DRUGGED DRIVING

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell-intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development...

Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown...

The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV)...

Sexual desire includes complex motivation and drive. In the context of biological and cognitive-emotive state art of science, it is often a neglected field in medicine. With regard to the treatment, study on women's sexual function received less attention compared to the men's sexuality. In the past, this endeavor was relatively not well disseminated in the scientific community. Recently, there was a revolutionized surge of drug targets available to treat women with low sexual desire. It is timely to review the relevant biological approach, especially in the context of pharmacotherapy to understand this interesting clinical entity which was modulated by numerous interactive psychosocial inter-play and factors...

BACKGROUND: Marijuana use has been associated with increased risk-taking and impulsive behavior. While pharmacologic effects of marijuana can lead to inhibitory impairment, expectancy of potential impairment may result in compensatory behavioral response by decreasing impulsive decisions and risky behaviors. With the increases in marijuana use and related problems, a better understanding of the individual characteristics associated with marijuana intoxication and risky behavior is needed...

Driving under the influence of drugs (DUID) is a worldwide problem. Several countries adopted DUID legislations which prove their deterrent effect and impact on road safety. However, use of new psychoactive substances (NPS) and prescription drugs is not known as the applied roadside screening tests are not yet adapted for these compounds. In this study, 558 blood samples obtained during roadside controls in Belgium (January to August 2015) after a positive Drugwipe 5S® test and 199 oral fluid (OF) samples obtained from negatively screened test pads were analyzed...

BACKGROUND: Clinical trial globalization is a major trend for industry-sponsored clinical trials. There has been a shift in clinical trial sites towards emerging regions of Eastern Europe, Latin America, Asia, the Middle East, and Africa. Our study objectives were to evaluate the current characteristics of clinical trials and to find out the associated multiple factors which could explain clinical trial globalization and its implications for clinical trial globalization in 2011-2013. METHODS: The data elements of "phase," "recruitment status," "type of sponsor," "age groups," and "design of trial" from 30 countries were extracted from the ClinicalTrials...

The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification...

The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties...

Drugged driving has become more prevalent than drunk driving and is quickly gaining national attention due to increased prescription drug abuse and recent cannabis legalization. Unlike alcohol, police officers do not generally have access to approved devices to screen for drugs at the roadside. Onsite drug screening devices do exist and are used in other countries, but have not garnered widespread approval for use in the United States in driving under the influence of drugs (DUID) cases. One reason for this is that the devices are designed to test oral fluid, which is not a commonly accepted specimen for DUID...

People held in prison are at a high risk of having hepatitis C virus (HCV) and there is a public health drive in the UK to increase HCV testing in prisons and Young Offender Institutions (YOIs), with opt-out testing. There is an oral antibody test for HCV; this project aims to determine its acceptability in an English YOI setting. This project offered HCV oral point-of-care testing (POCT) using the OraQuick® test to 107 male young offenders attending a sexual health service at an English YOI, monitoring HCV positivity and evaluating acceptability...

Here, we report new mechanistic insight into how chronic hypoxia increases 'stemness' in cancer cells. Using chemical inhibitors, we provide direct experimental evidence that ROS production and mitochondrial biogenesis are both required for the hypoxia-induced propagation of CSCs. More specifically, we show that hypoxic CSCs can be effectively targeted with i) simple mitochondrial anti-oxidants (Mito-TEMPO) and/or ii) inhibitors of mitochondrial biogenesis (Doxycycline). In this context, we discuss the idea that mitochondrial biogenesis itself may be a primary driver of "stemness" in hypoxic cancer cells, with metabolic links to fatty acid oxidation (FAO)...

Whole blood samples were examined for ∆(9) -Tetrahydrocannabinol (THC) over 2 years in drivers suspected of driving under the influence. Part one of the study examined the link between [THC] and performance on field sobriety tests. This portion examined objective signs, eye examinations and physiological indicators; and their relationship to the presence of THC. Several objective signs were excellent indicators of the presence of THC: red eyes (94%), droopy eyelids (85.6%), affected speech (87.6%), tongue coating (96...

The past decade has witnessed a significant expansion of our understanding about the regulated cell death mechanisms beyond apoptosis. The application of chemical biological approaches had played a major role in driving these exciting discoveries. The discovery and use of small molecule probes in cell death research has not only revealed significant insights into the regulatory mechanism of cell death but also provided new drug targets and lead drug candidates for developing therapeutics of human diseases with huge unmet need...

The existence of cellular, molecular and biochemical heterogeneity of human breast cancers reveals the intricacy of biomarkers complexity, stimulating studies on new approaches (like "liquid biopsies") for the improvements in precision medicine. Breast cancer is recognized as a leading cause of morbidity and mortality worldwide with tumors significantly diverse and containing many types of cells showing different genetic and epigenetic profiles. In this field, the technology of Liquid Biopsy (applied to a fluid produced by breast gland, named nipple aspirate fluids, NAF) highlights the power of combining basic and clinical research...

Among parasitic organisms, inbreeding has been implicated as a potential driver of host-parasite coevolution, drug-resistance evolution, and parasite diversification. Yet, fundamental topics about how parasite life histories impact inbreeding remain to be addressed. In particular, there are no direct selfing-rate estimates for hermaphroditic parasites in nature. Our objectives were to elucidate the mating system of a parasitic flatworm in nature and to understand how aspects of parasite transmission could influence the selfing rates of individual parasites...

The deciphering of the hedgehog (Hh) signaling pathway implicated in the tumorigenesis of basal cell carcinoma (BCC), led to the development of targeted drug therapies, e.g. the hedgehog pathway inhibitors (HPI), vismodegib and sonidegib. In the skin, physiologic Hh signaling is activated in growing hair follicles, where it is required for proliferation of the epithelium of hair follicles during morphogenesis and for their postnatal growth. The effects of HPI treatment leading to the regression of BCC and the development of alopecia, underpin the central role of the Hh pathway in BCC formation as well as hair cycling...

Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer...

BACKGROUND: Antidepressant prescribing continues to increase, with 5-16% of adults receiving antidepressants annually. Total prescribing growth is due in part to increased long-term use, greater selective serotonin re-uptake inhibitor (SSRI) use and the use of higher SSRI doses. Evidence does not support routine use of higher SSRI doses for depression treatment, and factors influencing the use of such doses are not well known. The aim of this study was to explore factors influencing GPs' use of antidepressants and their doses to treat depression...

Gene targeting by homologous recombination provides the definitive tool for analyzing gene function. Promoterless vectors, which do not possess a promoter to drive marker gene expression, confer higher targeting efficiencies than conventional vectors due to reduced number of drug-resistant clones. We here show that gene-targeting efficiency is typically ≥ 25% with the use of exon-trapping-type promoterless vectors in a human diploid cell line, Nalm-6. The efficiency of exon-trapping gene targeting was correlated with the level of target gene expression when a 2A peptide sequence was linked to the marker gene...