Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease

Six-year multicenter study on short-term peripheral venous catheters-related bloodstream infection rates in 246 intensive units of 83 hospitals in 52 cities of 14 countries of Middle East: Bahrain, Egypt, Iran, Jordan, Kingdom of Saudi Arabia, Kuwait, Lebanon, Morocco, Pakistan, Palestine, Sudan, Tunisia, Turkey, and United Arab Emirates—International Nosocomial Infection Control Consortium (INICC) findings

Short-term peripheral venous catheters-related bloodstream infections (PVCR-BSIs) rates have not been systematically studied, and data on their incidence by number of device-days is not available. Prospective, surveillance study on PVCR-BSI conducted from September 1st, 2013 to 31st Mays, 2019 in 246 intensive care units (ICUs), members of the International Nosocomial Infection Control Consortium (INICC), from 83 hospitals in 52 cities of 14 countries in the Middle East (Bahrain, Egypt, Iran, Jordan, Kingdom of Saudi Arabia, Kuwait, Lebanon, Morocco, Pakistan, Palestine, Sudan, Tunisia, Turkey, and United Arab Emirates). We applied U.S. We followed 31,083 ICU patients for 189,834 bed-days and 202,375 short term peripheral venous catheter (PVC)-days. We identified 470 PVCR-BSIs, amounting to a rate of 2.32/1000 PVC-days. Mortality in patients with PVC but without PVCR-BSI was 10.38%, and 29.36% in patients with PVC and PVCR-BSI. The mean length of stay in patients with PVC but without PVCR-BSI was 5.94 days, and 16.84 days in patients with PVC and PVCR-BSI. The microorganism profile showed 55.2 % of gram-positive bacteria, with Coagulase-negative Staphylococci (31%) and Staphylococcus aureus (14%) being the predominant ones. Gram-negative bacteria accounted for 39% of cases, and included: Escherichia coli (7%), Klebsiella pneumoniae (8%), Pseudomonas aeruginosa (5%), Enterobacter spp. (3%), and others (29.9%), such as Serratia marcescens. PVCR-BSI rates found in our ICUs were much higher than rates published from USA, Australia, and Italy. Infection prevention programs must be implemented to reduce the incidence of PVCR-BSIs

Serotonin regulates pancreatic beta cell mass during pregnancy

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the G alpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the G alpha(i)-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes