Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Downregulation of the silent potassium channel Kv8.1 increases motor neuron vulnerability in amyotrophic lateral sclerosis.

While voltage-gated potassium channels have critical roles in controlling neuronal excitability, they also have non-ion-conducting functions. Kv8.1, encoded by the KCNV1 gene, is a 'silent' ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in amyotrophic lateral sclerosis patient-derived motor neurons carrying a superoxide dismutase 1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1-deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected and distinct roles of Kv8.1 and Kv2.2 in amyotrophic lateral sclerosis-related neurodegeneration.

Bioprosthetic versus mechanical valves for mitral valve replacement in patients < 70 years: an updated pairwise meta-analysis.

BACKGROUND: The ideal conduit for mitral valve replacement (MVR) remains elusive, particularly among younger patients due to increased life expectancy. We perform a pairwise meta-analysis comparing the use of bioprosthetic valves (BPV) and mechanical mitral valves (MMV) in patients < 70 years old undergoing MVR. METHODS: We comprehensively searched medical databases to identify studies comparing the use of BPV and MMV in patients < 70 years old undergoing MVR. Pairwise meta-analysis was performed using the Mantel-Haenszel method in R version 4.0.2. Outcomes were pooled using the random effect model as risk ratios (RR) with their 95% confidence intervals (95% CI). RESULTS: 16,879 patients from 15 studies were pooled. Compared to MMV, BPV was associated with significantly higher rates of 30-day mortality (RR 1.53, p = 0.0006) but no difference in 30-day stroke (RR 0.70, p = 0.43). At a weighted mean follow-up duration of 14.1 years, BPV was associated with higher rates of long-term mortality (RR 1.28, p = 0.0054). No difference was seen between the two groups for risk of long-term stroke (RR 0.92, p = 0.67), reoperation(RR 1.72, p = 0.12), or major-bleeding (RR 0.57, p = 0.10) at a weighted mean follow-up duration of 11.7, 11.3, and 11.9 years, respectively. CONCLUSION: The use of MMV in patients < 70 undergoing MVR is associated with lower rates of 30-day/long-term mortality compared to BPV. No significant differences were observed for risk of 30-day/long-term stroke, long-term reoperation, and long-term major bleeding. These findings support the use of MMV in younger patients, although prospective, randomized trials are still needed.

Unicompartmental knee arthroplasty revised to total knee arthroplasty versus primary total knee arthroplasty: A meta-analysis of matched studies.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) offers a less invasive alternative to total knee arthroplasty (TKA), but is accompanied by a high revision risk. The aim of our study was to perform a meta-analysis comparing outcomes of UKA revised to TKA versus primary TKA, to assess if UKA is an effective treatment option, despite its potential need for revision. METHODS: Studies comparing matched cohorts of patients with UKA revised to TKA versus primary TKA were identified via the PubMed, Ovid EMBASE, and Scopus databases. The following outcome measures were compared between treatment modalities: postoperative reoperation or revision, total complications, range of motion, patient-reported outcome measures, and length of stay. RESULTS: Ten studies were included with 1,070 patients: 410 UKA to TKA and 660 primary TKA. At an average follow-up of 5.6 years in the UKA to TKA cohort and 5.7 years in the primary TKA cohort, there were no significant difference in risk of revision (p = 0.81), total complications (p = 0.54), range of motion (p = 0.09), or length of stay (p = 0.31). Both objective and functional Knee Society Score were significantly higher in patients with primary TKA (p < 0.01). However, there was no difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) or pain scores (p = 0.13 and p = 0.21, respectively). CONCLUSION: UKA revised to TKA produced comparable clinical and patient-reported outcomes to a primary TKA. UKA may be an effective treatment option in unicompartmental arthritis that would allow for improved functionality and satisfaction without the concern of outcomes deteriorating in patients where a revision becomes necessary.

General Anesthesia Versus Local Anesthesia in Patients Undergoing Transcatheter Aortic Valve Replacement: An Updated Meta-Analysis and Systematic Review.

OBJECTIVES: For patients with aortic stenosis, transcatheter aortic valve replacement (TAVR) offers a less invasive treatment modality than conventional surgical valve replacement. Although the surgery is performed traditionally under general anesthesia (GA), recent studies have described success with TAVR using local anesthesia (LA) and/or conscious sedation. The study authors performed a pairwise meta-analysis to compare the clinical outcomes of TAVR based on operative anesthesia management. DESIGN: A random effects pairwise meta-analysis via the Mantel-Haenszel method. SETTING: Not applicable, as this is a meta-analysis. PARTICIPANTS: No individual patient data were used. INTERVENTIONS: Not applicable, as this is a meta-analysis. MEASUREMENTS AND MAIN RESULTS: The authors comprehensively searched the PubMed, Embase, and Cochrane databases to identify studies comparing TAVR performed using LA or GA. Outcomes were pooled as risk ratios (RR) or standard mean differences (SMD) and their 95% CIs. The authors' pooled analysis included 14,388 patients from 40 studies (7,754 LA; 6,634 GA). Compared to GA TAVR, LA TAVR was associated with significantly lower rates of 30-day mortality (RR 0.69; p < 0.01) and stroke (RR 0.78; p = 0.02). Additionally, LA TAVR patients had lower rates of 30-day major and/or life-threatening bleeding (RR 0.64; p = 0.01), 30-day major vascular complications (RR 0.76; p = 0.02), and long-term mortality (RR 0.75; p = 0.009). No significant difference was seen between the 2 groups for a 30-day paravalvular leak (RR 0.88, p = 0.12). CONCLUSIONS: Transcatheter aortic valve replacement performed using LA is associated with lower rates of adverse clinical outcomes, including 30-day mortality and stroke. No difference was seen between the 2 groups for a 30-day paravalvular leak. These results support the use of minimally invasive forms of TAVR without GA.

Coronary Revascularization in Patients With Diabetes: A Meta-Analysis of Randomized Controlled Trials and Propensity-Matched Studies.

OBJECTIVE: Patients with diabetes have poorer outcomes with coronary artery disease (CAD) and pose a unique clinical population for revascularization. We performed a pairwise meta-analysis of randomized trials (RCTs) and propensity-matched observational studies (PMS) to compare the clinical outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with diabetes. METHODS: A comprehensive literature search was performed to identify RCT and PMS studies comparing CABG with PCI in patients with diabetes with concurrent CAD. Studies were pooled using the random-effects model to perform a pairwise meta-analysis. Primary outcomes included long-term all-cause mortality, cardiac mortality, myocardial infarction (MI), major adverse cardiac and cerebrovascular events (MACCE), and repeat revascularization. Meta-regression was used to explore the effects of baseline risk factors on primary outcomes with moderate to high heterogeneity. RESULTS: A total of 18 RCTs and 9 PMS with 28,846 patients were included. PCI was associated with increased long-term all-cause mortality (risk ratio [RR] = 1.34, P < 0.001), cardiac mortality (RR = 1.52, P < 0.001), MI (RR = 1.51, P = 0.009), MACCE (RR = 1.65, P < 0.001), and repeat revascularization (RR = 2.48, P < 0.001) compared with CABG. There was no difference in long-term stroke between the 2 groups (RR = 0.95, P = 0.82). At meta-regression, a greater proportion of female patients in studies was associated with a decreased protective benefit for CABG for long-term all-cause mortality but an increased protective benefit for long-term MI and repeat revascularization. CONCLUSIONS: Revascularization of patients with diabetes using CABG is associated with significantly reduced long-term mortality, MI, MACCE, and repeat revascularizations. Future studies exploring the influence of gender on revascularization outcomes are necessary to elucidate the ideal treatment modality in patients with diabetes.

Cannabidiol activates neuronal Kv7 channels.

Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale screen and found enhancement of flux through heterologously expressed human Kv7.2/7.3 channels by CBD. Patch-clamp recordings showed that CBD acts at submicromolar concentrations to shift the voltage dependence of Kv7.2/7.3 channels in the hyperpolarizing direction, producing a dramatic enhancement of current at voltages near -50 mV. CBD enhanced native M-current in mouse superior cervical ganglion starting at concentrations of 30 nM and also enhanced M-current in rat hippocampal neurons. The potent enhancement of Kv2/7.3 channels by CBD may contribute to its effectiveness as an antiepileptic drug by reducing neuronal hyperexcitability.

Decellularized versus cryopreserved pulmonary allografts for right ventricular outflow tract reconstruction during the Ross procedure: a meta-analysis of short- and long-term outcomes.

BACKGROUND: The ideal conduit for repair of the right ventricular outflow tract (RVOT) during the Ross procedure remains unclear and has yet to be fully elucidated. We perform a pairwise meta-analysis to compare the short-term and long-term outcomes of decellularized versus cryopreserved pulmonary allografts for RVOT reconstruction during the Ross procedure. MAIN BODY: After a comprehensive literature search, studies comparing decellularized and cryopreserved allografts for patients undergoing RVOT reconstruction during the Ross procedure were pooled to perform a pairwise meta-analysis using the random-effects model. Primary outcomes were early mortality and follow-up allograft dysfunction. Secondary outcomes were reintervention rates and follow-up endocarditis. A total of 4 studies including 1687 patients undergoing RVOT reconstruction during the Ross procedure were included. A total of 812 patients received a decellularized pulmonary allograft, while 875 received a cryopreserved pulmonary allograft. Compared to cryopreserved allografts, the decellularized group showed similar rates of early mortality (odds ratio, 0.55, 95% confidence interval, 0.21-1.41, P = 0.22). At a mean follow-up period of 5.89 years, no significant difference was observed between the two groups for follow-up allograft dysfunction (hazard ratio, 0.65, 95% confidence interval, 0.20-2.14, P = 0.48). Similarly, no difference was seen in reintervention rates (hazard ratio, 0.54, 95% confidence interval, 0.09-3.12, P = 0.49) nor endocarditis (hazard ratio, 0.30, 95% confidence interval, 0.07-1.35, P = 0.12) at a mean follow-up of 4.85 and 5.75 years, respectively. CONCLUSIONS: Decellularized and cryopreserved pulmonary allografts are associated with similar postoperative outcomes for RVOT reconstruction during the Ross procedure. Larger propensity-matched and randomized control trials are necessary to elucidate the efficacy of decellularized allografts compared to cryopreserved allografts in the setting of the Ross.

p38ß MAP kinase as a therapeutic target for pancreatic cancer.

Pancreatic cancer is very difficult to diagnose in its early stage. Molecular marker and imaging have not proven to be accurate modalities for screening of pancreatic cancer. This study aims to develop p38ß as a protein marker for pancreatic cancer and to design peptide inhibitor against the same. The serum p38ß level of pancreatic cancer (n = 35; 5.06 µg/mL) was twofold higher compared to that of the chronic pancreatitis (n = 10; 2.92 µg/mL) and matched normal control (n = 10; 2.86 µg/ml) (p < 0.0005). Peptide inhibitors were designed to inhibit the activity of p38ß and the kinetic assay had shown the dissociation constant, (K(D)) to be 3.16 × 10(-8) M and IC(50), 25 nM by Surface Plasmon Resonance (SPR) and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The peptide inhibitor also significantly reduced viability and induced cytotoxicity in Human Pancreatic carcinoma epithelial-like cell line (PANC-1) cells.