Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.

Background: The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season.

A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1β (IL-1β) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1β signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication.

PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease.

Effector memory T cells (T) are less capable of inducing graft-versus-host disease (GVHD) compared with naive T cells (T). Previously, in the TS1 TCR transgenic model of GVHD, wherein TS1 CD4 cells specific for a model minor histocompatibility Ag (miHA) induce GVHD in miHA-positive recipients, we found that cell-intrinsic properties of TS1 T reduced their GVHD potency relative to TS1 T Posttransplant, TS1 T progeny expressed higher levels of PD-1 than did TS1 T progeny, leading us to test the hypothesis that T induce less GVHD because of increased sensitivity to PD-ligands. In this study, we tested this hypothesis and found that indeed TS1 T induced more severe skin and liver GVHD in the absence of PD-ligands.

Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects.

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors.

LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation.

Aims: Liver kinase B1 (LKB1) is a protein kinase that activates the metabolic regulator AMP-activated protein kinase (AMPK) and other related kinases. Deletion of LKB1 in mice leads to cardiomyopathy and atrial fibrillation (AF). However, the specific role of the LKB1 pathway in early atrial biology remains unknown.

Use of arsenic trioxide in a hemodialysis-dependent patient with relapsed acute promyelocytic leukemia.

Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant.

Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease.

Unlabelled: Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD.

Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia.

Objectives: Pulmonary hypertension (PH) is a process of lung vascular remodeling, which can lead to right heart dysfunction and significant morbidity. The underlying mechanisms leading to PH are not well understood, and therapies are limited. Using intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified an important role for endothelial cell mitophagy via mitochondrial uncoupling protein 2 (Ucp2) in the development of IH-induced PH.

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways.

Cardiac disorders are the main cause of mortality in autosomal-dominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function.

Association between right ventricular dysfunction and restrictive lung disease in childhood cancer survivors as measured by quantitative echocardiography.

Background: Restrictive lung disease is a complication in childhood cancer survivors who received lung-toxic chemotherapy and/or thoracic radiation. Left ventricular dysfunction is documented in these survivors, but less is known about right ventricular (RV) function. Quantitative echocardiography may help detect subclinical RV dysfunction.

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart.

Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) on cardiomyocytes and confers protection against ischemia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis mitigates against ischemia/reperfusion injury remain incompletely delineated. Activation of AMP-activated protein kinase (AMPK) also limits cardiac damage during ischemia/reperfusion.

Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice.

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates.

Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning.

Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC).

Clinical vignettes: integrated care of cancer patients by oncologists and cardiologists.

Because of the paucity of large, randomized trials concerning the cardiac care of patients with cancer, treatment and prevention of chemotherapy-induced cardiotoxicity must rely on insights gained from small trials and case reports as well as the application of guidelines developed for the general population. In these clinical vignettes, we present patients referred by their oncologists to a cardiologist for specialized evaluation and management of cardiotoxicity with the goal of emphasizing the importance of identifying risk factors for cardiotoxicity, initiating evidence-based therapy, and establishing a close collaboration between oncologists and cardiologists.

Cardiotoxicity of molecularly targeted agents.

Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease.

Heliox in children with croup: a strategy to hasten improvement.

Objective: Upper airway obstruction is responsive to the reduction in airflow turbulence provided by helium/oxygen (heliox) admixture. Our pediatric critical care transport team (PCCTT) has used heliox for children with upper airway obstruction from croup. We sought to describe our experience with heliox on transport and hypothesized that heliox-treated children with croup would show a more rapid clinical improvement.

Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis.

Aims: Neuregulins (NRG) are growth factors that are synthesized by endothelial cells (ECs) and bind to erbB receptors. We have shown previously that NRG is proangiogenic in vitro, and that NRG/erbB signalling is important for autocrine endothelial angiogenic signalling in vitro. However, the role of NRG in the angiogenic response to ischaemia is unknown.

Endothelium-derived neuregulin protects the heart against ischemic injury.

Background: Removal of cardiac endothelial cells (EC) has been shown to produce significant detrimental effects on the function of adjacent cardiac myocytes, suggesting that EC play a critical role in autocrine/paracrine regulation of the heart. Despite this important observation, the mediators of the protective function of EC remain obscure. Neuregulin (NRG, a member of the epidermal growth factor family) is produced by EC and cardiac myocytes contain receptors (erbB) for this ligand.

Activation of the aryl hydrocarbon receptor by doxorubicin mediates cytoprotective effects in the heart.

Aims: Doxorubicin (DOX) is a highly effective chemotherapeutic agent; however, cumulative dose-dependent cardiotoxicity is a significant side effect of this therapy. Because DOX is a polyaromatic hydrocarbon, we hypothesized that it will be metabolized by the activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is involved in the metabolism of numerous xenobiotic agents. These studies were performed to determine whether DOX activates AhR and whether this activation modulates the toxicity of DOX in cardiomyocytes.

Renalase deficiency aggravates ischemic myocardial damage.

Chronic kidney disease (CKD) leads to an 18-fold increase in cardiovascular complications not fully explained by traditional risk factors. Levels of renalase, a recently discovered oxidase that metabolizes catecholamines, are decreased in CKD. Here we show that renalase deficiency in a mouse knockout model causes increased plasma catecholamine levels and hypertension.

Cytostatic drugs, neuregulin activation of erbB receptors, and angiogenesis.

Cytostatic drugs were developed to target specific molecular pathways shown to drive tumor growth. Although this approach has been very successful in treating cancers, its use is often hindered by off-target toxic effects. An example of this is trastuzumab, which targets the erbB2 kinase receptor.