Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis.

The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis - providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 µM awake and 117.6 ± 98.6 µM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis.

Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship study.

Platinum-acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build-click-screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1-B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum-acridine (P1-A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1-B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1-A1.

The MARS2013 Mars analog mission.

We report on the MARS2013 mission, a 4-week Mars analog field test in the northern Sahara. Nineteen experiments were conducted by a field crew in Morocco under simulated martian surface exploration conditions, supervised by a Mission Support Center in Innsbruck, Austria. A Remote Science Support team analyzed field data in near real time, providing planning input for the management of a complex system of field assets; two advanced space suit simulators, four robotic vehicles, an emergency shelter, and a stationary sensor platform in a realistic work flow were coordinated by a Flight Control Team. A dedicated flight planning group, external control centers for rover tele-operations, and a biomedical monitoring team supported the field operations. A 10 min satellite communication delay and other limitations pertinent to human planetary surface activities were introduced. The fields of research for the experiments were geology, human factors, astrobiology, robotics, tele-science, exploration, and operations research. This paper provides an overview of the geological context and environmental conditions of the test site and the mission architecture, in particular the communication infrastructure emulating the signal travel time between Earth and Mars. We report on the operational work flows and the experiments conducted, including a deployable shelter prototype for multiple-day extravehicular activities and contingency situations.