Ras, ROS and Proteotoxic Stress: A Delicate Balance

Ras-deregulated cells require reactive oxygen species for proliferation. They survive the resultant proteotoxic stress by maintaining sufficient levels of reduced glutathione and optimally functioning stress response machinery. In this issue of Cancer Cell, De Raedt et al. identify a novel strategy that utilizes this dependency to cause cell death

Vascular endothelial cells: heterogeneity and targeting approaches

Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations

Development of technology for hot drape forming and nozzles for torus sections Final report, Jun. 1963 - Dec. 1965

Hot drape forming and heat treatment of aluminum base alloy toroidal shell segment

Decreasing Ventromedial Prefrontal Cortex Activity During Sequential Risk-Taking: An fMRI Investigation of the Balloon Analog Risk Task

Functional imaging studies examining the neural correlates of risk have mainly relied on paradigms involving exposure to simple chance gambles and an economic definition of risk as variance in the probability distribution over possible outcomes. However, there is little evidence that choices made during gambling tasks predict naturalistic risk-taking behaviors such as drug use, extreme sports, or even equity investing. To better understand the neural basis of naturalistic risk-taking, we scanned participants using fMRI while they completed the Balloon Analog Risk Task, an experimental measure that includes an active decision/choice component and that has been found to correlate with a number of naturalistic risk-taking behaviors. In the task, as in many naturalistic settings, escalating risk-taking occurs under uncertainty and might be experienced either as the accumulation of greater potential rewards, or as exposure to increasing possible losses (and decreasing expected value). We found that areas previously linked to risk and risk-taking (bilateral anterior insula, anterior cingulate cortex, and right dorsolateral prefrontal cortex) were activated as participants continued to inflate balloons. Interestingly, we found that ventromedial prefrontal cortex (vmPFC) activity decreased as participants further expanded balloons. In light of previous findings implicating the vmPFC in value calculation, this result suggests that escalating risk-taking in the task might be perceived as exposure to increasing possible losses (and decreasing expected value) rather than the increasing potential total reward relative to the starting point of the trial. A better understanding of how neural activity changes with risk-taking behavior in the task offers insight into the potential neural mechanisms driving naturalistic risk-taking

Comparison of published core outcome sets with outcomes recommended in regulatory guidance from the US Food and Drug Administration and European Medicines Agency: cross sectional analysis

ObjectiveTo compare the outcomes in published core outcome sets with the outcomes recommended in corresponding guidance documents from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), matched by health condition.DesignCross sectional analysis.SettingUS and Europe.PopulationSample of core outcome sets related to drugs, devices, and gene therapy that involved patients in the consensus process, published between 1 January 2015 and 31 December 2019; and corresponding EMA and FDA guidance documents.Main outcome measuresThe extent of matches between outcomes included within core outcome sets and those recommended in corresponding EMA and FDA guidance documents were assessed. Matches were considered to be general (ie, non-specific) or specific (ie, exact). General matches were assessed to determine whether the core outcome set or guidance document outcome was narrower.ResultsRelevant guidance documents were found for for 38 (39%) of 98 eligible published core outcome sets. Among outcomes in core outcome sets, medians of 70% (interquartile range 48-86%) and 52% (33-77%) were matches with outcomes recommended in EMA and FDA documents, respectively. Medians of 46% (27-68%) and 26% (18-46%) were specific matches with outcomes in EMA and FDA documents, respectively. When outcomes were generally matched, the outcomes from core outcome sets were more frequently narrower than the regulatory outcomes (83% and 75% for EMA and FDA, respectively).ConclusionGreater adoption of, and reference to, core outcome sets in regulatory guidance documents can encourage clinical trialists, especially those in industry, to measure and report consistent and agreed outcomes and improve the quality of guidance. Given the overlap between outcomes in core outcome sets and regulatory guidance, and given that most core outcome sets now involve patients in the consensus process, these sets could serve as a useful resource for regulators when recommending outcomes for studies evaluating regulated products. Developers are encouraged to appraise recommended outcomes in salient regulatory documents when planning a core outcome set