Drug deconjugation-assisted peptide mapping by LC-MS/MS to identify conjugation sites and quantify site occupancy for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a heterogeneous mixture of conjugated species with varied drug loadings. Depending on conjugation sites, linkers and drugs can exhibit different stability as influenced by the solvent-accessibility and local charge, resulting in different ADC efficacy, pharmacokinetics, and toxicity. Conjugation site analysis is critical for ADC structural characterization to assure product quality and consistency. It enables early conjugation studies at site-specific levels, confirms the absence of unexpected products to support conjugation process development, and aids in ensuring lot-to-lot consistency for comparability studies. Peptide mapping using liquid chromatography-tandem mass spectrometry is the industry standard method for analyzing conjugation sites. However, some concerns remain for this approach as the large and hydrophobic drug moieties often result in poor MS/MS fragmentation quality and impede the identification of conjugation sites. Additionally, the ionization discrepancy between conjugated and unconjugated peptides can lead to a relatively large bias for site occupancy calculation. In this work, we present a simple drug deconjugation-assisted peptide mapping method to identify and quantify the drug conjugation for ADCs with protease-cleavable linkers. Papain-based drug deconjugation was used to remove the highly hydrophobic drug moiety, which significantly improved the quantitation accuracy of conjugation level and the fragmentation quality. Sample preparation conditions were optimized to avoid introducing artificial modifications, allowing the tracking of initial sample status and subsequent changes of quality attributes during process development and stability assessment. This method was applied to analyze thermally-stressed ADC samples to monitor changes of site-specific conjugation levels, DAR, succinimide hydrolysis of the linker, and various PTMs. We believe this is an effective and straightforward tool for conjugation site analysis while simultaneously monitoring multiple quality attributes for ADCs with protease-cleavable linkers.

Association between serum 25-hydroxyvitamin D and vitamin D dietary supplementation and risk of all-cause and cardiovascular mortality among adults with hypertension.

BACKGROUND: The relationship between vitamin D status and mortality among adults with hypertension remains unclear. METHODS: This prospective cohort study involved a sample of 19,500 adults with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. We utilized a weighted COX proportional hazard model to assess the association between vitamin D status and mortality. This statistical model calculates hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI). RESULTS: The study indicated that lower serum 25(OH)D concentration was associated with an increased risk of all-cause mortality among individuals with hypertension. Specially. Those with concentrations between 25.0 and 49.9 nmol/L (HR = 1.71, 95%CI = 1.22-2.40) and less than 25.0 nmol/L (HR = 1.97, 95%CI = 1.15-3.39) had higher hazard ratios for all-cause mortality. Individuals with hypertension who took vitamin D supplements had a lower risk of all-cause mortality, but not the risk of CVD mortality (HR 0.75, 95%CI 0.54-1.03), compared to those who did not supplement (HR = 0.76, 95%CI = 0.61-0.94). Subgroup analysis further revealed that vitamin D supplementation was associated with a reduced risk of all-cause mortality among individuals without diabetes (HR = 0.65, 95%CI = 0.52-0.81) and individuals without CVD (HR = 0.75, 95%CI = 0.58-0.97), and a decreased risk of CVD mortality among individuals without diabetes (HR = 0.63, 95%CI = 0.45-0.88) and without CVD (HR = 0.61, 95%CI = 0.40-0.92). Furthermore, higher-dose vitamin D supplementation was also associated with a greater reduction in all-cause mortality among hypertensive individuals, and there was the potential synergistic effect of combining normal-dose calcium and vitamin D supplementation, showing a superior effect on mortality compared to low-dose supplementation in adults with hypertension. CONCLUSIONS: This prospective cohort study demonstrated a significant association between lower serum 25 (OH)D concentration and increased all-cause mortality among adults with hypertension. Furthermore, the study found that vitamin D supplementation had a strong and significantly positive correlation with reduced all-cause and CVD mortality among hypertensive individuals without diabetes or CVD. This positive correlation suggests that vitamin D supplementation could potentially be an effective strategy to reduce the risk of mortality in this specific group of people.

Gcn5- and Bre1-mediated Set2 degradation promotes chronological aging of Saccharomyces cerevisiae.

Loss of transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3) contributes to shorter lifespans in eukaryotes. However, the molecular mechanism of the decline of H3K36me3 during aging remains poorly understood. Here, we report that the degradation of the methyltransferase Set2 is the cause of decreased H3K36me3 levels during chronological aging in budding yeast. We show that Set2 protein degradation during cellular senescence and chronological aging is mainly mediated by the ubiquitin-conjugating E2 enzyme Ubc3 and the E3 ligase Bre1. Lack of Bre1 or abolishment of the ubiquitination stabilizes Set2 protein, sustains H3K36me3 levels at the aging-related gene loci, and upregulates their gene expression, thus leading to extended chronological lifespan. We further illustrate that Gcn5-mediated Set2 acetylation is a prerequisite for Bre1-catalyzed Set2 polyubiquitination and proteolysis during aging. We propose that two sequential post-translational modifications regulate Set2 homeostasis, suggesting a potential strategy to target the Gcn5-Bre1-Set2 axis for intervention of longevity.

Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data.

BACKGROUND: Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists. METHODS: All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS. RESULTS: LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965-0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications. CONCLUSIONS: LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials.

AIM: We aimed to assess the association between the use of Glucagon-like peptide-1 receptor agonists and the risk of 12 respiratory diseases in patients with type 2 diabetes, obesity, or overweight. METHOD: The PubMed (MEDLINE), EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from the establishment of the database to December 24, 2022. Dichotomous outcomes were analyzed using RR and 95% CI calculated from fixed-effects models. RESULTS: Twenty-eight RCTs were ultimately included for analysis, involving a total of 77,485 participants. Compared to controls, patients with GLP-1RAs have a 14% lower risk of respiratory disease (RR 0.86, 95% CI 0.81-0.93 p < 0.0001), with Semaglutid (RR 0.82, 95% CI 0.68-0.97, p = 0.02), Liraglutide (RR 0.86. 95% CI 0.75-0.98, p = 0.03), Dulaglutide (RR 0.82, 95% CI 0.70-0.96, p = 0.02), Albiglutide (RR 0.93,95% CI 0.79-1.10, p = 0.40), Exenatide (RR 0.93, 95% CI 0.74-1.18, p = 0.55), Lixisenatide (RR 0.83, 95% CI 0.62-1.12, p = 0.22), and Efpeglenatide (RR 0.76, 95% CI 0.46-1.24, p = 0.27). Semaglutide, Liraglutide and Dulaglutide reduce the risk of respiratory diseases by 18%, 14% and 18%, respectively.Trial duration, control type, and indication were not associated with the impact of GLP-1 receptor agonists on overall respiratory disease. Among secondary outcomes, the risk of Pulmonary edema (RR 0.66, 95% CI 0.44-0.98, p = 0.04), and Bronchitis (RR 0.86, 95% CI 0.74-1.00, p = 0.04) was reduced. CONCLUSION: In conclusion, GLP-1RAs were linked to a lower risk of overall respiratory diseases, especially Pulmonary edema and Bronchitis. In the future, physicians should pay attention to the relationship between GLP-1 RA and the risk of respiratory diseases and evaluate the efficacy of GLP-1RAs in the primary and secondary prevention of respiratory diseases. Trial registration CRD42023396138.

Rapid and Online Detection of Foodborne Bacteria via a Novel Ultraviolet Photoionization Time-of-Flight Mass Spectrometry.

Foodborne bacteria are widespread contaminated sources of food; hence, the real-time monitoring of pathogenic bacteria in food production is important for the food industry. In this study, a novel rapid detection method based on microbial volatile organic compounds (MVOCs) emitted from foodborne bacteria was established by using ultraviolet photoionization time-of-flight mass spectrometry (UVP-TOF-MS). The results showed obvious differences of MVOCs among the five species of bacteria, and the characteristic MVOCs for each bacterium were selected by a feature selection algorithm. Online monitoring of MVOCs during bacterial growth displayed distinct metabolomic patterns of the five species. MVOCs were most abundant and varied among species during the logarithmic phase. Finally, MVOC production by bacteria in different food matrixes was explored. The machine learning models for bacteria cultured in different matrixes showed a good classification performance for the five species with an accuracy of over 0.95. This work based on MVOC analysis by online UVP-TOF-MS achieved effective rapid detection of bacteria and showed its great application potential in the food industry for bacterial monitoring.

Efficacy of atosiban for repeated embryo implantation failure: A systematic review and meta-analysis.

Background: Repeated embryo implantation failure (RIF) posed a significant challenge in assisted reproduction. Evidence of its therapeutic effectiveness including atosiban used around embryo transfer to improve pregnancy outcomes in RIF patients undergoing in vitro fertilization-embryo transfer (IVF-ET) remained inconsistent. This study aimed to explore the efficacy of atosiban on pregnancy outcomes of patients with RIF who received IVF-ET. Methods: The research was designed using the PICOS format. A systematic search of four English databases, PubMed, EMBASE, Web of Science, Cochrane Library, and one Chinse database, China National Knowledge Infrastructure (CNKI) was conducted. The time range was from inception to December 10, 2022. Then trials comparing the efficacy of atosiban and control group on pregnancy outcomes in RIF patients who receive IVF-ET were included. Subgroup analysis and sensitivity analysis were performed to reduce the influence of heterogeneity between included studies. Risk ratio (RR) and 95% confidence interval (CI) were calculated. The main outcome measure was clinical pregnancy rate (CPR). For the analyses, StataMP 17.0 (Stata Corporation, USA) was used. Results: Two prospective randomized controlled trials (RCTs), one prospective cohort study and four retrospective cohort studies were included. Our results showed that atosiban was associated with higher clinical pregnancy rate (RR=1.54, 95% CI: 1.365-1.735, P < 0.001, I2 = 0.0%). The results of subgroup analysis based on study types (prospective randomized controlled clinical trial, retrospective cohort study and prospective cohort study) showed that in all types of studies, CPR of atosiban group was significantly higher than controlled group. The results of subgroup analysis based upon the diagnostic criteria of number of previous embryo transfer failures showed that the intervention of atosiban improved the CPR whether in participants with 2 previous ET failures or in participants with 3 previous ET failures. Nevertheless, the incidence of ectopic pregnancy, multiple pregnancy, and miscarriages were not significantly different between the case and control groups. Conclusion: For women who are undergoing IVF-ET and have experienced repeated embryo implantation failure, atosiban may be an important factor in enhancing pregnancy outcomes. To confirm this conclusion, more thorough, prospective randomized controlled studies of sizable sample sizes with well design are required.

Feruloyl oligosaccharides, isolated from bacterial fermented wheat bran, exhibit antioxidant effects in IPEC-J2 cells and zebrafish model.

Feruloyl oligosaccharides (FOs) were produced by solid-state fermentation of wheat bran using Bacillus subtilis, Bacillus licheniformis, and Saccharomyces cerevisiae, and its antioxidant activity was investigated using IPEC-J2 cells and zebrafish embryo model. Preliminary structure analysis revealed that FOs has an average molecular weight of 11.81 kDa and consists of mannose, ribose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, xylose, arabinose, and fucose. The obtained FOs possess superior reducing power and DPPH and hydroxyl free radical scavenging activities. In IPEC-J2 cells, antioxidant enzymes activities and GSH level were significantly increased, while MDA level was reduced by FOs. Further studies showed that FOs achieved the aforementioned effects by activating Nrf2 signaling pathway. In zebrafish embryo, FOs effectively suppressed ROS production, lipid peroxidation, and cell death by increasing SOD and GSH-Px activities. Our findings suggested that FOs from solid-state fermented wheat bran with mixed bacteria can be used as an antioxidant food additive or drugs.

Graph Polish: A Novel Graph Generation Paradigm for Molecular Optimization.

Molecular optimization, which transforms a given input molecule X into another Y with desired properties, is essential in molecular drug discovery. The traditional approaches either suffer from sample-inefficient learning or ignore information that can be captured with the supervised learning of optimized molecule pairs. In this study, we present a novel molecular optimization paradigm, Graph Polish. In this paradigm, with the guidance of the source and target molecule pairs of the desired properties, a heuristic optimization solution can be derived: given an input molecule, we first predict which atom can be viewed as the optimization center, and then the nearby regions are optimized around this center. We then propose an effective and efficient learning framework, Teacher and Student polish, to capture the dependencies in the optimization steps. A teacher component automatically identifies and annotates the optimization centers and the preservation, removal, and addition of some parts of the molecules; a student component learns these knowledges and applies them to a new molecule. The proposed paradigm can offer an intuitive interpretation for the molecular optimization result. Experiments with multiple optimization tasks are conducted on several benchmark datasets. The proposed approach achieves a significant advantage over the six state-of-the-art baseline methods. Also, extensive studies are conducted to validate the effectiveness, explainability, and time savings of the novel optimization paradigm.

Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: An eight RCTs meta-analysis.

Purpose: To explore the risk of stroke (including ischemic and hemorrhagic stroke) in type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trials(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetics published in full-text journal databases such as Medline (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to May 1, 2022 were searched. We assess the quality of individual studies by using the Cochrane risk of bias algorithm. RevMan 5.4.1 software was use for calculating meta- analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported statistically significant effect on total stroke risk[RR=0.83, 95%CI(0.73, 0.95), p=0.005], and its subtypes such as ischemic Stroke [RR=0.83, 95%CI(0.73, 0.95), p=0.008] from treatment with GLP-1RA versus placebo, and have no significant effect on the risk of hemorrhagic stroke[RR=0.83, 95%CI(0.57, 1.20), p=0.31] and retinopathy [RR=1.54, 95%CI(0.74, 3.23), p=0.25]. Conclusion: GLP-1RA significantly reduces the risk of ischemic stroke in type 2 diabetics with cardiovascular risk factors.

Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis. METHODS: The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR. RESULTS: This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64-0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12-0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12-0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34-0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05-3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02-16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10-23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12-3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51-8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77-0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82-0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44-0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76-0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58-0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172-3.61, p = 0.01). CONCLUSIONS: The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF. TRIAL REGISTRATION: CRD42022336311.

Effects of different types of radiation therapy on cardiac-specific death in patients with thyroid malignancy.

Radiation therapy (RT) is one of the common and widely used treatment method for thyroid tumors. Considering that the thyroid is located close to the heart, the radiation generated during the treatment of thyroid tumors may have an adverse greater impact on the heart. This study is to explore the influencing factors, especially additional effects of RT, on cardiac-specific death among patients with malignant thyroid tumors. Collecting information from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database using SEER*Stat. Patients with malignant thyroid tumors were searched, whether receiving RT or not. Ultimately, 201, 346 eligible patients were included. Propensity Score Matching (PSM) was used to minimize bias of baseline characteristics by adjusting for confounding factors. COX (proportional hazards) and fine-gray (competing risk) model regression analysis were used to explore the effects of various influencing factors on cardiac-specific death. The present analysis showed that, compared with non-RT, RT based upon radioactive implants and beam radiation were associated with lower risk of cardiac-specific death in patients with thyroid malignancy, beam radiation therapy may had a similar effect. Besides, the remaining RT methods did not significantly increase the risk of cardiac-specific death. In addition, Asian or Pacific Islander ethnicity, female sex, marital status, combined summary stage (localized, regional, and distant), high-income, and later year of diagnosis were associated with lower risk of cardiac-specific death. While older age of diagnosis, African ethnicity, non-Hispanic ancestry, and derived AJCC stage (IV) were risk factors for cardiac-specific death. These results help to identify the factors influencing cardiac-specific death among patients with thyroid malignancies. Furthermore, it may helps to improve the clinical application of RT without too much concern about adverse cardiac effects.

Application Value of Systemic Inflammatory Indexes in the Clinical Evaluation of Patients with Heart Failure with Preserved Ejection Fraction (HFpEF).

Background: In areas where medical resources are scarce, an economical and convenient way to assess patients' condition so that treatment plans can be adjusted in a timely manner makes sense. The clinical value of systemic inflammatory indexes (SII) such as neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), albumin-to-gamma-glutamyl-transferase ratio (AGR), white-blood-cell-count-to-mean-platelet-volume ratio (WMR), high-density-lipoprotein-cholesterol-to-C-reactive-protein ratio (HCR), etc. were explored in heart failure (HF) with preserved ejection fraction (HFpEF) because of their easy availability and clinical value in the diagnosis, therapy and prognosis of cardiovascular diseases. Methods: 189 inpatients (including 48 patients with New York Heart Association (NYHA) I in the control group, and 141 patients with NYHA II-IV in the study group) from The First Affiliated Hospital of Jinan University, during the period July 2018 to March 2022, were included by retrieving electronic medical records. Logistic regression analysis, Spearman's correlation coefficient, operating characteristic curve, etc. were used to analyze the data. Results: In patients with HFpEF, LMR (OR = 0.463, 95% CI 0.348−0.617, p = 0.000), NLR and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independent predictors for the presence of HF, and LMR (OR = 2.630, 95% CI 2.016−3.435, p = 0.000), NLR, FAG, MHR, AGR and NT-proBNP were independent predictors for increased NYHA functional classification. There were good correlations (r > 0.4) between LMR (r = −0.667, p = 0.000), NLR, WMR, HCR, NT-proBNP (r = −0.681, p = 0.000) and NYHA functional classification, and LMR (AUC = 0.803, 95% CI 0.729−0.849, p = 0.0001), NLR and NT-proBNP (AUC = 0.805, 95% CI 0.738−0.861, p = 0.0001) had good diagnostic values (AUC > 0.7) for HF in patients with HFpEF. In addition, there were certain correlations between LMR, NT-proBNP and echocardiography indicators of cardiac structural. Conclusions: SII have a potential application value in the clinical evaluation of patients with HFpEF in the follow-up, especially in areas with limited medical resources, as they are more convenient and cost effective. Among different SII, LMR is probably the most promising metric. However, large-scale clinical trials are needed in the future to confirm these findings.

Effect of radiotherapy on cardiac-specific death in patients with non-malignant tumors of central nervous system and related clinical features.

Importance: Cardiac-specific death from radiation caused by radiation therapy (RT) in patients with malignant tumors has received extensive attention, however, little is known regarding the potential cardiotoxic effects of RT in patients with non-malignant tumors. Objectives and methods: In this study, we used the SEER data to explore the incidence of post-radiation cardiovascular complications in patients with non-malignant tumors of central nervous system (CNS), and identify the influencing factors of cardiac-specific death. Results: Ultimately 233, 306 patients were included (97.8% of patients had brain tumors and 2.2% had spinal cord tumors). For patients with non-malignant tumors of CNS, RT {yes (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.774-0.936, p = 0.001, before propensity score matching (PSM); OR 0.792, 95% CI 0.702-0.894, p < 0.001, after PSM) vs. no} was associated with lower risk of cardiac-specific death, other clinical features affecting cardiac death similar to those in patients with non-malignant tumors of CNS receiving RT. For patients with non-malignant tumors of CNS receiving RT, female, married status, Hispanic ethnicity, surgery, and tumor site (brain exclude nerve and endocrine, nervous system) were associated with lower risks of cardiac-specific death, while earlier year of diagnosis, older age of diagnosis, Black, larger tumor and bilateral tumor were risk factors for cardiac-specific death. Conclusions: Our study shows the influencing factors for cardiac-specific death in patients with non-malignant tumors of CNS, and found RT is associated with lower risk of cardiac-specific death. These results can facilitate the identification of patients with non-malignant tumors of CNS who can benefit from RT while avoiding cardiovascular events. In addition, this study helps to enhance the clinical use of RT in these populations, especially in patients who may have impaired cardiac function due to CNS tumors.

Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis.

Purpose: An update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences. Conclusion: In type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.

HADH may be the target molecule of early vascular endothelial impairment in T2DM.

Background: Type 2 diabetes mellitus (T2DM) will significantly increase the risk of atherosclerosis (AS). Vascular endothelial cell dysfunction (VECD) is the foundation of AS. Early identification and intervention of VECD caused by T2DM can help us effectively delay or even suppress the occurrence of AS. Methods: We downloaded the gene expression profiles from the Gene Expression Omnibus (GEO). The differential expression genes (DEGs) were identified in R software and weighted gene co-expression network analysis (WGCNA) was performed to further screen the target genes. In addition, we used the receiver operating characteristic curve (ROC curve) to verify the diagnostic efficiency of target genes. Finally, target genes were validated by quantitative polymerase chain reaction (qPCR). Results: Four target genes (CLUH, COG4, HADH, and MPZL2) were discovered in early vascular endothelial impairment caused by T2DM through differential expression analysis and WGCNA. The ROC curve of target genes showed that HADH had the best diagnostic efficacy in VECD and AS. qPCR showed that the mRNA level expression of HADH and MPZL2 were decreased in human coronary artery endothelial cells (HCAECs) treated with high glucose and palmitic acid. Conclusion: HADH may be the target gene in early VECD caused by T2DM.

Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objective: Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias. Methods and Results: RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73-0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51-0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37-0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32-0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48-0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47-0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74-1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83-1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82-1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias. Conclusion: Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.

Bioinformatics Analysis Identifies Potential Ferroptosis Key Gene in Type 2 Diabetic Islet Dysfunction.

Background: Islet ß cells dysfunction (IBCD) is a cortical component in pathogenesis of type 2 diabetic mellitus (T2DM). However, the relationship of ferroptosis and IBCD remains unknown. This study was aimed to screen potential ferroptosis key genes to reveal latent physiological and pathological process of IBCD in T2DM. Methods: Firstly, T2DM key genes were screened by combining with differentially expressed genes (DEGs) analysis and WGCNA. Then, ferroptosis-related genes (FRGs) in IBCD of T2DM were identified by taking the intersection between T2DM key genes and FRGs. Finally, T2DM-FRGs were validated in another T2DM dataset as well as islet single-cell RNA sequencing dataset and the miRNA regulated T2DM-FRG was predicted by using four miRNA databases. Results: 89 T2DM key genes were identified between DEGs and WGCNA. Then, 3 T2DM-FRGs were screened by taking the intersection of T2DM key genes and FRGs, namely ITGA6, MGST1 and ENO2. At last, MGST1 were validated as the T2DM-FRG in another T2DM islet issues dataset and islet single-cell RNA sequencing dataset. Conclusion: MGST1 may be the potential ferroptosis key gene of IBCD in T2DM.

Boundary-aware context neural network for medical image segmentation.

Medical image segmentation can provide a reliable basis for further clinical analysis and disease diagnosis. With the development of convolutional neural networks (CNNs), medical image segmentation performance has advanced significantly. However, most existing CNN-based methods often produce unsatisfactory segmentation masks without accurate object boundaries. This problem is caused by the limited context information and inadequate discriminative feature maps after consecutive pooling and convolution operations. Additionally, medical images are characterized by high intra-class variation, inter-class indistinction and noise, extracting powerful context and aggregating discriminative features for fine-grained segmentation remain challenging. In this study, we formulate a boundary-aware context neural network (BA-Net) for 2D medical image segmentation to capture richer context and preserve fine spatial information, which incorporates encoder-decoder architecture. In each stage of the encoder sub-network, a proposed pyramid edge extraction module first obtains multi-granularity edge information. Then a newly designed mini multi-task learning module for jointly learning segments the object masks and detects lesion boundaries, in which a new interactive attention layer is introduced to bridge the two tasks. In this way, information complementarity between different tasks is achieved, which effectively leverages the boundary information to offer strong cues for better segmentation prediction. Finally, a cross feature fusion module acts to selectively aggregate multi-level features from the entire encoder sub-network. By cascading these three modules, richer context and fine-grain features of each stage are encoded and then delivered to the decoder. The results of extensive experiments on five datasets show that the proposed BA-Net outperforms state-of-the-art techniques.

Differentially expressed tRNA-derived fragments and their roles in primary cardiomyocytes stimulated by high glucose.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus that can cause malignant arrhythmia and sudden death and is associated with cardiomyocyte dysfunction induced by hyperglycemia. Emerging evidence has revealed that transfer RNA-derived fragments (tRFs), a novel class of noncoding RNAs, play a crucial role in a variety of pathophysiologic processes, including cell death, cell growth and proliferation. However, it remains unknown whether and how tRFs are involved in cardiomyocyte dysfunction during the progression of DCM. In this study, we found that cardiomyocyte abnormalities were induced by high glucose (HG) treatment, as demonstrated by a decrease in cell viability and autophagy activation as well as an increase in cell death and proinflammatory cytokine release. Moreover, HG treatment resulted in differential expression of tRFs in cardiomyocytes, of which 4 upregulated and 1 downregulated tRFs were observed compared with the control group. The differential expression of 4 upregulated tRFs was primarily involved in cardiac dysfunction-related processes, such as autophagy, AGE-RAGE signaling pathway in diabetic complications, MAPK signaling pathway, insulin signaling pathway, FoxO signaling pathway, insulin resistance and peroxisome pathways based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, we found that tRF-5014a, the most significantly upregulated tRF among all tested tRFs, negatively regulated the expression of the autophagy-related protein ATG5. Importantly, inhibition of tRF-5014a not only abolished autophagy inactivation but also attenuated the decrease in cell viability and increase in cell death as well as proinflammatory cytokine release under HG conditions. These findings suggest that tRFs may contribute to HG-induced cardiomyocyte injury during DCM progression.