Pharmacogenomics
Significance of Pharmacogenomics in Precision Medicine.
Significance of Pharmacogenomics in Precision Medicine.
Clin Pharmacol Ther. 2018 May;103(5):732-735
Authors: Cascorbi I
Abstract
Precision medicine-a term widely used in modern medicine-emphasizes the goal to overcome still existing limitations of therapeutic interventions by tailoring medical treatments to individual patient characteristics. Pharmacogenetics was one of the first scientific approaches taking molecular biomarkers into consideration of diagnostics and therapeutic decisions. This issue of Clinical Pharmacology & Therapeutics on the significance of pharmacogenomics inprecision medicine discusses the ongoing challenges on different levels. Access and usage of clinical biobanks, gain of specific information of medication from electronic health records, and tools to combine clinical and molecular information in order to develop advanced clinical decision support are subjects of numerous research initiatives. Implementation in clinical routine, however, remains the subject of evaluation of clinical- and cost-effectiveness, so far.
PMID: 29660122 [PubMed - in process]
Androgen receptor‑mediated upregulation of quaking affects androgen receptor‑related prostate cancer development and anti‑androgen receptor therapy.
Androgen receptor‑mediated upregulation of quaking affects androgen receptor‑related prostate cancer development and anti‑androgen receptor therapy.
Mol Med Rep. 2018 Apr 13;:
Authors: Zhang K, Yan F, Lei X, Wei D, Lu H, Zhu Z, Xiang A, Ye Z, Wang L, Zheng W, Li X, Yuan J, Lu Z, Yuan J
Abstract
The androgen receptor (AR) has a crucial role in prostate cancer. RNA‑binding protein‑mediated post‑transcriptional regulation is important in the initiation and development of cancer. The present study attempted to elucidate the mutual association of AR and RNA‑binding protein quaking (QKI) in the development of prostate cancer. Dual‑luciferase reporter demonstrated that AR can positively regulate the expression of QKI in prostate cancer cell lines due to its effective transcription regulating function. In addition, QKI may increase expression of AR by heat shock protein 90, which is a coactivator of AR, and silencing QKI can increase the sensitive of Casodex, which is an antagonist of AR in castration‑resistant prostate cancer. This may be a new strategy for advanced prostate cancer.
PMID: 29658587 [PubMed - as supplied by publisher]
Dynamic Biomarkers of Response to Antiangiogenic Therapies in Colorectal Cancer: A Review.
Dynamic Biomarkers of Response to Antiangiogenic Therapies in Colorectal Cancer: A Review.
Curr Pharmacogenomics Person Med. 2017 Dec;15(2):81-85
Authors: Rodriguez-Pascual J, Cubillo A
Abstract
Background: Identification of clinical and molecular biomarkers to predict dynamic response or monitor in real-time the efficacy of antiangiogenic therapy represents a major point in the treatment of patients with advanced colorectal cancer. Several stu-dies have been conduced to identify some predictive biomarkers to select patients who will benefit from bevacizumab, the most widely used antiangiogenic monoclonal anti-body.
Conclusion: After a decade since the introduction of bevacizumab, no effective predictive biomarkers are available in routine clinical practice. In this review, we summarized the potential candidate dynamic biomarkers that may play a role in this setting.
PMID: 29657584 [PubMed]
Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress.
Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress.
Cancer Cell. 2018 Apr 03;:
Authors: Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, Wong DJL, Atefi M, Shirazi R, Wang X, Braas D, Grasso CS, Palaskas N, Ribas A, Graeber TG
Abstract
Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.
PMID: 29657129 [PubMed - as supplied by publisher]
Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.
Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.
Methods. 2017 Jul 01;123:102-118
Authors: Higgins GA, Allyn-Feuer A, Georgoff P, Nikolian V, Alam HB, Athey BD
Abstract
The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.
PMID: 28385536 [PubMed - indexed for MEDLINE]
IMPDH Pharmacogenetics in Hematopoietic Cell Transplantation Patients.
IMPDH Pharmacogenetics in Hematopoietic Cell Transplantation Patients.
Biol Blood Marrow Transplant. 2018 Apr 12;:
Authors: McCune JS, Storer B, Thomas S, McKiernan J, Gupta R, Sandmaier BM
Abstract
We evaluated inosine monophosphate dehydrogenase (IMPDH) 1 and IMPDH2 pharmacogenetics in 247 recipient-donor pairs after nonmyeloablative hematopoietic cell transplant (HCT) recipients. Patients were conditioned with total body irradiation + fludarabine, received grafts from related or unrelated donors (10% HLA mismatch), with post-graft immunosuppression of mycophenolate mofetil (MMF) with a calcineurin inhibitor. Recipient and donor IMPDH genotype (rs11706052, rs2278294, rs2278293) were not associated with day 28 T-cell chimerism, acute graft versus host disease, disease relapse, cytomegalovirus reactivation, non-relapse mortality, or overall survival. Recipient IMPDH1 rs2278293 genotype was associated with a lower incidence of chronic graft-versus-host disease (GVHD) (hazard ratio of 0.72, p=0.008) in nonmyeloablative HCT recipients. Additional studies are needed to confirm these results with the goal of identifying predictive biomarkers to MMF that lower GVHD.
PMID: 29656138 [PubMed - as supplied by publisher]
Genetic Testing in Clinical Settings.
Genetic Testing in Clinical Settings.
Am J Kidney Dis. 2018 Apr 11;:
Authors: Franceschini N, Frick A, Kopp JB
Abstract
Genetic testing is used for screening, diagnosis, and prognosis of diseases consistent with a genetic cause and to guide drug therapy to improve drug efficacy and avoid adverse effects (pharmacogenomics). This In Practice review aims to inform about DNA-related genetic test availability, interpretation, and recommended clinical actions based on results using evidence from clinical guidelines, when available. We discuss challenges that limit the widespread use of genetic information in the clinical care setting, including a small number of actionable genetic variants with strong evidence of clinical validity and utility, and the need for improving the health literacy of health care providers and the public, including for direct-to-consumer tests. Ethical, legal, and social issues and incidental findings also need to be addressed. Because our understanding of genetic factors associated with disease and drug response is rapidly increasing and new genetic tests are being developed that could be adopted by clinicians in the short term, we also provide extensive resources for information and education on genetic testing.
PMID: 29655499 [PubMed - as supplied by publisher]
Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC).
Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC).
Am Heart J. 2018 Apr;198:152-159
Authors: Bergmeijer TO, Reny JL, Pakyz RE, Gong L, Lewis JP, Kim EY, Aradi D, Fernandez-Cadenas I, Horenstein RB, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim HS, Déry JP, Gawaz M, Bliden K, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen MS, Shin JG, Simon T, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Hulot JS, Mitchell BD, Schwab M, Ritchie MD, Klein TE, Shuldiner AR, ICPC Investigators
Abstract
RATIONALE: The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.
STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.
RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40).
CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.
PMID: 29653637 [PubMed - in process]
Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Call for Optimum Patient Stratification and Theranostics via Pharmacogenomics.
Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Call for Optimum Patient Stratification and Theranostics via Pharmacogenomics.
Annu Rev Genomics Hum Genet. 2018 Apr 13;:
Authors: Sukasem C, Katsila T, Tempark T, Patrinos GP, Chantratita W
Abstract
The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions. This review focuses on the current understanding of the surveillance, pathogenesis, and treatment of SJS/TEN, including the role of genomics and pharmacogenomics in the etiology, treatment, and eradication of preventable causes of drug-induced SJS/TEN. Gaps, unmet needs, and priorities for future research have been identified for the optimal management of drug-induced SJS/TEN in various ethnic populations. Pharmacogenomics holds great promise for optimal patient stratification and theranostics, yet its clinical implementation needs to be cost-effective and sustainable. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
PMID: 29652519 [PubMed - as supplied by publisher]
A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.
A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.
Mol Diagn Ther. 2018 Apr 12;:
Authors: Mitchell D, Guertin JR, Dubois A, Dubé MP, Tardif JC, Iliza AC, Fanton-Aita F, Matteau A, LeLorier J
Abstract
BACKGROUND: Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown.
METHODS: We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters.
RESULTS: Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations.
CONCLUSION: We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.
PMID: 29651791 [PubMed - as supplied by publisher]
Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples.
Identification of Common Genes Refers to Colorectal Carcinogenesis with Paired Cancer and Noncancer Samples.
Dis Markers. 2018;2018:3452739
Authors: Zhang L, Yang Y, Cheng L, Cheng Y, Zhou HH, Tan ZR
Abstract
Colorectal cancer is a malignant tumor which harmed human beings' health. The aim of this study was to explore common biomarkers associated with colorectal carcinogenesis in paired cancer and noncancer samples. At first, fifty-nine pairs of colorectal cancer and noncancer samples from three gene expression datasets were collected and analyzed. Then, 181 upregulation and 282 downregulation common differential expression genes (DEGs) were found. Next, functional annotation was performed in the DAVID database with the DEGs. Finally, real-time polymerase chain reaction (PCR) assay was conducted to verify the analyses in sixteen colorectal cancer and individual-matched adjacent mucosa samples. Real-time PCR showed that MCM2, RNASEH2A, and TOP2A were upregulated in colorectal cancer compared with adjacent mucosa samples (MCM2, P < 0.001; RNASEH2A, P < 0.001; TOP2A, P = 0.001). These suggested that 463 DEGs might contribute to colorectal carcinogenesis.
PMID: 29651323 [PubMed - in process]
Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes.
Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes.
Diabetes. 2018 Apr 12;:
Authors: Rotroff DM, Yee SW, Zhou K, Marvel SW, Shah HS, Jack JR, Havener TM, Hedderson MM, Kubo M, Herman MA, Gao H, Mychaleckyi JC, McLeod HL, Doria A, Giacomini KM, Pearson ER, Wagner MJ, Buse JB, Motsinger-Reif AA, MetGen Investigators and the ACCORD/ACCORDion Investigators
Abstract
Metformin is the first line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment, and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6, were associated with worse and better metformin response, respectively (p<5×10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (p=1.2×10-8 and p=0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (p=1.78×10-6) and increased fasted circulating glucose (p=5.73×10-6). Furthermore, rare variants in STAT3 associated with worse metformin response(q<0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D.
PMID: 29650774 [PubMed - as supplied by publisher]
Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension?
Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension?
Circ Genom Precis Med. 2018 Apr;11(4):e002139
Authors: Alhenc-Gelas F, Menard J
PMID: 29650769 [PubMed - in process]
Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Circ Genom Precis Med. 2018 Apr;11(4):e001854
Authors: McDonough CW, Magvanjav O, Sá ACC, El Rouby NM, Dave C, Deitchman AN, Kawaguchi-Suzuki M, Mei W, Shen Y, Singh RSP, Solayman M, Bailey KR, Boerwinkle E, Chapman AB, Gums JG, Webb A, Scherer SE, Sadee W, Turner ST, Cooper-DeHoff RM, Gong Y, Johnson JA
Abstract
BACKGROUND: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).
METHODS: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).
RESULTS: Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; P=2.09×10-6) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided P=0.006). In addition, TXNDC11 expression differed by rs3784921 genotype (P=0.007), and rs1802409, a proxy SNP for rs3784921 (r2=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided P=0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
PMID: 29650764 [PubMed - in process]
Pharmacogenetics of androgen signaling in prostate cancer: Focus on castration resistance and predictive biomarkers of response to treatment.
Pharmacogenetics of androgen signaling in prostate cancer: Focus on castration resistance and predictive biomarkers of response to treatment.
Crit Rev Oncol Hematol. 2018 May;125:51-59
Authors: Del Re M, Crucitta S, Restante G, Rofi E, Arrigoni E, Biasco E, Sbrana A, Coppi E, Galli L, Bracarda S, Santini D, Danesi R
Abstract
Tumor heterogeneity strongly affects the molecular mechanisms driving resistance to hormonal therapies in castration-resistant prostate cancer. Since the current use of available treatments can be optimized on the basis of the molecular profile of tumor, the present review focuses on genetic biomarkers in prostate cancer and their application to a personalized treatment.
PMID: 29650277 [PubMed - in process]
Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.
Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.
BMC Cancer. 2017 Feb 06;17(1):107
Authors: Uboldi S, Craparotta I, Colella G, Ronchetti E, Beltrame L, Vicario S, Marchini S, Panini N, Dagrada G, Bozzi F, Pilotti S, Galmarini CM, D'Incalci M, Gatta R
Abstract
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera.
METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP).
RESULTS: JN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis.
CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.
PMID: 28166781 [PubMed - indexed for MEDLINE]
Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention.
Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention.
J Transl Med. 2018 Apr 11;16(1):92
Authors: Cavallari LH, Franchi F, Rollini F, Been L, Rivas A, Agarwal M, Smith DM, Newsom K, Gong Y, Elsey AR, Starostik P, Johnson JA, Angiolillo DJ
Abstract
BACKGROUND: The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation.
METHODS: Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping.
RESULTS: In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele).
CONCLUSION: These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7.
PMID: 29642909 [PubMed - in process]
Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways.
Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways.
Nutrients. 2017 Apr 28;9(5):
Authors: Mandal A, Bhatia D, Bishayee A
Abstract
Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2-5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling.
PMID: 28452959 [PubMed - indexed for MEDLINE]
Streptococcal pyrogenic exotoxin B inhibits apoptotic cell clearance by macrophages through protein S cleavage.
Streptococcal pyrogenic exotoxin B inhibits apoptotic cell clearance by macrophages through protein S cleavage.
Sci Rep. 2016 05 16;6:26026
Authors: Chen CL, Wu YY, Lin CF, Kuo CF, Han CL, Wang S, Chuang WJ, Chen CY, Wu JJ, Tsai PJ, Liu CC, Lin YS
Abstract
Clearance of apoptotic cells by macrophages plays an important role in maintaining tissue homeostasis. Previous study indicated that streptococcal pyrogenic exotoxin B (SPE B) reduces phagocytic activity in group A streptococcus (GAS) infection. Here, we demonstrate that SPE B causes an inhibitory effect on protein S-mediated phagocytosis. In the presence of SPE B, serum- and purified protein S-mediated phagocytosis of apoptotic cells were significantly inhibited. The binding abilities of protein S to apoptotic cells were decreased by treatment with SPE B. Bacterial culture supernatants from GAS NZ131 strain also caused a reduction of protein S binding to apoptotic cells, but speB mutant strain did not. SPE B directly cleaved protein S in vitro and in vivo, whereas a lower level of cleavage occurred in mice infected with a speB isogenic mutant strain. SPE B-mediated initial cleavage of protein S caused a disruption of phagocytosis, and also resulted in a loss of binding ability of protein S-associated C4b-binding protein to apoptotic cells. Taken together, these results suggest a novel pathogenic role of SPE B that initiates protein S degradation followed by the inhibition of apoptotic cell clearance by macrophages.
PMID: 27181595 [PubMed - indexed for MEDLINE]
A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.
A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.
Cell Rep. 2018 Apr 10;23(2):327-336
Authors: Frayling TM, Beaumont RN, Jones SE, Yaghootkar H, Tuke MA, Ruth KS, Casanova F, West B, Locke J, Sharp S, Ji Y, Thompson W, Harrison J, Etheridge AS, Gallins PJ, Jima D, Wright F, Zhou Y, Innocenti F, Lindgren CM, Grarup N, Murray A, Freathy RM, Weedon MN, Tyrrell J, Wood AR
Abstract
Fibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21's mechanisms and therapeutic potential.
PMID: 29641994 [PubMed - in process]