Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Angiographic profile and outcomes in persistent non-valvular atrial fibrillation: A study from tertiary care center in North India

BackgroundThe relationship of atrial fibrillation (AF) with coronary artery disease (CAD) is well established, yet it is often missed. There is evidence of myocardial ischemia on stress imaging in AF patients in the absence of obstructive CAD. In this prospective cohort, we studied the angiographic profiles of non-valvular AF patients.MethodsThe study was a nonrandomized, prospective, single-center observational study of consecutive patients of persistent non-valvular AF. Patients symptomatic for AF despite optimal medical therapy for 3 months were recruited and all underwent coronary angiograms (CAG). Patients with prior history of CAD were excluded.ResultsA total of 70 patients were followed for a mean duration of 12 ± 1.4 months. The mean age of the study group was 66.07 (±11.49) years. Hypertension was the commonest comorbidity seen in 74% patients. Obstructive CAD was present in 32 (46%) patients, non-obstructive (<50% stenosis) CAD in 17 (24%) patients and normal coronaries in 21 (30%) patients. Overall 49 (70%) patients had evidence of CAD. Amongst patients without obstructive CAD, slow flow was seen in 16 (42%) patients. Lower baseline ejection fraction, lower haemoglobin & albumin levels and higher creatinine levels was associated with increased mortality. In patients without obstructive CAD, hospitalizations for fast ventricular rate were significantly increased in those having slow flow on CAG (p = 0.005).ConclusionsMajority (70%) of our patients had evidence of atherosclerotic CAD on CAG. A large proportion of patients without obstructive CAD had slow flow on CAG.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Ocular dysfunctions and toxicities induced by antiepileptic medications: Types,pathogenic mechanisms,and treatment strategies

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug.

Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use.

Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.     

Complete recovery of filler-induced visual loss following subcutaneous hyaluronidase injection

The rise in popularity of hyaluronic acid (HA) dermal filler injection has caused an exceptional increase in the number of cases of reported irreversible blindness. Here, we reported a case of ischemic optic neuropathy and ophthalmoplegia following subcutaneous HA filler injection with complete visual recovery. A 31-year-old Chinese woman presented with sudden onset of right monocular visual impairment associated with diplopia. Patient had received a hyaluronic acid-containing ?ller injection for nasal dorsum augmentation twelve hours prior to presentation. Visual acuity of the right eye was counting finger. A right relative afferent pupillary defect was demonstrated with ophthalmoplegia. Humphrey visual field test disclosed a right inferior altitudinal field defect with impairment of colour vision. Computed tomography of the orbit revealed mild enlargement of the right medial and inferior recti muscles. Our patient showed a tremendous improvement of vision after a subcutaneous hyaluronidase injection with complete visual recovery within 2 weeks.     

A guide to oral vaccination: Highlighting electrospraying as a promising manufacturing technique toward a successful oral vaccine development

Most vaccines approved by regulatory bodies are administered via intramuscular or subcutaneous injections and have shortcomings, such as the risk of needle-associated blood infections, pain and swelling at the injection site. Orally administered vaccines are of interest, as they elicit both systemic and mucosal immunities, in which mucosal immunity would neutralize the mucosa invading pathogen before the onset of an infection. Hence, oral vaccination can eliminate the injection associated adverse effects and enhance the person's compliance. Conventional approaches to manufacturing oral vaccines, such as coacervation, spray drying, and membrane emulsification, tend to alter the structural proteins in vaccines that result from high temperature, organic and toxic solvents during production. Electrohydrodynamic processes, specifically electrospraying, could solve these challenges, as it also modulates antigen release and has a high loading efficiency. This review will highlight the mucosal immunity and biological basis of the gastrointestinal immune system, different oral vaccine delivery approaches, and the application of electrospraying in vaccines development.     

Associations between heart rate variability and maximal fat oxidation in two different cohorts of healthy sedentary adults

Background and aimsResting heart rate variability (HRV) and maximal fat oxidation (MFO) during exercise are both considered as a noninvasive biomarkers for early detection of cardiovascular risk factors. Thus, this study aimed to analyze the relationship between resting HRV parameters and MFO during exercise, and the intensity of exercise that elicit MFO (Fat_max) in healthy sedentary adults.Methods and resultsA total of 103 healthy young adults (22.2 ± 2.3 years old, 67% female; from the ACTIBATE cohort) and 67 healthy middle-aged adults (53.1 ± 5.0 years old, 52% female; from the FIT-AGEING cohort) were included in this cross-sectional study. HRV was assessed using a Polar RS800CX heart rate monitor, while MFO and Fat_max were determined during a graded exercise treadmill test using indirect calorimetry. No significant associations were observed for healthy young adults (standardized β coefficients ranged from ?0.063 to 0.094, and all P ≥ 0.347) and for middle-aged adults (standardized β coefficients ranged from ?0.234 to 0.090, and all P ≥ 0.056). Nevertheless, only a weak association was observed between one HRV parameter in time-domain (the percentage of R-R intervals that shows a difference higher than 50 ms [pNN50]) and MFO in the cohort of middle-aged adults (β coefficient = ?0.279, and P = 0.033).ConclusionThe results of this study suggest that resting HRV parameters are not associated with MFO and Fat_max during exercise in two independent cohorts of healthy sedentary young and middle-aged adults, respectively.     

On estimands arising from misspecified semiparametric rate-based analysis of recurrent episodic conditions

Marginal rate-based analyses are widely used for the analysis of recurrent events in clinical trials. In many areas of application, the events are not instantaneous but rather signal the onset of a symptomatic episode representing a recurrent infection, respiratory exacerbation, or bout of acute depression. In rate-based analyses, it is unclear how to best handle the time during which individuals are experiencing symptoms and hence are not at risk. We derive the limiting value of the Nelson-Aalen estimator and estimators of the regression coefficients under a semiparametric rate-based model in terms of an underlying two-state process. We investigate the impact of the distribution of the episode durations, heterogeneity, and dependence on the asymptotic and finite sample properties of standard estimators. We also consider the impact of these features on power in trials designed to test intervention effects on rate functions. An application to a trial of individuals with herpes simplex virus is given for illustration.