Pharmacokinetics and pharmacogenomics of ribociclib in black patients with metastatic breast cancer the LEANORA study.

Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women.

Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies.

Purpose: Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies.

Findings: Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor.

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.

Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.

Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes.

Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface.

Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress.

Erratum to: PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.

Erratum to: Breast Cancer Res Treat (2013),138:369–381,DOI 10.1007/s10549-012-2389-6. In the original publication of the article, the Fig.

A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.

Rationale: The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific.

Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2.

Background: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification.

Methods And Results: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population.

Association between anti-human heat shock protein-60 and interleukin-2 with coronary artery calcium score.

Introduction: Based upon evidence suggesting that concentrations of anti-heat shock protein-60 (anti-HSP60) and interleukin-2 (IL-2) are associated with atherogenesis, we tested the hypothesis that anti-HSP60 and IL-2 are associated with coronary artery calcium (CAC) score, a marker of subclinical atherosclerosis.

Methods: We evaluated 998 asymptomatic adults, age 45-84 years, without known coronary disease from the Multi-Ethnic Study of Atherosclerosis (MESA), who had anti-HSP60 measured at baseline. Tertiles of serum anti-HSP60 were evaluated.

Genome-wide identification of expression quantitative trait loci (eQTLs) in human heart.

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression.

Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

Objectives: The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

Background: A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene.

MicroRNA-20a constrains p300-driven myocardial angiogenic transcription by direct targeting of p300.

Objective: To characterize downstream effectors of p300 acetyltransferase in the myocardium.

Background: Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known.

Methods And Results: Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression.

Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants.

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association.

PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.

Oncogenic PI3K/mTOR activation is frequently observed in human cancers and activates cell motility via p27 phosphorylations at T157 and T198. Here we explored the potential for a novel PI3K/mTOR inhibitor to inhibit tumor invasion and metastasis. An MDA-MB-231 breast cancer line variant, MDA-MB-231-1833, with high metastatic bone tropism, was treated with a novel catalytic PI3K/mTOR inhibitor, PF-04691502, at nM doses that did not impair proliferation.

The virtue of just enough stress: a molecular model.

Molecular biology emphasizes the study of all-or-nothing phenomena and molecular events with a large dynamic range. However, many important physiologic parameters in the clinical setting are tightly constrained (e.g.

Dysfunctional potassium channel subunit interaction as a novel mechanism of long QT syndrome.

Background: The slowly-activating delayed rectifier current IKs contributes to repolarization of the cardiac action potential, and is composed of a pore-forming α-subunit, KCNQ1, and a modulatory β-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 exerts its extensive control over the kinetics of IKs remains unresolved

Objective: To evaluate the impact of a novel KCNQ1 mutation on IKs channel gating and kinetics

Methods: KCNQ1 mutations were expressed in Xenopus oocytes in the presence and absence of KCNE1.

Auto-acetylation stabilizes p300 in cardiac myocytes during acute oxidative stress, promoting STAT3 accumulation and cell survival.

The nuclear acetyltransferase p300 is rapidly and stably induced in the heart during hemodynamic stress, but the mechanism of this induction is unknown. To determine the role of oxidative stress in p300 induction, we exposed neonatal rat cardiac myocytes to doxorubicin (DOX, 1 μM) or its vehicle, and monitored p300 protein content and stability for 24 h. Levels of p300 rose substantially within 1 h and remained elevated for at least 24 h, while p300 transcript levels declined.