Major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States: Results from LC-FAOD Odyssey program.

Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU).

Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING.

CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism.

Three limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation-dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of melanogenesis-associated transcription factor (MITF). We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation.

Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Novel Luminescence-Based High-Throughput Approach for Cellular Resolution of Protein Ubiquitination Using Tandem Ubiquitin Binding Entities (TUBEs).

Protein turnover is highly regulated by the posttranslational process of ubiquitination. Deregulation of the ubiquitin proteasome system (UPS) has been implicated in cancer and neurodegenerative diseases, and modulating this system has proven to be a viable approach for therapeutic intervention. The development of novel technologies that enable high-throughput studies of substrate protein ubiquitination is key for UPS drug discovery.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines.

A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling.

We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discovering probes for immunology research. We used high content screening to measure the translocation from the cytoplasm to nucleus of IRF3 and NFkB in primary human macrophages; these transcription factors play a critical role in the activation of STING and other pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of these compounds did not cause activation of downstream pathways.

Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system.

Protein degradation is critical for proteostasis, and the addition of polyubiquitin chains to a substrate is necessary for its recognition by the 26S proteasome. Therapeutic intervention in the ubiquitin proteasome system has implications ranging from cancer to neurodegeneration. Novel screening methods and chemical biology tools for targeting E1-activating, E2-conjugating and deubiquitinating enzymes will be discussed in this review.

Triquetrohamate Impaction Syndrome: An Unrecognized Cause of Ulnar-Sided Wrist Pain; Its Presentation Further Defined.

Background: The aim of this review was to further define the clinical condition triquetrohamate (TH) impaction syndrome (THIS), an entity underreported and missed often. Its presentation, physical findings, and treatment are presented.

Methods: Between 2009 and 2014, 18 patients were diagnosed with THIS.

Assessing simulation-based clinical training: comparing the concurrent validity of students' self-reported satisfaction and confidence measures against objective clinical examinations.

Introduction: Simulation-based education (SBE) literature is replete with student satisfaction and confidence measures to infer educational outcomes. This research aims to test how well students' satisfaction and confidence measures correlate with expert assessments of students' improvements in competence following SBE activities.

Methods: N=85 paramedic students (mean age 23.

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself.

Effects of Low- Versus High-Fidelity Simulations on the Cognitive Burden and Performance of Entry-Level Paramedicine Students: A Mixed-Methods Comparison Trial Using Eye-Tracking, Continuous Heart Rate, Difficulty Rating Scales, Video Observation and Interviews.

Introduction: High-fidelity simulation-based training is often avoided for early-stage students because of the assumption that while practicing newly learned skills, they are ill suited to processing multiple demands, which can lead to "cognitive overload" and poorer learning outcomes. We tested this assumption using a mixed-methods experimental design manipulating psychological immersion.

Methods: Thirty-nine randomly assigned first-year paramedicine students completed low- or high-environmental fidelity simulations [low-environmental fidelity simulations (LF(en)S) vs.

Clinical Placement Before or After Simulated Learning Environments?: A Naturalistic Study of Clinical Skills Acquisition Among Early-Stage Paramedicine Students.

Background: There is conflicting evidence surrounding the merit of clinical placements (CPs) for early-stage health-profession students. Some contend that early-stage CPs facilitate contextualization of a subsequently learned theory. Others argue that training in simulated-learning experiences (SLEs) should occur before CP to ensure that students possess at least basic competency.

Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity.

Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation.

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A.

Quantification of opportunities for early-stage paramedicine students to practice clinical skills during clinical placements compared with an equal dose of simulation-based workshops.

Introduction: A reported advantage of simulation-based learning environments (SLE) over clinical placements (CPs) is that the former can provide a greater number and breadth of opportunities to practice level-appropriate clinical skills compared with the random patient presentations provided during the latter. Although logical and widely accepted as fact, we find no published evidence to demonstrate the magnitude, nor indeed veracity, of this assumption. We therefore sought to quantify the clinical skills practiced by entry-level paramedicine students attending a well-selected CP compared with an equal dosage of SLE.

Can one hear the shape of a population history?

Reconstructing past population size from present day genetic data is a major goal of population genetics. Recent empirical studies infer population size history using coalescent-based models applied to a small number of individuals. Here we provide tight bounds on the amount of exact coalescence time data needed to recover the population size history of a single, panmictic population at a certain level of accuracy.

In vitro clinical trials: the future of cell-based profiling.

The drug discovery process classically revolves around a set of biochemical and cellular assays to drive potency optimization and structural-activity relationship models. Layered on top of these concepts is the inclusion of molecular features that affect final drug use, things like: bioavailability, toxicity, stability, solubility, formulation, route of administration, etc. Paradoxically, most drugs entering clinical trials are only tested in a handful of human genetic backgrounds before they are given to people.

The Epstein-Barr virus microRNA BART11-5p targets the early B-cell transcription factor EBF1.

Epstein-Barr virus (EBV) is a ubiquitous B-cell trophic herpesvirus associated with a variety of histologically diverse B-cell lymphomas, each associated with specific viral-latency gene expression programs. Initial infection drives resting B-cells to differentiate via an atypical germinal centre reaction into memory B-cells, where the virus resides in a latent state. The mechanisms that underpin this process have yet to be fully elucidated.

Identification of small molecules for human hepatocyte expansion and iPS differentiation.

Cell-based therapies hold the potential to alleviate the growing burden of liver diseases. Such therapies require human hepatocytes, which, within the stromal context of the liver, are capable of many rounds of replication. However, this ability is lost ex vivo, and human hepatocyte sourcing has limited many fields of research for decades.

A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells.

The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR).

Expression profiling of Epstein-Barr virus-encoded microRNAs from paraffin-embedded formalin-fixed primary Epstein-Barr virus-positive B-cell lymphoma samples.

Epstein-Barr virus (EBV) is implicated in a range of B-cell malignancies and expresses unique microRNAs (EBV-miRNAs). Due to the requirements for high-quality RNA, studies profiling EBV-miRNA in EBV-positive lymphomas have been restricted to cell-lines or frozen samples. However, the most commonly available archived patient material is paraffin-embedded formalin-fixed (FFPE) tissue.

A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.

In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo.

STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability.

Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest in KRAS as a therapeutic target, direct blockade of KRAS function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels of protein kinases, KRAS-dependent cancer cells were proposed to have a unique requirement for the serine/threonine kinase STK33.