The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Co-infected Patients in Uganda in the SOUTH Study.

Clin Pharmacol Ther. 2019 Feb 19;:

Authors: Calcagno A, Cusato J, Sekaggya-Wiltshire C, von Braun A, Motta I, Turyasingura G, Castelnuovo B, Fehr J, Di Perri G, Lamorde M

Abstract
Unsatisfactory treatment outcomes have been reported in HIV/tuberculosis (TB) co-infected patients. Aim of this study was to assess the influence of single nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis were performed. The impact of SNPs on antitubercular drugs exposure, adverse events and treatment outcomes was evaluated in HIV/TB co-infected subjects receiving treatments for both conditions. In 221 participants NAT2 (rs1799930), SLCO1B1 (rs4149032) and PXR (rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163, 73.8%), yet PXR 63396TT carriers had a higher probability of death (p=0.007) and of worsening peripheral neuropathy (p=0.018). In this exploratory study in Ugandan HIV/TB coinfected patients genetic variants in PXR, SLCO1B1 and NAT2 were moderately associated with isoniazid exposure while PXR 63396TT carriers showed worse outcomes. This article is protected by copyright. All rights reserved.

PMID: 30779340 [PubMed - as supplied by publisher]

An ancillary genomics system to support the return of pharmacogenomic results.

J Am Med Inform Assoc. 2019 Feb 19;:

Authors: Rasmussen LV, Smith ME, Almaraz F, Persell SD, Rasmussen-Torvik LJ, Pacheco JA, Chisholm RL, Christensen C, Herr TM, Wehbe FH, Starren JB

Abstract
Existing approaches to managing genetic and genomic test results from external laboratories typically include filing of text reports within the electronic health record, making them unavailable in many cases for clinical decision support. Even when structured computable results are available, the lack of adopted standards requires considerations for processing the results into actionable knowledge, in addition to storage and management of the data. Here, we describe the design and implementation of an ancillary genomics system used to receive and process heterogeneous results from external laboratories, which returns a descriptive phenotype to the electronic health record in support of pharmacogenetic clinical decision support.

PMID: 30778576 [PubMed - as supplied by publisher]

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet. 2019 Feb 18;:

Authors: Justice AE, Karaderi T, Highland HM, Young KL, Graff M, Lu Y, Turcot V, Auer PL, Fine RS, Guo X, Schurmann C, Lempradl A, Marouli E, Mahajan A, Winkler TW, Locke AE, Medina-Gomez C, Esko T, Vedantam S, Giri A, Lo KS, Alfred T, Mudgal P, Ng MCY, Heard-Costa NL, Feitosa MF, Manning AK, Willems SM, Sivapalaratnam S, Abecasis G, Alam DS, Allison M, Amouyel P, Arzumanyan Z, Balkau B, Bastarache L, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bottinger EP, Bowden DW, Brandslund I, Broer L, Burt AA, Butterworth AS, Caulfield MJ, Cesana G, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Collins FS, Cook JP, Cox AJ, Crosslin DS, Danesh J, de Bakker PIW, Denus S, Mutsert R, Dedoussis G, Demerath EW, Dennis JG, Denny JC, Angelantonio ED, Dörr M, Drenos F, Dubé MP, Dunning AM, Easton DF, Elliott P, Evangelou E, Farmaki AE, Feng S, Ferrannini E, Ferrieres J, Florez JC, Fornage M, Fox CS, Franks PW, Friedrich N, Gan W, Gandin I, Gasparini P, Giedraitis V, Girotto G, Gorski M, Grallert H, Grarup N, Grove ML, Gustafsson S, Haessler J, Hansen T, Hattersley AT, Hayward C, Heid IM, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Hung YJ, Hveem K, Ikram MA, Ingelsson E, Jackson AU, Jarvik GP, Jia Y, Jørgensen T, Jousilahti P, Justesen JM, Kahali B, Karaleftheri M, Kardia SLR, Karpe F, Kee F, Kitajima H, Komulainen P, Kooner JS, Kovacs P, Krämer BK, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange LA, Langenberg C, Larson EB, Lee NR, Lee WJ, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Luan J, Lyytikäinen LP, MacGregor S, Mägi R, Männistö S, Marenne G, Marten J, Masca NGD, McCarthy MI, Meidtner K, Mihailov E, Moilanen L, Moitry M, Mook-Kanamori DO, Morgan A, Morris AP, Müller-Nurasyid M, Munroe PB, Narisu N, Nelson CP, Neville M, Ntalla I, O'Connell JR, Owen KR, Pedersen O, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Ewing A, Polasek O, Raitakari OT, Rasheed A, Raulerson CK, Rauramaa R, Reilly DF, Reiner AP, Ridker PM, Rivas MA, Robertson NR, Robino A, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe M, Sim X, Slater AJ, Small KS, Smith BH, Smith JA, Southam L, Spector TD, Speliotes EK, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swart KMA, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Torres M, Tsafantakis E, Tuomilehto J, Uitterlinden AG, Uusitupa M, van Duijn CM, Vanhala M, Varma R, Vermeulen SH, Vestergaard H, Vitart V, Vogt TF, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Wood AR, Wu Y, Yaghootkar H, Yao J, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zheng H, Zhou W, Zillikens MC, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira F, Borecki IB, Pospisilik JA, Deloukas P, Frayling TM, Lettre G, Mohlke KL, Rotter JI, Kutalik Z, Hirschhorn JN, Cupples LA, Loos RJF, North KE, Lindgren CM

Abstract
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

PMID: 30778226 [PubMed - as supplied by publisher]

Evaluation of the predictive performance of Bayesian dosing for warfarin in Chinese patients.

Pharmacogenomics. 2019 Feb 19;:

Authors: Dong J, Shi GH, Lu M, Huang S, Liu YH, Yao JC, Li WY, Li LX

Abstract
AIM: To evaluate the accuracy and predictive performance of Bayesian dosing for warfarin in Chinese patients.
MATERIALS & METHODS: Six multiple linear regression algorithms (Wei, Lou, Miao, Huang, Gage and IWPC) and a Bayesian method implemented in Warfarin Dose Calculator were compared with each other.
RESULTS: Six multiple linear regression warfarin dosing algorithms had similar predictive ability, except Miao and Lou. The mean prediction error of Bayesian priori and posteriori method were 0.01 mg/day (95% CI, -0.18 to 0.19) and 0.17 mg/day (95% CI, -0.05 to 0.29), respectively, and Bayesian posteriori method demonstrated better performance in all dose ranges.
CONCLUSION: The Bayesian method showed a good potential for warfarin maintenance dose prediction in Chinese patients requiring less than 6 mg/day.

PMID: 30777785 [PubMed - as supplied by publisher]

Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients.

Sci Rep. 2017 08 03;7(1):7244

Authors: Xiao FY, Luo JQ, Liu M, Chen BL, Cao S, Liu ZQ, Zhou HH, Zhou G, Zhang W

Abstract
Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. The effects of CES1 S75N (rs2307240,C>T) on clopidogrel response among 851 acute coronary syndrome patients who came from the north, central and south of China were studied. The occurrence ratios of each endpoint in the CC group were significantly higher than in the CT + TT group for cerebrovascular events (14% vs 4.8%, p < 0.001, OR = 0.31), acute myocardial infarction (15.1% vs 6.1%, p < 0.001, OR = 0.37) and unstable angina (62.8% vs 37.7%, p < 0.001, OR = 0.36). The results showed that there was a significant association between CES1 S75N (rs2307240) and the outcome of clopidogrel therapy. Moreover, the frequency of the T allele of rs2307240 in acute coronary syndrome patients (MAF = 0.22) was more than four times higher than that in the general public (MAF = 0.05).

PMID: 28775293 [PubMed - indexed for MEDLINE]

Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update.

J Thorac Dis. 2019 Jan;11(Suppl 1):S25-S36

Authors: Blons H, Garinet S, Laurent-Puig P, Oudart JB

Abstract
Immunotherapy represents one of the most promising therapeutic approaches in lung cancer, however 50% of lung cancer patients will not respond to this treatment, while others will have transitory or durable responses. Because side effects may be life threatening and treatment costs remain very high, the identification of predictive markers is mandatory and actually extensively studied. Factors that determine response to immune checkpoint inhibitors (ICI) are numerous including tumor microenvironment, immune tumor infiltrates, expression of immune checkpoint proteins (PD-1/PD-L1), gene expression signatures and molecular tumor profiles. Based on high impact factor publications and recent literature this review focuses on the potential predictive value of tumor molecular alterations and tumor mutation burden as predictive markers of response or resistance to ICI. We also discuss the role of circulating tumor DNA (ctDNA) to monitor ICI responses and propose an algorithm that integrates molecular markers upcoming recommendations for first line treatment.

PMID: 30775025 [PubMed]

Molecular Aspects of Depression: A review from neurobiology to treatment.

Eur J Pharmacol. 2019 Feb 15;:

Authors: Boas GRV, de Lacerda RB, Paes MM, Gubert P, da Cruz Almeida WL, Rescia VC, de Carvalho PMG, de Carvalho AAV, Oesterreich SA

Abstract
Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low self‑esteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors. This article integrates affective neuroscience, psychopharmacology, neuroanatomy and molecular biology data. In addition, there are two problems with current MDD treatments, namely: 1) Low rates of responsiveness to antidepressants and too slow onset of therapeutic effect; 2) Increased stress vulnerability and autonomy, which reduces the responses of currently available treatments. In the present review, we encourage the prospection of new bioactive agents for the development of treatments with post-transduction mechanisms, neurogenesis and pharmacogenetics inducers that bring greater benefits, with reduced risks and maximized access to patients, stimulating the field of research on mood disorders in order to use the potential of preclinical studies. For this purpose, improved animal models that incorporate the molecular and anatomical tools currently available can be applied. Besides, we encourage the study of drugs that do not present "classical application" as antidepressants, (e.g., the dissociative anesthetic ketamine and dextromethorphan) and drugs that have dual action mechanisms since they represent potential targets for novel drug development more useful for the treatment of MDD.

PMID: 30776369 [PubMed - as supplied by publisher]

TOR inhibitors: from mammalian outcomes to pharmacogenetics in plants and algae.

J Exp Bot. 2019 Feb 18;:

Authors: Montané MH, Menand B

Abstract
Target Of Rapamycin (TOR) is a conserved eukaryotic phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) that regulates growth and metabolism in response to environment in plants and algae. The study of the plant and algal TOR pathway largely depends on TOR inhibitors first developed for non-photosynthetic eukaryotes. In animals and yeast, fundamental works on the TOR pathway have benefited from the allosteric TOR inhibitor rapamycin and more recently from ATP-competitive TOR inhibitors (asTORis) that circumvent the limitations of rapamycin. The asTORis, developed for medical applications, inhibit TORC1 more efficiently than rapamycin and also inhibit rapamycin-resistant TOR complexes (TORCs). This review will present knowledge on TOR inhibitors from the mammalian field and underline important consideration for plant and algal biologists. We will discuss the use of rapamycin and asTORis in plants and algae and conclude with guidelines for physiological studies and genetic screens with TOR inhibitors.

PMID: 30773593 [PubMed - as supplied by publisher]

Pharmacoepidemiological research for the development and evaluation of drugs in pediatrics.

Therapie. 2019 Jan 31;:

Authors: Kaguelidou F, Durrieu G, Clavenna A

Abstract
New regulations have come into force in Europe and the US establishing the pediatric development as an integral part of the early development of medicinal products. Parallel to the advances in pediatric clinical research, it became obvious that all available sources and research tools to gather valuable information for the safe and efficacious prescription of medicines in children should be used. Real-life, pharmacoepidemiological studies provide information that contribute to the better knowledge of drug utilization, effects and safety in the pediatric population and thereby, a better prescribing in children. In this paper, we suggest some possible applications, provide examples of impact of pharmacoepidemiological and pharmacovigilance studies and expose future perspectives in pediatric pharmacoepidemiology.

PMID: 30773345 [PubMed - as supplied by publisher]

Association Between Level of Fecal Calprotectin and Progression of Crohn's Disease.

Clin Gastroenterol Hepatol. 2019 Feb 14;:

Authors: Kennedy NA, Jones GR, Plevris N, Patenden R, Arnott ID, Lees CW

Abstract
BACKGROUND & AIMS: Mucosal healing is associated with improved outcomes in patients with Crohn's disease (CD), but assessment typically requires ileocolonoscopy. Calprotectin can be measured in fecal samples to determine luminal disease activity in place of endoscopy-this measurement is an important component of the treat to target strategy. We investigated whether levels of fecal calprotectin associate with subsequent CD progression.
METHODS: We performed a retrospective study of 918 patients with CD (4218 patient-years of follow-up; median, 50.6 months; interquartile range [IQR], 32.8-76.0 months) managed at a tertiary medical center in Edinburgh, United Kingdom, from 2003 through 2015. Patients were included if they had 1 or more fecal calprotectin measurement made 3 months or more following their diagnosis. We collected clinical data and fecal calprotectin measurements and analyzed these data to identify factors associated with a composite outcome of progression in Montreal behavior, hospitalization, and resection.
RESULTS: Increased level of fecal calprotectin at index visit was associated with subsequent progression of CD, independent of symptoms or disease location. The median level of fecal calprotectin at the index visit was 432 μg/g (IQR, 1365-998 μg/g) in patients who reached the composite endpoint vs 180 μg/g (IQR, 50-665 μg/g) in patients who did not. In multivariable analysis, a cutoff of 115 μg/g calprotectin identified patients who met the endpoint with a hazard ratio on of 2.4 (95% CI, 1.8-3.1; P<.0001).
CONCLUSION: In a retrospective analysis of patients with CD, we found that measurements of fecal calprotectin made during routine monitoring can identify patients at risk for disease progression, independent of symptoms or disease location. It is therefore important to screen asymptomatic patients for mucosal inflammation and pursue complete resolution of inflammation.

PMID: 30772585 [PubMed - as supplied by publisher]

Deep-Resp-Forest: A deep forest model to predict anti-cancer drug response.

Methods. 2019 Feb 14;:

Authors: Su R, Liu X, Wei L, Zou Q

Abstract
The identification of therapeutic biomarkers predictive of drug response is crucial in personalized medicine. A number of computational models to predict response of anti-cancer drugs have been developed as the establishment of several pharmacogenomics screening databases. In our study, we proposed a deep cascaded forest model, Deep-Resp-Forest, to classify the anti-cancer drug response as "sensitive" or "resistant". We made three contributions in this study. Firstly, diverse molecular data could be effectively integrated to provide more information than single type of data for the classification. Combination of two types of data were tested here. Secondly, two structures based on the multi-grained scanning to transform the raw features into high-dimensional feature vectors and integrate the diverse data were proposed in our study. Thirdly, the original deep and time-consuming architecture of cascade forest was improved by a feature optimization operation, which emphasized the most discriminative features across layers. We evaluated the proposed method on the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) data sets and then compared with the Support Vector Machine. The proposed Deep-Resp-Forest has demonstrated the promising use of deep learning and deep forest approach on the drug response prediction tasks. The R implementation for running our experiments is available at https://github.com/RanSuLab/Deep-Resp-Forest.

PMID: 30772464 [PubMed - as supplied by publisher]

African American Ancestry Contribution to Asthma and Atopic Dermatitis.

Ann Allergy Asthma Immunol. 2019 Feb 14;:

Authors: Daya M, Barnes KC

PMID: 30772392 [PubMed - as supplied by publisher]

PDK1 mediates NOTCH1-mutated head and neck squamous carcinoma vulnerability to therapeutic PI3K/mTOR inhibition.

Clin Cancer Res. 2019 Feb 15;:

Authors: Sambandam V, Frederick MJ, Shen L, Tong P, Rao X, Peng S, Singh R, Mazumdar T, Huang C, Li Q, Pickering CR, Myers JN, Wang J, Johnson FM

Abstract
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function.
METHODS: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression.
RESULTS: PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1 MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1MUT but not NOTCH1WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1WT HNSCC but had little effect as single agents.
CONCLUSION: Our findings suggest that NOTCH1MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1WT HNSCC to PI3K/mTOR pathway inhibitors.

PMID: 30770351 [PubMed - as supplied by publisher]

15 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 2019/02/16

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.

Correction: Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

Pharmacogenomics J. 2019 Feb 14;:

Authors: Canet LM, Sánchez-Maldonado JM, Cáliz R, Rodríguez-Ramos A, Lupiañez CB, Canhão H, Martínez-Bueno M, Escudero A, Segura-Catena J, Sorensen SB, Hetland ML, Soto-Pino MJ, Ferrer MA, García A, Glintborg B, Filipescu I, Pérez-Pampin E, González-Utrilla A, Nevot MÁL, Conesa-Zamora P, den Broeder A, De Vita S, Jacobsen SEH, Collantes-Estevez E, Quartuccio L, Canzian F, Fonseca JE, Coenen MJH, Andersen V, Sainz J

Abstract
The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

PMID: 30760878 [PubMed - as supplied by publisher]

Candidate gene analyses for acute pain and morphine analgesia after pediatric day surgery: African American versus European Caucasian ancestry and dose prediction limits.

Pharmacogenomics J. 2019 Feb 14;:

Authors: Li J, Wei Z, Zhang J, Hakonarson H, Cook-Sather SD

Abstract
Acute pain and opioid analgesia demonstrate inter-individual variability and polygenic influence. In 241 children of African American and 277 of European Caucasian ancestry, we sought to replicate select candidate gene associations with morphine dose and postoperative pain and then to estimate dose prediction limits. Twenty-seven single-nucleotide polymorphisms (SNPs) from nine genes (ABCB1, ARRB2, COMT, DRD2, KCNJ6, MC1R, OPRD1, OPRM1, and UGT2B7) met selection criteria and were analyzed along with TAOK3. Few associations replicated: morphine dose (mcg/kg) in African American children and ABCB1 rs1045642 (A allele, β = -9.30, 95% CI: -17.25 to -1.35, p = 0.02) and OPRM1 rs1799971 (G allele, β = 23.19, 95% CI: 3.27-43.11, p = 0.02); KCNJ6 rs2211843 and high pain in African American subjects (T allele, OR 2.08, 95% CI: 1.17-3.71, p = 0.01) and in congruent European Caucasian pain phenotypes; and COMT rs740603 for high pain in European Caucasian subjects (A allele, OR: 0.69, 95% CI: 0.48-0.99, p = 0.046). With age, body mass index, and physical status as covariates, simple top SNP candidate gene models could explain theoretical maximums of 24.2% (European Caucasian) and 14.6% (African American) of morphine dose variances.

PMID: 30760877 [PubMed - as supplied by publisher]

Induction of GNMT by 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside through proteasome-independent MYC downregulation in hepatocellular carcinoma.

Sci Rep. 2019 Feb 13;9(1):1968

Authors: Kant R, Yen CH, Hung JH, Lu CK, Tung CY, Chang PC, Chen YH, Tyan YC, Chen YA

Abstract
Glycine-N-methyl transferase (GNMT) a tumor suppressor for hepatocellular carcinoma (HCC) plays a crucial role in liver homeostasis. Its expression is downregulated in almost all the tumor tissues of HCC while the mechanism of this downregulation is not yet fully understood. Recently, we identified 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside (PGG) as a GNMT promoter enhancer compound in HCC. In this study, we aimed to delineate the mechanism by which PGG enhances GNMT expression and to investigate its effect on GNMT suppression in HCC. Microarray and pathway enrichment analysis revealed that MYC was a major target of PGG. PGG suppressed MYC mRNA and protein expression in Huh7 and Hep G2 cells in a dose- and time-dependent fashion. Furthermore, MYC expression was also reduced in xenograft tumors in PGG treated mice. Moreover, shRNA-mediated knocked-down or pharmacological inhibition of MYC resulted in a significant induction of GNMT promoter activity and endogenous GNMT mRNA expression in Huh7 cells. In contrast, overexpression of MYC significantly inhibited GNMT promoter activity and endogenous GNMT protein expression. In addition, antibodies against MYC effectively precipitated the human GNMT promoter in a chromatin immunoprecipitation assay. Lastly, GNMT expression was negatively correlated with MYC expression in human HCC samples. Interestingly, PGG not only inhibited MYC gene expression but also promoted MYC protein degradation through proteasome-independent pathways. This work reveals a novel anticancer mechanism of PGG via downregulation of MYC expression and establishes a therapeutic rationale for treatment of MYC overexpressing cancers using PGG. Our data also provide a novel mechanistic understanding of GNMT regulation through MYC in the pathogenesis of HCC.

PMID: 30760754 [PubMed - in process]

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Arterioscler Thromb Vasc Biol. 2019 Feb 14;:ATVBAHA118311963

Authors: Klein MD, Williams AK, Lee CR, Stouffer GA

Abstract
Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.

PMID: 30760018 [PubMed - as supplied by publisher]

Improved locus-specific unmethylated controls for MS-HRM analysis derived from 5-aza-2-deoxycytidine-treated DNA.

Biotechniques. 2019 Feb 14;:

Authors: Čelešnik H, Potočnik U

Abstract
We report two restriction enzyme-based approaches for generating clean locus-specific unmethylated controls for methylation-sensitive high-resolution melting (MS-HRM) analyses. These unmethylated standards are derived from DNA treated with the demethylating agent 5-aza-2-deoxycytidine (5-Aza-dc). By using them, we overcome a limitation of 5-Aza-dc treatment - incomplete demethylation at various genomic regions. When 5-Aza-dc-treated DNA is used directly as unmethylated MS-HRM standard, partially demethylated DNA can give false methylation results. MS-HRM assay differentiates between methylated and unmethylated bisulfite-treated DNA based on the different melting profiles of PCR products amplified from them. To estimate test sample methylation levels, test sample melting profiles are compared to those of methylation standards. With our pure unmethylated controls, adequate standards of known methylation levels can be prepared for single-locus MS-HRM.

PMID: 30759991 [PubMed - as supplied by publisher]

12 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 2019/02/14

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.