Tricuspid Valve Nonbacterial Thrombotic Endocarditis in a Patient with Metastatic Pulmonary Malignancy

Nonbacterial thrombotic endocarditis (NBTE) is a pathologic state associated with autoimmune diseases and malignancy in which platelet thrombi are deposited on the heart valves in the absence of a bloodstream infection. NBTE is a diagnosis of exclusion that requires a high degree of clinical suspicion after infective endocarditis etiologies have been ruled out. The treatment of NBTE consists of systemic anticoagulation, with direct oral anticoagulants and surgery not having a clear role. The following case reviews a patient’s journey to the diagnosis of tricuspid valve nonbacterial thrombotic endocarditis in the setting of recently diagnosed metastatic lung cancer. This case adds to the growing literature on the diagnostic approach to NBTE

Do hospitals that participate in COVID-19 research differ from non-trial hospitals? A cross-sectional study of US hospitals

ObjectivesTo compare hospitals that did and did not participate in clinical trials evaluating potential inpatient COVID-19 therapeutics.MethodsWe conducted a cross-sectional study of hospitals participating in trials that were registered on clinicaltrials.gov between April and August 2020. Using the 2019 RAND Hospital Dataset and 2019 American Community Survey, we used logistic regression modeling to compare hospital-level traits including demographic features between trial and non-trial hospitals.ResultsWe included 488 hospitals that were participating in 298 interventional trials and 4232 non-participating hospitals. After controlling for demographic and other hospital traits, we found that teaching status (OR 2.11, 95% CI 1.52-2.95), higher patient acuity (OR 7.48, 4.39, 13.1), and location in the Northeast (OR 1.83, 95% CI 1.18, 2.85) and in wealthier counties (OR: 1.32, 95% CI 1.16-1.51) were associated with increased odds of trial participation, while being in counties with more White residents was associated with reduced odds (OR 0.98, 95% CI 0.98-0.99).ConclusionsHospitals participating and not participating in COVID-19 inpatient treatment clinical trials differed in many ways, resulting in important implications for the generalizability of trial data

MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes

Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue–specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysis and identified a set of BAT-specific miRNAs that are upregulated during brown adipocyte differentiation and enriched in brown fat compared with other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of miRNAs in the maintenance as well as in the differentiation of brown adipocytes

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Reactive oxygen species (ROS) such as hydrogen peroxide (H[subscript 2]O[subscript 2]) govern cellular homeostasis by inducing signaling. H[subscript 2]O[subscript 2] modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H[subscript 2]O[subscript 2] signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H[subscript 2]O[subscript 2] signaling colocalize as H[subscript 2]O[subscript 2] induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H[subscript 2]O[subscript 2] as the respiratory chain, Lyn, and Syk were similarly required for H[subscript 2]O[subscript 2] signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H[subscript 2]O[subscript 2] signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.Grant RO1 DK04761

A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling

Reactive oxygen species (ROS) such as hydrogen peroxide (H[subscript 2]O[subscript 2]) govern cellular homeostasis by inducing signaling. H[subscript 2]O[subscript 2] modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H[subscript 2]O[subscript 2] signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H[subscript 2]O[subscript 2] signaling colocalize as H[subscript 2]O[subscript 2] induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H[subscript 2]O[subscript 2] as the respiratory chain, Lyn, and Syk were similarly required for H[subscript 2]O[subscript 2] signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H[subscript 2]O[subscript 2] signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.Grant RO1 DK04761