PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

1. Download : Download high-res image (204KB)
2. Download : Download full-size image

     

Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Atrial fibrillation after cardiac surgery: A systematic review and meta-analysis

ObjectiveNew-onset postoperative atrial fibrillation (POAF) after cardiac surgery is common, with rates up to 60%. POAF has been associated with early and late stroke, but its association with other cardiovascular outcomes is less known. The objective was to perform a meta-analysis of the studies reporting the association of POAF with perioperative and long-term outcomes in patients with cardiac surgery.MethodsWe performed a systematic review and a meta-analysis of studies that presented outcomes for cardiac surgery on the basis of the presence or absence of POAF. MEDLINE, EMBASE, and the Cochrane Library were assessed; 57 studies (246,340 patients) were selected. Perioperative mortality was the primary outcome. Inverse variance method and random model were performed. Leave-one-out analysis, subgroup analyses, and metaregression were conducted.ResultsPOAF was associated with perioperative mortality (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.58-2.33), perioperative stroke (OR, 2.17; 95% CI, 1.90-2.49), perioperative myocardial infarction (OR, 1.28; 95% CI, 1.06-1.54), perioperative acute renal failure (OR, 2.74; 95% CI, 2.42-3.11), hospital (standardized mean difference, 0.80; 95% CI, 0.53-1.07) and intensive care unit stay (standardized mean difference, 0.55; 95% CI, 0.24-0.86), long-term mortality (incidence rate ratio [IRR], 1.54; 95% CI, 1.40-1.69), long-term stroke (IRR, 1.33; 95% CI, 1.21-1.46), and longstanding persistent atrial fibrillation (IRR, 4.73; 95% CI, 3.36-6.66).ConclusionsThe results suggest that POAF after cardiac surgery is associated with an increased occurrence of most short- and long-term cardiovascular adverse events. However, the causality of this association remains to be established.     

Hepatotoxicity of cantharidin is associated with the altered bile acid metabolism

Cantharidin (CTD) is an effective antitumor agent. However, it exhibits significant hepatotoxicity, the mechanism of which remains unclear. In this study, biochemical and histopathological analyses complemented with ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabolomic analysis of bile acids (BAs) were employed to investigate CTD-induced hepatotoxicity in rats. Sixteen male and female Sprague–Dawley rats were randomly divided into two groups: control and CTD (1.0 mg/kg) groups. Serum and liver samples were collected after 28 days of intervention. Biochemical, histopathological, and BA metabolomic analyses were performed for all samples. Further, the key biomarkers of CTD-induced hepatotoxicity were identified via multivariate and metabolic pathway analyses. In addition, metabolite–gene–enzyme network and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify the signaling pathways related to CTD-induced hepatotoxicity. The results revealed significantly increased levels of biochemical indices (alanine aminotransferase, aspartate aminotransferase, and total bile acid). Histopathological analysis revealed that the hepatocytes were damaged. Further, 20 endogenous BAs were quantitated via UHPLC-MS/MS, and multivariate and metabolic pathway analyses of BAs revealed that hyocholic acid, cholic acid, and chenodeoxycholic acid were the key biomarkers of CTD-induced hepatotoxicity. Meanwhile, primary and secondary BA biosynthesis and taurine and hypotaurine metabolism were found to be associated with the mechanism by which CTD induced hepatotoxicity in rats. This study provides useful insights for research on the mechanism of CTD-induced hepatotoxicity.     

Prior surgical fixation of proximal humerus fractures is associated with increased complications following subsequent reverse shoulder arthroplasty

BackgroundThe objective of this study was to compare complication rates between patients undergoing reverse shoulder arthroplasty (RSA) after a prior open reduction and internal fixation (ORIF) for proximal humerus fracture (PHF) to those undergoing RSA as a primary treatment for PHFs, glenohumeral osteoarthritis, or rotator cuff tear arthropathy (CTA).MethodsPatients who underwent RSA between 2015 and 2020 were identified in the Mariner database. Patients were separated into 3 mutually exclusive groups: (1) RSA for osteoarthritis, rotator cuff tear, or CTA (Control-RSA); (2) RSA as a primary treatment for PHF (PHF-RSA); and (3) RSA for patients with prior ORIF of PHFs (ORIF-RSA). Ninety-day medical and 2-year postoperative surgical complications were identified. In addition, patients in the PHF-RSA group were subdivided into those undergoing RSA for PHF within 3 months of the fracture (acute) vs. those treated greater than 3 months from diagnosis (delayed). Multivariate regression was performed to control for differences in comorbidities and demographics.ResultsA total of 30,824 patients underwent primary RSA for arthritis or CTA, 5389 patients underwent RSA as a primary treatment for a PHF, and 361 patients underwent RSA after ORIF of a PHF. ORIF before RSA was associated with an increased risk of overall revision (odds ratio [OR] 2.45, P = .002), infection (OR 2.40, P < .001), instability (OR 2.43, P < .001), fracture (OR 3.24, P = .001), minor medical complications (OR 1.59, P = .008), and readmission (OR 2.55, P = .001) compared with the Control-RSA cohort. RSA as a primary treatment for PHF was associated with an increased risk of 2-year revision (OR 1.60, P < .001), infection (OR 1.51, P < .001), instability (OR 2.84, P < .001), and fracture (OR 2.54, P < .001) in addition to major medical complications (OR 2.02, P < .001), minor medical complications (OR 1.92, P < .001), 90-day emergency department visits (OR 1.26, P < .001) and 90-day readmission (OR 2.03, P < .001) compared with the Control-RSA cohort. The ORIF-RSA group had an increased risk of periprosthetic infection (OR 1.94, P = .002) when compared with the PHF-RSA cohort. There were no differences in medical or surgical complications in the RSA-PHF cohort between patients treated in an acute or delayed fashion.ConclusionRSA following ORIF of a PHF is associated with increased complications compared with patients undergoing RSA for nonfracture indications. Prior ORIF of a PHF is also an independent risk factor for postoperative infection after RSA compared with patients who undergo RSA as a primary operation for fracture. The timing of RSA as a primary operation for PHF does not appear to impact the rates of postoperative medical and surgical complications.