Protocol to establish a genetically engineered mouse model of IDH1-mutant astrocytoma

Summary: Lower-grade gliomas exhibit a high prevalence of isocitrate dehydrogenase 1 (IDH1) mutations, but faithful models for studying these tumors are lacking. Here, we present a protocol to establish a genetically engineered mouse (GEM) model of grade 3 astrocytoma driven by the Idh1R132H oncogene. We describe steps for breeding compound transgenic mice and intracranially delivering adeno-associated virus particles, followed by post-surgical surveillance via magnetic resonance imaging. This protocol enables the generation and use of a GEM to study lower-grade IDH-mutant gliomas.For complete details on the use and execution of this protocol, please refer to Shi et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics

Adverse events related to COVID-19 vaccines:the need for strengthening pharmacovigilance monitoring systems

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new species of β-coronavirus genus named severe acute respiratory syndrome coronavirus 2. The COVID-19 pandemic, which started in late 2019 and continues as at mid-2021, has caused enormous damage to health and lives globally. The urgent public health need has led to the development of vaccines against COVID-19 in record-breaking time. The COVID-19 vaccines have been widely rolled out for the masses by many countries following approval for emergency use by the World Health Organization and regulatory agencies in many countries. In addition, several COVID-19 vaccine candidates are undergoing clinical trials. However, myths, fears, rumors, and misconceptions persist, particularly in regard to adverse events. In this commentary, we describe the adverse events associated with COVID-19 vaccines and discuss why it is essential to have a functional adverse event monitoring system in this context

Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas. Gliomas with IDH mutations show increased sensitivity to radiation in concert with glutaminase inhibition, offering a new approach to treating these tumors