Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma

An applied ecology of fear framework: linking theory to conservation practice

Research on the ecology of fear has highlighted the importance of perceived risk from predators and humans in shaping animal behavior and physiology, with potential demographic and ecosystem-wide consequences. Despite recent conceptual advances and potential management implications of the ecology of fear, theory and conservation practices have rarely been linked. Many challenges in animal conservation may be alleviated by actively harnessing or compensating for risk perception and risk avoidance behavior in wild animal populations. Integration of the ecology of fear into conservation and management practice can contribute to the recovery of threatened populations, human–wildlife conflict mitigation, invasive species management, maintenance of sustainable harvest and species reintroduction plans. Here, we present an applied framework that links conservation interventions to desired outcomes by manipulating ecology of fear dynamics. We discuss how to reduce or amplify fear in wild animals by manipulating habitat structure, sensory stimuli, animal experience (previous exposure to risk) and food safety trade-offs to achieve management objectives. Changing the optimal decision-making of individuals in managed populations can then further conservation goals by shaping the spatiotemporal distribution of animals, changing predation rates and altering risk effects that scale up to demographic consequences. We also outline future directions for applied research on fear ecology that will better inform conservation practices. Our framework can help scientists and practitioners anticipate and mitigate unintended consequences of management decisions, and highlight new levers for multi-species conservation strategies that promote human–wildlife coexistence

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar

Patient-reported symptom burden of Charcot-Marie-Tooth Disease Type 1A: findings from an observational digital lifestyle study

Objectives: This study aims to explore the impact of Charcot-Marie-Tooth disease type 1A (CMT1A) and its treatment on patients in European (France, Germany, Italy, Spain, and the United Kingdom) and US real-world practice. Methods: Adults with CMT1A (n = 937) were recruited to an ongoing observational study exploring the impact of CMT. Data were collected via CMT&Me, an app through which participants completed patient-reported outcome measures. Results: Symptoms ranked with highest importance were weakness in the extremities, difficulty in walking, and fatigue. Almost half of participants experienced a worsening of symptom severity since diagnosis. Anxiety and depression were each reported by over one-third of participants. Use of rehabilitative interventions, medications, and orthotics/walking aids was high. Conclusions: Patient-reported burden of CMT1A is high, influenced by difficulties in using limbs, fatigue, pain, and impaired quality of life. Burden severity appears to differ across the population, possibly driven by differences in rehabilitative and prescription-based interventions, and country-specific health care variability

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity. Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function

Tentative Evidence for Water Vapor in the Atmosphere of the Neptune-Size Exoplanet HD 106315 c

We present a transmission spectrum for the Neptune-size exoplanet HD 106315 c from optical to infrared wavelengths based on transit observations from the Hubble Space Telescope/Wide Field Camera 3, K2, and Spitzer. The spectrum shows tentative evidence for a water absorption feature in the 1.1−1.7μm wavelength range with a small amplitude of 30 ppm (corresponding to just 0.8±0.04 atmospheric scale heights). Based on an atmospheric retrieval analysis, the presence of water vapor is tentatively favored with a Bayes factor of 1.7 - 2.6 (depending on prior assumptions). The spectrum is most consistent with either enhanced metallicity, high altitude condensates, or both. Cloud-free solar composition atmospheres are ruled out at >5σ confidence. We compare the spectrum to grids of cloudy and hazy forward models and find that the spectrum is fit well by models with moderate cloud lofting or haze formation efficiency, over a wide range of metallicities (1−100× solar). We combine the constraints on the envelope composition with an interior structure model and estimate that the core mass fraction is ≳0.3. With a bulk composition reminiscent of that of Neptune and an orbital distance of 0.15 AU, HD 106315 c hints that planets may form out of broadly similar material and arrive at vastly different orbits later in their evolution

Tentative Evidence for Water Vapor in the Atmosphere of the Neptune-Size Exoplanet HD 106315 c

We present a transmission spectrum for the Neptune-size exoplanet HD 106315 c from optical to infrared wavelengths based on transit observations from the Hubble Space Telescope/Wide Field Camera 3, K2, and Spitzer. The spectrum shows tentative evidence for a water absorption feature in the $1.1 - 1.7\mu$m wavelength range with a small amplitude of 30 ppm (corresponding to just $0.8 \pm 0.04$ atmospheric scale heights). Based on an atmospheric retrieval analysis, the presence of water vapor is tentatively favored with a Bayes factor of 1.7 - 2.6 (depending on prior assumptions). The spectrum is most consistent with either enhanced metallicity, high altitude condensates, or both. Cloud-free solar composition atmospheres are ruled out at $>5\sigma$ confidence. We compare the spectrum to grids of cloudy and hazy forward models and find that the spectrum is fit well by models with moderate cloud lofting or haze formation efficiency, over a wide range of metallicities ($1 - 100\times$ solar). We combine the constraints on the envelope composition with an interior structure model and estimate that the core mass fraction is $\gtrsim0.3$. With a bulk composition reminiscent of that of Neptune and an orbital distance of 0.15 AU, HD 106315 c hints that planets may form out of broadly similar material and arrive at vastly different orbits later in their evolution.Comment: Submitted to AAS journals; 19 pages, 12 figure

Of Mice and Measures : A Project to Improve How We Advance Duchenne Muscular Dystrophy Therapies to the Clinic.

A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information and their potential value. The overall aim is to establish guidance on how to best use the D2/mdx mouse model in preclinical studies