The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.

Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.

Incidence, Racial Disparities and Factors Related to Psychosis among Black Individuals in Canada: A Scoping Review.

OBJECTIVE: Black communities are increasingly concerned about psychosis, a worry echoed by provincial health-care systems across Canada. Responding to the lack of evidence on psychosis in Black communities, this scoping review examined the incidence and prevalence of psychosis, access to care (pathways to care, coercive referrals, interventions, etc.), treatments received, and stigma faced by individuals with psychosis. METHOD: To identify studies, a comprehensive search strategy was developed and executed in December 2021 across 10 databases, including APA PsycInfo, CINAHL, MEDLINE and Web of Science. Subject headings and keywords relating to Black communities, psychosis, health inequalities, Canada and its provinces and territories were used and combined. The scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping review (PRISMA-ScR) reporting standard. RESULTS: A total of 15 studies met the inclusion criteria, all of them conducted in Ontario and Quebec. Results highlight different disparities in psychosis among Black communities. Compared to other Canadian ethnic groups, Black individuals are more likely to be diagnosed with psychosis. Black individuals with psychosis are more likely to have their first contact with health-care settings through emergency departments, to be referred by police and ambulance services, and to experience coercive referrals and interventions, and involuntary admission. Black individuals experience a lower quality of care and are the ethnic group most likely to disengage from treatment. CONCLUSION: This scoping review reveals many gaps in research, prevention, promotion and intervention on psychosis in Black individuals in Canada. Future studies should explore factors related to age, gender, social and economic factors, interpersonal, institutional and systemic racism, and psychosis-related stigma. Efforts should be directed toward developing trainings for health-care professionals and promotion and prevention programs within Black communities. Culturally adapted interventions, racially disaggregated data, and increased research funding are needed.

The global evolution of mental health problems during the COVID-19 pandemic: A systematic review and meta-analysis of longitudinal studies.

BACKGROUND: The COVID-19 pandemic impacted mental health, but the global evolution of mental health problems during the pandemic is unknown. We conducted a systematic review and meta-analysis of longitudinal studies to evaluate the global evolution of mental health problems during the pandemic. METHODS: To conduct this systematic review, we searched for published articles from APA PsycInfo (Ovid), CINAHL (EBSCOhost), Embase (Ovid), MEDLINE (Ovid), and Web of Science. Longitudinal (at least 2 waves during the COVID-19 pandemic) and peer-reviewed articles on mental health problems conducted as from 2020 and after were included in the current study. Of 394 eligible full texts, 64 articles were included in the analysis. We computed random effects, standardized mean differences, and log odds ratio (LOR) with 95 % CIs. The meta-analysis protocol was registered with PROSPERO (CRD42021273624). RESULTS: Results showed that anxiety (LOR = -0.33; 95 % CI, -0.54, -0.12) and depression symptoms (LOR = -0.12; 95 % CI, -0.21, -0.04) decreased from baseline to follow up. However, other mental health problems showed no change. Higher prevalence rates (40.9 %; 95 % CI, 16.1 %-65.8 %) of psychological distress were found in months after July 2020, respectively, while there were no significant month differences for the prevalence of other mental health problems. Higher means of anxiety (d = 3.63, 95 % CI, 1.66, 5.61), depression (d = 3.93; 95 % CI, 1.68, 6.17), and loneliness (d = 5.96; 95 % CI, 3.22, 8.70) were observed in May 2020. Higher prevalence of anxiety, depression, and PTSD and higher means of anxiety, depression and loneliness were observed in North America. The prevalence of psychological distress and insomnia was higher in Latin America and Europe, respectively. LIMITATIONS: There is a lack of longitudinal studies in some parts of the world, such as Africa, the Caribbean, India, the Middle East, in Latin America, and Asia. CONCLUSIONS: Results indicated that anxiety and depression symptoms decreased during the COVID-19 pandemic while other mental health problems showed no statistical change. The findings reveal that mental health problems peaked in April and May 2020. Prevalence of mental health problems remains high during the pandemic and mental health prevention, promotion and intervention programs should be implemented to mitigate the consequences of the COVID-19 pandemic on the global population.

Pharmacological targeting of Sam68 functions in colorectal cancer stem cells.

Cancer stem cells (CSCs) are documented to play a key role in tumorigenesis and therapy resistance. Despite significant progress in clinical oncology, CSC reservoirs remain elusive and difficult to eliminate. Reverse-turn peptidomimetics were characterized as disruptors of CBP/beta-Catenin interactions and represent a promising avenue to curb hyperactive canonical Wnt/beta-Catenin signaling in CSCs. Recent studies suggested Sam68 as a critical mediator of reverse-turn peptidomimetics response in CSC populations. Using computational and biochemical approaches we confirmed Sam68 as a primary target of reverse-turn peptidomimetics. Furthermore, we executed an in silico drug discovery pipeline to identify yet uncharacterized reverse-turn peptidomimetic structures displaying superior anti-CSC activity in transformed pluripotent and colorectal cancer cell models. Thus, we identified YB-0158 as a reverse-turn peptidomimetic small molecule with enhanced translational potential, altering key hallmarks of human colorectal CSCs in patient-derived ex vivo organoids and in vivo serial tumor transplantation.

A Data Mining Framework for Glaucoma Decision Support Based on Optic Nerve Image Analysis Using Machine Learning Methods.

Ocular imaging instruments, such as Confocal Scanning Laser Ophthalmoscopy (CSLO), captures high-quality images of the optic disc (also known as optic nerve head) that help clinicians to diagnose glaucoma. We present an integrated data analytics framework to aid clinicians in interpreting CSLO optic nerve images to diagnose and monitor the progression of glaucoma. To distinguish between healthy and glaucomatous optic discs, our framework derives shape information from CSLO images using image processing (Zernike moment method), selects salient features (hybrid feature selection), and then trains image classifiers (Multilayer Perceptron, Support Vector Machine, Bayesian Network). To monitor glaucoma progression over time, our framework uses a mathematical model of the optic disc to extract morphological features from CSLO images and applies clustering (Self-Organizing Maps) to visualize subtypes of glaucomatous optic disc damage. We contend that our data analytics framework offers an automated and objective analysis of optic nerve images that can potentially support both diagnosis and monitoring of glaucoma. We validated our framework with CSLO optic nerve images and our data analytics approach detected glaucomatous optic discs with a sensitivity of 0.86, a specificity of 0.80, an accuracy of 0.838, and an AUROC of 0.913 with a Bayesian network classifier using the optimal subset of Zernike features (six moments). Furthermore, our framework identified, using morphological features, five clusters of CSLO images, where each cluster stands for a subtype of optic nerve damage (two healthy subtypes and three glaucoma subtypes). The characteristics of each cluster-the subtype of the image-were determined by experts who examined the morphology of the images within each cluster and provided subtype characteristics to each cluster.

Development of in-house ELISA for detection of chloramphenicol in bovine milk with subsequent confirmatory analysis by LC-MS/MS.

This study was undertaken to develop and validate direct competitive ELISA for the determination of chloramphenicol residues in bovine milk. Antisera and an enzyme-tracer for chloramphenicol were prepared and used to develop an ELISA with inhibition concentrations, IC20 and IC50, of 0.09 and 0.44 ng mL-1, respectively. Milk samples were spiked with standards equivalent to 0, 0.2, 0.3, 0.5, 1.0 & 1.5 ng mL-1 and extracted in methanol. The mean recoveries were found to be 73-100% with coefficient of variance 7-11%. The decision limit (CCα) and detection capability (CCß) were calculated as 0.10 and 0.12 ng mL-1, respectively. The results were found comparable with the commercial ELISA, having recoveries of 87 to 100%, CCα 0.09 ng mL-1 and CCß 0.12 ng mL-1. As per Commission Decision 2002/657/EC, in-house ELISA was further validated by using LC-MS/MS. Mass spectral acquisition was done by using electrospray ionization in the negative ion mode applying single reaction monitoring of the diagnostic transition reaction for CAP (m/z 152, 194 and 257). The calibration curve showed good linearity in concentrations from 0.025 to 1.6 ng mL-1 with correction coefficient 0.9902. The mean recoveries were found to be 88 to 100%. The CCα was calculated as 0.057 ng mL-1 and CCß 0.10 ng mL-1. Since CCα and CCß are less than half of the MRPL (0.15 ng mL-1), the test was found suitable for screening and quantification of CAP residues in bovine milk samples. Results of surveillance studies indicated that out of 31 analyzed milk samples, 12.9% samples were found with CAP residues but only 3.2% samples were declared positive with maximum concentration 0.31 ng mL-1, slightly above the MRPL.

Synthesis, Characterization and Cholinesterase Inhibition Studies of New Arylidene Aminothiazolylethanone Derivatives.

BACKGROUND: Alzheimer's disease is caused by the destruction or loss of cholinergic cells that produce or use ACh in the brain, thereby reducing the availability of enzyme to other cells. The major treatment strategy for AD is to decrease the level of cholinesterase in the brain. OBJECTIVE: The aim of this study was to describe the effect of novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) as cholinesterase inhibitors (CEIs). METHOD: A novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) was synthesized by treating 3-chloropentane-2,4-dione (1) with urea followed by reaction with suitably substituted benzaldehydes. Structural confirmation of all the synthesized compounds was carried out by spectroscopic techniques (FTIR, 1H and 13CNMR) and elemental analysis. Furthermore, these derivatives were subjected to biological evaluation as potential inhibitors of cholinesterases i.e. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). RESULTS: In all synthesized compounds except two compounds i.e. 3a and 3f, all compounds were identified as selective inhibitors of AChE. Compound 3a exhibited potent inhibitory values against AChE (IC50± SEM = 1.78±0.11 µM), exhibiting ≈7 times greater selectivity for AChE over BChE. Kinetics studies were performed to find out the mechanism of inhibition against respective enzyme. In addition, molecular docking studies of most potent inhibitors were also carried out to determine the binding interactions with AChE and BChE, respectively. CONCLUSION: In this study, novel thiazole derivatives i.e. arylidene aminothiazolylethanones were successfully synthesized, characterized and further screened for threir potential as cholinesterase inhibitors. All compounds were found as potent selective inhibitors of AChE except two compounds which exhibited dual inhibitory activities but both of these compounds were highly selective toward AChE as compared to BChE.

Effects of aerobic exercise training in community-based subjects aged 80 and older: a pilot study.

OBJECTIVES: To assess the ability of sedentary, frail subjects aged 80 and older to train in a community-based exercise program and to evaluate clinical factors that predict improvements in peak oxygen consumption (VO2peak). DESIGN: Pretest, posttest. SETTING: Charlestown Retirement Community, Catonsville, Maryland PARTICIPANTS: Twenty-two (11 male, 11 female; mean age +/- standard deviation = 84 +/- 4.0, range 80-92) self-referred. INTERVENTION: Six months of moderate-intensity aerobic exercise training, two to three sessions/week, 20 to 30 minutes per session. Training modes included treadmill walking and/or stationary cycling. MEASUREMENTS: Baseline and follow-up maximal exercise treadmill tests (ETTs) with electrocardiogram monitoring and respiratory gas analysis. RESULTS: Six months of aerobic exercise training resulted in significant increases (mean +/- standard deviation) in ETT duration (11.9 +/- 3.3 vs 15.9 +/- 4.3 minutes; P =.01), VO2peak (1.23 +/- 0.37 vs 1.31 +/- 0.36 L/min; P =.04), and oxygen pulse (9.3 +/- 2.8 vs 10.1 +/- 3.2; P =.03). Mean heart rate was significantly lower during submaximal ETT stages 1 through 4 (P <.05), and resting systolic blood pressure decreased (146 +/- 18 vs 133 +/- 14 mmHg; P =.01) after training. Multiple regression analysis indicated that baseline VO2peak (r = 0.75, P =.002) and the total amount of time spent in exercise training (r = 0.55, P =.008) were independent predictors of the training-related improvements in VO2peak. CONCLUSION: Subjects aged 80 and older can increase aerobic capacity and reduce systolic blood pressure in a community-based exercise program of moderate intensity. The most important predictors of change in VO2peak were baseline VO2peak and the time spent in exercise training. Subjects with a lower baseline VO2peak had the greatest improvements in VO2peak after training.