Incidental Findings Suggestive of COVID-19 in Asymptomatic Patients Undergoing Nuclear Medicine Procedures in a High-Prevalence Region

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MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia

Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR's tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177 and cytoplasmic ABL1Y412/T735 dephosphorylation thereby provoking the rescue of the BCR's anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia

Evaluation of serum enzyme activities as predictors of passive transfer status in lambs

Objective-To determine the associations between serum IgG concentration and serum activities of gamma-glutamyltransferase (GGT), alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and pseudocholinesterase for the potential use of these serum enzymes as predictors of passive transfer status in neonatal lambs. Design-Prospective observational study. Animals-47 Sardinian lambs from birth to 2 days old. Procedure-Serum enzyme activities were measured by use of commercially available kits and a clinical biochemical analyzer. Serum IgG concentration was determined by single radial immunodiffusion. Associations between serum IgG concentration and the activity of each serum enzyme were established by use of regression analysis. Results-A significant correlation was detected between serum IgG concentration and serum GGT activity in 1- and 2-day-old lambs. Minimal correlations were detected between serum IgG concentration and serum alkaline phosphatase activity in 1-day-old lambs and serum pseudocholinesterase activity in 1- and 2-day-old lambs. No significant associations were detected between serum IgG concentration and serum activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. A multiple linear regression model was accurate for the estimation of the natural logarithm of serum IgG concentration as a function of the natural logarithm of serum GGT activity and of the age of lambs at the time of sampling (adjusted R-2 = 0.89). This model was then used to calculate the serum GGT activity equivalent to various serum IgG concentrations for 1- and 2-day-old lambs. Conclusions and Clinical Relevance-Results suggested that passive transfer status in neonatal lambs can be successfully predicted by measurement of serum GGT activity but not by measurement of the other enzymes tested.[...