Simulated driving performance among daily and occasional cannabis users.

Objective: Daily cannabis users develop tolerance to some drug effects, but the extent to which this diminishes driving impairment is uncertain. This study compared the impact of acute cannabis use on driving performance in occasional and daily cannabis users using a driving simulator.

Methods: We used a within-subjects design to observe driving performance in adults age 25 to 45 years with different cannabis use histories.

Genomic markers associated with successful treatment of hypertension with lisinopril: A pilot study.

Objective: To identify single nucleotide variants (SNVs) associated with lisinopril effectiveness.

Materials And Methods: This was an observational study using a candidate gene approach to examine SNVs associated with lisinopril effectiveness. Drug effectiveness was defined as 10% decrease in systolic blood pressure at 1 week follow-up.

Atg2, Atg9 and Atg18 in mitochondrial integrity, cardiac function and healthspan in Drosophila.

In yeast, the Atg2-Atg18 complex regulates Atg9 recycling from phagophore assembly site during autophagy; their function in higher eukaryotes remains largely unknown. In a targeted screening in Drosophila melanogaster, we show that Mef2-GAL4-RNAi-mediated knockdown of Atg2, Atg9 or Atg18 in the heart and indirect flight muscles led to shortened healthspan (declined locomotive function) and lifespan. These flies displayed an accelerated age-dependent loss of cardiac function along with cardiac hypertrophy (increased heart tube wall thickness) and structural abnormality (distortion of the lumen surface).

PD-L1 immunostaining scoring for non-small cell lung cancer based on immunosurveillance parameters.

Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death globally, and new immunotherapies developed and under development targeting PD-1/PD-L1 checkpoint inhibition require accurate patient selection to assure good clinical outcome. PD-L1 immunohistochemistry is the current biomarker assay used for patient selection, but still imprecise in predicting therapy response. Exploring this issue, we performed computational tissue analysis of PD-L1 immunostaining in procured NSCLC tissues (n = 50) using the Merck KGaA anti-PD-L1 clone MKP1A07310.

Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy.

Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3-12 h and mitophagy at 6 h post-exercise in skeletal muscle.

Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer.

Purpose: Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076.

Experimental Design: p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment.

Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors.

Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy.

Systematic analysis of tumour cell-extracellular matrix adhesion identifies independent prognostic factors in breast cancer.

Tumour cell-extracellular matrix (ECM) interactions are fundamental for discrete steps in breast cancer progression. In particular, cancer cell adhesion to ECM proteins present in the microenvironment is critical for accelerating tumour growth and facilitating metastatic spread. To assess the utility of tumour cell-ECM adhesion as a means for discovering prognostic factors in breast cancer survival, here we perform a systematic phenotypic screen and characterise the adhesion properties of a panel of human HER2 amplified breast cancer cell lines across six ECM proteins commonly deregulated in breast cancer.

An integrated bioinformatics analysis to dissect kinase dependency in triple negative breast cancer.

Background: Triple-Negative Breast Cancer (TNBC) is an aggressive disease with a poor prognosis. Clinically, TNBC patients have limited treatment options besides chemotherapy. The goal of this study was to determine the kinase dependency in TNBC cell lines and to predict compounds that could inhibit these kinases using integrative bioinformatics analysis.

Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

Motivation: Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret.

DSigDB: drug signatures database for gene set analysis.

Unlabelled: We report the creation of Drug Signatures Database (DSigDB), a new gene set resource that relates drugs/compounds and their target genes, for gene set enrichment analysis (GSEA). DSigDB currently holds 22 527 gene sets, consists of 17 389 unique compounds covering 19 531 genes. We also developed an online DSigDB resource that allows users to search, view and download drugs/compounds and gene sets.

Systems biology approaches for advancing the discovery of effective drug combinations.

Complex diseases like cancer are regulated by large, interconnected networks with many pathways affecting cell proliferation, invasion, and drug resistance. However, current cancer therapy predominantly relies on the reductionist approach of one gene-one disease. Combinations of drugs may overcome drug resistance by limiting mutations and induction of escape pathways, but given the enormous number of possible drug combinations, strategies to reduce the search space and prioritize experiments are needed.

Automated microscopy of cardiac myocyte hypertrophy: a case study on the role of intracellular α-adrenergic receptors.

Traditional approaches for measuring cardiac myocyte hypertrophy have been of low throughput and subjective, limiting the scope of experimental studies designed to understand it. Here, we describe an automated image acquisition and analysis platform for studying the dynamics of cardiac myocyte hypertrophy in vitro. Image acquisition scripts record 5 × 5 mosaic images of fluorescent protein-labeled neonatal rat ventricular myocytes from each well of a 96-well plate using the microscope's automated stage and focus.

A novel MitoTimer reporter gene for mitochondrial content, structure, stress, and damage in vivo.

Mitochondrial dysfunction plays important roles in many diseases, but there is no satisfactory method to assess mitochondrial health in vivo. Here, we engineered a MitoTimer reporter gene from the existing Timer reporter gene. MitoTimer encodes a mitochondria-targeted green fluorescent protein when newly synthesized, which shifts irreversibly to red fluorescence when oxidized.

Phenotypic screen quantifying differential regulation of cardiac myocyte hypertrophy identifies CITED4 regulation of myocyte elongation.

Cardiac hypertrophy is controlled by a highly connected signaling network with many effectors of cardiac myocyte size. Quantification of the contribution of individual pathways to specific changes in shape and transcript abundance is needed to better understand hypertrophy signaling and to improve heart failure therapies. We stimulated cardiac myocytes with 15 hypertrophic agonists and quantitatively characterized differential regulation of 5 shape features using high-throughput microscopy and transcript levels of 12 genes using qPCR.

Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling.

Cardiac hypertrophy is managed by a dense web of signaling pathways with many pathways influencing myocyte growth. A quantitative understanding of the contributions of individual pathways and their interactions is needed to better understand hypertrophy signaling and to develop more effective therapies for heart failure. We developed a computational model of the cardiac myocyte hypertrophy signaling network to determine how the components and network topology lead to differential regulation of transcription factors, gene expression, and myocyte size.

Automated imaging reveals a concentration dependent delay in reversibility of cardiac myocyte hypertrophy.

Cardiac hypertrophy is controlled by a dense signaling network with many pathways associated with cardiac myocyte growth. New large scale methodology is required to quantitatively characterize the pathways that distinguish reversible forms of hypertrophy from irreversible forms that lead to heart failure. Our automated image acquisition method records 5×5 mosaic images of fluorescent protein-labeled cardiac myocytes within each well of a 96-well plate using an automated stage and focus.

Automated image analysis identifies signaling pathways regulating distinct signatures of cardiac myocyte hypertrophy.

Cardiac hypertrophy is controlled by a complex signal transduction and gene regulatory network, containing multiple layers of crosstalk and feedback. While numerous individual components of this network have been identified, understanding how these elements are coordinated to regulate heart growth remains a challenge. Past approaches to measure cardiac myocyte hypertrophy have been manual and often qualitative, hindering the ability to systematically characterize the network's higher-order control structure and identify therapeutic targets.

Folic acid enhances early functional recovery in a piglet model of pediatric head injury.

For stroke and spinal cord injury, folic acid supplementation has been shown to enhance neurodevelopment and to provide neuroprotection. We hypothesized that folic acid would reduce brain injury and improve neurological outcome in a neonatal piglet model of traumatic brain injury (TBI), using 4 experimental groups of 3- to 5-day-old female piglets. Two groups were intubated, anesthetized and had moderate brain injury induced by rapid axial head rotation without impact.

In situ deformations in the immature brain during rapid rotations.

Head trauma is the leading cause of death and debilitating injury in children. Computational models are important tools used to understand head injury mechanisms but they must be validated with experimental data. In this communication we present in situ measurements of brain deformation during rapid, nonimpact head rotation in juvenile pigs of different ages.