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Abstract: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. It is known that macrophage autophagy plays a protective role in atherosclerosis and that hyperhomocysteinemia is strongly linked to autophagy. Therefore, it is of great significance to study the molecular mechanisms underlying the effect of homocysteine (Hcy) on macrophage autophagy. This study aimed to investigate the effects of Hcy on autophagy in a human acute monocytic leukemia cell line (THP-1). The Hcy-treated THP-1 cells exhibited increased levels of the autophagy substrate SQSTM1 (p62) and decreased levels of the autophagy markers LC3 II/I and Beclin-1, indicating a decrease in autophagy in vitro. Furthermore, Western blotting showed that Hcy significantly increased the levels of p-mTOR and nuclear TFEB and decreased the levels of p-AMPK and cytoplasmic TFEB. These data suggest that Hcy inhibits autophagosome formation in human THP-1 macrophages through the AMPK-mTOR-TFEB signaling pathway. Our findings provide new insights into the mechanisms of atherosclerotic diseases caused by Hcy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Circulating HIV subtypes in the Philippines have increasingly diversified, potentially affecting treatment. We monitored outcomes of a treatment-naïve cohort and their virus subtype prevalence.Retrospective/prospective study cohort.HIV-I-REACT clinic patients co-enrolled in the Virology Quality Assurance Program (RUSH-VQA) from 7/2017-6/2019 were included. Relevant demographic and laboratory information were collected. The ViroSeq HIV-1 Genotyping System v.3 and HIV-1 Integrase Genotyping Kit identified protease-reverse transcriptase and integrase drug resistance mutations (DRM). Sequence subtyping followed using the Stanford University Drug Resistance Database and the REGA HIV-1 Subtyping Tool v.3. The jpHMM HIV-1 Tool and REGA HIV-1 Subtyping Tool provided additional subtype analysis of this cohort's 5'LTR-VIF regions after Sanger sequencing. One-year outcomes included virologic suppression, mortality, and follow-up.86/88 patients were males. Median age was 30 (range 19-65) years; 61/88 were MSM. 15/85 carried baseline DRM. ViroSeq-generated sequences included subtypes CRF01_AE (66/85), B (14/85), and newer recombinants (4/85). Extensive sequencing (n = 71) of the 5'-LTR-GAG-Pol genes showed CRF01_AE (n = 50), subtype B (n = 7), and other recombinants (n = 13). Bootstrap analysis identified 7 pairs of highly related strains. Discordant DRM appeared in 2/7 pairs, where 1/2 strains displayed DRM. After 1 year, 87 individuals were alive, with 19 lost to care. Viral load (VL) was repeated for only 31/77 (40.2%). Follow-up CD4 testing for 39/77 (50.6%) showed an increase to a median of 327 cells/mm3.Our cohort currently carries subtype CRF01_AE (∼68%-70%), followed by subtype B and CRF01_AE/B recombinants. Outcomes were favorable, regardless of subtype after 1 year on cART., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are known to participate in regulating mitochondrial function. However, whether Total Salvianolic Acid Injection (TSI) protects against myocardial ischemia/reperfusion (I/R) injury through regulating Sirt1, Sirt3, and mitochondrial respiratory chain complexes is unclear. The aim of this study was to explore the effects of TSI on I/R-induced myocardial injury and the underlying mechanism. Male Sprague-Dawley rats were subjected to 30 min occlusion of the left anterior descending coronary artery followed by 90 min reperfusion with or without TSI treatment (8 mg/kg/h). The results demonstrated that TSI attenuated I/R-induced myocardial injury by the reduced infarct size, recovery of myocardial blood flow, and decreased cardiac apoptosis. Moreover, TSI protected heart from oxidative insults, such as elevation of myeloperoxidase, malondialdehyde, hydrogen peroxide, ROS, as well as attenuated I/R-elicited downregulation of Sirt1, Sirt3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 10 (NDUFA10), succinate dehydrogenase complex, subunit A, flavoprotein variant (SDHA), and restoring mitochondrial respiratory chain complexes activity. The in vitro study in H9c2 cells using siRNA transfection further confirmed the critical role of Sirt1 and Sirt3 in the effect of TSI on the expression of NDUFA10 and SDHA. These results demonstrated that TSI attenuated I/R-induced myocardial injury via inhibition of oxidative stress, which was related to the activation of NDUFA10 and SDHA through the upregulation of Sirt1 and Sirt3.

Currently, the association between sarcopenia and long-term prognosis after gastric cancer surgery has not been investigated. Moreover, the association between sarcopenia and postoperative complications remains controversial. This large-scale retrospective study aims to ascertain the prevalence of sarcopenia and assess its impact on postoperative complications and long-term survival in patients undergoing radical gastrectomy for gastric cancer. From December 2008 to April 2013, the clinical data of all patients who underwent elective radical gastrectomy for gastric cancer were collected prospectively. Only patients with available preoperative abdominal CT scan within 30 days of surgery were considered for analysis. Skeletal muscle mass was determined by abdominal (computed tomography) CT scan, and sarcopenia was diagnosed by the cut-off values obtained by means of optimum stratification. Univariate and multivariate analyses evaluating risk factors of postoperative complications and long-term survival were performed. A total of 937 patients were included in this study, and 389 (41.5%) patients were sarcopenic based on the diagnostic cut-off values (34.9 cm²/m² for women and 40.8 cm²/m² for men). Sarcopenia was an independent risk factor for severe postoperative complications (OR = 3.010, P < 0.001), but not for total complications. However, sarcopenia did not show significant association with operative mortality. Moreover, sarcopenia was an independent predictor for poorer overall survival (HR = 1.653, P < 0.001) and disease-free survival (HR = 1.620, P < 0.001). Under the adjusted tumor-node-metastasis (TNM) stage, sarcopenia remained an independent risk factor for overall survival and disease-free survival in patients with TNM stage II and III, but not in patients with TNM stage I. Sarcopenia is an independent predictive factor of severe postoperative complications after radical gastrectomy for gastric cancer. Moreover, sarcopenia is independently associated with overall and disease-free survival in patients with TNM stage II and III, but not in patients with TNM stage I., Competing Interests: The authors have no conflicts of interest to disclose.

Currently, there is a paucity of study investigating postoperative ileus in gastric cancer surgery. This prospective study aims to identify the risk factors for prolonged postoperative ileus (PPOI) and to use these risk factors to generate a risk stratification scoring system for the occurrence of PPOI.Patients who underwent radical gastrectomy for gastric cancer were included in this study. A multivariate logistic analysis was applied to identify independent risk factors for PPOI and to generate the scoring system. A receiver operating characteristic curve was generated and the area under the curve was calculated to demonstrate the predictive power of the scoring system.Finally, 296 patients were included and analyzed, of whom 96 (32.4%) developed PPOI. The multivariate analysis showed that age ≥65 years, operative duration ≥4 hours, tumor-node-metastasis (TNM) stage = III, open/converted operative technique, and total postoperative opiates dose (TOD) ≥0.3 mg/kg were independent risk factors for PPOI. Based on these factors, a risk stratification scoring system was generated, classified by low-risk (score 0-2), moderate-risk (score 3-4), and high-risk (score 5-6) groups. The incidence of PPOI increased by 7.5-fold from low-risk to high-risk group. The area under the curve of the scoring system was 0.841 (95% CI, 0.793-0.890), indicating a good predictive capability for the occurrence of PPOI.We have identified independent risk factors for the occurrence of PPOI and used these factors to construct a risk stratification scoring system.

Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non-small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of patients with NSCLC. Further studies with larger cohorts should be carried out to validate our findings in the clinical setting.