Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.Peer reviewe

Cardiac computed tomographic imaging in cardio-oncology: An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT). Endorsed by the International Cardio-Oncology Society (ICOS).

Cardio-Oncology is a rapidly growing sub-specialty of medicine, however, there is very limited guidance on the use of cardiac CT (CCT) in the care of Cardio-Oncology patients. In order to fill in the existing gaps, this Expert Consensus statement comprised of a multidisciplinary collaboration of experts in Cardiology, Radiology, Cardiovascular Multimodality Imaging, Cardio-Oncology, Oncology and Radiation Oncology aims to summarize current evidence for CCT applications in Cardio-Oncology and provide practice recommendations for clinicians

Legionella pneumophila occurrence in reduced-occupancy buildings in 11 cities during the COVID-19 pandemic

ABSTRACT: In spring 2020, numerous buildings were closed or operated at reduced occupancies to slow the spread of COVID-19. An unintended consequence of these social distancing measures was a reduction in water demand in many buildings. Concerns arose that contaminants associated with water stagnation, such as Legionella pneumophila, could become prevalent. To investigate the potential public health risk associated with L. pneumophila, samples from 26 reduced-occupancy buildings in 11 cities in the United States, Canada, and Switzerland were analyzed for L. pneumophila using liquid culture (Legiolert, n = 258) and DNA-based methods (qPCR/ddPCR, n = 138). L. pneumophila culture-positivity was largely associated with five buildings, each of which had specific design or operational deficiencies commonly associated with L. pneumophila occurrence. Samples from buildings with free chlorine residual disinfection had higher culture-positivity (37%) than samples from buildings with chloramine (1%). Additionally, 78% of culture-positive samples occurred when the disinfectant residual was ≤0.1 mg L−1 Cl2 and only three free chlorine samples were culture-positive when the disinfectant residual was >0.2 mg L−1 as Cl2. Although overall sample positivity using culture- and DNA-based methods was equivalent (34% vs. 35%), there was disagreement between the methods in 13% of samples (n = 18 of 138). Few buildings reported any water management activities, and L. pneumophila concentrations in flushed samples were occasionally greater than in first-draw samples. This study provides insight into how building plumbing characteristics and water management practices contribute to L. pneumophila occurrence during low water use periods and can inform targeted prevention and mitigation efforts