Explore the vast range of titles available.

The cellular response to stress is an important determinant of disease pathogenesis. Uncovering the molecular fingerprints of distinct stress responses may identify novel biomarkers and key signaling pathways for different diseases. Emerging evidence shows that transfer RNA‐derived small RNAs (tDRs) play pivotal roles in stress responses. However, RNA modifications present on tDRs are barriers to accurately quantifying tDRs using traditional small RNA sequencing. Here, AlkB‐facilitated methylation sequencing is used to generate a comprehensive landscape of cellular and extracellular tDR abundances in various cell types during different stress responses. Extracellular tDRs are found to have distinct fragmentation signatures from intracellular tDRs and these tDR signatures are better indicators of different stress responses than miRNAs. These distinct extracellular tDR fragmentation patterns and signatures are also observed in plasma from patients on cardiopulmonary bypass. It is additionally demonstrated that angiogenin and RNASE1 are themselves regulated by stressors and contribute to the stress‐modulated abundance of sub‐populations of cellular and extracellular tDRs. Finally, a sub‐population of extracellular tDRs is identified for which AGO2 appears to be required for their expression. Together, these findings provide a detailed profile of stress‐responsive tDRs and provide insight about tDR biogenesis and stability in response to cellular stressors. Using AlkB‐facilitated methylation sequencing, this work uncovers the distinct extracellular transfer RNA‐derived small RNA (tDR) fragmentation patterns from cellular tDRs and provides a detailed profile of stress‐responsive tDRs in a variety of cell culture systems and human patients. This work also provides insights about the biogenesis and stability of cellular and extracellular tDRs in response to cellular stressors.

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

Acute myocardial infarction is a leading cause of morbidity and mortality worldwide 1 . Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events 2 , 3 , 4 , 5 , 6 – 7 . However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL1 7 , 8 , 9 , 10 – 11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A) 12 , 13 , 14 , 15 – 16 —in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1–HIF2A–DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG) 16 , 17 as a rhythmic target of the BMAL1–HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1–HIF2A–AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway’s circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease. The core circadian transcription factor BMAL1 regulates circadian-dependent myocardial injury.

Background Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. Methods A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. Results mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p  = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p  < 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. Conclusions Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049

Edge-to-edge repair of the mitral valve (MV) has been described as a viable option used for the surgical management of mitral regurgitation (MR). Based on the significant changes in MV geometry associated with this technique, we hypothesized that edge-to-edge MV repairs are associated with higher intraoperative transmitral pressure gradients (TMPG) compared to conventional methods. Patient records and intraoperative transesophageal echocardiography (TEE) examinations of 552 consecutive patients undergoing MV repair at a single institution over a three year period were assessed. After separation from cardiopulmonary bypass (CPB), peak and mean TMPG were recorded for each patient and subsequently analyzed. 84 patients (15%) underwent edge-to-edge MV repair. Peak and mean TMPG were significantly higher compared to gradients in patients undergoing conventional repairs: 10.7 ± 0.5 mmHg vs 7.1 ± 0.2 mmHg; P<0.0001 and 4.3 ± 0.2 mmHg vs 2.8 ± 0.1 mmHg; P<0.0001. Only patients with mean TMPG ≥ 7 mmHg (n = 9) required prompt reoperation for iatrogenic mitral stenosis (MS). No differences in peak and mean TMPG were observed among edge-to-edge repairs performed in isolation, compared to those performed in combination with annuloplasty: 11.0 ± 0.7 mmHg vs 10.3 ± 0.6 mmHg and 4.4 ± 0.3 mmHg vs 4.3 ± 0.3 mmHg. There were no differences in TMPG between various types of annuloplasty techniques used in combination with the edge-to-edge repairs. Edge-to-edge MV repairs are associated with higher intraoperative peak and mean TMPG after separation from CPB compared to conventional repair techniques. Unless gradients are severely elevated, these findings are not necessarily suggestive of iatrogenic MS. Thus, in the immediate postoperative period mildly elevated TMPG can be expected and tolerated after edge-to-edge mitral repairs.

Outcomes after mitral valve (MV) repair are known to be worse in women. Less is known about sex-based differences in MV repair durability. All adult patients undergoing MV repair from 2002 to 2016 were reviewed. Of 2463 cases, 947 (39%) were women. Re-operation risk was defined as any intervention for repair failure or MV disease progression. Median follow-up was 8.2 years. Women were older with higher STS-risk scores and were more likely to have rheumatic disease (RHD). Operative mortality was clinically higher in women (2.7% vs 1.7%; P = 0.09). Although women had significantly higher 10-year re-operation risk (7% vs 4%), adjusted longitudinal analysis showed that this was associated with RHD in women (HR 4.04; P = 0.001). Female sex alone was not a significant predictor (P = 0.21). Re-operation following MV repair was infrequent. Women had increased re-operation risk that was largely attributable to their worse preoperative profiles rather than female sex alone. [Display omitted] •Re-operation following mitral valve (MV) repair was infrequent.•Risk of MV re-operation after MV repair was higher among women.•Increased risk among women was largely attributable to worse preoperative profiles.

Anomalous origin of a coronary artery from the opposite sinus of Valsalva is a rare congenital anomaly. The prevalence of familial clustering of coronary artery anomalies is unknown. Here we describe the case of a father and son, both of whom presented with major adverse cardiac events due to Anomalous origin of a coronary artery from the opposite sinus of Valsalva and both had right coronary artery arising from the left coronary cusp with an interarterial course.

Background: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. Methods and Results: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = −0.69, p = 1 × 10−23) and activation of cell death pathways (p < 6 × 10−9). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient −0.2, p = 0.002). Conclusion: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.

Interstitial lung disease (ILD) is a known risk factor for noncardiac surgery due to acute pulmonary exacerbations but its impact after cardiac surgery is not known. We examined perioperative outcomes and risk factors for long-term survival in ILD patients who underwent cardiac surgery. From January 2002 to June 2017, 294 cardiac surgery patients with a previous ILD diagnosis, including 75 patients with idiopathic pulmonary fibrosis (IPF), were identified. A comparison cohort of 1,481 non-ILD patients was selected based on a priori variables. Long-term survival was evaluated using Cox proportional hazard modeling. Median follow-up was 6.4 years. ILD patients had higher postoperative mortality, reintubation rates, longer intensive care unit stay, and higher 30-day readmission rates (all p <0.05). Kaplan-Meier estimates of survival at 1, 5, and 10 years were 89%, 62%, and 37% for the non-IPF ILD cohort, 89%, 50%, and 13% for the IPF cohort, and 95%, 82%, and 67% for the comparison cohort, respectively (overall p <0.001). These significant differences in survival persisted in our risk-adjusted survival analysis. Adjusted survival analysis identified IPF (hazard ratio 3.04) and ILD (non-IPF; hazard ratio 1.78) as significant contributors to all-cause mortality. However, there were no changes in pulmonary function tests after 48 months postprocedure. In conclusion, ILD patients who underwent cardiac surgery have increased operative mortality, reintubation rates, longer intensive care unit, and higher 30-day readmissions compared with non-ILD patients. Moreover, severity of ILD, especially in IPF, appears to be associated with shorter long-term survival. In these patients, pulmonary risk stratification and multidisciplinary team approach are crucial. [Display omitted]

Surgical aortic valve replacement (SAVR) in patients with porcelain aorta is considered a high-risk procedure. Hence, transcatheter aortic valve implantation (TAVI) is emerging as the intervention of choice. However, there is a paucity of data directly comparing TAVI with SAVR in patients with porcelain aorta. We compared outcomes of TAVI versus SAVR in high-risk patients with porcelain between March 2012 and June 2015. The TAVI group included 54 patients, whereas 130 SAVR patients with porcelain aorta were identified (operated on between 2004 and 2015). Both groups were matched 1:1 based on the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score with a 0.5% a priori caliper, resulting in 52 matched pairs. The mean STS-PROM was 7.3 ± 3.9 for both groups (p = 0.98), whereas mean age was 77.5 years for TAVI and 78.8 years for SAVR (p = 0.46). Compared with SAVR, TAVI patients had lower operative mortality (3.8% vs 17.3%; p = 0.052), significantly shorter median intensive care unit (40 vs 107 hours; p < 0.001) and hospital (5 vs. 7 days; p < 0.001) length of stay (LOS), but similar postoperative stroke rates (7.7% vs 11.5%; p = 0.74). One-year unadjusted survival was 81.7% (95% confidence interval [CI]: 69.8% to 93.5%) in the TAVI group versus 71.2% (95% CI: 61.0% to 85.1%) in the SAVR group, p = 0.093. Cox proportional hazard modeling identified preoperative chronic kidney disease (hazard ratio: 2.63 [95% CI: 1.03 to 6.70]; p = 0.043) and SAVR (hazard ratio: 2.641 [95% CI: 1.07 to 6.51]; p = 0.035) as significant predictors for decreased survival. Overall, TAVI was associated with reduced operative mortality, increased survival, and shorter intensive care unit and hospital length of stay compared with SAVR in patients with porcelain aorta. This study demonstrates that TAVI is a safe intervention in this high-risk population.