Cystic fibrosis transmembrane conductance regulator chloride channel blockers:Pharmacological,biophysical and physiological relevance

Dysfunction of the cystic fibrosis transmembrane con-ductance regulator(CFTR) chloride channel causes cys-tic fibrosis, while inappropriate activity of this channeloccurs in secretory diarrhea and polycystic kidney dis-ease. Drugs that interact directly with CFTR are there-fore of interest in the treatment of a number of diseasestates. This review focuses on one class of small mol-ecules that interacts directly with CFTR, namely inhibi-tors that act by directly blocking chloride movementthrough the open channel pore. In theory such com-pounds could be of use in the treatment of diarrheaand polycystic kidney disease, however in practice allknown substances acting by this mechanism to inhibitCFTR function lack either the potency or specificity forin vivo use. Nevertheless, this theoretical pharmaco-logical usefulness set the scene for the developmentof more potent, specific CFTR inhibitors. Biophysically,open channel blockers have proven most useful as ex-perimental probes of the structure and function of theCFTR chloride channel pore. Most importantly, the useof these blockers has been fundamental in developing afunctional model of the pore that includes a wide innervestibule that uses positively charged amino acid sidechains to attract both permeant and blocking anionsfrom the cell cytoplasm. CFTR channels are also subjectto this kind of blocking action by endogenous anionspresent in the cell cytoplasm, and recently this blocking effect has been suggested to play a role in the physio-logical control of CFTR channel function, in particular as a novel mechanism linking CFTR function dynamically to the composition of epithelial cell secretions. It has also been suggested that future drugs could target this same pathway as a way of pharmacologically increasing CFTR activity in cystic fibrosis. Studying open channel blockers and their mechanisms of action has resulted in significant advances in our understanding of CFTR as a pharmacological target in disease states, of CFTR chan-nel structure and function, and of how CFTR activity is controlled by its local environment.     

In silico assessment of drug safety in human heart applied to late sodium current blockers

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I_NaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K⁺ current (I_Kr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I_Kr/I_NaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I_NaL and I_Kr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC₅₀s for I_Kr and I_NaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I_NaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.     

The soil block test: Potential for improving our understanding of the role of soil source on performance

The soil block test is widely used in North America for evaluating the decay resistance of various wood-based materials. One drawback of this test is that soils from different sources may result in variable wood weight losses. Developing more definitive screening criteria for soils would help select soils that would be most appropriate for use in these procedures. Soils from seven different sources were characterized for soil texture, pH, water holding capacity, C:N ratio, bulk density and then used in soil block tests against two white rot and two brown rot fungi. While there were substantial differences in soil characteristics, none of the parameters were correlated with wood weight loss. The results illustrate the difficulty in predicting fungal behavior in laboratory tests based upon soil characteristics.     

Cancer cell cannibalism: Multiple triggers emerge for entosis

Entosis is a form of epithelial cell engulfment and cannibalism prevalent in human cancer. Until recently, the only known trigger for entosis was loss of attachment to the extracellular matrix, as often occurs in the tumour microenvironment. However, two new studies now reveal that entosis can also occur among adherent epithelial cells, induced by mitosis or glucose starvation. Together, these findings point to the intriguing notion that certain hallmark properties of cancer cells, including anchorage independence, aberrant proliferation and metabolic stress, can converge on the induction of cell cannibalism, a phenomenon so frequently observed in tumours. In this review, we explore the molecular, cellular and biophysical mechanisms underlying entosis and discuss the impact of cell cannibalism on tumour biology.     

2,4‑Di‑tert‑butylphenol,a potential HDAC6 inhibitor,induces senescence and mitotic catastrophe in human gastric adenocarcinoma AGS cells

The natural product 2,4?di?tert?butylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased β?galactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity.     

Universal Optimality of Nearest Neighbour Balanced Block Designs using Second Order Correlated Models

Block designs for observations correlated in one dimension are investigated. Santharam and Ponnusamy (1995) investigated the universal optimality of Nearest Neighbour balanced block designs (NNBD) using first order correlated models (AR(1), MA(1) and ARMA(1,1)). In this article we have investigated the universal optimality of NNBD using second order correlated models (ar(2), and MA (2)).     

2021 PACES expert consensus statement on the indications and management of cardiovascular implantable electronic devices in pediatric patients: Executive summary

Guidelines for the implantation of cardiac implantable electronic devices (CIEDs) have evolved since publication of the initial ACC/AHA pacemaker guidelines in 1984 [1]. CIEDs have evolved to include novel forms of cardiac pacing, the development of implantable cardioverter defibrillators (ICDs) and the introduction of devices for long term monitoring of heart rhythm and other physiologic parameters. In view of the increasing complexity of both devices and patients, practice guidelines, by necessity, have become increasingly specific. In 2018, the ACC/AHA/HRS published Guidelines on the Evaluation and Management of Patients with Bradycardia and Cardiac Conduction Delay [2], which were specific recommendations for patients >18 years of age. This age-specific threshold was established in view of the differing indications for CIEDs in young patients as well as size-specific technology factors. Therefore, the following document was developed to update and further delineate indications for the use and management of CIEDs in pediatric patients, defined as ≤21 years of age, with recognition that there is often overlap in the care of patents between 18 and 21 years of age.This document is an abbreviated expert consensus statement (ECS) intended to focus primarily on the indications for CIEDs in the setting of specific disease/diagnostic categories. This document will also provide guidance regarding the management of lead systems and follow-up evaluation for pediatric patients with CIEDs. The recommendations are presented in an abbreviated modular format, with each section including the complete table of recommendations along with a brief synopsis of supportive text and select references to provide some context for the recommendations. This document is not intended to provide an exhaustive discussion of the basis for each of the recommendations, which are further addressed in the comprehensive PACES-CIED document [3], with further data easily accessible in electronic searches or textbooks.