrated the potential utility of the sEV-miRNA d-signature in the diagnosis of PDAC via machine learning methods. A novel sEV biomarker, miR-664a-3p, was identified for the diagnosis of PDAC. It can also potentially promote angiogenesis and metastasis, provide insight into PDAC pathogenesis, and reveal novel regulators of this disease.

Analysis of the risk factors for secondary hemorrhage after abdominal surgery.

Introduction: This study aimed to conduct a clinical review and analysis to recommend options for the prevention and treatment of postoperative hemorrhage. Patients and Methods: A total of 138 patients who experienced postoperative hemorrhage after abdominal surgery in the period between January 2015 and December 2020 at the Sir Run Run Shaw Hospital, affiliated to Zhejiang University School of Medicine, participated in this study. They were divided into a group with primary bleeding only and a secondary bleeding group. Univariate and multivariate statistical analyses were performed, followed by plotting of cumulative hazard and survival curves for the two groups. Results: The main factors of interest found to be associated with secondary hemorrhage were duration of the operation, the time of the first bleeding incident, intervention time, performance of combined organ resection, use of surgical intervention, occurrence of abdominal infection, admission to the intensive care unit (ICU), postoperative length of stay, and total hospitalization expenses. Among these, a long operative duration (>5 h) and an extended intervention time (>5 h) were identified as independent predictors of risk of secondary hemorrhage. Conclusions: Secondary hemorrhage after abdominal surgery is mainly associated with subjective human factors, and it is an important cause of poor prognosis and even death. Proper reductions in operation time and implementation of a quick response to bleeding are the key factors in tackling bleeding. Further reduction in the rates of postoperative hemorrhage and mortality will require a concerted effort by surgeons in terms of both intraoperative surgical techniques and postoperative management.

ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer.

DNA damage repair is a major barrier for chemotherapy efficacy of pancreatic ductal adenocarcinoma (PDAC), including the efficacy of platinum-based and gemcitabine/nab-paclitaxel treatments. N6-methyladenosine modifications (m6A) have recently been reported to play a role in homologous recombination (HR) repair of DNA double strand breaks (DSBs); however, the mechanism of action remains unknown. Our previous work indicated that fisetin may be a promising anti-tumour agent that induces DNA damage. In this study, we reported that fisetin induced DSBs and suppressed HR repair through m6A modification in PDAC cells. The m6A writer ZC3H13 and PHF10, which is a subunit of the PBAF chromatin remodelling complex, were identified as the main molecules affected by fisetin treatment. To our knowledge, it's the first time that PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m6A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. In conclusion, our study demonstrates that fisetin enhanced DSBs via ZC3Hl3-mediated m6A modification of PHF10, which may provide insight into novel therapeutic approaches for PDAC.

Rapamycin improves renal injury induced by Iodixanol in diabetic rats by deactivating the mTOR/p70S6K signaling pathway.

AIMS: To study how to effectively prevent or reduce renal injury caused by contrast agents in diabetic patients. MAIN METHODS: Sprague Dawley (SD) rats were bred with a high-fat diet for eight weeks, then intraperitoneally injected with Streptozotocin (STZ) to prepare the diabetes model. Rats were treated with Iodixanol to prepare a contrast-induced acute kidney injury (CIAKI) model. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, was administrated to diabetic rats with or without Rapamycin treatment. Serum creatinine (SCr) and blood urea nitrogen (BUN) were examined using Biochemical detector. Kidney injury molecule-1 (KIM-1), N-acetyl-ß-D-amino glycosidase (NAG) in urine, inflammatory and oxidative stress factors in serum were determined by ELISA. The expression level of ROS was quantified by immunofluorescence (IF). The protein expressions of Bax, BCl-2, LC3, Beclin1, mTOR and p70S6K in renal tissue were detected by Western blot. KEY FINDINGS: Rapamycin was demonstrated to improve renal injury induced by Iodixanol diabetic rats, decrease the levels of SCr, BUN, KIM-1, NAG, improve renal functions, reduce inflammatory response and oxidative stress injury, down-regulate Bax, while up-regulate BCl-2 and inhibit apoptosis. Moreover, Rapamycin could inhibit the phosphorylation of mTOR/p70S6K pathway-associated proteins, activate autophagy and increase the levels of LC3 and Beclin1. After treatment with 3MA, an inhibitor of mTOR/p70S6K signaling pathway, the protective effects of Rapamycin on CIAKI were weakened. SIGNIFICANCE: Rapamycin can alleviate renal injury induced by Iodixanol diabetic rats, and its regulatory mechanisms may be related to the regulation of mTOR/p70S6K signaling pathway and the activating autophagy.

Body mass index and basal androstenedione are independent risk factors for miscarriage in polycystic ovary syndrome.

BACKGROUND: There is limited literature investigating the effects of body mass index (BMI) and androgen level on in vitro fertilization (IVF) outcomes with a gonadotropin-releasing hormone (GnRH)-antagonist protocol in polycystic ovary syndrome (PCOS). Androgen-related variation in the effect of body mass index (BMI) on IVF outcomes remains unknown. METHODS: In this retrospective study, 583 infertile women with PCOS who underwent IVF using the conventional GnRH-antagonist protocol were included. Patients were divided into four groups according to BMI and androgen level: overweight- hyperandrogenism(HA) group, n = 96, overweight-non-HA group, n = 117, non-overweight-HA group, n = 152, and non-overweight-non-HA group, n = 218. RESULTS: A significantly higher number of oocytes were retrieved, and the total Gn consumption as well Gn consumption per day was significantly lower, in the non-overweight groups than in the overweight groups. The number of available embryos was significantly higher in the HA groups than in the non-HA groups. Clinical pregnancy rate was of no significant difference among four groups. Live-birth rates in the overweight groups were significantly lower than those in non-overweight-non-HA group (23.9, 28.4% vs. 42.5%, P<0.05). The miscarriage rate in overweight-HA group was significantly higher than that in non-overweight-non-HA group (45.2% vs. 14.5%, P<0.05). Multivariate logistic regression analysis revealed that BMI and basal androstenedione (AND) both acted as significantly influent factors on miscarriage rate. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis for BMI and basal AND on miscarriage rate were 0.607 (P = 0.029) and 0.657 (P = 0.001), respectively, and the cut-off values of BMI and basal AND were 25.335 kg/m2 and 10.95 nmol/L, respectively. CONCLUSIONS: In IVF cycles with GnRH-antagonist protocol, economic benefits were seen in non-overweight patients with PCOS, with less Gn cost and more retrieved oocytes. BMI and basal AND were both significantly influential factors with moderate predictive ability on the miscarriage rate. The predictive value of basal AND on miscarriage was slightly stronger than BMI.

A novel scoring system to analyze combined effect of lifestyle factors on pancreatic cancer risk: a retrospective case-control study.

Although several risk factors for the onset of pancreatic ductal adenocarcinoma (PDAC) have been identified, currently, no scoring system to systemically evaluate the risk of PDAC has been established. In this study, we aimed to use a population of over 1200 patients to build a novel scoring system, and evaluated combined effects of risk factors for PDAC patients.A set of 4904 participants including 1274 PDAC patients and 3630 non-cancer individuals were recruited for the single-center study over 17-year period (1997~2013). Systematic logical analysis were presented for case and control groups, and a risk rating system was constructed to assess combined risk factors. Seven independent risk factors were identified with the increased risk of PDAC, were selected into the risk score. A merged risk assessment model was established, demonstrating significantly increased PDAC risk in following a number of rising scores. Individuals with scores from 1 to more than 4, the responding OR (95% CI) were 3.06 (2.57~3.65), 7.08 (5.63~8.91), 22.4 (14.2~35.4), and 31.4 (12.7~77.5), respectively. The integer-based risk score in the study can be used for risk stratification to accurately evaluate PDAC occurrence at an early stage. This scoring system provides an accurate risk assessment of PDAC risk.

The individualized choice of embryo transfer timing for patients with elevated serum progesterone level on the HCG day in IVF/ICSI cycles: a prospective randomized clinical study.

This study analyzed the clinical outcomes of patients with elevated progesterone level on the HCG day in IVF/ICSI cycles, with different timing of embryo transfer. A total of 123 patients were involved in this prospective randomized clinical study. Group 1: blastocyst transfer group, 38 cases; Group 2: frozen-thawed embryo transfer group (first FET cycle), 42 cases; Group 3: fresh embryo transfer group, 43 cases. The basal FSH level was comparable among three groups (6.7 ± 3 versus 7.0 ± 2 versus 6.9 ± 2.4, p = 0.897). The clinical pregnancy rate was highest in group 2, lowest in group 3, with significantly difference (31.6% versus 38.1% versus 13.9%, p = 0.037). The implantation rate and live birth rate were still lowest in group 3 (21.9% versus 19.8% versus 6.7%, p = 0.016 and 18.4% versus 31% versus 11.6%, p = 0.081). In conclusion, the elevated progesterone level will affect clinical pregnancy rate in fresh embryo transfer cycles. We suggest frozen-thawed embryo transfer for these patients. However, for those patients who expressed the wish to have fresh embryo transfer, they should be suggested fresh blastocyst transfer, if they have more than five good quality embryos.