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]

[Too early for pharmacogenetics in psychiatric practice].

Tijdschr Psychiatr. 2019;61(5):298-300

Authors: Vinkers CH

Abstract
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PMID: 31180566 [PubMed - in process]

Clinical Use of FSH in Male Infertility.

Front Endocrinol (Lausanne). 2019;10:322

Authors: Behre HM

Abstract
The established clinical indication for FSH use in male infertility is the treatment of patients with hypogonadotropic hypogonadism for stimulation of spermatogenesis that allows the induction of a clinical pregnancy in the female partner and finally the birth of a healthy child. Several clinical studies with urinary, purified, and recombinant FSH preparations in combination with hCG have demonstrated the high treatment efficacy regarding these clinical endpoints. Shortcomings of this hormone therapy are the long duration of treatment, sometimes longer than 2 years, and the inconvenience of injections every second or third day. However, improvements of therapy might be expected with new hormonal treatment options already available for infertility treatment in the female. FSH use for treatment of patients with normogonadotropic idiopathic infertility and oligozoospermia is still considered experimental in most countries. Recent meta-analyses have shown that FSH can significantly increase pregnancy rates in the female partners of these patients, but the effect-size is relatively low. Therefore, predictive factors for treatment success have to be identified, including FSH pharmacogenetics, to select the right normogonadotropic patients with idiopathic infertility for FSH therapy.

PMID: 31178827 [PubMed]

Colchicine Myopathy: A Case Series Including Muscle MRI and ABCB1 Polymorphism Data.

Front Neurol. 2019;10:553

Authors: Gupta M, Nikolic A, Ng D, Martens K, Ebadi H, Chhibber S, Pfeffer G

Abstract
Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.

PMID: 31178824 [PubMed]

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.

Front Pharmacol. 2019;10:520

Authors: García-Menaya JM, Cordobés-Durán C, García-Martín E, Agúndez JAG

Abstract
Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy.

PMID: 31178722 [PubMed]

ECCR1 and NFKB2 Polymorphisms as Potential Biomarkers of Non-small Cell Lung Cancer in a Polish Population.

Anticancer Res. 2019 Jun;39(6):3269-3272

Authors: Chaszczewska-Markowska M, Kosacka M, Chryplewicz A, Dyła T, Brzecka A, Bogunia-Kubik K

Abstract
BACKGROUND/AIM: Although genetic factors are presumed to account only for a part of the inter-individual variation in lung cancer susceptibility, the results are conflicting and there are no data available regarding the Polish population. We, therefore, performed a case-control study to investigate the association of seven selected single nucleotide polymorphisms (SNPs), in genes coding for excision repair cross-complimentary group 1 (ERCC1: rs11615, rs3212986, rs2298881), nuclear factor ĸB (NFKB2: rs7897947, rs12769316), bone morphogenetic protein 4 (BMP4: rs1957860), complement receptor 1 (CR1: rs7525160) and del/ins polymorphism in the family hypoxia inducible factor 2 gene (EGLN2: rs10680577), with non-small cell lung cancer (NSCLC) risk.
MATERIALS AND METHODS: Real-time PCR with melting curve analysis was used for genotyping of NSCLC patients and healthy individuals of Polish origin.
RESULTS: The ERCC1 rs11615 T allele and rs3212986 GG homozygosity were found to be associated with a higher risk of developing NSCLC. In addition, NFKB2 rs12769316 GG homozygosity was more frequently detected among male patients than controls, while no significant differences were found between the five polymorphisms.
CONCLUSION: ERCC1 polymorphisms may affect NSCLC risk in the Polish population, while the NFKB2 variant may be a possible marker of the disease in males.

PMID: 31177178 [PubMed - in process]

Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics.

Life Sci. 2019 Jun 06;:

Authors: Berthier J, Arnion H, Saint-Marcoux F, Picard N

Abstract
MRP4 is an ABC membrane transporter involved in clinical outcomes as it is located in many tissues that manages the transport and the elimination of many drugs. This review explores the implication of MRP4 in clinical pharmacology and the importance of its genetic variability. Although there is no specific recommendation regarding the study of MRP4 in drug development, it should be considered when drugs are eliminated by the kidney or liver or when drug-drug interactions are expected.

PMID: 31176778 [PubMed - as supplied by publisher]

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altering Expression of Hepatocellular Bile Transporters.

Mol Pharmacol. 2019 Jun 07;:

Authors: Sissung TM, Huang PA, Hauke RJ, McCrea EM, Peer CJ, Barbier RH, Strope JD, Ley AM, Zhang M, Hong JA, Venzon D, Jackson JP, Brouwer KR, Grohar P, Glod J, Widemann BC, Heller T, Schrump DS, Figg WD

Abstract
Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (MDR3) rs2302387 and ABCB11 (BSEP) rs4668115 reduce transporter expression (P<0.05) and were associated with mean ≥ Grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25mcg/kg, 6hr/infusion, qdx7, every 28 days; P<0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, NTCP, OST mean α/β) in several cell lines (Huh7, HepaRG, HepaRG BSEP (-/-)) and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P<0.0001), and mithramycin inhibited CDCA- and GW4046-induced FXR-GAL4 luciferase reporter activity (P<0.001). Mithramycin promoted GCDC-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P<0.01). Mithramycin is an FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a mechanism of hepatotoxicity in which an FXR inhibitor causes deregulation of bile homeostasis in liver, which is currently the rationale for a genotype-directed clinical trial using mithramycin (NCT01624090).

PMID: 31175181 [PubMed - as supplied by publisher]

Structural bioinformatics analysis of variants on GPCR function.

Curr Opin Struct Biol. 2019 Jun 04;55:161-177

Authors: Syed Haneef SA, Ranganathan S

Abstract
G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.

PMID: 31174013 [PubMed - as supplied by publisher]

Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids.

Drug Discov Today. 2019 Jun 04;:

Authors: Chen KG, Zhong P, Zheng W, Beekman JM

Abstract
Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.

PMID: 31173911 [PubMed - as supplied by publisher]

Investigation of bidirectional longitudinal associations between advanced epigenetic age and peripheral biomarkers of inflammation and metabolic syndrome.

Aging (Albany NY). 2019 Jun 07;:

Authors: Morrison FG, Logue MW, Guetta R, Maniates H, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Miller MW, Wolf EJ

Abstract
Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. The goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (PTSD) who were assessed over the course of two years. Analyses focused on two commonly investigated metrics of advanced DNAm age derived from the Horvath (developed across multiple tissue types) and Hannum (developed in whole blood) DNAm age algorithms. Results of cross-lagged panel models revealed that advanced Hannum DNAm age at Time 1 (T1) was associated with increased (i.e., accounting for T1 levels) metabolic syndrome (MetS) severity at Time 2 (T2; p = < 0.001). This association was specific to worsening lipid panels and indicators of abdominal obesity (p = 0.001). In contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. No associations emerged between advanced Horvath DNAm age and any of the examined biological parameters. Results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. This carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.

PMID: 31173577 [PubMed - as supplied by publisher]

Three-Dimensional Spheroid Primary Human Hepatocytes in Monoculture and Coculture with Nonparenchymal Cells.

Tissue Eng Part C Methods. 2018 09;24(9):534-545

Authors: Baze A, Parmentier C, Hendriks DFG, Hurrell T, Heyd B, Bachellier P, Schuster C, Ingelman-Sundberg M, Richert L

Abstract
Recent advances in the development of various culture platforms are promising for achieving more physiologically relevant in vitro hepatic models using primary human hepatocytes (PHHs). Previous studies have shown the value of PHHs three-dimensional (3D) spheroid models, cultured in low cell number (1330-2000 cells/3D spheroid), to study long-term liver function as well as pharmacological drug effects and toxicity. In this study, we report that only plateable PHHs aggregate and form compact 3D spheroids with a success rate of 79%, and 96% reproducibility. Out of 3D spheroid forming PHH lots, 65% were considered stable (<50% ATP decrease) over the subsequent 14 days of culture, with reproducibility of a given PHH lot being 82%. We also report successful coculturing of PHHs with human liver nonparenchymal cells (NPCs). Crude P1c-NPC fractions were obtained by low centrifugation of the PHH supernatant fraction followed by a few days of culture before harvesting and cryopreservation. At aggregation of PHHs/P1c-NPCs (2:1 ratio 3D spheroids), liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells were successfully integrated and remained present throughout the subsequent 14-day culture period as revealed by mRNA expression markers and immunostaining. Increased mRNA expression of albumin (ALB), apolipoprotein B (APOB), cytochrome P450 3A4 (CYP3A4), and increased albumin secretion compared to PHH 3D spheroid monocultures highlighted that in a 3D spheroid coculture, configuration with NPCs, PHH functionality is increased. We thus achieved the development of a more integrated coculture model system requiring low cell numbers, of particular interest due to the scarcity of human liver NPCs.

PMID: 30101670 [PubMed - indexed for MEDLINE]

CYP2C19 pharmacogenetics in patients undergoing coronary stent placement: Is it time to test everyone?

Catheter Cardiovasc Interv. 2019 Jun 01;93(7):1253-1254

Authors: Price DJ, Levy MS

Abstract
Although there are no current guidelines for when to test patients for CYP2C19 loss of function alleles, the current state of evidence suggests that testing high-risk patients should be considered. Based on this meta-analysis, there is no reduction in major adverse cardiovascular events (MACE) in patients that receive genotype-guided antiplatelet therapy, but there is a significant reduction in MACE when including only patients who present with acute coronary syndromes and a significant reduction in myocardial infarction. Genotype-guided therapy shows promise but requires further study to solidify this approach, and to determine which patients derive the most benefit.

PMID: 31172678 [PubMed - in process]