Cell Senescence-Related Genes as Biomarkers for Prognosis and Immunotherapeutic Response in Colon Cancer.

Colon adenocarcinoma (COAD) stands out as the most prevalent malignancy diagnosed within the gastrointestinal tract, bearing substantial incidence and mortality rates. The processes of ageing and senescence intricately intertwine with tumorigenesis and immune regulation, concurrently exerting influence on the remodelling of the tumor microenvironment (TME). This phenomenon, in turn, significantly impacts the efficacy of immunotherapeutic interventions. Despite this awareness, the comprehensive understanding of the intricate interplay between cellular senescence and TME in the context of COAD remains elusive. Further inquiry is imperative to comprehensively gauge the relevance of cellular senescence-related genes (CSGs) in the realms of immune infiltration and the prognostication of COAD. Differentially expressed cell senescence-related genes (DE-CSGs) within COAD tumors and normal specimens were discerned through analysis of the TCGA-COAD dataset. Leveraging univariate, LASSO, and multivariate Cox regression analyses, we formulated a prognostic risk signature. Subsequent validation utilised two independent GEO datasets. Furthermore, a nomogram was devised to gauge the prognostic significance of this signature. Additionally, the immune landscape of the Cell Senescence-related Signature (CSS) was characterised using CIBERSORT and TIMER algorithms. The expression levels of CSGs were quantified through RT-PCR in COAD specimens. Drawing upon mRNA expression profiles of 191 DE-CSGs, we successfully established a 9-gene CSS, demonstrating its autonomy as a prognostic determinant for COAD patients. Those assigned high-risk scores exhibited an immunosuppressive phenotype, marked by elevated proportions of resting CD4+memory T cells and macrophages M0, correlating with diminished overall survival. Subsequent analyses uncovered that the amalgamation of CSS with the expression profiles of immune checkpoint key genes effectively predicted patient prognosis. Furthermore, patients with low-risk scores demonstrated a potential association with more favourable therapeutic outcomes in the context of immunotherapy. This study has culminated in the development of a prognostic risk signature grounded in cell senescence-related genes for COAD. We posit that the CSS plays a regulatory role in immune infiltration, emerging as a robust biomarker for prognosis and a predictive indicator for immunotherapeutic responsiveness within the COAD landscape.

[Knowledge Graph-Based Prediction of Potentially Inappropriate Medication].

Objective: To improve the accuracy of potentially inappropriate medication (PIM) prediction, a PIM prediction model that combines knowledge graph and machine learning was proposed. Methods: Firstly, based on Beers criteria 2019 and using the knowledge graph as the basic structure, a PIM knowledge representation framework with logical expression capabilities was constructed, and a PIM inference process was implemented from patient information nodes to PIM nodes. Secondly, a machine learning prediction model for each PIM label was established based on the classifier chain algorithm, to learn the potential feature associations from the data. Finally, based on a threshold of sample size, a portion of reasoning results from the knowledge graph was used as output labels on the classifier chain to enhance the reliability of the prediction results of low-frequency PIMs. Results: 11 741 prescriptions from 9 medical institutions in Chengdu were used to evaluate the effectiveness of the model. Experimental results show that the accuracy of the model for PIM quantity prediction is 98.10%, the F1 is 93.66%, the Hamming loss for PIM multi-label prediction is 0.06%, and the macroF1 is 66.09%, which has higher prediction accuracy than the existing models. Conclusion: The method proposed has better prediction performance for potentially inappropriate medication and significantly improves the recognition of low-frequency PIM labels.

Administration of H2S improves erectile dysfunction by inhibiting phenotypic modulation of corpus cavernosum smooth muscle in bilateral cavernous nerve injury rats.

Phenotypic modulation of Corpus Cavernosum Smooth Muscle Cells (CCSMCs) is an important step in the development and progression of bilateral cavernous nerve injury induced erectile dysfunction (BCNI-ED). To investigate the effect of exogenous hydrogen sulfide (H2S) on the phenotypic modulation of CCSMCs in BCNI-ED rats, a total of 18 male Sprague-Dawley rats were equally divided into 3 groups, including sham-operated (Sham) group, BCNI group and BCNI treated with NaHS (BCNI + NaHS) group. The treated group received intraperitoneal injection of NaHS (100 µmol kg-1day-1) for 4 weeks starting day 1 postoperatively. Erectile function was measured by the ratio of intracavernous pressure (ICP)/mean arterial pressure (MAP), and relevant tissues were harvested for Immunohistochemistry, Hematoxylin and eosin (H&E), Masson's trichrome staining, H2S fluorescent probe WSP-1 and Western blot. The primary CCSMCs were isolated and pretreatment with NaHS before exposed to PDGF-BB (platelet-derived growth factor). Relative expression mRNA and protein of phenotypic biomarkers, RhoA, ROCK-1 and cell cycle proteins were detected. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST) and H2S levels in penile tissue was significantly decreased in the BCNI group compared with the Sham group. Compared with the BCNI group, administration of NaHS significantly increased the ratio of ICP/MAP, ratio of smooth muscle to collagen, expressions of a-SMA, calponin and decreased the expression of OPN, collagen-I, RhoA, ROCK1 in the penile tissue. PDGF-BB-treated CCSMCs exhibited higher expression of OPN, RhoA, ROCK1, and lower α-SMA, calponin, which were attenuated by NaHS pretreatment. NaHS suppressed RhoA/ROCK activity and decreased the expression of CDK2, Cyclin E1, while increased the expression of P27kip1 induced by PDGF-BB in CCSMCs. Taken together, this study indicated that exogenous H2S inhibited the phenotypic modulation of CCSMCs by suppressing RhoA/ROCK1 signaling and affecting its downstream factor, CDK2, Cyclin E1, P27kip1, thereby improved BCNI rat erectile function.

Effect of Intraoperative Dexamethasone on Major Complications and Mortality Among Infants Undergoing Cardiac Surgery: The DECISION Randomized Clinical Trial.

Importance: Corticosteroids are widely used in pediatric cardiac surgery to blunt systemic inflammatory response and to reduce complications; nevertheless, their clinical efficacy is uncertain. Objective: To determine whether intraoperative administration of dexamethasone is more effective than placebo for reducing major complications and mortality during pediatric cardiac surgery. Design, Setting, and Participants: The Intraoperative Dexamethasone in Pediatric Cardiac Surgery was an investigator-initiated, double-blind, multicenter randomized trial that involved 4 centers in China, Brazil, and Russia. A total of 394 infants younger than 12 months, undergoing cardiac surgery with cardiopulmonary bypass were enrolled from December 2015 to October 2018, with follow-up completed in November 2018. Interventions: The dexamethasone group (n = 194) received 1 mg/kg of dexamethasone; the control group (n = 200) received an equivolume of 0.9% sodium chloride intravenously after anesthesia induction. Main Outcomes and Measures: The primary end point was a composite of death, nonfatal myocardial infarction, need for extracorporeal membrane oxygenation, need for cardiopulmonary resuscitation, acute kidney injury, prolonged mechanical ventilation, or neurological complications within 30 days after surgery. There were 17 secondary end points, including the individual components of the primary end point, and duration of mechanical ventilation, inotropic index, intensive care unit stay, readmission to intensive care unit, and length of hospitalization. Results: All of the 394 patients randomized (median age, 6 months; 47.2% boys) completed the trial. The primary end point occurred in 74 patients (38.1%) in the dexamethasone group vs 91 patients (45.5%) in the control group (absolute risk reduction, 7.4%; 95% CI, -0.8% to 15.3%; hazard ratio, 0.82; 95% CI, 0.60 to 1.10; P = .20). Of the 17 prespecified secondary end points, none showed a statistically significant difference between groups. Infections occurred in 4 patients (2.0%) in the dexamethasone group vs 3 patients (1.5%) in the control group. Conclusions and Relevance: Among infants younger than 12 months undergoing cardiac surgery with cardiopulmonary bypass, intraoperative administration of dexamethasone, compared with placebo, did not significantly reduce major complications and mortality at 30 days. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02615262.

Purification and characterization of a thermostable laccase with unique oxidative characteristics from Trametes hirsuta.

A laccase was purified from Trametes hirsuta. This laccase was classified as a "white" or "yellow" laccase. pH 2.4 was optimal for the oxidation of ABTS and pH 2.5 for DMP. DMP oxidation was optimal at 85 degrees C. The half-life of this laccase was 70 min at 75 degrees C, and 5 h at 65 degrees C. Non-phenolic dyes, such as Methyl Red, were oxidized by purified laccase without mediators. The enzyme was not inhibited by Cu(2+), Mn(2+), or EDTA. These are atypical laccase characteristics that make it a good candidate for theoretical and applied research.

Genetic variants in microRNAs predict non-small cell lung cancer prognosis in Chinese female population in a prospective cohort study.

To investigate the prognostic effect of microRNA single nucleotide polymorphisms (SNP) on non-small cell lung cancer (NSCLC) patients, 658 female participants from northeast China were enrolled in our prospective cohort study and followed up from 2010 to 2015. C-containing genotypes of miR-149 rs2292832 were associated with better overall survival (OS). The joint effect of miR-149 and miR-196a2 and the joint effect of miR-149 and miR-608 were also observed in our study. To verify the function of miR-149 rs2292832, A549 cell lines were stably transfected with lenti-virus containing miR-149-C vector, miR-149-T vector and empty vector. Cells containing C allele assumed a higher expression level of miR-149, a decrease in cell growth and the sensitivity to anticancer drug when compared with cells containing T allele. The role of miR-149 playing in cancer prognosis may function through DNA topoisomerases 1 (TOP1) pathway, according to the results from luciferase reporter assays. In conclusion, miR-149 C allele may be a prognostic biomarker for better NSCLC OS.

Low-intensity international normalized ratio (INR) oral anticoagulant therapy in Chinese patients with mechanical heart valve prostheses.

The purpose of this study was to define the optimal international normalized ratio (INR) intensity of oral anticoagulant therapy in Chinese patients with valve replacement surgery. We studied 1,658 patients who underwent mechanical valve replacement in Beijing Anzhen Hospital; the focus of the study was on correlation between intensity of anticoagulant therapy and thromboembolism/hemorrhage complications. We further followed up 1,508 patients for 46 ± 16 months (range 1-61 months). Average INR was 2.13 ± 0.56, and warfarin dose was 3.09 ± 0.85 mg/day. The incidence rate of anticoagulation-related thromboembolism was 1.17 per 100 patient-years (%/pt-y), and the incidence rate of anticoagulation-related hemorrhage was 2.02%/pt-y. The incidence rate of total complications (i.e., combined thromboembolism and hemorrhages) was 3.24%/pt-y. The rate of total complications in group on INR 1.3-2.3 (aortic valve replacement: 1.3-1.8; mitral valve replacement and double valve replacement: 1.8-2.3) was the lowest among all anticoagulant therapy regimens followed. In conclusion, the relatively low anticoagulant strategy presented above efficiently prevents thrombosis and hemorrhage complications.