Challenges and Solutions for Future Pharmacy Practice in the Era of Precision Medicine.

Am J Pharm Educ. 2018 Aug;82(6):6652

Authors: Dong OM, Howard RM, Church R, Cottrell M, Forrest A, Innocenti F, Mosedale M, Kashuba A, Gonzalez D, Wiltshire T

Abstract
As precision medicine research and its clinical applications continue to advance, it is critical for pharmacists to be involved in these developments to deliver optimal, tailored drug therapies for patients. To ensure pharmacists remain leaders in the field, the annual Pharmaceutical Sciences Conference convened by the University of North Carolina at Chapel Hill Eshelman School of Pharmacy focused on the role of pharmacy within precision medicine. This is a summary of the conference, highlighting the major challenges and solutions that will help advance individualized pharmacological methods within practice and research.

PMID: 30181675 [PubMed - in process]

BDNF Val66Met polymorphism and clinical response to antipsychotic treatment in schizophrenia and schizoaffective disorder patients: a meta-analysis.

Pharmacogenomics J. 2018 Sep 05;:

Authors: Huang E, Hettige NC, Zai G, Tomasi J, Huang J, Zai CC, Pivac N, Nikolac Perkovic M, Tiwari AK, Kennedy JL

Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in dopaminergic and serotonergic neurotransmission by modulating dopaminergic neuron differentiation and establishment. Multiple studies have analyzed the functional BDNF Val66Met variant in relation to antipsychotic response in schizophrenia (SCZ) patients, yielding mixed results. A meta-analysis was thus performed to examine the relationship between this variant and symptom improvement during antipsychotic treatment. Searches using PubMed, Web of Science, and PsycInfo until October 2017 yielded 11 studies that met inclusion criteria (total n = 3774). These studies investigated the BDNF Val66Met variant and antipsychotic response in patients with SCZ or schizoaffective disorder. Responders to antipsychotics were defined using the original criteria applied in each study. Effect sizes were computed using odds ratios, which were pooled according to the Mantel-Haenszel method. The BDNF Val66Met variant was not associated with the total number of responders and non-responders (p > 0.05) under dominant, recessive, or allelic models. Secondary analyses stratifying for individuals of each ethnicity and drug type also revealed no significant associations. Our findings suggest that the BDNF Val66Met variant is not associated with response to antipsychotics in individuals with SCZ. However, considering the current sample size, small effects cannot be ruled out. Moreover, recent studies have suggested that Val66Met forms haplotypes with other BDNF variants. Future studies should examine the Val66Met variant in conjunction with these other variants in relation to antipsychotic response. Moreover, since illness duration appears to influence BDNF levels in SCZ patients, future studies should aim to control for this potential confounding factor in response analyses.

PMID: 30181602 [PubMed - as supplied by publisher]

Cystic fibrosis in the era of precision medicine.

Paediatr Respir Rev. 2018 Jan;25:64-72

Authors: Paranjape SM, Mogayzel PJ

Abstract
The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.

PMID: 28372929 [PubMed - indexed for MEDLINE]

An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy.

Nat Commun. 2016 11 07;7:13443

Authors: Chen Y, Xia R, Huang Y, Zhao W, Li J, Zhang X, Wang P, Venkataramanan R, Fan J, Xie W, Ma X, Lu B, Li S

Abstract
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.

PMID: 27819653 [PubMed - indexed for MEDLINE]

A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC.

Nat Commun. 2016 06 15;7:11743

Authors: Schell MJ, Yang M, Teer JK, Lo FY, Madan A, Coppola D, Monteiro AN, Nebozhyn MV, Yue B, Loboda A, Bien-Willner GA, Greenawalt DM, Yeatman TJ

Abstract
Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

PMID: 27302369 [PubMed - indexed for MEDLINE]

Label-free toxicology screening of primary human mesenchymal cells and iPS-derived neurons.

PLoS One. 2018;13(9):e0201671

Authors: Piccinno MS, Petrachi T, Resca E, Strusi V, Bergamini V, Mulas GA, Mari G, Dominici M, Veronesi E

Abstract
The high-throughput, label-free Corning Epic assay has applications in drug discovery, pharmacogenomics, cell receptor signaling, cell migration, and viral titration. The utility of Epic technology for biocompatibility testing has not been well established. In manufacturing of medical devices, in vitro and in vivo biocompatibility assessments are mandatory, according to ISO 10993. The new medical device regulation MDR 745/2017 specifies that ex vivo assays that can closely recapitulate in vivo scenarios are needed to better evaluate biomedical devices. We propose herein that Epic technology-which enables detection of variations in cell mass distribution-is suitable for biocompatibility screening of compounds. In this study, we challenged primary human osteoblasts, endothelial cells, and neurons derived from induced pluripotent stem cells with specific concentrations of methyl methacrylate (MMA). Polymeric MMA has long been applied in cranioplasty, where it makes contact with multiple cell types. Application of Epic technology yielded real-time cytotoxicity profiles for all considered cell types. The results were compared with those from microscopic observation of the same culture plate used in the Epic analyses. The Epic assay should be further examined for its utility for cell biology, genomics, and proteomics companion assays. Our results suggest that Epic technology can be applied to biocompatibility evaluation of human cells in medical device development.

PMID: 30180158 [PubMed - in process]

Role of CYP1A1, ABCG2, CYP24A1 and VDR gene polymorphisms on the evaluation of cardiac iron overload in thalassaemia patients.

Pharmacogenet Genomics. 2018 Sep 01;:

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

Abstract
OBJECTIVES: Iron-burden-induced arrhythmia and heart failure are among the leading causes of morbidity and mortality in β-thalassaemia major patients. T2* cardiac magnetic resonance remains the only reliable noninvasive method for the heart iron excess assessment. We explored the role of single nucleotide polymorphisms involved in vitamin D metabolism, transport and activity and in deferasirox (DFX) metabolism on cardiac iron burden.
PATIENTS AND METHODS: One hundred and five β-thalassaemia patients, treated with DFX, were enrolled in the present study. Drug plasma Ctrough was measured by a high-performance liquid chromatography-ultraviolet method. Allelic discrimination was carried out using the real-time PCR.
RESULTS: CYP1A1*1189 CC, ABCG2 421 GA, CYP24A1 8620 GG and VDR TaqI CC single nucleotide polymorphisms influenced T2* values. Age, serum ferritin, ABCG2 421 GA, ABCG2 1194 +928 TC/CC, CYP24A1 22776 TT and VDR TaqI TC/CC were retained in linear regression model.
CONCLUSION: Our results suggested, for the first time, the role of DFX and vitamin D pharmacogenetics on cardiac iron overload.

PMID: 30179981 [PubMed - as supplied by publisher]

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

Acta Ophthalmol. 2018 Sep 04;:

Authors: Meng W, Shah KP, Pollack S, Toppila I, Hebert HL, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Daniell M, Kaidonis G, Craig JE, Mitchell P, Liew G, Kifley A, Wang JJ, Christiansen MW, Jensen RA, Penman A, Hancock HA, Chen CJ, Correa A, Kuo JZ, Li X, Chen YI, Rotter JI, Klein R, Klein B, Wong TY, Morris AD, Doney ASF, Colhoun HM, Price AL, Burdon KP, Groop PH, Sandholm N, Grassi MA, Sobrin L, Palmer CNA, Wellcome Trust Case Control Consortium 2 (WTCCC2), Surrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) study group

Abstract
PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.
METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.
RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).
CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

PMID: 30178632 [PubMed - as supplied by publisher]

In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics.

Eur J Clin Pharmacol. 2018 Apr;74(4):455-464

Authors: Jin Y, Borell H, Gardin A, Ufer M, Huth F, Camenisch G

Abstract
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism.
METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software.
RESULTS: Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0-2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype.
CONCLUSION: .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.

PMID: 29273968 [PubMed - indexed for MEDLINE]

Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China.

Eur J Clin Pharmacol. 2018 Apr;74(4):423-431

Authors: Zhong Z, Hou J, Zhang Q, Li B, Li C, Liu Z, Yang M, Zhong W, He X, Wu H, Zhong M, Zhao P

Abstract
BACKGROUND AND OBJECTIVES: The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China.
METHODS: Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150-mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke.
RESULTS: The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044).
CONCLUSIONS: Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China.

PMID: 29243114 [PubMed - indexed for MEDLINE]

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

Eur J Clin Pharmacol. 2018 Apr;74(4):433-442

Authors: Wang P, Lin XQ, Cai WK, Xu GL, Zhou MD, Yang M, He GH

Abstract
PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA.
METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship.
RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA.
CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

PMID: 29243113 [PubMed - indexed for MEDLINE]

[Use of Pharmacogenetic Information for Therapeutic Drug Monitoring of an Antiarrhythmic Drug].

Yakugaku Zasshi. 2018;138(9):1145-1150

Authors: Doki K

Abstract
　Antiarrhythmic drugs require therapeutic drug monitoring (TDM) to avoid adverse effects such as proarrhythmia. However, TDM is not necessarily used to adjust the dosage of antiarrhythmic drugs because there is a lack of information regarding the therapeutic range of the serum concentration and the selection of patients who require TDM. The aim of this review was to provide an overview of the pharmacogenetic information on the pharmacokinetics and drug response of flecainide, a class Ic antiarrhythmic drug with a sodium channel-blocking effect. A population pharmacokinetic analysis revealed that the CYP2D6 genotype was a determining factor of the age-related decline in flecainide clearance. Elderly patients show large interindividual variability of flecainide clearance because they have a more pronounced effect of the CYP2D6 genotype and require more frequent monitoring of serum flecainide concentrations. Carriers of an Asian-specific promoter haplotype B of the cardiac sodium channel gene (SCN5A) more frequently achieve clinically relevant flecainide efficacy even at lower concentrations. This suggests that the therapeutic range of serum flecainide concentrations is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes. The β1-adrenergic receptor Gly389 polymorphism decreases the antiarrhythmic efficacy of flecainide when co-administered with β-blockers. Carriers of Gly389 with co-administration of β-blockers may not achieve clinically relevant flecainide efficacy even when the serum flecainide concentrations are within the therapeutic range. These findings provide pharmacogenetic information for the effective utilization of TDM in antiarrhythmic drug therapy.

PMID: 30175758 [PubMed - in process]

Pharmacogenetic Labeling of FDA-Approved Drugs: A Regulatory Retrospective.

JACC Basic Transl Sci. 2018 Aug;3(4):545-549

Authors: Drozda K, Pacanowski MA, Grimstein C, Zineh I

Abstract
The U.S. Food and Drug Administration recently marked 10 years since first updating the labeling for warfarin (often referred to as the "poster child" of pharmacogenomics) to include information regarding the potential impact of CYP2C9 and VKORC1 genetic variation on warfarin dosing requirements and risks. Herein, we opine on the experience updating the warfarin labeling, highlighting more generally the enabling factors and challenges encountered when considering incorporation of pharmacogenomic information into the prescribing recommendations for already approved drugs. We also provide a historical perspective of implemented changes in regulatory policies related to personalized medicine.

PMID: 30175278 [PubMed]

Association between polymorphisms in SLC15A1 and PLA2G16 genes and development of obesity in Chinese subjects.

Diabetes Metab Syndr Obes. 2018;11:439-446

Authors: Wang CY, Liu S, Xie XN, Luo ZY, Yang L, Tan ZR

Abstract
Introduction: The small peptide transporter 1 (PepT-1) and adipose phospholipase A2 (AdPLA) play a key role in the development of obesity. However, there are no data assessing the impact of PepT-1 (SLC15A1) and AdPLA (PLA2G16) variants on obesity susceptibility. Therefore, we assessed the contribution of 9 single-nucleotide polymorphisms (SNPs) between these two genes on obesity susceptibility in Chinese subjects.
Materials and methods: A total of 611 participants were enrolled in the study, and 9 SNPs in the SLC15A1 and PLA2G16 genes were selected. Blood samples were collected for genotyping. Overweight and obesity were established by body mass index. Regression analyses were performed to test for any association of genetic polymorphisms with weight abnormality.
Results: The genotype frequencies (P=0.04 for rs9557029, P=0.027 for rs1289389) were significantly different between obese or overweight subjects and healthy controls. However, no significant difference in allele was found between these three groups (P>0.05). Further logistic regression analyses adjusted for age and sex also failed to reveal significant associations between overweight, obesity, and the selected SNPs (P>0.05).
Conclusion: Data indicate that the selected 9 SNPs in SLC15A1 and PLA2G16 genes were not related to obesity susceptibility in the Han Chinese population.

PMID: 30174451 [PubMed]

A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

Nat Commun. 2016 08 09;7:12342

Authors: Rivas MA, Graham D, Sulem P, Stevens C, Desch AN, Goyette P, Gudbjartsson D, Jonsdottir I, Thorsteinsdottir U, Degenhardt F, Mucha S, Kurki MI, Li D, D'Amato M, Annese V, Vermeire S, Weersma RK, Halfvarson J, Paavola-Sakki P, Lappalainen M, Lek M, Cummings B, Tukiainen T, Haritunians T, Halme L, Koskinen LL, Ananthakrishnan AN, Luo Y, Heap GA, Visschedijk MC, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, MacArthur DG, Neale BM, Ahmad T, Anderson CA, Brant SR, Duerr RH, Silverberg MS, Cho JH, Palotie A, Saavalainen P, Kontula K, Färkkilä M, McGovern DP, Franke A, Stefansson K, Rioux JD, Xavier RJ, Daly MJ, Barrett J, de Lane K, Edwards C, Hart A, Hawkey C, Jostins L, Kennedy N, Lamb C, Lee J, Lees C, Mansfield J, Mathew C, Mowatt C, Newman B, Nimmo E, Parkes M, Pollard M, Prescott N, Randall J, Rice D, Satsangi J, Simmons A, Tremelling M, Uhlig H, Wilson D, Abraham C, Achkar JP, Bitton A, Boucher G, Croitoru K, Fleshner P, Glas J, Kugathasan S, Limbergen JV, Milgrom R, Proctor D, Regueiro M, Schumm PL, Sharma Y, Stempak JM, Targan SR, Wang MH

Abstract
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

PMID: 27503255 [PubMed - indexed for MEDLINE]

Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.

Nat Commun. 2016 06 08;7:11762

Authors: Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, Belt BA, Alspach E, Leahy K, Luo J, Schaffer A, Edwards JR, Longmore G, Faccio R, DeNardo DG, Stewart SA

Abstract
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.

PMID: 27272654 [PubMed - indexed for MEDLINE]

The ABCB1, CYP2C19, CYP3A5 and CYP4F2 genetic polymorphisms and platelet reactivity in the early phases of acute coronary syndromes.

Drug Metab Pers Ther. 2018 Sep 25;33(3):109-118

Authors: Mirzaev KB, Rytkin E, Ryzhikova KA, Grishina EA, Sozaeva ZA, Fedorinov DS, Konova OD, Giliarov MI, Belyakova GA, Andreev DA, Sychev DA

PMID: 30171809 [PubMed - in process]

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pharmacogenomics

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11 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 2018/09/01

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.

A simple UHPLC-PDA method with a fast dilute-and-shot sample preparation for the quantification of canrenone and its prodrug spironolactone in human urine samples.

J Pharmacol Toxicol Methods. 2018 Aug 27;:

Authors: Avataneo V, De Nicolò A, Rabbia F, Sciandra M, Tosello F, Cusato J, Perlo E, Fatiguso G, Allegra S, Favata F, Mulatero P, Veglio F, Di Perri G, D'Avolio A

Abstract
INTRODUCTION: Nowadays, the treatment of hypertension represents an important issue, particularly in developed countries. While in most cases the standard therapeutic approaches, consisting in the administration of 1 to 3 drugs, are adequate to reach adequate blood pressure levels, in some cases more drugs are needed: this condition is called "resistant hypertension". In this context, the administration of a diuretic, such as spironolactone or canrenoate salts, represents a standard practice. Since a reliable discrimination of real cases of resistant hypertension from cases of poor therapeutic adherence is currently difficult to obtain, the adoption of therapeutic drug monitoring has been suggested as a useful tool for this purpose. In this work, the authors developed and validated a simple, cheap and fast dilute-and-shot method with UHPLC-PDA analysis for the quantification of spironolactone and its metabolite canrenone in human urine samples.
METHODS: Standards and quality controls were prepared in urine. Only 100 μL of sample were added with 80 μL of internal standard (6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline) working solution and 820 μL of phosphate buffer 10 mM pH 3.2 (phase A):acetonitrile (phase B) 90:10 v:v solution. Chromatographic separation was performed on an Acquity® UPLC HSS T3 1.8 μm 2.1 × 150 mm column, with a binary gradient for 11 min at 40 °C.
RESULTS: Accuracy, intra-day and inter-day precision, selectivity and sensitivity fitted FDA guidelines for all analytes (LLOQ and LOD were 156.25 ng/mL and 78.12 ng/mL, respectively, for both analytes) and recovery resulted high and reproducible. Method performances were tested on urine samples from hypertensive patients with good results.
DISCUSSION: This simple analytical method could represent a useful tool for the management of antihypertensive therapy.

PMID: 30165207 [PubMed - as supplied by publisher]