ABSTRACT
Acute myeloid leukemia (AML) is fatal in majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting IQGAP1-GRD domain, and conducted SAR of ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, G2/M arrest, and colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. IQGAP1/F-actin showed co-localization and UR778Br induced filopodia formation in U937 cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows dependency on IQGAP1 and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.
Subject(s)
Leukemia, Myeloid, Acute , LeukemiaABSTRACT
The extent of gendered COVID-19 impact remains undetermined for the lack of sex-disaggregated data. The prevailing view puts males nearly twice as impacted as females. Globally, access to resources and their usage are gendered- mostly favoring males. Gender gaps widen during natural/man-made calamities and pandemics. Modeling estimates of impact for top 70 countries reporting >300 sex-disaggregated COVID-19 deaths (>80% of total), indicates average mortality sex (male:female) ratio (COVID-MSR) of 1.37{+/-}0.30 (95% confidence interval:1.30-1.44; range:0.85-2.47) against prevalent pre-pandemic MSR of 1.79{+/-}0.41 (1.70-1.89; range:0.93-2.99). Contrary to the prevailing view, widened gender gaps globally increased female mortality by 19.57{+/-}21.16% (14.62%-24.88%; range: -22.46 to +68.50%) causing an estimated 22.03% excess deaths (360 thousand by 30 December 2021). Identification of factors favoring gendered impacts is needed for equitable pandemic management.
Subject(s)
COVID-19ABSTRACT
Endeavors to identify protective variables that could be potentially responsible for reduced COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their bacillus Calmette-Guerin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within the first 5 years of life while most of the COVID-19 cases as well as deaths have been observed in adults especially the aged with comorbidities. Since the supposed desired protection being investigated could come from heterologous trained immunity conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of trained immunity of populations currently available as latent tuberculosis infection (LTBI) of populations would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (twenty-four) as well as erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher trained immunity prevalence consistently display reduced COVID-19 impact as compared to their lower trained immunity prevalence neighbors. The incidences, mortality, and interim case fatality rates (i-CFR) of COVID-19 are found negatively correlated with the trained immunity of populations that have comparable underlying confounders not the BCG coverage per se. It is submitted that to decisively arrive at dependable conclusions about the potential protective benefit that can be gained from BCG vaccination in COVID-19, the ongoing/planned randomized controlled trials should consciously consider including measures of trained immunity as - a) all individuals immunized do not respond equally, b) small study groups of higher background trained immunity could fail to indicate any protective effect.
Subject(s)
COVID-19 , TuberculosisABSTRACT
The effect of Zinc (Zn) sufficiency/supplementation of the populations on the occurrence of COVID-19 and associated severe illness/mortality remains unknown. Worldwide, general recommendations for Zn sufficiency and immune-boosting for COVID-19 are in place. A time-series association study was conducted on 23 different Zn sufficiency level but socially similar European populations/countries (Population: 522.47 million; experiencing up to >150 fold difference in death rates) with supposedly similar confounders and stage of the pandemic, covering the period from pre-peak-of-infections to post-peak-of-infections till flattening of the 1st wave of infections (12 March to 26 June). Comparison of these populations, consistently displayed a strong and significant correlation/covariation of populations' Zn sufficiency/supplementation status with the COVID-19 mortality [Pearson's r(23): 0.7893 to 0.6849, p-value<0.0003] and cases per million [r(23):0.8084 to 0.5658; p-value<0.005], without requiring adjustments or extra exclusion/inclusion criterion being applied elsewhere, e.g., age, age distribution, comorbidities, sex, urbanization. Among the analyzed countries, elevated 9X mortality risk was observed for populations with >92.5 % Zn sufficiency levels at all times as compared to populations with lower Zn sufficiency. The presence of a small percentage of adults/elderly with conditions/comorbidities in the populations susceptible to higher Zn intake/supplementation related pathologies (Prasad et al., JAMA.1978; 240(20):2166-2168) could be suspected for the paradoxical observation. Controlled trials or retrospective analysis of the adverse event patients' data seem warranted for ascertaining the basis of the observation in uncertain terms for allowing the harnessing of the full protective potential of the Zn supplementation for populations.
Subject(s)
COVID-19ABSTRACT
Protective variables for COVID-19 are unknown. Trained immunity of the populace as a result of BCG immunization policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of trained immunity or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity - a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations, is found consistently negatively correlated with COVID-19 infections and mortality per million population, at all the time points evaluated. We propose that on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes may actively consider, if not already, the inclusion of controls for underlying trained immunity and heterologous cell-mediated immunity prevalence that may be pre-existing or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning their potential benefit.