Optimisation of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis.

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF.

Differential Inflammatory Cytokine Elaboration in Serum from Brick Kiln Workers in Bhaktapur, Nepal.

Previous studies involving workers at brick kilns in the Kathmandu Valley of Nepal have investigated chronic exposure to hazardous levels of fine particulate matter (PM) common in ambient and occupational environments. Such exposures are known to cause and/or exacerbate chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. However, there is a paucity of data regarding the status of systemic inflammation observed in exposed workers at brick manufacturing facilities within the country.

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo.

Background: Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?

Methods: Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF.

Respirable dust and crystalline silica concentrations among workers at a brick kiln in Bhaktapur, Nepal.

Exposure to respirable dust and crystalline silica (SiO) has been linked to chronic obstructive pulmonary disease, silicosis, cancer, heart disease, and other respiratory diseases. Relatively few studies have measured respirable dust and SiO concentrations among workers at brick kilns in low- and middle-income countries. The purpose of this study was to measure personal breathing zone (PBZ) respirable dust and SiO concentrations among workers at one brick kiln in Bhaktapur, Nepal.

Aerosol Measurement Degradation in Low-Cost Particle Sensors Using Laboratory Calibration and Field Validation.

Increasing concern over air pollution has led to the development of low-cost sensors suitable for wide-scale deployment and use by citizen scientists. This project investigated the AirU low-cost particle sensor using two methods: (1) a comparison of pre- and post-deployment calibration equations for 24 devices following use in a field study, and (2) an in-home comparison between 3 AirUs and a reference instrument, the GRIMM 1.109.

Indoor and outdoor air pollution and couple fecundability: a systematic review.

Background: Air pollution is both a sensory blight and a threat to human health. Inhaled environmental pollutants can be naturally occurring or human-made, and include traffic-related air pollution (TRAP), ozone, particulate matter (PM) and volatile organic compounds, among other substances, including those from secondhand smoking. Studies of air pollution on reproductive and endocrine systems have reported associations of TRAP, secondhand smoke (SHS), organic solvents and biomass fueled-cooking with adverse birth outcomes.

Regulation of Gramicidin Channel Function Solely by Changes in Lipid Intrinsic Curvature.

Membrane protein function is regulated by the lipid bilayer composition. In many cases the changes in function correlate with changes in the lipid intrinsic curvature ( ), and is considered a determinant of protein function. Yet, water-soluble amphiphiles that cause either negative or positive changes in curvature have similar effects on membrane protein function, showing that changes in lipid bilayer properties other than are important-and may be dominant.

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit as a potentiator of mutant human F508del and wild-type CFTR channels is reported.

Indoor Air Quality Issues for Rocky Mountain West Tribes.

Native American populations face considerable health disparities, especially among those who live on reservations, where access to healthcare, education, and safe housing can be limited. Previous research on tribal housing has raised concerns about housing construction, damage, and possible linkage to adverse health effects (e.g.

Potentiating TMEM16A does not stimulate airway mucus secretion or bronchial and pulmonary arterial smooth muscle contraction.

The calcium-activated chloride channel (CaCC) TMEM16A enables chloride secretion across several transporting epithelia, including in the airways. Additional roles for TMEM16A have been proposed, which include regulating mucus production and secretion and stimulating smooth muscle contraction. The aim of the present study was to test whether the pharmacological regulation of TMEM16A channel function, could affect any of these proposed biological roles in the airways.

Investigating Measurement Variation of Modified Low-Cost Particle Sensors.

Particulate matter (PM) has demonstrably increased rates of cardiovascular and respiratory related disease; thus, a low-cost sensor that accurately measures PM is desirable including for smaller and more private environments such as residential homes. The low-cost Dylos and the Utah Modified Dylos Sensor (UMDS) have been shown to be highly correlated with references instruments for measuring particle counts and aerosol concentrations, which makes them useful tools for air quality studies. An analytical calibration equation (calibration) is used to describe the linear relationship between the UMDS and a reference instrument, providing the best estimate of PM concentrations when the UMDS is operated.

TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.

Enhancing non-CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport.

Development of a calibration chamber to evaluate the performance of low-cost particulate matter sensors.

Low-cost particulate matter (PM) air quality sensors are becoming widely available and are being increasingly deployed in ambient and home/workplace environments due to their low cost, compactness, and ability to provide more highly resolved spatiotemporal PM concentrations. However, the PM data from these sensors are often of questionable quality, and the sensors need to be characterized individually for the environmental conditions under which they will be making measurements. In this study, we designed and assessed a cost-effective (∼$700) calibration chamber capable of continuously providing a uniform PM concentration simultaneously to multiple low-cost PM sensors and robust calibration relationships that are independent of sensor position.

Meloxicam in the management of post-operative pain: Narrative review.

Oral formulations of meloxicam, a preferential cyclooxygenase-2 (COX-2) inhibitor, have long been used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as various pain syndromes of skeletomuscular origin (e.g., low back pain).

Laboratory evaluation of a low-cost, real-time, aerosol multi-sensor.

Exposure to occupational aerosols are a known hazard in many industry sectors and can be a risk factor for several respiratory diseases. In this study, a laboratory evaluation of low-cost aerosol sensors, the Dylos DC1700 and a modified Dylos known as the Utah Modified Dylos Sensor (UMDS), was performed to assess the sensors' efficiency in sampling respirable and inhalable dust at high concentrations, which are most common in occupational settings. Dust concentrations were measured in a low-speed wind tunnel with 3 UMDSs, collocated with an aerosol spectrometer (Grimm 1.

Heterogeneity of Outcomes in D'Amico Intermediate-Risk Prostate Cancer Patients after Radical Prostatectomy: Influence of Primary and Secondary Gleason Score.

Aim: The aim of this study was to clarify and examine the outcomes of prostate cancer patients classified as intermediate risk (IR) using the D'Amico risk classification system, specifically focusing on the influence of primary and secondary biopsy Gleason score (BGS).

Patients And Methods: An institutional review board-approved database of robotic-assisted radical prostatectomies performed after 2006 was stratified by standard D'Amico criteria. IR patients were then sub-stratified by BGS.

The Modulating Effects of Benign Prostate Enlargement Medications on Upgrading Predictors in Patients with Gleason 6 at Biopsy.

Background: Upgrading following prostate biopsy is very common in clinical practice. This study investigated whether the use of 5-alpha reductase inhibitors (ARI) and alpha blockers affect known clinical predictors of Gleason score upgrading or not.

Materials And Methods: A retrospective study on 998 patients treated with robotic assisted laparoscopic prostatectomy for clinically localized biopsy Gleason score 6 prostate cancer were studied.

Riding (High) into the danger zone: a review of potential differences in chemical exposures in fighter pilots resulting from high altitude and G-forces.

When in flight, pilots of high performance aircraft experience conditions unique to their profession. Training flights, performed as often as several times a week, can expose these pilots to altitudes in excess of 15 km (~50,000 ft, with a cabin pressurized to an altitude of ~20,000 ft), and the maneuvers performed in flight can exacerbate the G-forces felt by the pilot. While the pilots specifically train to withstand these extreme conditions, the physiologic stress could very likely lead to differences in the disposition of chemicals in the body, and consequently, dangerously high exposures.

Are magnetic resonance imaging undetectable prostate tumours clinically significant? Results of histopathological analyses.

Objective: To investigate whether tumours at threshold values for detection on magnetic resonance imaging (MRI) represent clinically significant tumours or not, and therefore the utility of MRI in active surveillance (AS) protocols.

Patients And Methods: A retrospective analysis of a single institution database was performed after Institutional Review Board approval. Between 2010 and 2013, 1633 patients underwent robot-assisted laparoscopic prostatectomy (RALP) at a single institution by a single surgeon.

Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.

Factors associated with biosafety level-2 research workers' laboratory exit handwashing behaviors and glove removal compliance.

Biosafety level-2 laboratories are designated for work with human-derived samples or moderate-risk microorganisms that transmit primarily by direct contact exposures. Many laboratory procedures generate unseen droplets that contaminate workers' hands, equipment, and work surfaces. Workers' strict adherence to glove removal and handwashing is required prior to laboratory exit to prevent inadvertent transmission of pathogens to self or others.

Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C-Terminal Substitution on Biological Activity.

The duocarmycins are potent antitumor agents with potential for use in the development of antibody-drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents.

Comparison of Single-Point and Continuous Sampling Methods for Estimating Residential Indoor Temperature and Humidity.

Residential temperature and humidity are associated with multiple health effects. Studies commonly use single-point measures to estimate indoor temperature and humidity exposures, but there is little evidence to support this sampling strategy. This study evaluated the relationship between single-point and continuous monitoring of air temperature, apparent temperature, relative humidity, and absolute humidity over four exposure intervals (5-min, 30-min, 24-hr, and 12-days) in 9 northern Utah homes, from March-June 2012.

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD.