Identification of Novel Pathways in Idelalisib Metabolism and Bioactivation.

Chem Res Toxicol. 2018 07 16;31(7):548-555

Authors: Zhu J, Wang P, Shehu AI, Lu J, Bi H, Ma X

Abstract
Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity, and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine, and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB. Identification of ILB-GSH adduct (M2) suggests the formation of reactive metabolites of ILB. We also found that M1 can produce reactive metabolites and form M1-GSH adducts. The GSH-conjugates identified in mouse liver were also found in the incubations of ILB and M1 with human liver microsomes. Furthermore, we illustrated that CYP3A4 and 2C9 are the key enzymes contributing to the bioactivation pathway of ILB and M1. In summary, our work revealed that both ILB and its major metabolite M1 can undergo bioactivation to produce reactive metabolites in the liver. Further studies are required to determine whether these metabolic pathways contribute to ILB hepatotoxicity.

PMID: 29896955 [PubMed - indexed for MEDLINE]

Combination of PARP inhibitor and temozolomide to suppress chordoma progression.

J Mol Med (Berl). 2019 Jun 14;:

Authors: Cao X, Lu Y, Liu Y, Zhou Y, Song H, Zhang W, Davis D, Cui J, Hao S, Jung J, Wu Q, Park DM, Yang C

Abstract
Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma. KEY MESSAGES: The PARP DNA repair pathway enhances chemoresistance in chordoma cells. Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity. PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.

PMID: 31201471 [PubMed - as supplied by publisher]

LC-MS-based lipid profile in colorectal cancer patients: TAGs are the main disturbed lipid markers of colorectal cancer progression.

Anal Bioanal Chem. 2019 Jun 14;:

Authors: Liu T, Peng F, Yu J, Tan Z, Rao T, Chen Y, Wang Y, Liu Z, Zhou H, Peng J

Abstract
Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide. Emerging evidence has shown that lipid metabolism plays important roles in the occurrence and progression of CRC. The identification of potential biomarkers for CRC progression is critical for precise diagnosis and treatment. Therefore, the aim of this study is to explore the potential lipid markers in relation to CRC progression. The plasma of patients with stage I/II CRC (n = 20) and stage III/IV CRC (n = 20) was collected. Lipidomic screening was performed by ultrahigh-performance liquid chromatography-mass spectrometry. After multivariate data analysis, including orthogonal partial least squares discriminant analysis, determination of the fold change, and the Mann-Whitney U test, eight lipid species with altered levels with p < 0.05 and fold change greater than 2 were selected as potential lipid biomarkers. Compared with patients with early-stage CRC, patients with advanced-stage CRC showed significantly higher levels of cholesteryl ester (20:4) and some triglycerides with a saturated fatty acid chain and a lower level of fatty acid ester of hydroxy fatty acid 27:1 (9:0-18:1) in plasma. Furthermore, the receiver operating characteristic including these potential lipid biomarkers yielded a sensitivity of 85% and specificity of 80% for separation of early-stage CRC patients from advanced-stage CRC patients. In all, this is the first report showing that the levels of triglycerides, the major contents of lipid droplets, increase in plasma of advanced-stage CRC patients compared with early-stage CRC patients. These data indicate that lipid droplets may be target organelles for the study of CRC progression and treatment. Graphical abstract.

PMID: 31201454 [PubMed - as supplied by publisher]

NO2 functionalized coumarin derivatives suppress cancer progression and facilitate apoptotic cell death in KRAS mutant colon cancer.

Chem Biol Interact. 2019 Jun 11;:

Authors: Lin MH, Wang JS, Hsieh YC, Zheng JH, Cho EC

Abstract
Colon cancer is one of the most lethal cancers worldwide even with the significant progress made in screening techniques and therapeutic agents. Genetic mutations in tumors complicated the treatments, and the survival rate remains low for patients at late or metastatic stages. KRAS gene mutation which leads to failure of the EGFR targeted therapies stands for an example of the challenges in clinical sites. Therefore, development of novel agents for colon cancer treatment is in need. Natural and synthetic coumarin derivatives have been suggested with various biological activities with pharmacologic potential including anti-cancer capacity. Here in this study, five coumarin derivatives, include trifluoromethyl-, dimethoxy-, and/or nitro-substitutions at different positions, were synthesized. Their cancer inhibition potential was investigated in various cancer cell lines. Our data demonstrated that one nitro-coumarin derivate, 5,7-Dimethoxy-4-methyl-6-nitro-chromen-2-one, exhibits cytotoxicity specifically towards colon cancer cells under competitive EC50. Our results showed that this compound can effectively suppress colon cancer cells harboring either wild type or mutant KRAS genes, and that it could inhibit short-term proliferation, long term proliferation, and migration capacities of cancer cells. Finally, we demonstrated that this coumarin derivate facilitates cancer cell death through activation of apoptosis pathway. Our results suggest that this coumarin derivate is a promising lead drug worth further investigation and development for future cancer treatment.

PMID: 31199928 [PubMed - as supplied by publisher]

A New Approach to Measure Adherence to Medicines Using Biomarkers and Sensors.

OMICS. 2019 Jun 14;:

Authors: Özdemir V, Endrenyi L

Abstract
Approximately one in two patients with a chronic disease does not take their medicines as prescribed. Poor adherence is a worldwide epidemic and a major source of variability in pharmacokinetics (PK) and pharmacodynamics. Without addressing adherence, precision medicine is unlikely to come to fruition. In drug development, poor adherence confounds the estimates for efficacy and safety of drug candidates. Accurate and high-resolution measurement of adherence is a first step toward effective interventions against poor adherence. We describe a new cross-technology platform to measure adherence. The approach involves, first, building PK models to explain dose-exposure relationships. The model incorporates PK biomarkers by genotyping or phenotyping of drug metabolism, transport and other drug clearance pathways. Importantly, dose-exposure data for model building are obtained in healthy volunteer and/or patient cohorts who are ascertained for full adherence, using edible ingestion sensors (IS) that digitize orally administered medicines. Second, the built model is harnessed to back calculate the dose actually ingested by patients, given the empirically observed drug exposure, PK biomarker, demographic, and other patient data. The proposed platform is envisioned to result in development of both drug and drug-specific companion software for adherence measurement. In terms of feasibility, the new approach overlaps with current drug development timelines spanning the Phase 1 to 4 clinical trial continuum, and thus, could conceivably be implemented without requiring significant changes to the time sensitive clinical trial processes. For the IS-powered tools, the proposed platform creates a new space for applications in clinical trials to ensure adherence.

PMID: 31199695 [PubMed - as supplied by publisher]

Are Global Health Systems Ready for Transformative Therapies?

Value Health. 2019 Jun;22(6):627-641

Authors: Faulkner E, Spinner DS, Ringo M, Carroll M

Abstract
BACKGROUND: We have seen significant advancement in a range of health technologies, some with transformative or curative potential. Nevertheless, it is often unclear how global health systems recognize or reward innovation.
OBJECTIVES: To consider what is transformative, challenges for transformative therapies, and downstream health ecosystem effects.
METHODS: A systematic review of publications in English between 2012 and 2018 was conducted with a focus on value assessment processes and health system effects of a range of breakthrough health technology categories. After screening 9012 records, 222 unique studies were identified. The study also included an analysis of 100 health technology assessments (HTAs) from 5 markets to consider how and in what ways global HTA bodies evaluate transformative therapies. Global sales and technology/procedure utilization data were also evaluated to gain insights into patient access and commercial impact.
RESULTS: This article evaluated uncertainties around evidence of efficacy, safety, and duration of effect, as well as underlying study quality and methodological considerations in the target categories. Although many HTA evaluations had similar approaches to assessing parameters such as safety, there were significant differences across technology categories. Technology-driven trends also surfaced where global HTA and payer systems may not yet be prepared to recognize and reward emerging technology impacts, including use of next-generation diagnostic results to guide care, considering novel impacts on therapy sequencing and clinical pathway management, and changes in payment and health delivery models.
CONCLUSIONS: Some trends stemming from rapid evolution of breakthrough therapies will prompt reconsideration of our conventional value assessment and reward models, because health system measurement and management processes have not fully anticipated their effects.

PMID: 31198179 [PubMed - in process]

Circular RNA screening from EIF3a in lung cancer.

Cancer Med. 2019 Jun 13;:

Authors: Huang MS, Yuan FQ, Gao Y, Liu JY, Chen YX, Wang CJ, He BM, Zhou HH, Liu ZQ

Abstract
Eukaryotic initiation factor 3 (EIF3) is one of the largest and most complex translation initiation factors, which consists of 13 subunits named eukaryotic translation initiation factor 3 subunit A (EIF3a) to EIF3m. EIF3a is the largest subunit of EIF3. Previous studies suggested that EIF3a is a housekeeping gene, recent results have found that EIF3a is closely related to the tumorigenesis and drug resistance. Circular RNAs (circRNAs) derived from biologically important gene can play an important role in gene regulation. However, the mechanism underlying circRNAs' biological functions is not well understood yet. In this work, we screened 31 EIF3a-derived circRNAs, in which two circEIF3as were identified to be correlated with cisplatin drug sensitivity in lung cancer. Two circEIF3as were found involved in RNA-binding proteins-mediated biological processes and may be related to translational regulation according to bioinformatics analyses. CircEIF3as, the transcriptional initiation factor EIF3a transcribed circRNAs, are associated with both drug sensitivity and translation regulation. These findings mean that they may have a functional synergy effect with EIF3a or be valuable therapeutic targets for treatment like EIF3a. This is the first study that exploits circRNAs screening from EIF3a in lung cancer, our findings provide a novel perspective on the function of EIF3a and circEIF3as in lung cancer.

PMID: 31197975 [PubMed - as supplied by publisher]

Estimated nationwide impact of implementing a preemptive pharmacogenetic panel approach to guide drug prescribing in primary care in The Netherlands.

BMC Med. 2019 Jun 14;17(1):110

Authors: Bank PCD, Swen JJ, Guchelaar HJ

Abstract
BACKGROUND: Pharmacogenetics (PGx) is currently implemented in hospitals to optimize therapy with high-risk drugs. However, many drugs with dosing recommendations from the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium are used in primary care. Actionable phenotypes for the genes covered in these guidelines are common with estimates ranging from 85 to 95% of the population carrying at least one actionable phenotype. The goal of this study was to estimate the clinical impact of implementation of an upfront panel-based pharmacogenetic screening for eight genes related to drugs used in primary care for 2016.
METHODS: For this study, dispensing data concerning first prescription for the period January 1-December 31, 2016, were combined with frequency data obtained in the "Implementation of Pharmacogenetics into Primary Care Project" (IP3) study to estimate the occurrence of actionable gene-drug pairs in daily practice in community pharmacies.
RESULTS: In 23.6% of all new prescriptions of 45 drugs (n = 856,002 new prescriptions/year), an actionable gene-drug interaction (GDI) was present according to the guidelines of the Dutch Pharmacogenetics Working Group. More importantly, these GDIs would result in a dose adjustment or switch to another drug in 5.4% of all new prescriptions.
CONCLUSIONS: Consequently, with an anticipated near future where healthcare professionals will be regularly confronted with PGx test results, adjusting pharmacotherapy based on this information will become a routine task in healthcare.

PMID: 31196067 [PubMed - in process]

Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aβ deposition.

J Pharmacol Sci. 2019 Mar;139(3):223-230

Authors: Zong W, Zeng X, Chen S, Chen L, Zhou L, Wang X, Gao Q, Zeng G, Hu K, Ouyang D

Abstract
Ginsenoside compound K (CK) is the main metabolite of protopanaxadiol-type ginsenosides and has been demonstrated to exert neuroprotective and cognition-enhancing effects. The effects of CK on cognitive function in vascular dementia (VD) has not been elucidated. Therefore, the present study aims to elucidate the effects of CK on memory function as well as its potential mechanism in VD rats. Sprague-Dawley rats were subjected to Chronic Cerebral Hypoperfusion (CCH) by permanent bilateral common carotid artery occlusion (2VO). CCH induced neuronal damage and aggravated the aggregation of Amyloid-β1-42 peptides (Aβ1-42), which plays a critical role in the neurotoxicity and cognitive impairment. CK treatment attenuated CCH-induced Aβ1-42 deposition and ameliorated cognition impairment. Furthermore, CK enhanced the activity of the pSer9-Glycogen synthase kinase 3β (pSer9-GSK3β) and the insulin degrading enzyme (IDE), which mainly involved the production and clearance of Aβ1-42. Moreover, CK treatment enhanced the activity of protein kinase B (PKB/Akt), a key kinase in phosphatidylinositol 3 kinase (PI3K)/Akt pathway that can regulate the activity of GSK-3β and IDE. In short, our findings provide the first evidence that CK might attenuate cognitive deficits and Aβ1-42 deposition in the hippocampus via enhancing the expression of pSer9-GSK-3β and IDE.

PMID: 30799178 [PubMed - indexed for MEDLINE]

Regulation of brain drug metabolizing enzymes and transporters by nuclear receptors.

Drug Metab Rev. 2018 11;50(4):407-414

Authors: Xu D, Huang S, Wang H, Xie W

Abstract
Nuclear receptors (NRs) belong to a family of ligand-dependent transcription factors. The target genes of NRs include many drug metabolizing enzymes and transporters. The central nervous system (CNS) bears the expression of NRs, drug metabolizing enzymes and transporters. NRs that express in the brain can be divided into three groups according to their characteristics of ligand binding: steroid hormone receptors, non-steroid hormone receptors, and orphan receptors. The NR-mediated regulation of drug metabolizing enzymes and transporters plays important roles in the metabolism and disposition of drugs in the CNS and the penetration of endogenous and exogenous substances through the blood-brain barrier (BBB). NR-mediated regulation of drug metabolizing enzymes and transporters can cause the toxicological effects of xenobiotics in the CNS and also lead to drug resistance in the centrum. The regulatory pathways of drug metabolizing enzymes and transporters can provide new strategies for selective regulation of the BBB permeability and drug metabolism in the brain. This review focuses on the importance of NR-mediated regulation of drug metabolizing enzymes and transporters in the CNS and the implications of this regulation in the therapeutic effect of CNS drugs and CNS side effects of drugs and other xenotoxicants.

PMID: 30501435 [PubMed - indexed for MEDLINE]

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Brain Volume-Related Polymorphisms of the Glycogen Synthase Kinase-3β Gene and Their Effect on Antidepressant Treatment in Major Depressive Disorder.

Neuropsychobiology. 2019 Jun 12;:1-9

Authors: Sunada N, Takekita Y, Nonen S, Wakeno M, Koshikawa Y, Ogata H, Kinoshita T, Kato M

Abstract
BACKGROUND: Glycogen synthase kinase-3β (GSK-3β) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3β gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown.
OBJECTIVES: In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3β gene and antidepressant treatment effects in patients with MDD.
METHODS: Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3β gene (rs6438552 and rs12630592) that influence brain volume in the hippocampus were genotyped. For the primary outcome, the relationship between genetic variations in the SNPs and the percent change in the Hamilton Rating Scale for Depression (HAM-D) score at week 6 was examined. In addition, rs334558, which has been reported repeatedly, was also genotyped.
RESULTS: There was a significant correlation between the two SNPs and the percent change in the HAM-D scores at week 6 (rs6438552 A/A vs. A/G + G/G: p = 0.016; rs12630592 G/G vs. G/T + T/T: p = 0.016). There was high linkage disequilibrium between the rs6438552 and rs12630592 SNPs. The correlation between high therapeutic response over time and the two SNPs were also confirmed (rs6438552 A/A vs. others: p = 0.031; rs12630592 G/G vs. others: p = 0.031).
CONCLUSIONS: Our results suggest that two GSK-3β variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.

PMID: 31189175 [PubMed - as supplied by publisher]

Generic Cost-Effectiveness Models: A Proof of Concept of a Tool for Informed Decision-Making for Public Health Precision Medicine.

Public Health Genomics. 2019 Jun 12;:1-11

Authors: Snyder SR, Hao J, Cavallari LH, Geng Z, Elsey A, Johnson JA, Mohamed Z, Chaiyakunapruk N, Chong HY, Dahlui M, Shabaruddin FH, Patrinos GP, Mitropoulou C, Williams MS

Abstract
BACKGROUND/AIMS: Economic evaluation is integral to informed public health decision-making in the rapidly growing field of precision and personalized medicine (PM); however, this research requires specialized expertise and significant resources. Generic models are a novel innovation to efficiently address a critical PM evidence shortage and implementation barrier by enabling use of population-specific input values. This is a generic PM economic evaluation model proof-of-concept study for a pharmacogenomic use case.
METHODS: An 8-step generic economic model development process was applied to the use case of human leukocyte antigen (HLA)-B*15:02genotyping for prediction of carbamazepine-induced cutaneous reactions, with a user-friendly decision-making tool relying on user-provided input values. This generic model was transparently documented and validated, including cross-validation comparing cost-effectiveness results with 3 country-specific models.
RESULTS: A generic pharmacogenomic use case cost-effectiveness model with decision-making tool was successfully developed and cross-validated using input values for 6 populations which produced consistent results for HLA-B*15:02 screening at country-specific cost-effectiveness threshold values. Differences between the generic and country-specific model results were largely due to differences in model structure and assumptions.
CONCLUSION: This proof on concept demonstrates the feasibility of generic models to provide useful PM economic evidence, supporting their use as a pragmatic and timely approach to address a growing need.

PMID: 31189173 [PubMed - as supplied by publisher]

Appropriateness of repetitive therapeutic drug monitoring and laboratory turnaround time.

Clin Chem Lab Med. 2019 Jun 08;:

Authors: Sarli V, Ciofi L, Lastella M, Muscatello B, Pisaturo F, Paolilli O, Luci G, Cucchiara F, Pellegrini G, Bocci G, Danesi R, Di Paolo A

PMID: 31188753 [PubMed - as supplied by publisher]

Pharmacogenetics of Metformin for Medication-Induced Weight Gain in Autism Spectrum Disorder.

J Child Adolesc Psychopharmacol. 2019 Jun 12;:

Authors: Garfunkel D, Anagnostou EA, Aman MG, Handen BL, Sanders KB, Macklin EA, Chan J, Veenstra-VanderWeele J

Abstract
Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM, SLC2A2, MATE1, MATE2, and OCT1. Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

PMID: 31188026 [PubMed - as supplied by publisher]

Population study of thrombophilic markers and pharmacogenetic markers of warfarin prevalence in Bosnia and Herzegovina.

Croat Med J. 2019 Jun 13;60(3):212-220

Authors: Ašić A, Salazar R, Storm N, Doğan S, Höppner W, Marjanović D, Primorac D

Abstract
AIM: To investigate the prevalence of common genetic variants that can serve as markers of thrombophilia and warfarin pharmacogenetics in Bosnia and Herzegovina.
METHODS: The study was performed between August and October 2017 on 130 healthy unrelated adult volunteers from Bosnian-Herzegovinian population sample. The prevalence of the following genetic variants was determined: F5 c.1601G>A (factor V Leiden), F2 c.*97G>A (factor II or prothrombin mutation), F13A1 (factor XIII) c.103G>T, MTHFR (methylenetetrahydrofolate reductase) c.665C>T and c.1286A>C, as well as PAI-1 (plasminogen activator inhibitor 1) c.-816A>G and c.-844G>A as markers of thrombophilia risk, and *2 and *3 alleles of CYP2C9 (cytochrome P450 2C9) and five variants of VKORC1 (vitamin K epoxide reductase complex subunit 1) as markers of warfarin pharmacogenetics. DNA was isolated from buccal swabs using salting out method, while genotyping was performed using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry.
RESULTS: Minor allele frequencies for two main thrombophilia risk factors, F5 c.1601G>A and F2 c.*97G>A were 0.023 and 0.008, respectively. Combined data for the markers of warfarin pharmacogenetics imply that 57.4% study participants can be expected to metabolize warfarin at an extensive, 40.3% at intermediate, and 2.3% at a poor rate.
CONCLUSION: This study reports the first extensive population genetic data for thrombophilia and warfarin pharmacogenetic markers in Bosnia and Herzegovina. Allele frequencies of genetic variants are within the general average for European populations, and their presence implies the necessity of introduction of personalized medicine in warfarin-mediated antithrombotic therapy.

PMID: 31187948 [PubMed - in process]

The Potential Role of Genomic Medicine in the Therapeutic Management of Rheumatoid Arthritis.

J Clin Med. 2019 Jun 10;8(6):

Authors: Acosta-Herrera M, González-Serna D, Martín J

Abstract
During the last decade, important advances have occurred regarding understanding of the pathogenesis and treatment of rheumatoid arthritis (RA). Nevertheless, response to treatment is not universal, and choosing among different therapies is currently based on a trial and error approach. The specific patient's genetic background influences the response to therapy for many drugs: In this sense, genomic studies on RA have produced promising insights that could help us find an effective therapy for each patient. On the other hand, despite the great knowledge generated regarding the genetics of RA, most of the investigations performed to date have focused on identifying common variants associated with RA, which cannot explain the complete heritability of the disease. In this regard, rare variants could also contribute to this missing heritability as well as act as biomarkers that help in choosing the right therapy. In the present article, different aspects of genetics in the pathogenesis and treatment of RA are reviewed, from large-scale genomic studies to specific rare variant analyses. We also discuss the shared genetic architecture existing among autoimmune diseases and its implications for RA therapy, such as drug repositioning.

PMID: 31185701 [PubMed]

GenPipes: an open-source framework for distributed and scalable genomic analyses.

Gigascience. 2019 Jun 01;8(6):

Authors: Bourgey M, Dali R, Eveleigh R, Chen KC, Letourneau L, Fillon J, Michaud M, Caron M, Sandoval J, Lefebvre F, Leveque G, Mercier E, Bujold D, Marquis P, Van PT, Anderson de Lima Morais D, Tremblay J, Shao X, Henrion E, Gonzalez E, Quirion PO, Caron B, Bourque G

Abstract
BACKGROUND: With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing.
FINDINGS: Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for high-performance computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA sequencing, chromatin immunoprecipitation sequencing, DNA sequencing, methylation sequencing, Hi-C, capture Hi-C, metagenomics, and Pacific Biosciences long-read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has already been configured on several servers, and a Docker image is also available to facilitate additional installations.
CONCLUSIONS: GenPipes offers genomics researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.

PMID: 31185495 [PubMed - in process]

[Genetic and non-genetic factors of laboratory resistance to clopidogrel in patients with ischemic stroke].

Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(3. Vyp. 2):45-52

Authors: Sychev DA, Shprakh VV, Kitaeva EY, Mirzaev KB, Mickhalevich IM

Abstract
To identify clinical and pharmacogenetic predictors of the efficacy of clopidogrel in patients with AI based on CYP2C19 and ABCB1 genotyping. MATERIAL AND METHODS: Clinical and laboratory examinations were performed in 121 patients with AI, and CYP2C19 polymorphisms (CYP2C19*2 (G681A, rs4244285), CYP2C19*3 (G363A, rs4986893), CYP2C19*17 (C806T, rs12248560), ABCB1 (C3435T, rs1045642), associated with a disturbance of antiplatelet action of clopidogrel. The carriage of polymorphic markers of the studied genes was determined by the method of polymerase chain reaction in real time. RESULTS AND CONCLUSION: In the group with laboratory resistance to clopidogrel, women prevailed (p<0.0001), atherothrombotic subtype was 80% (p=0.0384), the frequency of obesity ischemic stroke was 60% (p<0.0001). Univariate analysis of variance of CYP2C19 polymorphisms CYP2C19 (CYP2C19*2 (G681A, rs4244285), CYP2C19*3 (G363A, rs4986893), CYP2C19*17 (C806T, rs12248560), ABCB1 (C3435T, rs1045642) in patients with ischemic stroke, demonstrated a significant effect of CYP2C19 genotypes on the indicators of residual reactivity of platelets.

PMID: 31184624 [PubMed - in process]

UPLC/MS/MS assay for the simultaneous determination of seven antibiotics in human serum-Application to pediatric studies.

J Pharm Biomed Anal. 2019 Mar 07;174:256-262

Authors: Magréault S, Leroux S, Touati J, Storme T, Jacqz-Aigrain E

Abstract
A rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed for quantification of 7 antibiotics in low sample volumes (50 μL): amoxicillin, azithromycin, cefotaxime, ciprofloxacin, meropenem, metronidazole and piperacillin, for both routine monitoring and pharmacokinetic studies. After protein precipitation by acetonitrile, the antibiotics were separated on an Acquity UPLC HSS T3 column (run time, 4 min). The mobile phase consisted of a mixture of (A) ammonium acetate (pH 2.4; 5 mM) and (B) acetonitrile acidified with 0.1% formic acid, delivered at 500 μl/min in a gradient elution mode. Total time run was 2.75 min. Ions were detected in the turbo-ion-spray-positive and multiple-reaction-monitoring modes. The assay was accurate and reproductible for the quantification of the seven antibiotics in serum samples over large concentration ranges.

PMID: 31181488 [PubMed - as supplied by publisher]