A safety screening platform for individualized cardiotoxicity assessment.

Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy.

The IRAK-M death domain: a tale of three surfaces.

The anti-inflammatory interleukin-1 receptor associated kinase-M (IRAK-M) is a negative regulator of MyD88/IRAK-4/IRAK-1 signaling. However, IRAK-M has also been reported to activate NF-κB through the MyD88/IRAK-4/IRAK-M myddosome in a MEKK-3 dependent manner. Here we provide support that IRAK-M uses three surfaces of its Death Domain (DD) to activate NF-κB downstream of MyD88/IRAK-4/IRAK-M.

The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes.

Western diet triggers cardiac dysfunction in heterozygous -targeted knock-in mice: A two-hit model of hypertrophic cardiomyopathy.

Background And Aim: Phenotypic expression of hypertrophic cardiomyopathy (HCM) and disease course are associated with unfavorable metabolic health. We investigated if Western diet (WD) feeding is sufficient to trigger cardiac hypertrophy and dysfunction in heterozygous (HET) knock-in mice.

Methods And Results: Wild-type (WT) and HET mice (3-months-old) were fed a WD or normal chow (NC) for 8 weeks.

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

Aims: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM).

Equal force generation potential of trabecular and compact wall ventricular cardiomyocytes.

Trabecular myocardium makes up most of the ventricular wall of the human embryo. A process of compaction in the fetal period presumably changes ventricular wall morphology by converting ostensibly weaker trabecular myocardium into stronger compact myocardium. Using developmental series of embryonic and fetal humans, mice and chickens, we show ventricular morphogenesis is driven by differential rates of growth of trabecular and compact layers rather than a process of compaction.

Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling.

Background: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease.

SUMOylation does not affect cardiac troponin I stability but alters indirectly the development of force in response to Ca.

Post-translational modification of the myofilament protein troponin I by phosphorylation is known to trigger functional changes that support enhanced contraction and relaxation of the heart. We report for the first time that human troponin I can also be modified by SUMOylation at lysine 177. Functionally, TnI SUMOylation is not a factor in the development of passive and maximal force generation in response to calcium, however this modification seems to act indirectly by preventing SUMOylation of other myofilament proteins to alter calcium sensitivity and cooperativity of myofilaments.

Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype-phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits.

Large-Scale Contractility Measurements Reveal Large Atrioventricular and Subtle Interventricular Differences in Cultured Unloaded Rat Cardiomyocytes.

The chambers of the heart fulfill different hemodynamic functions, which are reflected in their structural and contractile properties. While the atria are highly elastic to allow filling from the venous system, the ventricles need to be able to produce sufficiently high pressures to eject blood into the circulation. The right ventricle (RV) pumps into the low pressure pulmonary circulation, while the left ventricle (LV) needs to overcome the high pressure of the systemic circulation.

Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer.

The androgen receptor (AR) is the major driver of prostate cancer growth and survival. However, almost all patients relapse with castration-resistant disease (CRPC) when treated with anti-androgen therapy. In CRPC, AR is often aberrantly activated independent of androgen.

Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.

Bone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors.

Bone Marrow-Derived Progenitor Cells Are Functionally Impaired in Ischemic Heart Disease.

To determine whether the presence of ischemic heart disease (IHD) per se, or rather the co-presence of heart failure (HF), is the primum movens for less effective stem cell products in autologous stem cell therapy, we assessed numbers and function of bone marrow (BM)-derived progenitor cells in patients with coronary artery disease (n = 17), HF due to ischemic cardiomyopathy (n = 8), non-ischemic HF (n = 7), and control subjects (n = 11). Myeloid and erythroid differentiation capacity of BM-derived mononuclear cells was impaired in patients with underlying IHD but not with non-ischemic HF. Migration capacity decreased with increasing IHD severity.

Improving stem cell therapy in cardiovascular diseases: the potential role of microRNA.

The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy.

Bone matrix vesicle-bound alkaline phosphatase for the assessment of peripheral blood admixture to human bone marrow aspirates.

Purpose: Peripheral blood (PB) admixture should be minimized during numerical and functional, as well as cytokinetic analysis of bone marrow (BM) aspirates for research purposes. Therefore, purity assessment of the BM aspirate should be performed in advance. We investigated whether bone matrix vesicle (BMV)-bound bone alkaline phosphatase (ALP) could serve as a marker for the purity of BM aspirates.

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D.

Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.

Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors.

Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis.

The mechanisms by which Myc overexpression or Pten loss promotes prostate cancer development are poorly understood. We identified the chromatin remodeling protein, ING4, as a crucial switch downstream of Myc and Pten that is required for human prostate epithelial differentiation. Myc-induced transient expression of ING4 is required for the differentiation of basal epithelial cells into luminal cells, while sustained ING4 expression induces apoptosis.

Platelet gel supernatant as a potential tool to repopulate acellular heart valves.

Objective: The aim of this study was to repopulate decellularized heart valve matrices with ovine mesenchymal stem cells (oMSCs) by the use of platelet gel (PG) supernatant, a storage vehicle for growth factors.

Methods: oMSCs were exposed to different concentrations of PG-released supernatant and cell proliferation was evaluated using the MTS assay. oMSC motility and invasiveness were assayed using a Boyden chamber.

[Histological progression of paucibacillary leprosy during treatment with various therapeutic regimens].

Histopathological examination of skin biopsies from PB patients during the first 12-18 months of treatment did not reveal any significant difference in the time necessary for disappearance of the lesions. The regimens studied were: DDS 100 mg 7/7, RMP 600 mg 1/30 6x, RMP 600 mg 6/6 6x, RMP 900 mg 1/7 8x and 12x, RMP 1500 mg 1x and 1 year of DDS, RMP 4 mg/K 1x.

Prospective study on the relationship between intensive bactericidal therapy and leprosy reactions.

A systematic study was performed on the reactions occurring during several short-course therapy regimens for the treatment of paucibacillary and multibacillary patients. Most type 1 upgrading reactions in paucibacillary (PB) leprosy were mild to moderate and of short duration, while the time of onset was extremely variable. Their incidence was higher in the regimen rifampin (RMP) 900 mg once weekly for ten weeks than when a single dose of RMP 40 mg/kg body weight was given or 1500 mg in one dose followed by one year of dapsone (DDS) 100 mg daily.