Warfarin Dosing in Patients With CYP2C9*5 Variant Alleles.

Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain.

Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model.

The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown.

Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.

Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation.

Differential β3 Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components.

Extracellular matrix (ECM) derived from whole organ decellularization has been successfully used in a variety of tissue engineering applications. ECM contains a complex mixture of functional and structural molecules that are ideally suited for the tissue from which the ECM is harvested. However, decellularization disrupts the structural properties and protein composition of the ECM, which may impact function when cells such as the fibroblast are reintroduced during recellularization.

Pharmacogenomic assessment of Mexican and Peruvian populations.

Background: Clinically relevant polymorphisms often demonstrate population-specific allele frequencies. Central and South America remain largely uncategorized in the context of pharmacogenomics.

Materials & Methods: We assessed 15 polymorphisms from 12 genes (ABCB1 3435C>T, ABCG2 Q141K, CYP1B1*3, CYP2C19*2, CYP3A4*1B, CYP3A5*3C, ERCC1 N118N, ERCC2 K751Q, GSTP1 I105V, TPMT 238G>C, TPMT 460G>A, TPMT 719A>G, TYMS TSER, UGT1A1*28 and UGT1A1 -3156G>A) in 81 Peruvian and 95 Mexican individuals.

Pyrosequencing of clinically relevant polymorphisms.

Despite the influx of high throughput sequencing techniques, there is still a niche for low-medium throughput genotyping technologies for small-scale screening and validation purposes. Pyrosequencing is a genotyping assay based on sequencing-by-synthesis. Short runs of sequence around each polymorphism are generated, allowing for internal controls for each sample.

Gamma-glutamyl carboxylase and its influence on warfarin dose.

Via generation of vitamin K-dependent proteins, gamma-glutamyl carboxylase (GGCX) plays a critical role in the vitamin K cycle. Single nucleotide polymorphisms (SNPs) in GGCX, therefore, may affect dosing of the vitamin K antagonist, warfarin. In a multi-centered, cross-sectional study of 985 patients prescribed warfarin therapy, we genotyped for two GGCX SNPs (rs11676382 and rs12714145) and quantified their relationship to therapeutic dose.

Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.

Purpose: With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.

Patients And Methods: Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study.

Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose.

Initiation of warfarin therapy is associated with bleeding owing to its narrow therapeutic window and unpredictable therapeutic dose. Pharmacogenetic-based dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 commercial systems: INFINITI analyzer (AutoGenomics, Carlsbad, CA), Invader assay (Third Wave Technologies, Madison, WI), Tag-It Mutation Detection assay (Luminex Molecular Diagnostics, formerly Tm Bioscience, Toronto, Canada), and Pyrosequencing (Biotage, Uppsala, Sweden).

CYP4F2 genetic variant alters required warfarin dose.

Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved.

Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish Randomised Trial in Ovarian Cancer.

Purpose: Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane, which has a 5-year survival rate of approximately 45%. The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.

Patients And Methods: We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery.

Identification of NR1I2 genetic variation using resequencing.

Objective: The nuclear receptor NR1I2 (also called PXR or SXR) is primarily expressed in mouse and human liver and intestines. Direct activation of NR1I2 occurs in response to a range of xenobiotics, which causes the formation of a heterodimer with the RXR receptor. This heterodimer binds to the nuclear receptor response elements of downstream genes such as ABCB1, CYP2C, and CYP3A.

Pyrosequencing: a simple method for accurate genotyping.

Pharmacogenetic research benefits first-hand from the abundance of information provided by the completion of the Human Genome Project. With such a tremendous amount of data available comes an explosion of genotyping methods. Pyrosequencing is one of the most thorough yet simple methods to date used to analyze polymorphisms.

Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes.

Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC.

Pyrosequencing of clinically relevant polymorphisms.

The data generated from the Human Genome Project has led to an explosion of technology for low-, medium-, and high-throughput genotyping methods. Pyrosequencing is a genotyping assay based on sequencing by synthesis. Short runs of sequence around each polymorphism are generated, allowing for internal controls for each sample.

Distribution of ITPA P32T alleles in multiple world populations.

Dose-limiting toxicity from azathioprine treatment affects up to 37% of patients. Screening for thiopurine methyltransferase (TPMT) polymorphisms will prospectively identify approximately 10% of patients. Recently, a polymorphism in the inosine triphosphate pyrophosphatase gene (ITPA) has been associated with severe azathioprine toxicity.

Application of pharmacogenomics in the individualization of chemotherapy for gastrointestinal malignancies.

The large number of active combination chemotherapy regimens for the treatment of gastrointestinal cancers has led to the need for better information to guide the "standard" treatment for each patient. In an attempt to individualize therapy, pharmacogenomics evaluates the hereditary basis for interindividual differences in drug response. This report will focus on the results of studies assessing the effects of polymorphisms in drug-metabolizing enzymes and drug targets on the toxicity and response to chemotherapy drugs commonly used to treat gastrointestinal malignancies.