HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas

Abstract Background Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphcytes for its potential clinical use. Results Preclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2. Conclusions Our data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Effects of Coriandrum Sativum Extract and Simvastatin in Isopreterenol Induced Heart Failure in Rats

Heart failure is a syndrome, caused due to structural and functional cardiac abnormalities, characterized by changes in the hemodynamic and neurohumoral mechanisms. It is becoming a major health burden worldwide. More effective therapies are desperately needed. Coriandrum sativum (C. sativum), a traditional spice crop has been known to possess many biological and medicinal properties. The present study was designed to investigate the cardioprotective efficacy of C. sativum in rat model of isoproterenol induced heart failure. Heart failure was produced by injecting isoproterenol subcutaneously (85 mg/kg twice at an interval of 24 h). Oral efficacy of seed extract was assessed on hemodynamic profile, antioxidant enzyme activities, lipid peroxidation, lipid profile, atherogenic indices, mRNA and protein expression of endothelin receptors (ETA and ETB) and histopathology. Treatment of heart failure rats with C. sativum orally (1g/kg b.wt) improved the altered hemodynamics, restored the cardiac antioxidant enzymes armory, attenuated oxidative stress, improved lipid profile, lowered atherogenic indices, decreased the levels of ETA and ETB receptor mRNA and protein, and restored the cardiac morphology. In conclusion, our results suggest C. sativum to be a cardioprotective agent in heart failure, possibly by the virtue of its ability to alleviate oxidative stress, improve lipid profile and endothelial dysfunction

Low-Complexity Beamforming Design for a Cooperative Reconfigurable Intelligent Surface-Aided Cell-Free Network

Cell-free (CF) networks are proposed to suppress the interference among collocated cells by deploying several BSs without cell boundaries. Nevertheless, as installing several base stations (BSs) may require high power consumption, cooperative CF networks integrated with a reconfigurable intelligent surface (RIS)/metasurface can avoid this problem. In such cooperative RIS-aided MIMO networks, efficient beamforming schemes are essential to boost their spectral and energy efficiency. However, most of the existing available beamforming schemes to maximize spectral and energy efficiency are complex and entail high complexity due to the matrix inversions. To this end, in this work we present a computationally efficient stochastic optimization-based particle swarm optimization (PSO) algorithm to amplify the spectral efficiency of the cooperative RIS-aided CF MIMO system. In the proposed PSO algorithm, several swarms are generated, while the direction of each swarm is tuned in each iteration based on the sum-rate performance to obtain the best solution. Our simulation results show that our proposed scheme can approximate the performance of the existing solutions for both the performance metrics, i.e., spectral and energy efficiency, at a very low complexity

Mapping routine measles vaccination in low- and middle-income countries

The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)1–4. Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)5–8. Here we generated annual estimates of routine childhood MCV1 coverage at 5 × 5-km2 pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children

MAPPING LOCAL PATTERNS OF CHILDHOOD OVERWEIGHT AND WASTING IN LOW- AND MIDDLE-INCOME COUNTRIES BETWEEN 2000 AND 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic