Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice.

Brain Sci. 2019 Jan 01;9(1):

Authors: Crabbe JC, Metten P, Savarese AM, Ozburn AR, Schlumbohm JP, Spence SE, Hack WR

Abstract
Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.

PMID: 30609665 [PubMed]

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Am J Hum Genet. 2019 Jan 03;104(1):76-93

Authors: Ceyhan-Birsoy O, Murry JB, Machini K, Lebo MS, Yu TW, Fayer S, Genetti CA, Schwartz TS, Agrawal PB, Parad RB, Holm IA, McGuire AL, Green RC, Rehm HL, Beggs AH, BabySeq Project Team

Abstract
Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

PMID: 30609409 [PubMed - in process]

LC-MS application for therapeutic drug monitoring in alternative matrices.

J Pharm Biomed Anal. 2018 Dec 29;166:40-51

Authors: Avataneo V, D'Avolio A, Cusato J, Cantù M, De Nicolò A

Abstract
Nowadays the practice of therapeutic drug monitoring, consisting in the measurement of drugs concentrations in biological matrices in order to guide possible posological adjustments, is becoming more and more important for the management and optimization of several treatments, especially when drugs with narrow therapeutic indexes are administered. Although TDM on plasma samples is currently considered the gold standard, this practice shows some limitations: it requires venous blood sampling, centrifugation and, if necessary, shipment with refrigeration; moreover, drug concentrations in plasma or blood do not necessarily reflect the ones in the target tissues or cells. Therefore, in the recent years great attention has been given to alternative matrices for TDM purpose, in order to reduce invasiveness, costs or to obtain better information about drug concentrations at the active sites. This evolution is strongly sustained by the spreading use of liquid chromatography coupled with mass spectrometry (LC-MS) techniques for the analysis of small molecules, which is constantly increasing sensitivity and specificity of TDM assays. In this review, we present and summarize recently published LC-MS applications providing alternatives to plasma testing, in order to avoid blood withdrawal, plasma separation, refrigerated shipment or, if possible, to obtain better information about drug exposure in target cells. By analyzing the last 5 years of literature, reported in PubMed website, LC-MS/MS applications have been reported, with particular focus on the ones with higher probability to enter in the near future in clinical practice. Microsampling strategies and alternative biological matrices, from urine to tissue samples, have been included.

PMID: 30609393 [PubMed - as supplied by publisher]

Pharmacogenetic Correlates of Antipsychotic-Induced Weight Gain in the Chinese Population.

Neurosci Bull. 2019 Jan 03;:

Authors: Luo C, Liu J, Wang X, Mao X, Zhou H, Liu Z

Abstract
Antipsychotic-induced weight gain (AIWG) is a common adverse effect of this treatment, particularly with second-generation antipsychotics, and it is a major health problem around the world. We aimed to review the progress of pharmacogenetic studies on AIWG in the Chinese population to compare the results for Chinese with other ethnic populations, identify the limitations and problems of current studies, and provide future research directions in China. Both English and Chinese electronic databases were searched to identify eligible studies. We determined that > 25 single-nucleotide polymorphisms in 19 genes have been investigated in association with AIWG in Chinese patients over the past few decades. HTR2C rs3813929 is the most frequently studied single-nucleotide polymorphism, and it seems to be the most strongly associated with AIWG in the Chinese population. However, many genes that have been reported to be associated with AIWG in other ethnic populations have not been included in Chinese studies. To explain the pharmacogenetic reasons for AIWG in the Chinese population, genome-wide association studies and multiple-center, standard, unified, and large samples are needed.

PMID: 30607769 [PubMed - as supplied by publisher]

Interleukin-8 release by endothelial colony-forming cells isolated from idiopathic pulmonary fibrosis patients might contribute to their pathogenicity.

Angiogenesis. 2019 Jan 03;:

Authors: Blandinières A, Gendron N, Bacha N, Bièche I, Chocron R, Nunes H, Nevo N, Rossi E, Crestani B, Lecourt S, Chevret S, Lokajczyk A, Mignon V, Kisaoglu A, Juvin K, Bertil S, Valeyre D, Cras A, Gaussem P, Israël-Biet D, Smadja DM

Abstract
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms involve a concomitant accumulation of scar tissue together with myofibroblasts activation and a strong abnormal vascular remodeling. Endothelial progenitor cells (ECFC subtype) have been investigated in several human lung diseases as a potential actor in IPF. We previously demonstrated that ECFCs are down-regulated in IPF in contrast to healthy controls. We postulated here that ECFCs might behave as a liquid biopsy in IPF patients and that they exert modified vasculogenic properties.
METHODS AND RESULTS: ECFCs isolated from controls and IPF patients expressed markers of the endothelial lineage and did not differ concerning adhesion, migration, and differentiation in vitro and in vivo. However, senescent and apoptotic states were increased in ECFCs from IPF patients as shown by galactosidase staining, p16 expression, and annexin-V staining. Furthermore, conditioned medium of IPF-ECFCs had increased level of interleukin-8 that induced migration of neutrophils in vitro and in vivo. In addition, an infiltration by neutrophils was shown in IPF lung biopsies and we found in a prospective clinical study that a high level of neutrophils in peripheral blood of IPF patients was associated to a poor prognosis.
CONCLUSION: To conclude, our study shows that IPF patients have a senescent ECFC phenotype associated with an increased IL-8 secretion potential that might contribute to lung neutrophils invasion during IPF.

PMID: 30607696 [PubMed - as supplied by publisher]

[A Multifaceted Approach regarding the Association of the DsbA-L Gene with the Risk of Obesity-related Diseases Based on Clinical Pharmacogenetics].

Yakugaku Zasshi. 2019;139(1):53-60

Authors: Oniki K, Saruwatari J

Abstract
Adiponectin, the most abundant adipose tissue-derived adipocytokine, improves insulin sensitivity and has anti-inflammatory properties. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a key molecule in the multimerization of adiponectin (i.e., activation of adiponectin). In mice, liver-specific knockout of the Dsba-L gene impaired the mitochondrial function in hepatocytes and exacerbated the high-fat-diet-induced fatty liver. In addition, the DsbA-L mRNA level is negatively correlated with body mass index (BMI) in humans. We recently investigated the clinical impact of the DsbA-L gene on lifestyle-related diseases in Japanese subjects. We confirmed the influence of the common DsbA-L rs1917760 polymorphism on the multimerization of adiponectin, as well as the association of the polymorphism with the risk of obesity and non-alcoholic fatty liver disease, using prediction models based on a non-linear mixed effect model and/or structural equation models among elderly participants in a health screening program. We also observed a decreasing effect of DsbA-L polymorphism on the DsbA-L mRNA level in peripheral blood mononuclear cells, and an increasing effect of the polymorphism on the prevalence of excessive weight among schizophrenia patients at a high risk for obesity. These findings suggest that DsbA-L may be a key molecule associated with the development and progression of obesity and its related diseases. Therefore, genotyping the DsbA-L polymorphism and identifying patients at a high risk of developing obesity may help prevent obesity and its complications by facilitating targeted prevention and treatment programs for high-risk individuals.

PMID: 30606929 [PubMed - in process]

A Pharmacogenomics Clinical Decision Support Service Based on FHIR and CDS Hooks.

Methods Inf Med. 2019 Jan 03;:

Authors: Dolin RH, Boxwala A, Shalaby J

Abstract
OBJECTIVES:  Pharmacogenomics (PGx) is often considered a low-hanging fruit for genomics-electronic health record (EHR) integrations, and many have expressed the notion that drug-gene interaction checking might one day become as much a commodity in EHRs as drug-drug and drug-allergy checking. In addition, the U.S. Office of the National Coordinator has recognized the trend toward storing complete sequencing data outside the EHR in a Genomic Archiving and Communication System (GACS) and has emphasized the need for "pilots that test Fast Healthcare Interoperability Resources (FHIR) Genomics for GACS integration with EHRs." We sought to develop a PGx clinical decision support (CDS) service, leveraging the emerging FHIR and CDS Hooks standards, and based on an assumption that pharmacogene sequencing data would be stored alongside the EHR in a GACS.
METHODS:  We developed a PGx CDS service as a functional prototype. The service is triggered by a medication order in the EHR. When evoked, the service looks for relevant genetic data in a GACS and returns corresponding recommendations back to the ordering clinician. Where the patient has no genetic data on file, the service can recommend pretreatment genetic testing where applicable.
RESULTS:  Overall, we were able to meet our objectives and deploy a functional prototype, interfaced with a commercial EHR. We identified several areas where FHIR or CDS Hooks lacked necessary semantics or have implementation ambiguity. Primary FHIR challenges included multiple ways to say the same thing, which exacerbated the complexity of variant to allele conversion and lack of representation of deoxyribonucleic acid region(s) studied. Primary CDS Hooks challenges included the complexity of executing an authenticated query against one system (GACS) upon being triggered by a different system (the EHR), and limitations in the types of actionable recommendations that can be returned to the EHR.
CONCLUSIONS:  In conclusion, we have found that PGx CDS based on FHIR and CDS Hooks appears to represent a promising means of genomics-EHR integration. More real-world testing along with a set of use-case driven GACS interface requirements will push us closer to the U.S. National Human Genome Research Institute vision of a plug-in PGx app.

PMID: 30605914 [PubMed - as supplied by publisher]

MADEx: A System for Detecting Medications, Adverse Drug Events, and Their Relations from Clinical Notes.

Drug Saf. 2019 Jan 02;:

Authors: Yang X, Bian J, Gong Y, Hogan WR, Wu Y

Abstract
INTRODUCTION: Early detection of adverse drug events (ADEs) from electronic health records is an important, challenging task to support pharmacovigilance and drug safety surveillance. A well-known challenge to use clinical text for detection of ADEs is that much of the detailed information is documented in a narrative manner. Clinical natural language processing (NLP) is the key technology to extract information from unstructured clinical text.
OBJECTIVE: We present a machine learning-based clinical NLP system-MADEx-for detecting medications, ADEs, and their relations from clinical notes.
METHODS: We developed a recurrent neural network (RNN) model using a long short-term memory (LSTM) strategy for clinical name entity recognition (NER) and compared it with baseline conditional random fields (CRFs). We also developed a modified training strategy for the RNN, which outperformed the widely used early stop strategy. For relation extraction, we compared support vector machines (SVMs) and random forests on single-sentence relations and cross-sentence relations. In addition, we developed an integrated pipeline to extract entities and relations together by combining RNNs and SVMs.
RESULTS: MADEx achieved the top-three best performances (F1 score of 0.8233) for clinical NER in the 2018 Medication and Adverse Drug Events (MADE1.0) challenge. The post-challenge evaluation showed that the relation extraction module and integrated pipeline (identify entity and relation together) of MADEx are comparable with the best systems developed in this challenge.
CONCLUSION: This study demonstrated the efficiency of deep learning methods for automatic extraction of medications, ADEs, and their relations from clinical text to support pharmacovigilance and drug safety surveillance.

PMID: 30600484 [PubMed - as supplied by publisher]

Effect of CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients.

Biol Blood Marrow Transplant. 2018 Dec 28;:

Authors: Hamadeh IS, Zhang Q, Steuerwald N, Hamilton A, Druhan LJ, McSwain M, Diez Y, Rusin S, Han Y, Symanowski J, Gerber J, Grunwald MR, Ghosh N, Plesca D, Arnall J, Trivedi J, Avalos B, Copelan E, Patel JN

Abstract
Pharmacogenetics influences oral tacrolimus exposure; however, little data exist with intravenous tacrolimus. Herein, we investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on intravenous tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germ-line DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5 and ABCB1 polymorphisms. Continuous intravenous infusion of tacrolimus 0.03 mg/kg/day was initiated on day +5 post-transplant and steady-state blood concentrations were measured 4 days later. We evaluated the association between phenotypes and prevalence of non-therapeutic target concentrations (below or above 5-15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15 ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared to rapid) and those with at least one ABCB1 C2677T loss-of-function allele (p<0.05). ABCB1 C2677T was significantly associated with concentrations >15 ng/mL (OR 6.2, 95% CI:1.8-23.6, p=0.004) and tacrolimus-related toxicities (OR 7.5, 95% CI:1.6-55.2, p=0.02). ABCB1 C2677T and CYP3A4 are important determinants of intravenous tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in SCT.

PMID: 30597277 [PubMed - as supplied by publisher]

Aryl-urea fatty acids that activate the p38 MAP kinase and down-regulate multiple cyclins decrease the viability of MDA-MB-231 breast cancer cells.

Eur J Pharm Sci. 2018 Dec 28;:

Authors: Al-Zubaidi Y, Pazderka C, Koolaji N, Rahman MK, Choucair H, Umashankar B, Bourget K, Chen Y, Rawling T, Murray M

Abstract
We recently developed a novel aryl-urea fatty acid (CTU; 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that impaired the viability of MDA-MB-231 breast cancer cells in vitro and in mouse xenograft models in vivo. At present there is a deficiency of information on the structural requirements for the activity of CTU. Our initial study suggested that electron withdrawing groups were required on the aryl ring, and in this study we further evaluated the influence of the electronic properties of aromatic substitution on the capacity of CTU analogues to decrease MDA-MB-231 breast cancer cell viability. Analogues that contained strong electron-withdrawing groups in the meta- and para-positions of the aryl ring exhibited improved activity over CTU. Effective analogues down-regulated the cyclins D1, E1 and B1, and the cyclin-dependent kinases (CDKs) 4 and 6, that form complexes to coordinate cell cycle progression. Active CTU analogues also stimulated the phosphorylation and activation of the p38 MAP kinase signalling pathway in cells and both decreased proliferation (5-bromo-2'-deoxyuridine (brdU) incorporation) and activated apoptosis (executioner caspase-3/7 activity). These agents offer a new approach to target the cell cycle at multiple phases in order to efficiently prevent cancer cell expansion. Inclusion of the present structural information in drug design approaches could enhance the development of optimal analogues of aryl-urea fatty acids as potential anti-cancer agents.

PMID: 30597206 [PubMed - as supplied by publisher]

Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects.

Indian Heart J. 2018 Dec;70 Suppl 3:S120-S125

Authors: Ramakumari N, Indumathi B, Katkam SK, Kutala VK

Abstract
OBJECTIVES: Statins are the most commonly prescribed medications for the treatment of atherosclerotic cardiovascular disease. Statin-associated adverse effects occur in ∼10% of patients and are associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. In the present study, we examine the association between cytochrome P450 3A5*3 (CYP3A5*3) T>C (rs776746), COQ G>C (rs4693075), and SLCO1B1 T>C (rs4149056) genetic variants with the risk of myopathy in South Indian patients on statin therapy.
METHODS: A total of 202 patients on atorvastatin or rosuvastatin therapy for 12 years were recruited in the study. Genotyping of drug metabolic CYP3A5*3 gene variant and drug transporter genes COQ G>C (rs4693075) and SLCO1B1 T>C (rs4149056) was analyzed by Sanger's sequencing.
RESULTS: In our study subjects, the percentage of patients diagnosed to have statin-induced myopathy was 18%. The majority of the patients were on 10 mg/day dose of either atorvastatin or rosuvastatin. The homozygous nonexpressors genotype CYP3A5*3/3 frequency of the CYP3A5 polymorphism was higher in patients with myopathy. But we could not find association of CYP3A5, COQ, and SLCO1B1 gene polymorphisms with either rosuvastatin or atorvastatin.
CONCLUSION: Our results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group. We did not find significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy.

PMID: 30595243 [PubMed - in process]

Value of VKORC1 (-1639G>A) rs9923231 genotyping in predicting warfarin dose: A replication study in South Indian population.

Indian Heart J. 2018 Dec;70 Suppl 3:S110-S115

Authors: Harikrishnan S, Koshy L, Subramanian R, Sanjay G, Vineeth CP, Nair AJ, Nair GM, Sudhakaran PR

Abstract
OBJECTIVE: Warfarin is the most commonly prescribed oral anticoagulant, although having a narrow therapeutic index and wide interindividual variability. The aim of this study was to replicate the utility of VKORC1 (-1639G>A) rs9923231 genotyping in predicting the mean daily dose and to evaluate its ability to categorize warfarin-treated patients to high-, intermediate-, or low-dose categories in the South Indian population.
MATERIALS AND METHODS: A cohort of 222 warfarin-treated patients was genotyped using restriction fragment length polymorphism method. The influence of the rs9923231 polymorphism on the variations in the mean daily dose was compared using one-way analysis of variance and linear regression analysis. Discriminatory ability of the rs9923231 polymorphism to group the patients into ordered dose categories was assessed by estimating the proportional odds ratios using the ordered logit regression analysis.
RESULTS: The frequency of AA genotype and A allele in the study sample was found to be 1.8% and 9.23%, respectively, which was similar to reports from other South Indian populations. The mean daily dose required to achieve the optimum international normalized ratio was significantly lower in AA homozygous genotype carriers (3.99 ± 1.67 mg/day) and GA heterozygous (4.26 ± 1.57 mg/day) compared to the GG genotype carriers (5.51 ± 2.13 mg/day), p = 0.003. The A allele carriers (GA+AA genotypes) had a 3.23 higher odds of being grouped as a low-dose requiring category compared to non-carriers (95% CI 1.49-6.98, p = 0.003).
CONCLUSIONS: These preliminary results strongly support the use of VKORC1 (-1639G>A) rs9923231 polymorphism for genetically guided initial warfarin dosing in South Indian patients with heart valve replacements.

PMID: 30595241 [PubMed - in process]

[THE PROGNOSTIC VALUE OF OBESITY AND HYPONATERMIA IN PROGRESSING OF CHRONIC HEART FAILER: CARDIOVASCULAR MORTALITY AND CARDIORENAL SYNDROME].

Georgian Med News. 2018 Sep;(282):65-73

Authors: Lazidi E, Rudyk I

Abstract
Aim - to study the predictors of cardiovascular events in patients with chronic heart failure (CHF) with preserved left ventricular ejection fraction role of traditional and non-traditional risk factors, to analyze the prognostic role of hyponatremia. Analysis of the clinical features of CHF was provided by retrospective research of medical cards in 308 patients, with endpoint verification during long-term period from 2010 to 2015. Among the examined patients 81 addmitted to the intensive care unit. The study showed that in obesity patients with body mass index (BMI) more than 30 kg/m2, the incidence of CHF decompensation was higher (p<0,05), but a significant mortality in CHF is only possible with abdominal obesity. It was proved the significant increase of CHF decompensation at patients with diabetes mellitus (p<0,05), the gender specificity of the disease was the higher risk of cardiovascular mortality in males (p<0,05).It was found that the most often in patients with CHF decompensation was reduced systolic pressure with an absolute risk of 82,7%. It was established a significantly higher risk of cardiovascular mortality in CHF with a sodium level less than 135 mmol/l, an increase from 19,0 to 45,0%, the "cut-off point" was established at the Na+ level between 115.0-125.0 mmol/l. After analyzing of the "combined" risk with hyponatremia and obesity, cardiovascular mortality increased to 23,0%.In the group with severe decompensation of CHF, it was set the lower hemoglobin level (p<0,05), lower hematocrit (p<0,05), higher ESR (p<0,05) and total leukocyte count(p<0,05).Absolute risk of cardiovascular mortality with hemoglobin level before 120 g/l was 48,0% vs. 16,0% of patients with normal hemoglobin level. Significant factors, combined with frequent hospitalization were age over 65 years (p<0,05), body mass index more than 30 kg/m2 (p<0,05), III and IV functional classes of CHF (p<0,05),hemoglobin level less than 120 g/l (p<0,05), hyponatremia (p<0,05).It was set the reliable influence of combined hyponatremia and obesity on the frequency of hospitalizations in CHF patients with an increase of absolute risk with 55,0%, reliable RR and OR (p<0,05).

PMID: 30358543 [PubMed - indexed for MEDLINE]

Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis

Asian Pac J Cancer Prev. 2018 Aug 24;19(8):2057-2070

Authors: Elfaki I, Mir R, Almutairi FM, Duhier FMA

Abstract
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.

PMID: 30139042 [PubMed - indexed for MEDLINE]

Increased susceptibility to oxidative stress-induced toxicological evaluation by genetically modified nrf2a-deficient zebrafish.

J Pharmacol Toxicol Methods. 2018 Dec 27;:

Authors: Yamashita A, Deguchi J, Honda Y, Yamada T, Miyawaki I, Nishimura Y, Tanaka T

Abstract
INTRODUCTION: Oxidative stress plays an important role in drug-induced toxicity. Oxidative stress-mediated toxicities can be detected using conventional animal models but their sensitivity is insufficient, and novel models to improve susceptibility to oxidative stress have been researched. In recent years, gene targeting methods in zebrafish have been developed, making it possible to generate homozygous null mutants. In this study, we established zebrafish deficient in the nuclear factor erythroid 2-related factor 2a (nrf2a), a key antioxidant-responsive gene, and its potential to detect oxidative stress-mediated toxicity was examined.
METHODS: Nrf2a-deficient zebrafish were generated using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 technique. The loss of nrf2a function was confirmed by the tolerability to hydrogen peroxide and hydrogen peroxide-induced gene expression profiles being related to antioxidant response element (ARE)-dependent signaling. Subsequently, vulnerability of nrf2a-deficient zebrafish to acetaminophen (APAP)- or doxorubicin (DOX)-induced toxicity was investigated.
RESULTS: Nrf2a-deficient zebrafish showed higher mortality than wild type accompanied by less induction of ARE-dependent genes with hydrogen peroxide treatment. Subsequently, this model showed increased severity and incidence of APAP-induced hepatotoxicity or DOX-induced cardiotoxicity than wild type.
DISCUSSION: Our results demonstrated that anti-oxidative response might not fully function in this model, and resulted in higher sensitivity to drug-induced oxidative stress. Our data support the usefulness of nrf2a-deficient model as a tool for evaluation of oxidative stress-related toxicity in drug discovery research.

PMID: 30594530 [PubMed - as supplied by publisher]

Roles of pharmacogenomics in non-anthracycline antineoplastic-induced cardiovascular toxicities: A systematic review and meta-analysis of genotypes effect.

Int J Cardiol. 2018 Dec 19;:

Authors: Leong SL, Chaiyakunapruk N, Tassaneeyakul W, Arunmanakul P, Nathisuwan S, Lee SWH

Abstract
BACKGROUND: Exploration on genetic roles in antineoplastic-related cardiovascular toxicity has increased with the advancement of genotyping technology. However, knowledge on the extent of genetic determinants in affecting the susceptibility to the cardiovascular toxicities of antineoplastic is limited. This study aims to identify potential single nucleotide polymorphism (SNP) in predicting non-anthracycline antineoplastic-related cardiovascular toxicity.
METHODS: We systematically searched for original research in PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, EMBASE and HuGE Navigator from database inception until January 2018. Studies on association between polymorphism and antineoplastic-induced cardiovascular toxicity in patients treated for cancer of all antineoplastic agents were included except for anthracycline. Case reports, conference abstracts, reviews and non-patient studies were excluded. Data extracted by two independent reviewers were combined with random-effects model and reported according to PRISMA and MOOSE guidelines.
RESULTS: The 35 studies included examined a total of 219 SNPs in 80 genes, 11 antineoplastic and 5 types of cardiovascular toxicities. Meta-analyses showed that human epidermal growth factor receptor 2 (HER2) rs1136201, a risk variants (pooled OR: 2.43; 1.17-5.06, p = 0.018) is a potential predictors for trastuzumab-related cardiotoxicity. Gene dose effect analysis showed number of variant allele may contribute to the risk too.
CONCLUSIONS: This review found that HER2 rs1136201 can have the potential in predicting trastuzumab-related heart failure. As such, further studies are needed to confirm the validity of these results as well as determine the economic aspect of using SNPs prior to its implementation as a clinical practice.

PMID: 30594345 [PubMed - as supplied by publisher]

Population genetic difference of pharmacogenomic VIP gene variants in the Lisu population from Yunnan Province.

Medicine (Baltimore). 2018 Dec;97(52):e13674

Authors: Zhang C, Jiang X, Chen W, Li Q, Yun F, Yang X, Dai R, Cheng Y

Abstract
Individual differences in drug clinical response are related to pharmacogenomics. The genetic variation of drug-metabolizing enzymes, drug receptors, and their downstream protein genes is the main factor causing individual differences in drug response. The genetic backgrounds among different ethnic groups are quite different. In this study, we aimed to detect the distribution difference of genotype frequency in very important pharmacogenetic (VIP) gene variants in the Lisu.Using the chi-squared test, we compared the genotype frequencies of the VIP variants in 105 Lisu people with those in 26 populations from the 1000 Genome project separately. Bonferroni's multiple adjustment was also conducted (P < .05/(26*49)). Moreover, Arlequin v3.5 and Structure v2.3.4 software were used to analyze the genetic distance and genetic structure.There were 9, 9, 11, 12, 11, 11, 9, 17, 13, 13, 16, 5, 3, 5, 3, 4, 17, 14, 16, 17, 16, 10, 13, 12, 10, and 9 single nucleotide polymorphisms that differed in frequency distribution, when Lisu people compared with the 26 populations separately. Only CYP2E1 rs2070676 was different in the Lisu population compared with the 26 groups from the 1000 Genome project. PTGS2 rs5275 and CYP2D6 rs1065852 were different in the Lisu population compared with most of the populations. Additionally, genetic backgrounds of Lisu and Han Chinese in Beijing were closest according to the lowest F-statistics value and resemblance in genetic structures.Our results complete the information of the Lisu population in pharmacogenomics database.

PMID: 30593137 [PubMed - in process]

The ACCOuNT Consortium: a model for the discovery, translation and implementation of precision medicine in African Americans.

Clin Transl Sci. 2018 Dec 28;:

Authors: Friedman PN, Shaazuddin M, Gong L, Grossman RL, Harralson AF, Klein TE, Lee NH, Miller DC, Nutescu EA, O'Brien TJ, O'Donnell PH, O'Leary KJ, Tuck M, Meltzer DO, Perera MA

Abstract
The majority of pharmacogenomic studies have been conducted on European ancestry populations, thereby excluding minority populations and impeding the discovery and translation of African American specific genetic variation into precision medicine. Without accounting for variants found in African Americans, clinical recommendations based solely on genetic biomarkers found in European populations could result in misclassification of drug response in African Americans patients. To address these challenges, we formed the Transdisciplinary Collaborative Center (TCC), ACCOuNT (African American Cardiovascular Pharmacogenetic Consortium), to discover novel genetic variants in African Americans related to clinically actionable cardiovascular phenotypes and to incorporate African American-specific sequence variations into clinical recommendations at the point of care. The TCC consists of two research projects focused on discovery and translation of genetic findings and four cores that support the projects. In addition, the largest repository of pharmacogenomic information on African Americans is being established as well as lasting infrastructure that can be utilized to spur continued research in this understudied population. This article is protected by copyright. All rights reserved.

PMID: 30592548 [PubMed - as supplied by publisher]

Application of transfer learning for cancer drug sensitivity prediction.

BMC Bioinformatics. 2018 Dec 28;19(Suppl 17):497

Authors: Dhruba SR, Rahman R, Matlock K, Ghosh S, Pal R

Abstract
BACKGROUND: In precision medicine, scarcity of suitable biological data often hinders the design of an appropriate predictive model. In this regard, large scale pharmacogenomics studies, like CCLE and GDSC hold the promise to mitigate the issue. However, one cannot directly employ data from multiple sources together due to the existing distribution shift in data. One way to solve this problem is to utilize the transfer learning methodologies tailored to fit in this specific context.
RESULTS: In this paper, we present two novel approaches for incorporating information from a secondary database for improving the prediction in a target database. The first approach is based on latent variable cost optimization and the second approach considers polynomial mapping between the two databases. Utilizing CCLE and GDSC databases, we illustrate that the proposed approaches accomplish a better prediction of drug sensitivities for different scenarios as compared to the existing approaches.
CONCLUSION: We have compared the performance of the proposed predictive models with database-specific individual models as well as existing transfer learning approaches. We note that our proposed approaches exhibit superior performance compared to the abovementioned alternative techniques for predicting sensitivity for different anti-cancer compounds, particularly the nonlinear mapping model shows the best overall performance.

PMID: 30591023 [PubMed - in process]

Pharmacogenomic clinical decision support design and multi-site process outcomes analysis in the eMERGE Network.

J Am Med Inform Assoc. 2018 Dec 24;:

Authors: Herr TM, Peterson JF, Rasmussen LV, Caraballo PJ, Peissig PL, Starren JB

Abstract
To better understand the real-world effects of pharmacogenomic (PGx) alerts, this study aimed to characterize alert design within the eMERGE Network, and to establish a method for sharing PGx alert response data for aggregate analysis. Seven eMERGE sites submitted design details and established an alert logging data dictionary. Six sites participated in a pilot study, sharing alert response data from their electronic health record systems. PGx alert design varied, with some consensus around the use of active, post-test alerts to convey Clinical Pharmacogenetics Implementation Consortium recommendations. Sites successfully shared response data, with wide variation in acceptance and follow rates. Results reflect the lack of standardization in PGx alert design. Standards and/or larger studies will be necessary to fully understand PGx impact. This study demonstrated a method for sharing PGx alert response data and established that variation in system design is a significant barrier for multi-site analyses.

PMID: 30590574 [PubMed - as supplied by publisher]