Mediator Subunit 12 Is Required for Neutrophil Development in Zebrafish

Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator

Cyclic AMP signalling pathways in the regulation of uterine relaxation

Studying the mechanism(s) of uterine relaxation is important and will be helpful in the prevention of obstetric difficulties such as preterm labour, which remains a major cause of perinatal mortality and morbidity. Multiple signalling pathways regulate the balance between maintaining relative uterine quiescence during gestation, and the transition to the contractile state at the onset of parturition. Elevation of intracellular cyclic AMP promotes myometrial relaxation, and thus quiescence, via effects on multiple intracellular targets including calcium channels, potassium channels and myosin light chain kinase. A complete understanding of cAMP regulatory pathways (synthesis and hydrolysis) would assist in the development of better tocolytics to delay or inhibit preterm labour. Here we review the enzymes involved in cAMP homoeostasis (adenylyl cyclases and phosphodiesterases) and possible myometrial substrates for the cAMP dependent protein kinase. We must emphasise the need to identify novel pharmacological targets in human pregnant myometrium to achieve safe and selective uterine relaxation when this is indicated in preterm labour or other obstetric complications

Azacitidine and Durvalumab in First-line Treatment of Elderly Patients With Acute Myeloid Leukemia.

Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1-7 with (Arm A, n= 64) or without (Arm B, n=65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery [CRi]) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (A, 13.0 months; B, 14.4 months) and duration of response (A, 24.6 weeks; B, 51.7 weeks; P=0.0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (A, 42.2%; B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible, but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903

The Business of Robots and AI

The paper studies the involvement of business in the development of ethics for robots and A