Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia

BACKGROUND: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings. METHODS: The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA. RESULTS: Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation. CONCLUSIONS: Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.1U01 CA168409 - NCI NIH HHS; P01 CA 87497 - NCI NIH HHS; P30 CA008748 - NCI NIH HHS; MOP-106530 - Canadian Institutes of Health Research; P01 CA013106 - NCI NIH HH

Worth the wait: effects of age of onset of marijuana use on white matter and impulsivity

Rationale: Marijuana (MJ) use continues to rise, and as the perceived risk of using MJ approaches an all-time historic low, initiation of MJ use is occurring at even younger ages. As adolescence is a critical period of neuromaturation, teens and emerging adults are at greater risk for experiencing the negative effects of MJ on the brain. In particular, MJ use has been shown to be associated with alterations in frontal white matter microstructure, which may be related to reports of increased levels of impulsivity in this population. Objectives: The aim of this study was to examine the relationship between age of onset of MJ use, white matter microstructure, and reported impulsivity in chronic, heavy MJ smokers. Methods: Twenty-five MJ smokers and 18 healthy controls underwent diffusion tensor imaging and completed the Barratt Impulsiveness Scale. MJ smokers were also divided into early onset (regular use prior to age 16) and late onset (age 16 or later) groups in order to clarify the impact of age of onset of MJ use on these variables. Results: MJ smokers exhibited significantly reduced fractional anisotropy (FA) relative to controls, as well as higher levels of impulsivity. Earlier MJ onset was also associated with lower levels of FA. Interestingly, within the early onset group, higher impulsivity scores were correlated with lower FA, a relationship that was not observed in the late onset smokers. Conclusions: MJ use is associated with white matter development and reported impulsivity, particularly in early onset smokers

Designing Gamification Concepts for Expert Explainable Artificial Intelligence Evaluation Tasks: A Problem Space Exploration

Artificial intelligence (AI) models are often complex and require additional explanations for use in high-stakes decision-making contexts like healthcare. To this end, explainable AI (XAI) developers must evaluate their explanations with domain experts to ensure understandability. As these evaluations are tedious and repetitive, we look at gamification as a means to motivate and engage experts in XAI evaluation tasks. We explore the problem space associated with gamified expert XAI evaluation. Based on a literature review of 22 relevant studies and seven interviews with experts in XAI evaluation, we elicit knowledge about affected stakeholders, eight needs, eight goals, and seven requirements. Our results help us understand better the problems associated with expert XAI evaluation and paint a broad application potential for gamification to improve XAI expert evaluations. In doing so, we lay the foundation for the design of successful gamification concepts for expert XAI evaluation

Bupropion Reduces Some of the Symptoms of Marihuana Withdrawal in Chronic Marihuana Users: A Pilot Study

Bupropion’s (Zyban® SR) effectiveness to treat symptoms experienced in marihuana withdrawal was tested in a double-blind, placebo-controlled study with chronic, heavy marihuana users. Participants maintained their usual marihuana intake until Quit Day after which they were required to cease intake of THC products for 14 days. A Withdrawal Discomfort Score revealed that for 7 days immediately following cessation, placebo-treated subjects reported more symptoms than bupropion-treated subjects. Self-reported craving for marihuana increased for the placebo-treated group but not for those treated with bupropion. Measures of sleep and cognitive performance were not different between the two groups. Participants in the bupropion treatment arm were more likely to complete the study than those randomized to the placebo arm (50% completion for bupropion vs. 33% completion for placebo). These results suggest that bupropion may be useful for alleviating marihuana withdrawal symptoms and be useful in subject retention during long-term cessation programs

ARES:Adaptive receding-horizon synthesis of optimal plans

We introduce ARES, an efficient approximation algorithm for generating optimal plans (action sequences) that take an initial state of a Markov Decision Process (MDP) to a state whose cost is below a specified (convergence) threshold. ARES uses Particle Swarm Optimization, with adaptive sizing for both the receding horizon and the particle swarm. Inspired by Importance Splitting, the length of the horizon and the number of particles are chosen such that at least one particle reaches a next-level state, that is, a state where the cost decreases by a required delta from the previous-level state. The level relation on states and the plans constructed by ARES implicitly define a Lyapunov function and an optimal policy, respectively, both of which could be explicitly generated by applying ARES to all states of the MDP, up to some topological equivalence relation. We also assess the effectiveness of ARES by statistically evaluating its rate of success in generating optimal plans. The ARES algorithm resulted from our desire to clarify if flying in V-formation is a flocking policy that optimizes energy conservation, clear view, and velocity alignment. That is, we were interested to see if one could find optimal plans that bring a flock from an arbitrary initial state to a state exhibiting a single connected V-formation. For flocks with 7 birds, ARES is able to generate a plan that leads to a V-formation in 95% of the 8,000 random initial configurations within 63 s, on average. ARES can also be easily customized into a model-predictive controller (MPC) with an adaptive receding horizon and statistical guarantees of convergence. To the best of our knowledge, our adaptive-sizing approach is the first to provide convergence guarantees in receding-horizon techniques

Recommended Methods for Monitoring Skeletal Health in Astronauts to Distinguish Specific Effects of Prolonged Spaceflight

NASA uses areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) to monitor skeletal health in astronauts after typical 180-day spaceflights. The osteoporosis field and NASA, however, recognize the insufficiency of DXA aBMD as a sole surrogate for fracture risk. This is an even greater concern for NASA as it attempts to expand fracture risk assessment in astronauts, given the complicated nature of spaceflight-induced bone changes and the fact that multiple 1-year missions are planned. In the past decade, emerging analyses for additional surrogates have been tested in clinical trials; the potential use of these technologies to monitor the biomechanical integrity of the astronaut skeleton will be presented. OVERVIEW: An advisory panel of osteoporosis policy-makers provided NASA with an evidence-based assessment of astronaut biomedical and research data. The panel concluded that spaceflight and terrestrial bone loss have significant differences and certain factors may predispose astronauts to premature fractures. Based on these concerns, a proposed surveillance program is presented which a) uses Quantitative Computed Tomography (QCT) scans of the hip to monitor the recovery of spaceflight-induced deficits in trabecular BMD by 2 years after return, b) develops Finite Element Models [FEM] of QCT data to evaluate spaceflight effect on calculated hip bone strength and c) generates Trabecular Bone Score [TBS] from serial DXA scans of the lumbar spine to evaluate the effect of age, spaceflight and countermeasures on this novel index of bone microarchitecture. SIGNIFICANCE: DXA aBMD is a widely-applied, evidence-based predictor for fractures but not applicable as a fracture surrogate for premenopausal females and males <50 years. Its inability to detect structural parameters is a limitation for assessing changes in bone integrity with and without countermeasures. Collective use of aBMD, TBS, QCT, and FEM analysis for astronaut surveillance could accommodate NASA's aggressive schedule for risk definition and inform a NASA-developed model which assesses the probability of overloading bones during mechanically-loaded mission tasks and possibly for physical activities after return to Earth

Effects of Sleep Deprivation on Brain Bioenergetics, Sleep, and Cognitive Performance in Cocaine-Dependent Individuals

In cocaine-dependent individuals, sleep is disturbed during cocaine use and abstinence, highlighting the importance of examining the behavioral and homeostatic response to acute sleep loss in these individuals. The current study was designed to identify a differential effect of sleep deprivation on brain bioenergetics, cognitive performance, and sleep between cocaine-dependent and healthy control participants. 14 healthy control and 8 cocaine-dependent participants experienced consecutive nights of baseline, total sleep deprivation, and recovery sleep in the research laboratory. Participants underwent [31]P magnetic resonance spectroscopy (MRS) brain imaging, polysomnography, Continuous Performance Task, and Digit Symbol Substitution Task. Following recovery sleep, [31]P MRS scans revealed that cocaine-dependent participants exhibited elevated global brain β-NTP (direct measure of adenosine triphosphate), α-NTP, and total NTP levels compared to those of healthy controls. Cocaine-dependent participants performed worse on the Continuous Performance Task and Digit Symbol Substitution Task at baseline compared to healthy control participants, but sleep deprivation did not worsen cognitive performance in either group. Enhancements of brain ATP levels in cocaine dependent participants following recovery sleep may reflect a greater impact of sleep deprivation on sleep homeostasis, which may highlight the importance of monitoring sleep during abstinence and the potential influence of sleep loss in drug relapse

Structure-Activity Studies Of 7-Heteroaryl-3-Azabicyclo[3.3.1]Non-6-Enes: A Novel Class Of Highly Potent Nicotinic Receptor Ligands

The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes. © 2012 American Chemical Society