Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review

Background: Variants in the SCN5A gene, that encodes the cardiac sodium channel, Nav1.5, are associated with a highly arrhythmogenic form of dilated cardiomyopathy (DCM). Our aim was to review the phenotypes, natural history, functional effects, and treatment outcomes of DCM-associated rare SCN5A variants. Methods: A systematic review of reported DCM-associated rare SCN5A variants was undertaken using PubMed and Embase. Results: Eighteen SCN5A rare variants in 29 families with DCM (173 affected individuals) were identified. Eleven variants had undergone experimental evaluation, with 7 of these resulting in increased sustained current flow during the action potential (eg, increased window current) and at resting membrane potentials (eg, creation of a new gating pore current). These variants were located in transmembrane voltage-sensing domains and had a consistent phenotype characterized by frequent multifocal narrow and broad complex ventricular premature beats (VPB; 72% of affected relatives), ventricular arrhythmias (33%), atrial arrhythmias (32%), sudden cardiac death (13%), and DCM (56%). This VPB-predominant phenotype was not seen with 1 variant that increased late sodium current, or with variants that reduced peak current density or had mixed effects. In the latter groups, affected individuals mainly showed sinus node dysfunction, conduction defects, and atrial arrhythmias, with infrequent VPB and VA. DCM did not occur in the absence of arrhythmias for any variant. Twelve studies (23 total patients) reported treatment success in the VPB-predominant cardiomyopathy using sodium channel-blocking drug therapy. Conclusions: SCN5A variants can present with a diverse spectrum of primary arrhythmic features. A majority of DCM-associated variants cause a multifocal VPB-predominant cardiomyopathy that is reversible with sodium channel blocking drug therapy. Early recognition of the distinctive phenotype and prompt genetic testing to identify variant carriers are needed. Our findings have implications for interpretation and management of SCN5A variants found in DCM patients with and without arrhythmias.

USP24 promotes drug resistance during cancer therapy

Drug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.

MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants

Perioperative hypersensitivity (POH) to the neuromuscular blocking drug (NMBD) rocuronium was previously thought to be IgE and mast cell (MC)-mediated. However, the recent seminal observation that rocuronium induces degranulation in murine peritoneal MCs (PMCs) via Mas-related G protein-coupled receptor B2 (MrgprB2) led to the idea that POH to this drug involves the activation of MRGPRX2 (human ortholog of MrgprB2). Furthermore, based on the demonstration that a patient with POH to rocuronium displayed three missense mutations (M196I, L226P and L237P) in MRGPRX2’s transmembrane domains, it was proposed that this hypersensitivity reaction resulted from aberrant activation of this receptor. We found that rocuronium at 20 µg/mL caused degranulation in mouse PMCs via MrgprB2 but required at least 500 µg/mL to induce degranulation in human MCs via MRGPRX2. Furthermore, RBL-2H3 cells transiently expressing M196I, L226P and L237P variants did not display enhanced degranulation in response to rocuronium when compared to the wild-type receptor. These findings provide the first demonstration that rocuronium induces degranulation in human MCs via MRGPRX2. Furthermore, the important differences between MrgprB2 and MRGPRX2 and the inability of rocuronium to induce enhanced response in cells expressing MRGPRX2 variants suggest that the mechanism of its POH is more complex than previously thought.

Substitution maintenance therapy – effective prevention or way of committing a crime?

The scientific work focuses on the features of the program of substitution maintenance therapy and its preventive function for the prevention of drug crime. It is proved that general preventive measures such as appearing in the media, personal interviews, publication of the facts of detected offenses, blocking drug trafficking channels are not enough. The international experience of functioning of substitution maintenance therapy is analyzed. Based on the discussions on this program, their preventive role is noted.

Natural Products: A Potential Source of Malaria Transmission Blocking Drugs?

The ability to block human-to-mosquito and mosquito-to-human transmission of Plasmodium parasites is fundamental to accomplish the ambitious goal of malaria elimination. The WHO currently recommends only primaquine as a transmission-blocking drug but its use is severely restricted by toxicity in some populations. New, safe and clinically effective transmission-blocking drugs therefore need to be discovered. While natural products have been extensively investigated for the development of chemotherapeutic antimalarial agents, their potential use as transmission-blocking drugs is comparatively poorly explored. Here, we provide a comprehensive summary of the activities of natural products (and their derivatives) of plant and microbial origins against sexual stages of Plasmodium parasites and the Anopheles mosquito vector. We identify the prevailing challenges and opportunities and suggest how these can be mitigated and/or exploited in an endeavor to expedite transmission-blocking drug discovery efforts from natural products.

Recent advances in transmission-blocking drugs for malaria elimination

The scientific community worldwide has realized that malaria elimination will not be possible without development of safe and effective transmission-blocking interventions. Primaquine, the only WHO recommended transmission-blocking drug, is not extensively utilized because of the toxicity issues in G6PD deficient individuals. Therefore, there is an urgent need to develop novel therapeutic interventions that can target malaria parasites and effectively block transmission. But at first, it is imperative to unravel the existing portfolio of transmission-blocking drugs. This review highlights transmission-blocking potential of current antimalarial drugs and drugs that are in various stages of clinical development. The collective analysis of the relationships between the structure and the activity of transmission-blocking drugs is expected to help in the design of new transmission-blocking antimalarials.

Hereditary Long Q-T Without Congenital Deafness (Romano-Ward) Syndrome

We report a case o fhereditary long Q-T syndrome without congenital deafness (Romano-Ward syndrome). In four members of a family, a father and his daughters, the Q-T intervals on the EKG were found to be prolonged. There were no other accompanying familial anomalies such as deafness or a tendency to extracellular hypokalemia The youngest daughter which had the longest. Q-T interval had several Adams-Stokes attacks, and died in the last attack at the age of 23 months. Her two older siblings died at the age of 15 and 10 months with the same typical clinical histories. The eldest daughter, a 12-year old girl, has no clinical symptoms at all, while the fourth child, 5-yeltr old girl has several occasions of near fainting attacks. The EKG of the father showed several runs of supraventricular premature contractions that ceased spontaneously, besides evidence of the prolongation of Q-T interval. The beta-adrenergic blocking drug (propranalol) given in a relatively small maintenance dose, proved to be effective in preventing attacks of the father and the fourth child, despite the unchanged prolongation of the Q-T interval.