Combined BRAF and MEK blockade for BRAF-mutant gliomas.

BRAF is a common finding in glioma (about 10-60% depending on histopathologic subclassification). BRAF monotherapy shows modest preclinical efficacy against BRAF gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAF inhibition in glioma.

Cholesterol: An Achilles' Heel for Glioblastoma?

In this issue of Cancer Cell, Villa et al. report that survival of glioblastoma cells is dependent on uptake of cholesterol. A synthetic agonist of the Liver X receptor depleted cholesterol in GBM cells, slowing growth of GBM xenografts.

Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumour occurring in childhood and has a diverse clinical presentation and course depending on the tumour biology. Unique features of these neuroendocrine tumours are the early age of onset, the high frequency of metastatic disease at diagnosis and the tendency for spontaneous regression of tumours in infancy. The most malignant tumours have amplification of the MYCN oncogene (encoding a transcription factor), which is usually associated with poor survival, even in localized disease.

BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas.

Purpose: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAF and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway.

Experimental Design: We used human glioma lines containing BRAF (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAF-expressing murine brain cells.

The use of a lot quality assurance sampling methodology to assess and manage primary health interventions in conflict-affected West Darfur, Sudan.

Background: Organizations working in conflict-affected areas have a need to monitor and evaluate their programs, however this is often difficult due to the logistical challenges of conflict areas. Lot quality assurance sampling may be a suitable method of assessing programs in these situations.

Methods: We conducted a secondary data analysis of information collected during Medair's routine program management functions.

Technical Decision Making With Higher Order Structure Data: Perspectives on Higher Order Structure Characterization From the Biopharmaceutical Industry.

Characterization of the higher order structure (HOS) of protein-based biopharmaceutical products is an important aspect of their development. Opinions vary about how best to apply biophysical methods, in which contexts to use these methods, and how to use the resulting data to make technical decisions as drug candidates are commercialized [Gabrielson JP, Weiss WF IV. J Pharm Sci.

Vitamin D status of dairy cattle: Outcomes of current practices in the dairy industry.

The need for vitamin D supplementation of dairy cattle has been known for the better part of the last century and is well appreciated by dairy producers and nutritionists. Whether current recommendations and practices for supplemental vitamin D are meeting the needs of dairy cattle, however, is not well known. The vitamin D status of animals is reliably indicated by the concentration of the 25-hydroxyvitamin D [25(OH)D] metabolite in serum or plasma, with a concentration of 30ng/mL proposed as a lower threshold for sufficiency.

IKK/NF-κB signaling contributes to glioblastoma stem cell maintenance.

Glioblastoma multiforme (GBM) carries a poor prognosis and continues to lack effective treatments. Glioblastoma stem cells (GSCs) drive tumor formation, invasion, and drug resistance and, as such, are the focus of studies to identify new therapies for disease control. Here, we identify the involvement of IKK and NF-κB signaling in the maintenance of GSCs.

Variability in Flow-Imaging Microscopy Measurements and Considerations for Biopharmaceutical Development.

Flow-imaging microscopy is widely used in the biopharmaceutical industry to characterize populations of subvisible (1-100 μm) particles due to high sensitivity and the ability to discriminate different particle morphologies. The present work provides a comprehensive assessment of the capabilities of flow-imaging microscopy by exploring the impacts of a variety of factors on the observed variability of these measurements. A novel graphical presentation is proposed to facilitate both determination of expected levels and detection of potential atypical results.

Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas.

Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials.

Trends in quality of screening colonoscopy in Austria.

Screening colonoscopy only effectively prevents colorectal cancer if performed with high quality. The aim of this study was to analyze the detection rates of premalignant colorectal lesions in screening colonoscopies performed within a nationwide quality control program for screening colonoscopy in Austria. Data from electronic records of the screening program from its implementation in 2007 until December 2014 were analyzed in order to calculate detection rates for adenomas, advanced adenomas, polyps, and proximal lesions, and rates of cecal intubation, sedation, complications, and adequate bowel preparation.

Estimating analytical variability in two-dimensional data.

Throughout the course of drug development there are many instances in which a variability assessment within a set of analytical data is required, which may be challenging for techniques that produce two-dimensional data. This note describes an interval-based approach to variability assessment and demonstrates its applicability for analysis of near-UV circular dichroism (CD) spectra. The approach is generalizable and could be applied to two-dimensional data from other analytical techniques as well.

Protecting Public Health in Nuclear Emergencies-the Need to Broaden the Process.

It is necessary for the radiation protection system to broaden beyond radioactive dose, the view on impact of nuclear accidents, taking in consideration the psychological, social and economic determinants impacting the vulnerability of the exposed population, as well as the impacts of emergency countermeasures. It is strongly recommended to pursue strategies, approaches and services that will address these aspects within the general health protection system and will be applied before, during and after an emergency. The paper raises awareness and proposes a three-step development process for an integrated framework based on the social determinants of health approach.

Radiological Protection Issues Arising During and After the Fukushima Nuclear Reactor Accident-Memorandum of TG 84 of ICRP.

Observations and lessons identified after the Fukushima accident have been collected and assessed by ICRP Task Group 84. Together with the observations of other expert organizations, they are being used to further develop the current system of protection. While many of the established protection criteria remain valid, improvements are needed in three areas.

Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors.

MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths. We designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein.

Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections.

Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S.

Pediatric high-grade glioma: biologically and clinically in need of new thinking.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace.

Convergent evolution of pregnancy-specific glycoproteins in human and horse.

Pregnancy-specific glycoproteins (PSGs) are members of the carcinoembryonic antigen cell adhesion molecule (CEACAM) family that are secreted by trophoblast cells. PSGs may modulate immune, angiogenic and platelet responses during pregnancy. Until now, PSGs are only found in species that have a highly invasive (hemochorial) placentation including humans, mice and rats.

Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models.

NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development.

Randomized, multicenter study: on-demand versus continuous maintenance treatment with esomeprazole in patients with non-erosive gastroesophageal reflux disease.

Background: Most patients with gastroesophageal reflux disease experience symptomatic relapse after stopping acid-suppressive medication. The aim of this study was to compare willingness to continue treatment with esomeprazole on-demand versus continuous maintenance therapy for symptom control in patients with non-erosive reflux disease (NERD) after 6 months.

Methods: This multicenter, open-label, randomized, parallel-group study enrolled adults with NERD who were heartburn-free after 4 weeks' treatment with esomeprazole 20 mg daily.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.

Generating trunk neural crest from human pluripotent stem cells.

Neural crest cells (NCC) are stem cells that generate different lineages, including neuroendocrine, melanocytic, cartilage, and bone. The differentiation potential of NCC varies according to the level from which cells emerge along the neural tube. For example, only anterior "cranial" NCC form craniofacial bone, whereas solely posterior "trunk" NCC contribute to sympathoadrenal cells.

Health service utilization and access to medicines among Syrian refugee children in Jordan.

Background: With over one million Syrian refugee children in the region, we undertook this study to characterize care-seeking behaviors and health service utilization for child refugees with the aim of informing humanitarian programming for non-camp settings in Jordan.

Methods: A survey of Syrian refugees living outside of camps in Jordan was conducted using a 125 × 12 cluster design with probability proportional to size sampling to obtain a representative sample. The questionnaire focused on access to health services, including a module on care seeking for children.