6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/03/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/03/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Notice NOT-OD-18-154 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-059 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-058 from the NIH Guide for Grants and Contracts

Notice NOT-AA-18-008 from the NIH Guide for Grants and Contracts

Notice NOT-NS-18-042 from the NIH Guide for Grants and Contracts

Notice NOT-DE-18-015 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-RM-18-010 from the NIH Guide for Grants and Contracts. The NIH Directors Early Independence Award supports exceptional investigators who wish to pursue independent research essentially directly after completion of their terminal doctoral/research degree or end of post-graduate clinical training, thereby forgoing the traditional post-doctoral training period and accelerating their entry into an independent research career. Applications are welcome from individuals of diverse backgrounds and perspectives and in any topic of relevance to the broad mission of NIH. The NIH Directors Early Independence Award is a component of the High-Risk, High-Reward Research program of the NIH Common Fund.

The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis.

Curr Treat Options Gastroenterol. 2018 Mar 23;:

Authors: Moctezuma-Velázquez C, Abraldes JG, Montano-Loza AJ

Abstract
PURPOSE OF REVIEW: Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis.
RECENT FINDINGS: Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury. Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.

PMID: 29572618 [PubMed - as supplied by publisher]

N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells.

Redox Biol. 2018 Mar 14;16:294-302

Authors: Valdivieso ÁG, Dugour AV, Sotomayor V, Clauzure M, Figueroa JM, Santa-Coloma TA

Abstract
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are lethal pulmonary diseases. Cigarette consumption is the main cause for development of COPD, while CF is produced by mutations in the CFTR gene. Although these diseases have a different etiology, both share a CFTR activity impairment and proinflammatory state even under sterile conditions. The aim of this work was to study the extent of the protective effect of the antioxidant N-acetylcysteine (NAC) over the proinflammatory state (IL-6 and IL-8), oxidative stress (reactive oxygen species, ROS), and CFTR levels, caused by Cigarette Smoke Extract (CSE) in Calu-3 airway epithelial cells. CSE treatment (100 µg/ml during 24 h) decreased CFTR mRNA expression and activity, and increased the release of IL-6 and IL-8. The effect on these cytokines was inhibited by N-acetyl cysteine (NAC, 5 mM) or the NF-kB inhibitor, IKK-2 (10 µM). CSE treatment also increased cellular and mitochondrial ROS levels. The cellular ROS levels were normalized to control values by NAC treatment, although significant effects on mitochondrial ROS levels were observed only at short times (5´) and effects on CFTR levels were not observed. In addition, CSE reduced the mitochondrial NADH-cytochrome c oxidoreductase (mCx I-III) activity, an effect that was not reverted by NAC. The reduced CFTR expression and the mitochondrial damage induced by CSE could not be normalized by NAC treatment, evidencing the need for a more specific reagent. In conclusion, CSE causes a sterile proinflammatory state and mitochondrial damage in Calu-3 cells that was partially recovered by NAC treatment.

PMID: 29573703 [PubMed - as supplied by publisher]

Bronchiectasis in the Kimberley region of Western Australia.

Aust J Rural Health. 2018 Mar 24;:

Authors: Barton J, Scott L, Maguire G

Abstract
OBJECTIVE: To review the work-up and inpatient management of non-cystic fibrosis bronchiectasis exacerbations against best practice guidelines in Kimberley, a remote region of Western Australia, with the ultimate goal of improving treatment in the region.
DESIGN: Retrospective cohort study and audit of remote adult bronchiectasis hospital admissions between 2011 and 2016.
SETTING: Remote hospital inpatients.
PARTICIPANTS: Thirty-two patients and 110 hospital admissions were included. Patients were ≥15 years old, had computed tomography confirmed bronchiectasis and at least one hospital admission for acute respiratory illness prior to January 2011.
MAIN OUTCOMES MEASURED: The 5-year mortality and compliance to a Lung Foundation position statement on non-cystic fibrosis bronchiectasis which suggests investigating for an underlying cause at diagnosis and during exacerbations prolonged antibiotics (10-14 days) and prolonged hospital admissions (≥7 days) are required.
RESULTS: The overall 5-year mortality was 21.8%, with the median age at death of 37 years (interquartile range, 27-63). The median duration of hospital admission was shorter than the recommended 3 days (interquartile range, 2-5) with 11 of 100 (11%) patients admitted for ≥7 days. The median duration of antibiotics was also shorter than the recommended 7 days (interquartile range, 4-10), with 31 of the 98 (32%) patients prescribed ≥10 days and 6 of the 98 (6%) prescribed ≥14 days of therapy.
CONCLUSION: We found under-treatment and under-investigation of non-cystic fibrosis bronchiectasis in the Kimberley region. Five-year mortality was highly consistent with other rural Australian Indigenous cohorts. Following this audit, a strategy to improve awareness, as well as update and promote regional guidelines has been developed.

PMID: 29573520 [PubMed - as supplied by publisher]

Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin.

Sci Rep. 2018 Mar 23;8(1):5094

Authors: McWilliam SJ, Antoine DJ, Jorgensen AL, Smyth RL, Pirmohamed M

Abstract
Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies.

PMID: 29572451 [PubMed - in process]

A transcription factor network represses CFTR gene expression in airway epithelial cells.

Biochem J. 2018 Mar 23;:

Authors: Mutolo MJ, Leir SH, Fossum SL, Browne JA, Harris A

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene cause the inherited disorder cystic fibrosis (CF). Lung disease is the major cause of CF morbidity, though CFTR expression levels are substantially lower in the airway epithelium than in pancreatic duct and intestinal epithelia, which also show compromised function in CF. Recently developed small molecule therapeutics for CF are highly successful for one specific CFTR mutation and may have a positive impact on others. However, the low abundance of CFTR transcripts in the airway limits the opportunity for drugs to correct the defective substrate. Elucidation of the transcriptional mechanisms for the CFTR locus has largely focused on intragenic and intergenic tissue-specific enhancers and their activating trans-factors. Here we investigate whether the low CFTR levels in the airway epithelium result from the recruitment of repressive proteins directly to the locus. Using an siRNA screen to deplete ~1500 transcription factors (TFs) and associated regulatory proteins in Calu-3 lung epithelial cells we identified nearly 40 factors that upon depletion elevated CFTR mRNA levels more than two-fold. A subset of these TFs was validated in primary human bronchial epithelial (HBE) cells. Among the strongest repressors of airway expression of CFTR were Krüppel like factor 5 (KLF5) and Ets homologous factor (EHF), both of which have pivotal roles in the airway epithelium. Depletion of these factors, which are both recruited to an airway-selective cis -regulatory element at -35kb from the CFTR promoter, improved CFTR production and function, thus defining novel therapeutic targets for enhancement of CFTR.

PMID: 29572268 [PubMed - as supplied by publisher]

Strategies for newborn screening for cystic fibrosis: A systematic review of health economic evaluations.

J Cyst Fibros. 2018 Mar 20;:

Authors: Schmidt M, Werbrouck A, Verhaeghe N, De Wachter E, Simoens S, Annemans L, Putman K

Abstract
BACKGROUND: Early detection of cystic fibrosis through newborn screening has significant clinical benefits. Cost-effectiveness plays an important role in selecting the optimal screening strategy from the many available options.
OBJECTIVES: The objectives of this study are (1) to summarize study estimates of cost-effectiveness of cystic fibrosis newborn screening (CFNBS) strategies as compared to other strategies, (2) to assess the quality of the studies identified, and (3) to identify determinants of cost-effectiveness.
METHODS: Electronic databases were searched from 2007 to June 2017. Health economic evaluations describing the cost-effectiveness of two or more CFNBS strategies were included.
RESULTS: Six health economic evaluations were found. Where included in the comparison, IRT/PAP consistently was the most cost-effective strategy in terms of cost per case detected or life years gained. However, some heterogeneity with respect to cut-off values used and the number of DNA mutations included in the screening strategies was observed, and the methodological quality differed considerably between studies.
CONCLUSIONS: The evidence suggested that (i) all screening strategies are cost-effective as compared to the no-screening option and (ii) IRT-PAP seems to be the most cost-effective screening strategy towards CFNBS. Methodological and contextual differences of the individual studies make it difficult to derive strong conclusions from this evidence. Nevertheless, from a health-economic perspective, IRT-PAP should be included as an alternative when deciding on the screening strategy in the implementation of CFNBS.

PMID: 29572018 [PubMed - as supplied by publisher]

Non-contrast enhanced magnetic resonance imaging detects mosaic signal intensity in early cystic fibrosis lung disease.

Eur J Radiol. 2018 Apr;101:178-183

Authors: Leutz-Schmidt P, Stahl M, Sommerburg O, Eichinger M, Puderbach MU, Schenk JP, Alrajab A, Triphan SMF, Kauczor HU, Mall MA, Wielpütz MO

Abstract
OBJECTIVES: To determine if morphological non-contrast enhanced magnetic resonance imaging (MRI) of the lung is sensitive to detect mosaic signal intensity in infants and preschool children with cystic fibrosis (CF).
MATERIALS AND METHODS: 50 infant and preschool CF patients (mean age 3.5 ± 1.4y, range 0-6y) routinely underwent morphological (T2-weighted turbo-spin echo sequence with half-Fourier acquisition, HASTE) and contrast-enhanced 4D perfusion MRI (gradient echo sequence with parallel imaging and echo sharing, TWIST). MRI studies were independently scored by two readers blinded for patient age and clinical data (experienced Reader 1 = R1, inexperienced Reader 2 = R2). The extent of lung parenchyma signal abnormalities on HASTE was rated for each lobe from 0 (normal), 1 (<50% of lobe affected) to 2 (≥50% of lobe affected). Perfusion MRI was rated according to the previously established MRI score, and served as the standard of reference.
RESULTS: Inter-method agreement between MRI mosaic score and perfusion score was moderate with κ = 0.58 (confidence interval 0.45-0.71) for R1, and with κ = 0.59 (0.46-0.72) for R2. Bland-Altman analysis revealed a slight tendency of the mosaic score to underestimate perfusion abnormalities with a score bias of 0.48 for R1 and 0.46 for R2. Inter-reader agreement for mosaic score was substantial with κ = 0.71 (0.62-0.79), and a low bias of 0.02.
CONCLUSIONS: This study demonstrates that non-contrast enhanced MRI reliably detects mosaic signal intensity in infants and preschool children with CF, reflecting pulmonary blood volume distribution. It may thus be used as a surrogate for perfusion MRI if contrast material is contra-indicated or alternative techniques are not available.

PMID: 29571794 [PubMed - in process]

Liquid biopsy by NGS: differential presence of exons (DPE) in cell-free DNA reveals different patterns in metastatic and nonmetastatic colorectal cancer.

Cancer Med. 2018 Mar 23;:

Authors: Olmedillas-López S, García-Olmo DC, García-Arranz M, Peiró-Pastor R, Aguado B, García-Olmo D

Abstract
Next-generation sequencing (NGS) has been proposed as a suitable tool for liquid biopsy in colorectal cancer (CRC), although most studies to date have focused almost exclusively on sequencing of panels of potential clinically actionable genes. We evaluated the clinical value of whole-exome sequencing (WES) of cell-free DNA (cfDNA) circulating in plasma, with the goal of identifying differential clinical profiles in patients with CRC. To this end, we applied an original concept, "differential presence of exons" (DPE). We determined differences in levels of 379 exons in plasma cfDNA and used DPE analysis to cluster and classify patients with disseminated and localized disease. The resultant bioinformatics analysis pipeline allowed us to design a predictive DPE algorithm in a small subset of patients that could not be initially classified based on the selection criteria. This DPE suggests that these nucleic acids could be actively released by both tumor and nontumor cells as a means of intercellular communication and might thus play a role in the process of malignant transformation. DPE is a new technique for the study of plasma cfDNA by WES that might have predictive and prognostic value in patients with CRC.

PMID: 29573240 [PubMed - as supplied by publisher]

A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy and microcephaly.

Hum Mutat. 2018 Mar 23;:

Authors: Pagnamenta AT, Murakami Y, Anzilotti C, Titheradge H, Oates AJ, Morton J, DDD Study, Kinoshita T, Kini U, Taylor JC

Abstract
Defective GPI-anchor biogenesis can cause a spectrum of predominantly neurological problems. For 8 genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7833 parent-child trios and 1792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly and behavioural difficulties. Although only 2/2 reads harboured this c.1A > T transversion, the presence of ∼25Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilisation of an in-frame start-site at codon 63. In summary, we describe siblings harbouring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions. This article is protected by copyright. All rights reserved.

PMID: 29573052 [PubMed - as supplied by publisher]

A large-scale, exome-wide association study of Han Chinese women identifies three novel loci predisposing to breast cancer.

Cancer Res. 2018 Mar 23;:

Authors: Zhang B, Chen MY, Sheng YJ, Zhuo XB, Gao P, Zhou FS, Liang B, Zu J, Zhang Q, Suleman S, Xu YH, Xu MG, Xu JK, Liu CC, Giannareas N, Xia JH, Zhao Y, Huang ZL, Yang Z, Cheng H, Li N, Hong YY, Li W, Zhang MJ, Yu KD, Li G, Sun MH, Chen ZD, Wei GH, Shao ZM

Abstract
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g. ESR1, FGFR2 and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new non-coding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 x 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 x 10-8) and CNFN (P = 3.77 x 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.

PMID: 29572226 [PubMed - as supplied by publisher]