Chemokines protect vascular smooth muscle cells from cell death induced by cyclic mechanical stretch.

Sci Rep. 2017 Nov 23;7(1):16128

Authors: Zhao J, Nishimura Y, Kimura A, Ozawa K, Kondo T, Tanaka T, Yoshizumi M

Abstract
The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to cyclic mechanical stretch (CMS), which evokes VSMC proliferation, cell death, phenotypic switching, and migration, leading to vascular remodeling. These responses have been observed in many cardiovascular diseases; however, the underlying mechanisms remain unclear. We have revealed that CMS of rat aortic smooth muscle cells (RASMCs) causes JNK- and p38-dependent cell death and that a calcium channel blocker and angiotensin II receptor antagonist decreased the phosphorylation of JNK and p38 and subsequently decreased cell death by CMS. In the present study, we showed that the expression of Cxcl1 and Cx3cl1 was induced by CMS in a JNK-dependent manner. The expression of Cxcl1 was also induced in VSMCs by hypertension produced by abdominal aortic constriction (AAC). In addition, antagonists against the receptors for CXCL1 and CX3CL1 increased cell death, indicating that CXCL1 and CX3CL1 protect RASMCs from CMS-induced cell death. We also revealed that STAT1 is activated in RASMCs subjected to CMS. Taken together, these results indicate that CMS of VSMCs induces inflammation-related gene expression, including that of CXCL1 and CX3CL1, which may play important roles in the stress response against CMS caused by hypertension.

PMID: 29170451 [PubMed - in process]

Major role of nitrite-oxidizing bacteria in dark ocean carbon fixation.

Science. 2017 Nov 24;358(6366):1046-1051

Authors: Pachiadaki MG, Sintes E, Bergauer K, Brown JM, Record NR, Swan BK, Mathyer ME, Hallam SJ, Lopez-Garcia P, Takaki Y, Nunoura T, Woyke T, Herndl GJ, Stepanauskas R

Abstract
Carbon fixation by chemoautotrophic microorganisms in the dark ocean has a major impact on global carbon cycling and ecological relationships in the ocean's interior, but the relevant taxa and energy sources remain enigmatic. We show evidence that nitrite-oxidizing bacteria affiliated with the Nitrospinae phylum are important in dark ocean chemoautotrophy. Single-cell genomics and community metagenomics revealed that Nitrospinae are the most abundant and globally distributed nitrite-oxidizing bacteria in the ocean. Metaproteomics and metatranscriptomics analyses suggest that nitrite oxidation is the main pathway of energy production in Nitrospinae. Microautoradiography, linked with catalyzed reporter deposition fluorescence in situ hybridization, indicated that Nitrospinae fix 15 to 45% of inorganic carbon in the mesopelagic western North Atlantic. Nitrite oxidation may have a greater impact on the carbon cycle than previously assumed.

PMID: 29170234 [PubMed - in process]

Genome-wide DNA methylation profiling reveals novel epigenetic signatures in squamous cell lung cancer.

BMC Genomics. 2017 Nov 23;18(1):901

Authors: Shi YX, Wang Y, Li X, Zhang W, Zhou HH, Yin JY, Liu ZQ

Abstract
BACKGROUND: Epigenetic alterations are strongly associated with the development of cancer. The aim of this study was to identify epigenetic pattern in squamous cell lung cancer (LUSC) on a genome-wide scale.
RESULTS: Here we performed DNA methylation profiling on 24 LUSC and paired non-tumor lung (NTL) tissues by Illumina Human Methylation 450 K BeadArrays, and identified 5214 differentially methylated probes. By integrating DNA methylation and mRNA expression data, 449 aberrantly methylated genes accompanied with altered expression were identified. Ingenuity Pathway analysis highlighted these genes which were closely related to the carcinogenesis of LUSC, such as ERK family, NFKB signaling pathway, Hedgehog signaling pathway, providing new clues for understanding the molecular mechanisms of LUSC pathogenesis. To verify the results of high-throughput screening, we used 56 paired independent tissues for clinical validation by pyrosequencing. Subsequently, another 343 tumor tissues from the Cancer Genome Atlas (TCGA) database were utilized for further validation. Then, we identified a panel of DNA methylation biomarkers (CLDN1, TP63, TBX5, TCF21, ADHFE1 and HNF1B) in LUSC. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the performance of biomarkers individually, suggesting that they could be suitable as potential diagnostic biomarkers for LUSC. Moreover, hierarchical clustering analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation.
CONCLUSIONS: Collectively, these results suggest that DNA methylation plays critical roles in lung tumorigenesis and may potentially be proposed as a diagnostic biomarker.
TRIAL REGISTRATION: ChiCTR-RCC-12002830 Date of registration: 2012-12-17.

PMID: 29169318 [PubMed - in process]

The comparative effectiveness of electroencephalographic indices in predicting response to escitalopram therapy in depression: A pilot study.

J Affect Disord. 2017 Nov 03;227:542-549

Authors: Baskaran A, Farzan F, Milev R, Brenner CA, Alturi S, Pat McAndrews M, Blier P, Evans K, Foster JA, Frey BN, Giacobbe P, Lam RW, Leri F, MacQueen GM, Müller DJ, Parikh SV, Rotzinger S, Soares CN, Strother SC, Turecki G, Kennedy SH, CAN-BIND Investigators Team

Abstract
BACKGROUND: This study aims to compare the effectiveness of EEG frequency band activity including interhemispheric asymmetry and prefrontal theta cordance in predicting response to escitalopram therapy at 8-weeks post-treatment, in a multi-site initiative.
METHODS: Resting state 64-channel EEG data were recorded from 44 patients with a diagnosis of major depressive disorder (MDD) as part of a larger, multisite discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). Clinical response was measured at 8-weeks post-treatment as change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 50% or more. EEG measures were analyzed at (1) pre-treatment baseline (2) 2 weeks post-treatment and (3) as an ''early change" variable defined as change in EEG from baseline to 2 weeks post-treatment.
RESULTS: At baseline, treatment responders showed elevated absolute alpha power in the left hemisphere while non-responders showed the opposite. Responders further exhibited a cortical asymmetry in the parietal region. Groups also differed in pre-treatment relative delta power with responders showing greater power in the right hemisphere over the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to the right and the opposite was noted for non-responders. A reverse pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reductions in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance.
CONCLUSIONS: Hemispheric asymmetries in the alpha and delta bands at baseline and at 2 weeks post-treatment have moderately strong predictive utility in predicting response to antidepressant treatment.

PMID: 29169123 [PubMed - as supplied by publisher]

Molecular & genetic characteristics of Mycobacterium tuberculosis strains circulating in the southern part of West Siberia.

Indian J Med Res. 2017 Jul;146(1):49-55

Authors: Pasechnik O, Dymova MA, Stasenko VL, Blokh AI, Tatarintseva MP, Kolesnikova LP, Filipenko ML

Abstract
BACKGROUND & OBJECTIVES: A complicated epidemiological situation characterized by significantly high tuberculosis (TB) morbidity is observed in West Siberia. This study was aimed to investigate the genetic characteristics of Mycobacterium tuberculosis circulating in the southern part of West Siberia (in the Omsk region).
METHODS: From March 2013 to January 2015, 100 isolates of M. tuberculosis were obtained from patients with pulmonary TB living in the Omsk region. Drug susceptibility testing was performed on Lowenstein-Jensen medium (absolute concentration method). Genetic typing of isolates was carried out by variable number tandem repeats of mycobacterial interspersed repetitive units (MIRU-VNTR) typing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The genetic types and characteristics of cluster strains were determined using 15 MIRU-VNTR loci.
RESULTS: Thirty six VNTR types were found. Twenty six (26.0%) isolates had a unique profile, and the remaining 74 were grouped in 10 clusters containing from 2 to 23 isolates. The Beijing genotype was found in 72 isolates, 61 (85.0%) of which were part of five clusters that included two large clusters containing 23 isolates. Other genetic families, such as Latin-American Mediterranean (LAM, 11.0%), S family (2.0%) and Haarlem (4.0%), were also detected. The genetic family of 11 isolates could not be determined. Six different VNTR profiles were found in these non-classified isolates. Only 16 per cent of isolates were sensitive to anti-TB drugs. The katG315 (94.8%) and rpoB531 (92.2%) mutations were identified in 77 multidrug-resistant M. tuberculosis isolates.
INTERPRETATION & CONCLUSIONS: This study showed that the M. tuberculosis population in the Omsk region was heterogeneous. The Beijing genotype predominated and was actively spreading. The findings obtained point to the need for the implementation of more effective preventive measures to stop the spread of drug-resistant M. tuberculosis strains.

PMID: 29168460 [PubMed - in process]

Global substrate specificity profiling of post-translational modifying enzymes.

Protein Sci. 2017 Nov 23;:

Authors: Ivry SL, Meyer NO, Winter MB, Bohn MF, Knudsen GM, O'Donoghue AJ, Craik CS

Abstract
Enzymes that modify the proteome, referred to as post-translational modifying (PTM) enzymes, are central regulators of cellular signaling. Determining the substrate specificity of PTM enzymes is a critical step in unraveling their biological functions both in normal physiological processes and in disease states. Advances in peptide chemistry over the last century have enabled the rapid generation of peptide libraries for querying substrate recognition by PTM enzymes. In this review, we highlight various peptide-based approaches for analysis of PTM enzyme substrate specificity. We focus on the application of these technologies to proteases but also discuss specific examples in which they have been used to uncover the substrate specificity of other types of PTM enzymes, such as kinases. In particular, we highlight our Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) assay, which uses a rationally designed, physicochemically diverse library of tetradecapeptides. We show how this method has been applied to PTM enzymes to uncover biological function, as well as guide substrate and inhibitor design. We also briefly discuss how this technique can be combined with other methods to gain a systems-level understanding of PTM enzyme regulation and function. This article is protected by copyright. All rights reserved.

PMID: 29168252 [PubMed - as supplied by publisher]

Pharmacogenetics of Methadone Response.

Mol Diagn Ther. 2017 Nov 22;:

Authors: Fonseca F, Torrens M

Abstract
The efficacy of methadone maintenance treatment (MMT) in opioid use disorder is well established but responses vary. The influence of methadone pharmacodynamics and pharmacokinetics on dose requirements and program outcomes remains controversial despite the increasing number of studies evaluating genetic influences on response to methadone treatment. Furthermore, patients require different doses (usually between 60 and 100 mg/day), and there are no clear data on a plasma concentration associated with treatment success. We review the evidence regarding the influence of genetics on pharmacokinetic and pharmacodynamic factors in terms of MMT outcome. We also analyse the influence of genetics on the occurrence of severe adverse events such as respiratory depression and ventricular arrhythmia in methadone treatment. The outcomes of MMT may be influenced by a combination of environmental, drug-induced, and genetic factors. The influence of pharmacokinetic genetic variability can be clinically managed by modifying the posology. A better understanding of pharmacodynamic factors could help in selecting the best opioid for substitution treatment, but patient phenotype must still be considered when establishing a maintenance treatment. Pharmacogenetic studies represent a promising field that aims to individualize treatments according to genetic backgrounds, adapting medication and doses according to possible outcomes and the risk of adverse events.

PMID: 29168075 [PubMed - as supplied by publisher]

Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics.

Sci Rep. 2017 Nov 22;7(1):16068

Authors: Sá ACC, Webb A, Gong Y, McDonough CW, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA

Abstract
Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10(-11)) and TSC22D3 (p = 1.9 × 10(-9)) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.

PMID: 29167564 [PubMed - in process]

Author Correction: Genetic polymorphisms of lncRNA-p53 regulatory network genes are associated with concurrent chemoradiotherapy toxicities and efficacy in nasopharyngeal carcinoma patients.

Sci Rep. 2017 Nov 22;7(1):16389

Authors: Wang Y, Guo Z, Zhao Y, Jin Y, An L, Wu B, Liu Z, Chen X, Chen X, Zhou H, Wang H, Zhang W

Abstract
A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

PMID: 29167523 [PubMed - in process]

AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells.

Autophagy. 2017 Nov 22;:1-43

Authors: Ni Z, He J, Wu Y, Hu C, Dai X, Yan X, Li B, Li X, Xiong H, Li Y, Li S, Xu L, Li Y, Lian J, He F

Abstract
Phosphorylation is a major type of post-translational modification, which can influence the cellular physiological function. ATG4B, a key macroautophagy/autophagy-related protein, has a potential effect on the survival of tumor cells. However, it is still unknown as to the role of ATG4B phosphorylation in cancers. In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells. The phosphorylation of ATG4B at Ser34 had little effect on autophagic flux, but promoted the Warburg effect including the increase of L-lactate production and glucose consumption, and the decrease of oxygen consumption in HCC cells. The Ser34 phosphorylation of ATG4B also contributed to the impairment of mitochondrial activity including the inhibition of F1Fo-ATP synthase activity and the elevation of mitochondrial ROS in HCC cells. Moreover, the phosphorylation of ATG4B at Ser34 enhanced its mitochondrial location and the subsequent colocalization with F1Fo-ATP synthase in HCC cells. Furthermore, recombinant human ATG4B protein suppressed the activity of F1Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues in vitro. In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. Our findings reveal a noncanonical working pattern of ATG4B under pathological conditions, which may provide a scientific basis for developing novel strategies for HCC treatment by targeting ATG4B and its Ser34 phosphorylation.

PMID: 29165041 [PubMed - as supplied by publisher]

Have we successfully implemented CYP2D6 genotyping in psychiatry?

Expert Opin Drug Metab Toxicol. 2017 Nov 22;:1-3

Authors: de Leon J

PMID: 29164956 [PubMed - as supplied by publisher]

Assessment of Pharmacogenomic Panel Assay for Prediction of Taxane Toxicities: Preliminary Results.

Front Pharmacol. 2017;8:797

Authors: Di Francia R, Atripaldi L, Di Martino S, Fierro C, Muto T, Crispo A, Rossetti S, Facchini G, Berretta M

Abstract
Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported. Methods: An extensive panel of five polymorphisms on four candidate genes (ABCB1, CYP2C8(*)3, CYP3A4(*)1B, XRCC3), previously validated as significant markers related to paclitaxel and Docetaxel toxicity, are analyzed and discussed. We genotyped 76 cancer patients, and 35 of them received paclitaxel or docetaxel-based therapy. What is more, an early outline evaluation of the genotyping costs and benefit was assessed. Results: Out of 35 patients treated with a taxane, six (17.1%) had adverse neuropathy events. Pharmacogenomics analysis showed no correlation between candidate gene polymorphisms and toxicity, except for the XRCC3 AG+GG allele [OR 2.61 (95% CI: 0.91-7.61)] which showed a weak significant trend of risk of neurotoxicities vs. the AG allele [OR 1.52 (95% CI: 0.51-4.91)] P = 0.03. Summary: Based on our experimental results and data from the literature, we propose a useful and low-cost genotyping panel assay for the prevention of toxicity in patients undergoing taxane-based therapy. With the individual pharmacogenomics profile, clinicians will have additional information to plan the better treatment for their patients to minimize toxicity and maximize benefits, including determining cost-effectiveness for national healthcare sustainability.

PMID: 29163177 [PubMed]

Unravelling the link between embryogenesis and cancer metastasis.

Gene. 2017 Nov 18;:

Authors: Shah K, Patel S, Mirza S, Rawal RM

Abstract
PURPOSE: Cancer as opposed to embryonic development is characterized by dysregulated, uncontrolled and clonal growth of cells. Inspite of that they share certain commonality in gene expression patterns and a number of cellular & molecular features. Consequently, in the present study we aimed to evaluate the role of a definite set of genes in fetal liver, primary liver cancers and metastatic liver tissue.
METHODS: The relative expression of fourteen candidate genes obtained by data mining and manual curation of published data (CXCL12, CXCR4, CK7, CDH1, CTNNB1, CLDN4, VEGFA, HIF1A, MMP9, p53, OPN, CDKN2A, TGFBR2, MUC16, β-actin) were performed on 62 tissues (32 liver metastasis tissues and 30 primary Liver cancer tissues), Fetal liver tissues (below and above 20weeks of gestation) and 2 sets of control samples by real-time quantitative reverse transcription PCR (qRT-PCR).
RESULTS: Results showed significant down-regulation of MMP9 and TP53 in Fetal liver above 20weeks of gestation whereas it was up-regulated in fetal liver below 20weeks of gestation, primary liver cancers and liver metastasis. Contradictory to that OPN and CDKN2A were significantly up-regulated in primary liver cancer, liver metastasis; down-regulated in fetal liver above 20weeks of gestation but were not expressed during early embryo development (below 20weeks of gestation). Moreover, MMP9 and TP53 demonstrated a strong correlation with MUC16 whereas CDKN2A and OPN showed correlation with CXCL12/CXCR4 signifying that MUC16, CXCL12/CXCR4 might be involved in the complex process of cancer metastasis.
CONCLUSION: MMP9, OPN, TP53 and CDKN2A were the identified markers that were expressed in a similar pattern in early embryonic development and cancer development & invasion suggesting that these genes are activated during embryogenesis and might be re-expressed in cancer metastasis. Moreover, these genes govern a pathway that might be activated during cancer metastasis. Thus, targeting these molecules may provide better treatment for metastatic liver cancers.

PMID: 29162510 [PubMed - as supplied by publisher]

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients.

Am J Kidney Dis. 2017 Nov 18;:

Authors: Trofe-Clark J, Brennan DC, West-Thielke P, Milone MC, Lim MA, Neubauer R, Nigro V, Bloom RD

Abstract
BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile.
STUDY DESIGN: Randomized prospective crossover study.
SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing.
INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose.
OUTCOMES: Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype.
MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles.
RESULTS: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4).
LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes.
CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT.
TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922.

PMID: 29162334 [PubMed - as supplied by publisher]

The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.

Pharmacogenomics J. 2017 Nov 21;:

Authors: Pillai S, Duvvuru S, Bhatnagar P, Foster W, Farmen M, Shankar S, Harris C, Bastyr E, Hoogwerf B, Haupt A

Abstract
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.The Pharmacogenomics Journal advance online publication, 21 November 2017; doi:10.1038/tpj.2017.45.

PMID: 29160303 [PubMed - as supplied by publisher]

Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes.

Pharmacogenomics J. 2017 Nov 21;:

Authors: Allegra S, Cusato J, De Francia S, Arduino A, Longo F, Pirro E, Massano D, De Nicolò A, Piga A, D'Avolio A

Abstract
β-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 μg ml(-1) and 360 μg ml(-1) h(-1), respectively; nonresponse AUC limit of 250 μg ml(-1) h(-1)). Ninety-nine β-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.The Pharmacogenomics Journal advance online publication, 21 November 2017; doi:10.1038/tpj.2017.43.

PMID: 29160302 [PubMed - as supplied by publisher]

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Pharmacogenomics J. 2017 Nov 21;:

Authors: Fabbri C, Tansey KE, Perlis RH, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Breen G, Curtis C, Sang-Hyuk L, Newhouse S, Patel H, Guipponi M, Perroud N, Bondolfi G, O'Donovan M, Lewis G, Biernacka JM, Weinshilboum RM, Farmer A, Aitchison KJ, Craig I, McGuffin P, Uher R, Lewis CM

Abstract
Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.The Pharmacogenomics Journal advance online publication, 21 November 2017; doi:10.1038/tpj.2017.44.

PMID: 29160301 [PubMed - as supplied by publisher]

Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients.

Pharmacogenomics J. 2017 Nov 21;:

Authors: Oetting WS, Wu B, Schladt DP, Guan W, Remmel RP, Mannon RB, Matas AJ, Israni AK, Jacobson PA

Abstract
The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.The Pharmacogenomics Journal advance online publication, 21 November 2017; doi:10.1038/tpj.2017.49.

PMID: 29160300 [PubMed - as supplied by publisher]

Pharmacokinetics and tolerability of MB12066, a beta-lapachone derivative targeting NAD(P)H: quinone oxidoreductase 1: two independent, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials.

Drug Des Devel Ther. 2017;11:3187-3195

Authors: Kim S, Lee S, Cho JY, Yoon SH, Jang IJ, Yu KS

Abstract
MB12066 is a molecule derived from β-lapachone that shown effects on obesity in previous studies. The present studies were conducted to evaluate the tolerability and pharmacokinetics (PK) of MB12066 after the oral administration of single and multiple doses to healthy volunteers. The study comprised 2 independent, randomized, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials to evaluate the safety, tolerability and PK of MB12066 in healthy Korean volunteers. Subjects were randomly assigned to receive a single 10, 30, 100, 150, 200, 300 or 400 mg of MB12066 and multiple 100 or 200 mg of MB12066. The subjects' vital signs, 12-lead electrocardiograms, clinical laboratory tests, adverse event statuses, and physical examinations were assessed during the study. Blood and urine samples were collected to determine the concentration of MB12066 from predose to 72 hours after the single administration and from predose to 96 hours postdose of day 7 after the multiple administration. NADH:quinone oxidoreductase 1 genotyping was performed to analyze the association between genetic polymorphisms and PK. MB12066 was well tolerated after oral administration of single and multiple doses. The systemic exposure to MB12066 after a single administration tended to increase in a dose-dependent manner in the dose range of 30-200 mg. The overall fraction of MB12066 excreted unchanged in urine was <1% of the administered dose. A significant relationship was observed between NADH:quinone oxidoreductase 1 polymorphisms and exposure to MB12066 after multiple administrations, but the result was not conclusive because of the small number of subjects. A single dose of MB12066 within the dose range of 10-400 mg and multiple doses of 100 and 200 mg of MB12066 were safe and tolerated in healthy subjects. Additionally, MB12066 was mainly eliminated through metabolism in humans.

PMID: 29158665 [PubMed - in process]

ASHP Foundation Pharmacy Forecast 2018: Strategic Planning Advice for Pharmacy Departments in Hospitals and Health Systems.

Am J Health Syst Pharm. 2017 Nov 20;:

Authors: Vermeulen LC, Kolesar J, Crismon ML, Flynn AJ, Stevenson JG, Almeter PJ, Heath WM, Short GT, Enright SM, Ploetz P, Swarthout MD, Zellmer WA, Saenz R, Devereaux DS, Zilz D, Hoffman JM, Evans WE, Knoer SJ, Ray MD

PMID: 29158305 [PubMed - as supplied by publisher]