NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis

Effect of growth hormone replacement therapy in a boy with Dent's disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Dent's disease is an X-linked recessive proximal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. To the best of our knowledge, this is only the third report on the use of growth hormone therapy in a child with poor growth associated with Dent's disease.</p> <p>Case presentation</p> <p>We report on a 7-year-old Montenegrin boy with proteinuria, hypercalciuria, nephrocalcinosis, rickets and short stature with unimpaired growth hormone secretion. A molecular genetic analysis showed S244L substitution on the CLCN5 gene. After two years of conventional treatment with hydrochlorothiazide, laboratory tests revealed more prominent proteinuria, mild hypophosphatemia, increased values of alkaline phosphatase and features of rickets. Phosphate salts, calcitriol, potassium citrate and growth hormone were included in the therapy. After three years of therapy, his adjusted parental stature was 1.53 standard deviations higher than at the initiation of growth hormone therapy. His global kidney functions and levels of proteinuria and calciuria remained relatively stable. In spite of the growth hormone therapy, his tubular reabsorption of phosphate deteriorated.</p> <p>Conclusion</p> <p>Treatment with recombinant human growth hormone may have a positive effect on final height in poorly growing children with Dent's disease and hypophosphatemic rickets. However, it is not possible to reach definite conclusions due to the small sample within the literature and the brief duration of the therapy.</p

Temperament and Impulsivity Predictors of Smoking Cessation Outcomes

Aims: Temperament and impulsivity are powerful predictors of addiction treatment outcomes. However, a comprehensive assessment of these features has not been examined in relation to smoking cessation outcomes.Methods: Naturalistic prospective study. Treatment-seeking smokers (n = 140) were recruited as they engaged in an occupational health clinic providing smoking cessation treatment between 2009 and 2013. Participants were assessed at baseline with measures of temperament (Temperament and Character Inventory), trait impulsivity (Barratt Impulsivity Scale), and cognitive impulsivity (Go/No Go, Delay Discounting and Iowa Gambling Task). The outcome measure was treatment status, coded as “dropout” versus “relapse” versus “abstinence” at 3, 6, and 12 months endpoints. Participants were telephonically contacted and reminded of follow-up face to face assessments at each endpoint. The participants that failed to answer the phone calls or self-reported discontinuation of treatment and failed to attend the upcoming follow-up session were coded as dropouts. The participants that self-reported continuing treatment, and successfully attended the upcoming follow-up session were coded as either “relapse” or “abstinence”, based on the results of smoking behavior self-reports cross-validated with co-oximetry hemoglobin levels. Multinomial regression models were conducted to test whether temperament and impulsivity measures predicted dropout and relapse relative to abstinence outcomes.Results: Higher scores on temperament dimensions of novelty seeking and reward dependence predicted poorer retention across endpoints, whereas only higher scores on persistence predicted greater relapse. Higher scores on the trait dimension of non-planning impulsivity but not performance on cognitive impulsivity predicted poorer retention. Higher non-planning impulsivity and poorer performance in the Iowa Gambling Task predicted greater relapse at 3 and 6 months and 6 months respectively.Conclusion: Temperament measures, and specifically novelty seeking and reward dependence, predict smoking cessation treatment retention, whereas persistence, non-planning impulsivity and poor decision-making predict smoking relapse.This research was funded by the Occupational Medicine Area (Prevention Service); Department of Personality, Assessment and Psychological Treatment, University of Granada (Spain); and Ministerio de Economía y Competitividad grant (MINICO, ref. # PSI2013-45055-P) for the first and second authors

Delay discounting differences in brain activation, connectivity, and structure in individuals with addiction: a systematic review protocol

Abstract Background Delayed reward discounting (DRD), the degree to which future rewards are discounted relative to immediate rewards, is used as an index of impulsive decision-making and has been associated with a number of problematic health behaviors. Given the robust behavioral association between DRD and addictive behavior, there is an expanding literature investigating the differences in the functional and structural correlates of DRD in the brain between addicted and healthy individuals. However, there has yet to be a systematic review which characterizes differences in regional brain activation, functional connectivity, and structure and places them in the larger context of the DRD literature. The objective of this systematic review is to summarize and critically appraise the existing literature examining differences between addicted and healthy individuals in the neural correlates of DRD using magnetic resonance imaging (MRI) or functional magnetic resonance imaging (fMRI). Methods A systematic search strategy will be implemented that uses Boolean search terms in PubMed/MEDLINE and PsycINFO, as well as manual search methods, to identify the studies comprehensively. This review will include studies using MRI or fMRI in humans to directly compare brain activation, functional connectivity, or structure in relation to DRD between addicted and healthy individuals or continuously assess addiction severity in the context of DRD. Two independent reviewers will determine studies that meet the inclusion criteria for this review, extract data from included studies, and assess the quality of included studies using the Grading of Recommendations Assessment, Development and Evaluation framework. Then, narrative review will be used to explicate the differences in structural and functional correlates of DRD implicated by the literature and assess the strength of evidence for this conclusion. Discussion This review will provide a needed critical exegesis of the MRI studies that have been conducted investigating brain differences in addictive behavior in relation to healthy samples in the context of DRD. This will provide clarity on the elements of neural activation, connectivity, and structure that are most implicated in the differences in DRD seen in addicted individuals. Systematic review registration PROSPERO CRD4201705685