Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease

The Molecular Clockwork of the Fire Ant Solenopsis invicta

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

Bulk Axions, Brane Back-reaction and Fluxes

Extra-dimensional models can involve bulk pseudo-Goldstone bosons (pGBs) whose shift symmetry is explicitly broken only by physics localized on branes. Reliable calculation of their low-energy potential is often difficult because it requires details of the stabilization of the extra dimensions. In rugby ball solutions, for which two compact extra dimensions are stabilized in the presence of only positive-tension brane sources, the effects of brane back-reaction can be computed explicitly. This allows the calculation of the shape of the low-energy pGB potential and response of the extra dimensional geometry as a function of the perturbing brane properties. If the pGB-dependence is a small part of the total brane tension a very general analysis is possible, permitting an exploration of how the system responds to frustration when the two branes disagree on what the proper scalar vacuum should be. We show how the low-energy potential is given by the sum of brane tensions (in agreement with common lore) when only the brane tensions couple to the pGB. We also show how a direct brane coupling to the flux stabilizing the extra dimensions corrects this result in a way that does not simply amount to the contribution of the flux to the brane tensions. We calculate the mass of the would-be zero mode, and briefly describe several potential applications, including a brane realization of `natural inflation,' and a dynamical mechanism for suppressing the couplings of the pGB to matter localized on the branes. Since the scalar can be light enough to be relevant to precision tests of gravity (in a technically natural way) this mechanism can be relevant to evading phenomenological bounds.Comment: 36 pages, JHEP styl

Outcomes from massive paracetamol overdose: a retrospective observational study

LINKED ARTICLE: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163–5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl) and treatment nomogram thresholds at those time points (APAPt) provides a useful assessment tool. METHODS: This is a retrospective observational study of all patients (n = 545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250 mg l−1, or reported ingestions ≥30 g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAPpl:APAPt ratio (based on a treatment line through 100 mg l−1 at 4 h), and time to acetylcysteine. RESULTS: Ingestions of ≥30 g paracetamol correlated with higher peak serum aminotransferase (r = 0.212, P < 0.0001) and creatinine (r = 0.138, P = 0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAPpl:APAPt ≥ 3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04–16.68), 35.95 (8.80–158.1) and 8.34 (4.43–15.84), respectively (P < 0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8 h of overdose. CONCLUSION: Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAPpl:APAPt ≥ 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort

Institutions, Human Capital, and Development

In this article, we revisit the relationship among institutions, human capital, and development. We argue that empirical models that treat institutions and human capital as exogenous are misspecified, both because of the usual omitted variable bias problems and because of differential measurement error in these variables, and that this misspecification is at the root of the very large returns of human capital, about four to five times greater than that implied by micro (Mincerian) estimates, found in the previous literature. Using cross-country and cross-regional regressions, we show that when we focus on historically determined differences in human capital and control for the effect of institutions, the impact of institutions on long-run development is robust, whereas the estimates of the effect of human capital are much diminished and become consistent with micro estimates. Using historical and cross-country regression evidence, we also show that there is no support for the view that differences in the human capital endowments of early European colonists have been a major factor in the subsequent institutional development of former colonies.Comisión Nacional de Investigación Ciencia y Tecnología (Chile) (CONICYT/Programa de Investigación Asociativa (project SOC1102))United States. Army Research Office (ARO MURI W911NF-12-1-0509

Learning by hiring: the effects of scientists’ inbound mobility on research performance in academia

This study investigates the effects of scientists’ inbound mobility on the research performance of incumbent scientists in an academic setting. The theoretical framework integrates insights from learning theory and social comparison theory to suggest two main mechanisms behind these effects, localized learning and social comparison. The authors propose several hypotheses about the conditions that might intensify or weaken such effects. Specifically, the arrival of new scientific personnel is likely to exert stronger positive effects on the performance of incumbent scientists with shorter (cf. longer) organizational tenure; in addition, academic departments with less diversified expertise and with higher levels of internal collaborations likely reap greater benefits from learning by hiring. The empirical findings, based on a longitudinal analysis of a sample of 94 U.S. academic chemical engineering departments, provide empirical support for these contentions

Successful treatment of fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions

<p>Abstract</p> <p>Background</p> <p>Ecthyma gangrenosum (EG) manifests as a skin lesion affecting patients suffering extreme neutropenia and is commonly associated with <it>Pseudomonas aeruginosa </it>in immunocompromised patients. Leukocyte adhesion deficiency I (LAD I) which count among primary immunodeficiency syndromes of the innate immunity, is an autosomal recessive disorder characterized in its severe phenotype by a complete defect in CD18 expression on neutrophils, delayed cord separation, chronic skin ulcers mainly due to recurrent bacterial and fungal infections, leucocytosis with high numbers of circulating neutrophils and an accumulation of abnormally low number of neutrophils at sites of infection.</p> <p>Case Presentation</p> <p>We report at our knowledge the first case of a child affected by LAD-1, who experienced during her disease course a multi-bacterial and fungal EG lesion caused by <it>fusarium solani</it>. Despite targeted antibiotics and anti-fungi therapy, the lesion extended for as long as 18 months and only massive granulocytes pockets transfusions in association with G-CSF had the capacity to cure this lesion.</p> <p>Conclusion</p> <p>We propose that granulocytes pockets transfusions will be beneficial to heal EG especially in severely immunocompromised patients.</p

Capture the fracture: a best practice framework and global campaign to break the fragility fracture cycle

Summary The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. Introduction FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. Methods Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. Results The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award ‘Capture the Fracture Best Practice Recognition’ to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. Conclusion Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.</p