Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. HPV infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying non-viral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol (DAG) mimic phorbol-myristic acid (PMA) resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NFκB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter implicating non-canonical NFκB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NFκB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases.

Purpose: We aimed to determine the association between sepsis and long-term cardiovascular events. Methods:We conducted a systematic review of observational studies evaluating post-sepsis cardiovascular outcomes in adult sepsis survivors. MEDLINE, Embase, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched from inception until April 21st, 2021. Two reviewers independently extracted individual study data and evaluated risk of bias. Random-effects models estimated the pooled crude cumulative incidence and adjusted hazard ratios (aHRs) of cardiovascular events compared to either non-septic hospital survivors or population controls. Primary outcomes included myocardial infarction, stroke, and congestive heart failure; outcomes were analysed at maximum reported follow-up (from 30 days to beyond 5 years post-discharge).Results: Of 12,649 screened citations, 27 studies (25 cohort studies, 2 case-crossover studies) were included with a median of 4,289 (IQR 502-68,125) sepsis survivors and 18,399 (IQR 4,506) controls per study. The pooled cumulative incidence of myocardial infarction, stroke, and heart failure in sepsis survivors ranged from 3 to 9% at longest reported follow-up. Sepsis was associated with a higher long-term risk of myocardial infarction (aHR 1.77 [95% CI 1.26 to 2.48]; low certainty), stroke (aHR 1.67 [95% CI 1.37 to 2.05]; low certainty), and congestive heart failure (aHR 1.65 [95% CI 1.46 to 1.86]; very low certainty) compared to non-sepsis controls.Conclusions: Surviving sepsis may be associated with a long-term, excess hazard of late cardiovascular events which may persist for at least 5 years following hospital discharge.

Aims  While myocardial ischaemia plays a major role in the pathogenesis of heart failure (HF), the indications for coronary angiography during acute HF are not established. We determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization. Methods and results  In a two-stage sampling process, we identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined whether they underwent early coronary angiography within 14 days after presentation using administrative databases. After clinical record review, we defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. We oversampled patients undergoing angiography. We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met inclusion criteria [median age 75 (interquartile range 65–83) years; 40.9% women]. Early angiography was performed in 1567 patients (52.3%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.61–0.90, P = 0.002], cardiovascular death (HR 0.72, 95% CI 0.56–0.93, P = 0.012), and HF readmissions (HR 0.84, 95% CI 0.71–0.99, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, 95% CI 1.73–3.86, P < 0.001) and coronary artery bypass grafting (HR 2.94, 95% CI 1.75–4.93, P < 0.001) within 2 years. Conclusions  Early coronary angiography was associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia.

Background Metabolic predictors and potential mediators of survival in sepsis have been incompletely characterized. We examined whether machine learning (ML) tools applied to the human plasma metabolome could consistently identify and prioritize metabolites implicated in sepsis survivorship, and whether these methods improved upon conventional statistical approaches. Methods Plasma gas chromatography–liquid chromatography mass spectrometry quantified 411 metabolites measured ≤ 72 h of ICU admission in 60 patients with sepsis at a single center (Brigham and Women’s Hospital, Boston, USA). Seven ML approaches were trained to differentiate survivors from non-survivors. Model performance predicting 28 day mortality was assessed through internal cross-validation, and innate top-feature (metabolite) selection and rankings were compared across the 7 ML approaches and with conventional statistical methods (logistic regression). Metabolites were consensus ranked by a summary, ensemble ML ranking procedure weighing their contribution to mortality risk prediction across multiple ML models. Results Median (IQR) patient age was 58 (47, 62) years, 45% were women, and median (IQR) SOFA score was 9 (6, 12). Mortality at 28 days was 42%. The models’ specificity ranged from 0.619 to 0.821. Partial least squares regression-discriminant analysis and nearest shrunken centroids prioritized the greatest number of metabolites identified by at least one other method. Penalized logistic regression demonstrated top-feature results that were consistent with many ML methods. Across the plasma metabolome, the 13 metabolites with the strongest linkage to mortality defined through an ensemble ML importance score included lactate, bilirubin, kynurenine, glycochenodeoxycholate, phenylalanine, and others. Four of these top 13 metabolites (3-hydroxyisobutyrate, indoleacetate, fucose, and glycolithocholate sulfate) have not been previously associated with sepsis survival. Many of the prioritized metabolites are constituents of the tryptophan, pyruvate, phenylalanine, pentose phosphate, and bile acid pathways. Conclusions We identified metabolites linked with sepsis survival, some confirming prior observations, and others representing new associations. The application of ensemble ML feature-ranking tools to metabolomic data may represent a promising statistical platform to support biologic target discovery.