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.     

Effect of Preclinical Simulation on Family Nurse Practitioner Student’s Readiness for Practice

This project aimed to enhance clinical education preparation in a family nurse practitioner graduate program in rural central Appalachian by providing a psychomotor skills-based simulation with the use of the defusing, discovering, and deepening (3D) debriefing method. The students were surveyed after graduation to determine effectiveness. Program outcomes to measure readiness to practice were graduation, employment, and certification rates. The postgraduation surveys indicated the simulation contributed to an increase in psychomotor skill performance, practicing safe patient care, and making independent decisions in practice. Common themes emerged of feeling “prepared for practice” and being “more marketable” with the procedural skills learned in the simulation.     

A review of dementia,focusing on the distinct roles of viral protein corona and MMP9 in dementia: Potential pharmacotherapeutic priorities

Dementia, in particular, is a defining feature of Alzheimer's and Parkinson's diseases. Because of the combination of motor and cognitive impairments, Parkinson's disease dementia (PDD) has a greater impact on affected people than Alzheimer's disease dementia (ADD) and others. If one family member develops dementia, the other members will suffer greatly in terms of social and occupational functioning. Currently, no relevant treatment is available based on an examination of the absolute pathophysiology of dementia. As a result, our objective of current review encouraged to look for dementia pharmacotherapy based on their pathogenesis. We systematically searched electronic databases such as PubMed, Scopus, and ESCI for information on the pathophysiology of demetia, as well as their treatment with allopathic and herbal medications. By modulating intermediate proteins, oxidative stress, viral protein corona, and MMP9 are etiological factors that cause dementia. The pathophysiology of ADD was described by two hypotheses: the amyloid cascade hypothesis and the tau and tangle hypothesis. ADD is caused by an increase in amyloid-beta (Aβ) and neurofibrillary tangles in the cerebrum. The viral protein corona (VPC) is more contagious and helps to form amyloid-beta (Aβ) plaques and neurofibrillary tangles in the cerebrum. Thioredoxin interacting protein (TXNIP) inside the BBB encourages Aβ to become more engaged. PDD is caused by decreased or absent dopamine secretion from nerve cells in the substantia nigra, as well as PRKN gene deletion/duplication mutations, and shift in the PRKN-PACRG organisation, all of which are linked to ageing. This article discussed the pathophysiology of dementia, as well as a list of herbal medications that can easily cross the BBB and have a therapeutic effect on dementia.     

Clinico-hematological and Outcome Profile of Pediatric B-other-ALL and BCR::ABL1-like pre-B-ALL: An Integrated Genomic Study From North India

PurposeBCR::ABL1-like pre-B-ALL comprises a myriad of genetic lesions making molecular diagnosis challenging and expensive. Its frequency and outcome are less studied in resource-constraint settings.Methods154 pre-B-ALL cases (0-12 years) were enrolled as group 1 (37 cases of B-other-ALL) and group 2 (117 patients with recurrent translocations/ hyperdiploidy). Group 1 was evaluated for BCR::ABL1-like genetic lesions and copy-number abnormalities (CNAs) as per our published PACE approach supplemented with targeted RNA sequencing.ResultsBCR::ABL1-like frequency was 5.2% (8 of 154) and 22% (8 of 37) with the PACE approach alone in the whole and B-other-ALL cohort, respectively. The addition of targeted RNA-sequencing had led to the frequency increasing to 9% (14 of 154) and 38% (14 of 37) in the whole and B-other-ALL cohort, respectively. P2RY8::CRLF2, IGH::CRLF2, and RCSD1::ABL1 were noted in 8 (57.1%), 4 (28.6%), and 2 (14.3%) patients, respectively. CNAs were noted in 56.7% (21 of 37) of patients. The BCR::ABL1-like group had a significantly higher initial WBC count of ≥ 50,000/mm³ (71.4%; P < .001) than group 2. The 4-year OS, EFS, RFS of group 1 was not statistically different from group 2, though RFS was borderline poor (84.2%, 51.7%, 56.9% Vs. 82.6%, 62.9%, 78% [P - .42, P - .53, P - .059]). The 4-year EFS and RFS for BCR::ABL1-like cases was 70.7% and 76.6%, respectively.ConclusionsThe sensitivity of detecting BCR::ABL1-like lesions had increased significantly from 22% using the PACE approach alone to 38% in B-other-ALLs with the integrated approach. Although outcomes were not statistically different, a higher percentage of relapses were noted in the B-other-ALL group.     

Moving Knowledge to Action: Aware,Adopt, Adapt (A3)

This article begins with an overview of the knowledge translation (KT) process, introduces commonly used KT terms and the Aware-Adopt-Adapt (A³) KT map. The A³ was created by a nurse practitioner (NP) for practitioners and NP students to provide a map for those who wish to move existing knowledge to practice, yet do not know where to start or do not have the time to take a deeper dive into specific KT theories.     

Survival and Outcomes of Newly Diagnosed Multiple Myeloma Patients Stratified by Transplant Status 2007-2018: Retrospective Analysis from the Canadian Myeloma Research Group Database

BackgroundConsiderable progress has been made in therapeutic options for multiple myeloma (MM). Understanding the current landscape of MM treatment options and associated outcomes in the real world is important in providing key insights into clinical and knowledge gaps which could be targeted for further optimization.MethodsThe Canadian Myeloma Research Group Database (CMRG-DB) is a prospectively maintained disease-specific database with >7000 patients. The objective of this study was to describe the trends in the treatment landscape and outcomes including early mortality, time to next treatment, and overall survival (OS) in each line of treatment stratified by autologous stem cell transplant (ASCT) receipt among newly-diagnosed MM patients in Canada between 2007 and 2018.ResultsA total of 5154 patients were identified among which 3030 patients (58.8%) received an upfront ASCT and 2124 (41.2%) did not. At diagnosis, the median age was 64 years and 58.6% were males. Bortezomib and lenalidomide were most frequently used (>50%) in first and second-line treatment respectively among both the ASCT and non-ASCT cohort. The median OS was 122.0 months (95% Cl 115.0-135.0 months) and 54.3 months (95% CI 50.8-58.8 months) for the ASCT and non-ASCT cohort respectively with an incremental decrease in OS in each subsequent line of treatment.ConclusionWe present the largest study to date in the Canadian landscape showing the characteristics, therapy usage, and outcomes among MM patients. This information will be critical in benchmarking current outcomes and provide key insight into areas of unmet needs and gaps for improvement of MM patients nationally.     

STAC3 related congenital myopathy: A case series of seven Comorian patients

The Bailey-Bloch congenital myopathy, also known as Native American myopathy (NAM), is an autosomal recessive congenital myopathy first reported in the Lumbee tribe people settled in North Carolina (USA), and characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia. NAM is linked to STAC3 gene coding for a component of excitation-contraction coupling in skeletal muscles. A homozygous missense variant (c.851G > C; p.Trp284Ser) in STAC3 segregated with NAM in the Lumbee families. Non-Native American patients with STAC3 related congenital myopathy, and with other various variants of STAC3 have been reported. Here, we present seven patients from the Comoros Islands (located in the Mozambique Channel) diagnosed with STAC3 related congenital myopathy and having the recurrent variant identified in the Lumbee people. The series is the second largest series of patients having STAC3 related congenital myopathy with a shared ethnicity after le Lumbee series. Local history and geography may explain the overrepresentation of NAM in the Comorian Archipelago with a founder effect. Further researches would be necessary for the understanding of the onset of the NAM in Comorian population as search of the “classical” STAC3 variant in East African population, and haplotypes comparison between Comorian and Lumbee patients.