Literature Watch
Notice to Extend the Expiration Date for PAR-15-349 "Health Disparities and Alzheimer's Disease (R01)"
Extramural Loan Repayment Program for Pediatric Research (LRP-PR)
Extramural Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds (LRP-IDB)
Extramural Loan Repayment Program for Health Disparities Research (LRP-HDR)
Extramural Loan Repayment Program for Contraception and Infertility Research (LRP-CIR)
Global Infectious Disease Research Training Program (D43 Clinical Trial Optional)
L-Captopril and its derivatives as potential inhibitors of microbial enzyme DapE: A combined approach of drug repurposing and similarity screening.
L-Captopril and its derivatives as potential inhibitors of microbial enzyme DapE: A combined approach of drug repurposing and similarity screening.
J Mol Graph Model. 2018 Jun 18;84:82-89
Authors: Dutta D, Mishra S
Abstract
The perils of antimicrobial drug resistance can be overcome by finding novel antibiotic targets and corresponding small molecule inhibitors. Microbial enzyme DapE is a promising antibiotic target due to its importance to the bacterial survival. The potency of L-Captopril, a well known angiotensin-converting enzyme inhibitor, as an inhibitor of DapE enzyme has been evaluated by analyzing its binding modes and binding affinity towards DapE enzyme. L-Captopril is found to bind the metal centers of DapE enzyme either via its thiolate group or through its carboxylate group. While the latter binding mode is found to be thermodynamically favorable, the former binding mode, also seen in the crystal structure, is kinetically favored. To optimize the binding affinity of the inhibitor towards DapE enzyme, a series of L-Captopril-based inhibitors have been modelled by changing the side groups of L-Captopril. The introduction of a bipolar functional group at the C4 position of the pyrrolidine ring of L-Captopril and the substitution of the thiol group with a carboxylate group, have been shown to provide excellent enzyme affinity that supersedes the binding affinity of DapE enzyme towards its natural substrate, thus making this molecule a potential inhibitor with great promise.
PMID: 29936366 [PubMed - as supplied by publisher]
The poor design of clinical trials of statins in oncology may explain their failure - Lessons for drug repurposing.
The poor design of clinical trials of statins in oncology may explain their failure - Lessons for drug repurposing.
Cancer Treat Rev. 2018 Jun 18;69:84-89
Authors: Abdullah MI, de Wolf E, Jawad MJ, Richardson A
Abstract
Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.
PMID: 29936313 [PubMed - as supplied by publisher]
Alzheimer's disease master regulators analysis: search for potential molecular targets and drug repositioning candidates.
Alzheimer's disease master regulators analysis: search for potential molecular targets and drug repositioning candidates.
Alzheimers Res Ther. 2018 Jun 23;10(1):59
Authors: Vargas DM, De Bastiani MA, Zimmer ER, Klamt F
Abstract
BACKGROUND: Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets.
METHODS: In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing.
RESULTS: We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat).
CONCLUSIONS: Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.
PMID: 29935546 [PubMed - in process]
CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.
CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.
Br J Anaesth. 2018 Jul;121(1):58-65
Authors: Klenke S, de Vries GJ, Schiefer L, Seyffert N, Bachmann HS, Peters J, Frey UH
Abstract
BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk.
METHODS: In a prospective, controlled study, 454 subjects undergoing elective surgery were genotyped for rs2165870 and its association with PONV was investigated with log-binomial regression analysis. Subjects were randomised to receive acustimulation/dexamethasone, acustimulation/vehicle, sham acustimulation/dexamethasone, or sham acustimulation/vehicle to investigate their effects on PONV risk.
RESULTS: Early PONV occurred in 37% of subjects. The rs2165870 genotype distribution was GG in 191, GA in 207, and AA in 56 subjects. The CHRM3 polymorphism was associated with a relative risk (RR) of 1.5 for GA vs GG [95% confidence interval (CI): 1.1-1.9; P=0.003] and 1.6 for AA vs GG (95% CI: 1.1-2.2; P=0.009) genotypes to develop PONV, and this was independent from the Apfel score (RR per Apfel point: 1.3, 95% CI: 1.2-1.5; P<0.0001). While dexamethasone and acustimulation each reduced the PONV risk by 30% in AA genotype carriers with low Apfel score, combined therapy reduced the risk by 86% (P=0.015).
CONCLUSIONS: The CHRM3 polymorphism and the Apfel score independently predict PONV susceptibility. Dexamethasone/acustimulation should be considered in patients with low Apfel score but at high genetic risk.
CLINICAL TRIAL REGISTRATION: DRKS00005664.
PMID: 29935595 [PubMed - in process]
Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.
Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.
Clin Pharmacokinet. 2018 Jun 23;:
Authors: Bulitta JB, Jiao Y, Drescher SK, Oliver A, Louie A, Moya B, Tao X, Wittau M, Tsuji BT, Zavascki AP, Shin BS, Drusano GL, Sörgel F, Landersdorfer CB
Abstract
The pharmacokinetics (PK) of β-lactam antibiotics in cystic fibrosis (CF) patients has been compared with that in healthy volunteers for over four decades; however, no quantitative models exist that explain the PK differences between CF patients and healthy volunteers in older and newer studies. Our aims were to critically evaluate these studies and explain the PK differences between CF patients and healthy volunteers. We reviewed all 16 studies that compared the PK of β-lactams between CF patients and healthy volunteers within the same study. Analysis of covariance (ANCOVA) models were developed. In four early studies that compared adolescent, lean CF patients with adult healthy volunteers, clearance (CL) in CF divided by that in healthy volunteers was 1.72 ± 0.90 (average ± standard deviation); in four additional studies comparing age-matched (primarily adult) CF patients with healthy volunteers, this ratio was 1.46 ± 0.16. The CL ratio was 1.15 ± 0.11 in all eight studies that compared CF patients and healthy volunteers who were matched in age, body size and body composition, or that employed allometric scaling by lean body mass (LBM). Volume of distribution was similar between subject groups after scaling by body size. For highly protein-bound β-lactams, the unbound fraction was up to 2.07-fold higher in older studies that compared presumably sicker CF patients with healthy volunteers. These protein-binding differences explained over half of the variance for the CL ratio (p < 0.0001, ANCOVA). Body size, body composition and lower protein binding in presumably sicker CF patients explained the PK alterations in this population. Dosing CF patients according to LBM seems suitable to achieve antibiotic target exposures.
PMID: 29936678 [PubMed - as supplied by publisher]
Rescue of CFTR NBD2 mutants N1303K and S1235R is influenced by the functioning of the autophagosome.
Rescue of CFTR NBD2 mutants N1303K and S1235R is influenced by the functioning of the autophagosome.
J Cyst Fibros. 2018 Jun 20;:
Authors: Liu Q, Sabirzhanova I, Yanda MK, Bergbower EAS, Boinot C, Guggino WB, Cebotaru L
Abstract
The missing phenylalanine at position 508, located in nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane regulator (CFTR), is the most common cystic fibrosis mutation. Severe disease-causing mutations also occur in NBD2. To provide information on potential therapeutic strategies for mutations in NBD2, we used a combination of biochemical, cell biological and electrophysiological approaches and newly created cell lines to study two disease-causing NBD2 mutants, N1303K and S1235R. We observed that neither was sensitive to E64, a cysteine protease inhibitor. However, further investigation showed that when treated with a combination of correctors, C4 + C18, both mutants also responded to E64. Further exploration to assess aggresome throughput using the autophagy regulator LC3 as a marker showed that, in the absence of correctors, N1303K showed a stalled throughput of LC3-II to the aggresome. The throughput became active again after treatment with the corrector combination C4 + C18. Confocal microscopic studies showed that the N1303K and S1235R mutant proteins both co-localized with LC3, but this co-localization was abolished by the corrector combination and, to a lesser extent, by VX-809. Both the corrector combination and VX-809 increased the CFTR chloride channel function of both mutants. We conclude that correctors have a dual effect, particularly on N1303K: they improve trafficking and function at the plasma membrane and reduce the association with autophagosomes. After treatment with correctors persistent degradation by the autophagosome may limit restoration of function. Thus, mutations in NBD2 of CFTR, in contrast to ΔF508-CFTR, may require additional personalized strategies to rescue them.
PMID: 29936070 [PubMed - as supplied by publisher]
SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum.
SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum.
J Cyst Fibros. 2018 Jun 20;:
Authors: Sesma JI, Wu B, Stuhlmiller TJ, Scott DW
Abstract
BACKGROUND: In healthy lungs, epithelial sodium channel (ENaC) is regulated by short, palate, lung, and nasal clone 1 (SPLUNC1). In cystic fibrosis (CF), ENaC is hyperactivated in part due to a loss of SPLUNC1 function. We have developed SPX-101 to replace the lost function of SPLUNC1 in the CF lung.
METHODS: Expression of SPLUNC1 was determined in sputum from healthy and CF donors. Stability of SPLUNC1, S18 (the ENaC regulatory domain of SPLUNC1), and SPX-101 was determined in sputum from CF donors and towards neutrophil elastase. Activity of SPX-101 after exposure to CF sputum was determined in airway epithelial cells from CF donors and in the βENaC transgenic mouse model.
RESULTS: SPLUNC1 protein expression is significantly reduced in CF as compared to healthy sputum. SPLUNC1 is rapidly degraded in CF sputum as well as by a number of individual proteases known to be found in the sputum. SPX-101, but not S18, is stable in CF sputum. Finally, SPX-101 retains its ability to internalize ENaC, regulate airway surface liquid height, and increase survival of βENaC mice after exposure to CF sputum.
CONCLUSIONS: Our results demonstrate that SPX-101, but not SPLUNC1 or S18, is stable in CF sputum. These results support the therapeutic development of SPX-101 for the treatment of cystic fibrosis.
PMID: 29936069 [PubMed - as supplied by publisher]
Adult Cystic Fibrosis: A Possible Cause of Bronchiectasis in COPD Patients.
Adult Cystic Fibrosis: A Possible Cause of Bronchiectasis in COPD Patients.
Arch Bronconeumol. 2018 Jun 20;:
Authors: Benito Bernáldez C, Almadana Pacheco V, Valido Morales AS, Rodríguez Martín PJ
PMID: 29935777 [PubMed - as supplied by publisher]
Notice of Change to Application Types Allowed in PA-17-239 "Secondary Analysis and Integration of Existing Data to Elucidate the Genetic Architecture of Cancer Risk and Related Outcomes (R01)"
NIDA Division of Neuroscience and Behavior Will Give High Programmatic Priority to Opioid Related Basic Research
Request for Administrative Supplements for Basic Research on Opioids to Existing Grant Awards
Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.
Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology.
Eur Urol. 2018 Jun 20;:
Authors: Loveday C, Law P, Litchfield K, Levy M, Holroyd A, Broderick P, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, UK Testicular Cancer Collaboration, The PRACTICAL Consortium, Reid A, Huddart RA, Houlston RS, Turnbull C
Abstract
Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84-100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene.
PATIENT SUMMARY: To date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.
PMID: 29935977 [PubMed - as supplied by publisher]
Regulatory RNA binding proteins contribute to the transcriptome-wide splicing alterations in human cellular senescence.
Regulatory RNA binding proteins contribute to the transcriptome-wide splicing alterations in human cellular senescence.
Aging (Albany NY). 2018 Jun 24;:
Authors: Dong Q, Wei L, Zhang MQ, Wang X
Abstract
Dysregulation of mRNA splicing has been observed in certain cellular senescence process. However, the common splicing alterations on the whole transcriptome shared by various types of senescence are poorly understood. In order to systematically identify senescence-associated transcriptomic changes in genome-wide scale, we collected RNA sequencing datasets of different human cell types with a variety of senescence-inducing methods from public databases and performed meta-analysis. First, we discovered that a group of RNA binding proteins were consistently down-regulated in diverse senescent samples and identified 406 senescence-associated common differential splicing events. Then, eight differentially expressed RNA binding proteins were predicted to regulate these senescence-associated splicing alterations through an enrichment analysis of their RNA binding information, including motif scanning and enhanced cross-linking immunoprecipitation data. In addition, we constructed the splicing regulatory modules that might contribute to senescence-associated biological processes. Finally, it was confirmed that knockdown of the predicted senescence-associated potential splicing regulators through shRNAs in HepG2 cell line could result in senescence-like splicing changes. Taken together, our work demonstrated a broad range of common changes in mRNA splicing switches and detected their central regulatory RNA binding proteins during senescence. These findings would help to better understand the coordinating splicing alterations in cellular senescence.
PMID: 29936497 [PubMed - as supplied by publisher]
The limited role of genetics explaining the atherosclerotic process and coronary artery disease and the holistic perspective of systems biology.
The limited role of genetics explaining the atherosclerotic process and coronary artery disease and the holistic perspective of systems biology.
Hellenic J Cardiol. 2018 Jun 21;:
Authors: Louridas GE
PMID: 29936321 [PubMed - as supplied by publisher]
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