Erbin is a negative modulator of cardiac hypertrophy

ErbB2 interacting protein (Erbin) is a widely expressed protein and participates in inhibition of several intracellular signaling pathways. Its mRNA has been found to be present in relatively high levels in the heart. However, its physiological role in the heart has not been explored. In the present work, we elucidated the role of Erbin in cardiac hypertrophy. Cardiac hypertrophy was induced in mice either by isoproterenol administration or by aortic constriction. The level of Erbin was significantly decreased in both models. Erbin^−/− mice rapidly develop decompensated cardiac hypertrophy, and following severe pressure overload all Erbin^−/− mice died from heart failure. Down-regulation of Erbin expression was also observed in biopsies derived from human failing hearts. It is known that Erbin inhibits Ras-mediated activation of the extracellular signal-regulated kinase (ERK) by binding to Soc-2 suppressor of clear homolog (Shoc2). Our data clearly show that ERK phosphorylation is enhanced in the heart tissues of Erbin^−/− mice. Furthermore, we clearly demonstrate here that Erbin associates with Shoc2 in both whole hearts and in cardiomyocytes, and that in the absence of Erbin, Raf is phosphorylated and binds Shoc2, resulting in ERK phosphorylation. In conclusion, Erbin is an inhibitor of pathological cardiac hypertrophy, and this inhibition is mediated, at least in part, by modulating ERK signaling.Cardiovascular disease remains the number one cause of mortality in the Western world, with heart failure representing the fastest-growing subclass over the past decade (1, 2). In myocardial hypertrophy caused by exercise, pregnancy, or developmental signals, cardiac structure and function are normal. However, in response to insults such as sustained excessive workloads, pathological cardiac hypertrophy is characterized by changes in contractility, loss of myocytes with fibrosis, systolic or diastolic dysfunction, and fetal gene reactivation. Pathological cardiac hypertrophy predisposes individuals to heart failure, arrhythmia, and sudden death (1, 2). The tyrosine kinase receptor avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2), also known in humans as Her2, is an important regulator in cardiac hypertrophy development and heart failure (3). ErbB2-deficient conditional mutants develop dilated cardiomyopathy (3). ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy. However, the mechanism by which ErbB2 exerts its cardiac effects in general, and on cardiac hypertrophy in particular, is poorly defined.ErbB2 interacting protein (Erbin), a member of the leucine-rich repeat and PDZ domain proteins (4), was originally reported as a binding partner of Her2/neu (ErbB2) (4). Erbin is a widely expressed protein, and high levels of Erbin are present in the heart (5). Recently, Erbin has been demonstrated to form a complex with Her2 and β2-adrenergic receptor in cardiomyocytes. Also, Erbin has been shown to protect cardiomyocytes from apoptosis induced by chronic catecholamine stimulation (6). However, its physiological cardiac function and its role in cardiac hypertrophy are unknown. Erbin^−/− mice have defective remyelination following axonal injury (7), but no further pathology has been described to date.The regulatory roles assigned to Erbin have recently expanded. Erbin participates in the inhibition of a variety of cellular signaling pathways, including Ras-mediated activation of extracellular signal-regulated kinase (ERK) (8, 9), nuclear factor κB (10), and transforming growth factor β signaling pathways (11). Interestingly, these three signaling pathways have been shown to play a significant role in cardiac hypertrophy (12–15).In the current study, we demonstrate that Erbin expression is decreased in cardiac hypertrophy induced in mice by either isoproterenol administration or aortic constriction. Erbin expression was significantly decreased in end-stage heart failure in humans. Exaggerated pathological cardiac hypertrophy was observed in Erbin^−/− mice compared with wild-type (WT) mice. The levels of B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) were significantly increased in isoproterenol-administered Erbin^−/− mice, indicating fetal gene reactivation typical of pathological cardiac hypertrophy. Moreover, aortic constriction resulted in rapidly decompensated response in Erbin^−/− mice as well as heart failure and death.Thus, our results indicate that Erbin serves as a major inhibitor of pathological cardiac hypertrophy.     

XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters

Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. The prodrug demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of (14)C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of (3)H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.     

Prevalence of tinea pedis in psoriasis,compared to atopic dermatitis and normal controls – a prospective study

There are discrepancies in the literature regarding the prevalence of tinea pedis in psoriasis. The aim of this investigation was to conduct a cross‐sectional study of the prevalence of tinea pedis in psoriasis compared to atopic dermatitis patients and normal controls. We enrolled 232 psoriatic patients, 190 atopic dermatitis patients and 202 normal controls, between the years 2010 and 2013. The prevalence of tinea pedis was 13.8% in psoriasis patients, not significantly different from that in atopic dermatitis patients 8.4% (P = 0.092)), but significantly higher than in normal controls 7.4% (P = 0.043). Both gender and age affected the prevalence of tinea pedis in psoriasis and normal controls, while only age affected the prevalence of tinea pedis in atopic dermatitis. Regarding gender, there was higher prevalence of tinea pedis in men: 19.1% (P = 0.019) in psoriasis and 12.1% (P = 0.013) in normal controls. Age affected the prevalence of tinea pedis in normal controls (P < 0.001), psoriasis patients (P = 0.001) and atopic dermatitis patients (P = 0.001), with higher prevalence with increasing age. Trichophyton rubrum was the most common species in psoriasis (71.9%), atopic dermatitis (75.0%) and normal controls (73.3%). Our study found a relatively high prevalence of tinea pedis among psoriasis patients.     

Intercellular adhesion molecule-1 concentration,in utero,decreases after antibiotic treatment

A parturient suffering from preterm premature rupture of membranes at 29-weeks of gestation was hospitalized and staphylococcus was detected in her amniotic fluid. After treatment with antibiotics she delivered a healthy neonate three weeks later. ICAM-1 levels decreased by 20 fold correlating with elimination of the bacteria and prolongation of the pregnancy.     

Gastroretentive Accordion Pill: Enhancement of riboflavin bioavailability in humans.

The purpose of this study was to evaluate the ability of the Accordion Pill (AP), a novel controlled release gastroretentive unfolding dosage form (DF), to increase the bioavailability of riboflavin (RF) in humans. Three formulations containing 75 mg of RF and differing in release rate (immediate release (IR) capsule, AP#1, and AP#2) were administered with a low-calorie meal. Gastric residence time (GRT) of the AP was assessed by magnetic resonance imaging. Serial blood and urine samples were taken and assayed for RF. The AP demonstrated prolonged (up to 10.5 h) GRT in humans. Significant elevation in RF bioavailability (209+/-37%, mean+/-S.E.) was achieved by the AP#1 in comparison to the IR capsule. A correlation was established between the in-vitro release rates from DF and bioavailability of RF in humans, and it was modeled taking into account the saturable nature of RF absorption transport and its narrow absorption window (NAW) in the upper gastro-intestinal tract. It is anticipated that the AP will provide a valuable pharmaceutical solution to enhance therapy with NAW drugs.     

Sexual Well-Being and Quality of Life Among High-Functioning Adults with Autism

The current research addresses the effect that being in an intimate relationship has on quality of life and well-being among high-functioning young adults on the autism spectrum (HFA). The research included 31 participants: 14 involved in intimate relationships (HFA-R) and 17 not (HFA-NR). In this integrated (quantitative and qualitative) research, participants completed on-line questionnaires on demographics, quality of life and sexuality. We hypothesized that HFA-R will report higher quality of life and sexual well-being than HFA-NR. Further, a correlation was predicted between quality of life (including: satisfaction, productive capacity, social belonging/community inclusion and independence and empowerment) and sexual well-being (including: self-esteem, sexual depression and sexual preoccupation/sexual worries), especially among HFA-R. Despite the lack of significant differences in quality of life, differences were found in the indices’ content areas. There was a higher sense of social belonging/community inclusion among HFA-R, and a positive correlation between sexual well-being and productive capacity among this group. A correlation was found between high productive capacity and low sexual worries among HFA-R, but not among HFA-NR. Contrary to expectations, a positive correlation was found between sexual well-being and satisfaction among HFA-NR, while no such correlation was found among HFA-R. The findings are discussed in the context of healthy sexuality and social development and acclimation of people with HFA. The results highlight the importance of promoting social dialogue and research on the subject.     

Everolimus Plus Letrozole for Treatment of Patients With HR+, HER2– Advanced Breast Cancer Progressing on Endocrine Therapy: An Open-label,Phase II Trial

Purpose

In the Breast cancer trials of OraL EveROlimus-2 (BOLERO-2) trial, everolimus plus exemestane improved progression-free survival (PFS) in patients with hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2-negative (HER2^?) advanced breast cancer (ABC) recurring or progressing on/after prior endocrine therapy (ET), suggesting that dual blockade using targeted therapy and ET was an effective treatment option. Here, we investigated the clinical benefit of combining everolimus with different endocrine partner, letrozole, in a similar patient population.

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011–2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR?=?3.3, 95% CI 1.1–9.9, p?=?0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.