The 'omics of obesity in B-cell acute lymphoblastic leukemia.

The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.

Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes.

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.

COVID-19 and Type 2 Diabetes Mellitus: HCQ may be the Holy Grail.

The novel coronavirus disease (COVID-19) is on the rampage claiming over 297000 lives globally. Disease severity and mortality rates are higher in patients with underlying diabetes mellitus. Till date, there exists no effective vaccine or therapy against COVID-19. However, with limited clinical data, HCQ is being used for treatment and prophylaxis in patients with COVID-19. HCQ is also used as an anti-diabetic drug and has been approved in India as an adjunct to diet and exercise to improve glycemic control of patients with Type 2 Diabetes Mellitus (T2DM) on metformin and sulfonylurea combination in Type 2 Diabetes Mellitus (T2DM). Thus, although indiscriminate use of HCQ is fraught with danger, HCQ can be considered as a third-line add on anti-diabetic agent in people with T2DM amid the ongoing pandemic after having ruled out the contraindications to the use of this drug.

SARS-CoV-2 morbidity and mortality in racial/ethnic minority populations: A window into the stress related inflammatory basis of health disparities?

Health disparity related to race/ethnicity has been cited as "the most serious and shameful health care issue of our time"(Peterson et al., 2018). A portion of the now recognized disproportionate impact of the COVID-19 pandemic among Black, Indigenous and People of Color (BIPOC) communities is attributable to social determinants such as socioeconomic status (SES), physical living situation, health care access, and the psychosocial factors associated with socioenvironmental circumstances such as bias, victimization, trauma and toxic stress as well as structural factors that reduce the capacity to practice physical distancing (Agurs-Collins et al., 2019). In this paper, we hypothesize that, prior to the COVID-19 pandemic, disproportionate socio-economic and environmental stressors in the BIPOC population promoted heightened stress-associated neurobiological activity (Stress-NbA). This chronic elevation in Stress-NbA results in down-stream complications of chronic stress including underactivation of anti-viral type I IFN pathway genes. This results in an increase in susceptibility to viral diseases, including coronavirus illnesses. Additionally, Stress-NbA chronically potentiates systemic inflammation (from hematopoietic system activation with myelopoiesis) increasing the prevalence of metabolic syndrome (MetS) and setting the stage for stress-related chronic non-communicable diseases (NCDs). This process was propelled by overactivation of immune cell gene expression in the nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB) activation pathway and underactivation of gene expression in the anti-viral type I interferon (IFN) pathway. The higher prevalence of MetS and NCDs in minority populations turned out to be predictive of the elevated risk they would face in the presence of a highly contagious viral pandemic. The stress-related generation of a chronic non-pathogen associated molecular pattern (non-PAMP) immunoactivation state led to decreased viral immune defense and increased susceptibility to SARS-CoV-2 infection with increased risk of severe illness induced by cytokine storm syndrome (CSS).