Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease.

Expert Opin Biol Ther. 2016 Jun 22;

Authors: Pouillon L, Bossuyt P, Peyrin-Biroulet L

Abstract
INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD).
AREAS COVERED: Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary non-response and secondary loss of response are discussed. The questions of de-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are all marked. Finally, the future directions of anti-TNF therapy are emphasized.
EXPERT OPINION: Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.

PMID: 27329436 [PubMed - as supplied by publisher]

Precision medicine: The future in diabetes care?

Diabetes Res Clin Pract. 2016 Jul;117:12-21

Authors: Scheen AJ

Abstract
Personalized medicine aims at better targeting therapeutic intervention to the individual to maximize benefit and minimize harm. Type 2 diabetes (T2D) is a heterogeneous disease from a genetic, pathophysiological and clinical point of view. Thus, the response to any antidiabetic medication may considerably vary between individuals. Numerous glucose-lowering agents, with different mechanisms of action, have been developed, a diversified armamentarium that offers the possibility of a patient-centred therapeutic approach. In the current clinical practice, a personalized approach is only based upon phenotype, taking into account patient and disease individual characteristics. If this approach may help increase both efficacy and safety outcomes, there remains considerable room for improvement. In recent years, many efforts were taken to identify genetic and genotype SNP's (Single Nucleotide Polymorphism's) variants that influence the pharmacokinetics, pharmacodynamics, and ultimately the therapeutic response of oral glucose-lowering drugs. This approach mainly concerns metformin, sulphonylureas, meglitinides and thiazolidinediones, with only scarce data concerning gliptins and gliflozins yet. However, the contribution of pharmacogenetics and pharmacogenomics to personalized therapy still needs to mature greatly before routine clinical implementation is possible. This review discusses both opportunities and challenges of precision medicine and how this new paradigm may lead to a better individualized treatment of T2D.

PMID: 27329017 [PubMed - in process]

Sodium channel Nav1.8: Emerging links to human disease.

Neurology. 2016 Feb 2;86(5):473-83

Authors: Han C, Huang J, Waxman SG

Abstract
The NaV1.8 sodium channel, encoded by gene SCN10A, was initially termed sensory neuron-specific (SNS) due to prominent expression in primary sensory neurons including dorsal root ganglion (DRG) neurons. Early studies on rodent NaV1.8 demonstrated depolarized voltage dependence of channel inactivation, a slow rate of inactivation, and rapid recovery from inactivation. As a result of these biophysical properties, NaV1.8 supports repetitive firing in response to sustained depolarization. This article reviews recent studies that reveal multiple links of NaV1.8 to human disease: (1) It has recently been shown that functional attributes that distinguish NaV1.8 from other sodium channel subtypes are exaggerated in human NaV1.8; its influence on neuronal activity is thus greater than previously thought. (2) Gain-of-function mutations of NaV1.8 that produce DRG neuron hyperexcitability have been found in 3% of patients with painful neuropathy, establishing a role in pathogenesis. (3) NaV1.8 is ectopically expressed within Purkinje neurons in multiple sclerosis (MS), where it perturbs electrical activity. Recent evidence indicates that variants of SCN10A predict the degree of cerebellar dysfunction in MS. (4) Emerging evidence has linked SCN10A variants to disorders of cardiac rhythm, via mechanisms that may include an effect on cardiac innervation. Involvement of NaV1.8 in neurologic disease may have therapeutic implications. NaV1.8-specific blocking agents, under development, ameliorate pain and attenuate MS-like deficits in animal models. Recent studies suggest that pharmacogenomics may permit the matching of specific channel blocking agents to particular patients. The new links of NaV1.8 in human disease raise new questions, but also suggest new therapeutic strategies.

PMID: 26747884 [PubMed - indexed for MEDLINE]

Pharmacogenomics and Implications for Nursing Practice.

J Nurs Scholarsh. 2015 Nov;47(6):496-504

Authors: Cheek DJ, Bashore L, Brazeau DA

Abstract
PURPOSE: This article aims to introduce the nurse to pharmacogenomics and its implications for clinical practice with regard to drug therapy.
ORGANIZING CONSTRUCTS: Pharmacogenomics is discussed with regard to the basic tenets, relationships to common health conditions, education and practice resources, and implications for nursing practice.
METHODS: Peer-reviewed literature, websites, and expert professional guidelines were reviewed with relation to pharmacogenomics and nursing practice.
FINDINGS: The genetic-genomic literature has grown significantly since the completion of the Human Genome Project in 2003. This information is now being translated into practice with regard to the patient's genetic profile and the impact on drug therapy, which is pharmacogenomics.
CONCLUSIONS: The utilization of the patient genetic-genomic profile is beginning to have an impact on patient drug therapy in clinical practice.
CLINICAL RELEVANCE: Nurses are in the position to make sure, with the increased translation of pharmacogenomics into clinical practice, that adverse drug reactions are avoided and doses are optimized.

PMID: 26470020 [PubMed - indexed for MEDLINE]

Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options.

Oncotarget. 2016 Jun 15;

Authors: Brown RE, Buryanek J, Katz AM, Paz K, Wolff JE

Abstract
Alveolar rhabdomyosarcoma (ARMS) represents a block in differentiation of malignant myoblasts. Genomic events implicated in the pathogenesis of ARMS involve PAX3-FKHR (FOXO1) or PAX7-FKHR (FOXO1) translocation with corresponding fusion transcripts and fusion proteins. Commonalities in ARMS include uncontrollable proliferation and failure to differentiate. The genomic-molecular correlates contributing to the etiopathogenesis of ARMS incorporate PAX3-FKHR (FOXO1) fusion protein stimulation of the IGF-1R, c-Met and GSK3-β pathways. With sequential morphoproteomic profiling on such a case in conjunction with personalized tumor graft testing, we provide an expanded definition of the biology of PAX3-FKHR (FOXO1) ARMS that integrates genomics, proteomics and pharmacogenomics. Moreover, therapies that target the genomic and molecular biology and lead to tumoral regression and/or tumoral growth inhibition in a xenograft model of ARMS are identified.
SIGNIFICANCE: This case study could serve as a model for clinical trials using relatively low toxicity agents in both initial and maintenance therapies to induce remission and reduce the risk of recurrent disease in PAX3-FKHR (FOXO1) subtype of ARMS.

PMID: 27323832 [PubMed - as supplied by publisher]

Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers in Hypertensive African Americans.

Hypertension. 2016 Mar;67(3):556-63

Authors: Gong Y, Wang Z, Beitelshees AL, McDonough CW, Langaee TY, Hall K, Schmidt SO, Curry RW, Gums JG, Bailey KR, Boerwinkle E, Chapman AB, Turner ST, Cooper-DeHoff RM, Johnson JA

Abstract
African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), β=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and β=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

PMID: 26729753 [PubMed - indexed for MEDLINE]

EMR Documentation of Physician-Patient Communication Following Genomic Counseling for Actionable Complex Disease and Pharmacogenomic Results.

Clin Genet. 2016 Jun 20;

Authors: Sweet K, Sturm AC, Schmidlen T, Hovick S, Peng J, Manickam K, Salikhova A, McElroy J, Scheinfeldt L, Toland AE, Scott Roberts J, Christman M

Abstract
Genomic risk information for potentially actionable complex diseases and pharmacogenomics communicated through genomic counseling may motivate physicians and patients to take preventive actions. The Ohio State University-Coriell Personalized Medicine Collaborative is a randomized trial to measure the effects of in-person genomic counseling on chronic disease patients provided with multiplex results. Nine personalized genomic risk reports were provided to patients through a web portal, and to physicians via electronic medical record (EMR). Active arm participants (98, 39% female) received genomic counseling within one month of report viewing; control arm subjects (101, 54% female) could access counseling 3-months post-report viewing. We examined whether genomic counseling affected documentation of physician-patient communication by reviewing the first clinical note following the patient's genomic counseling visit or report upload to the EMR. Multivariable logistic regression modeling estimated the independent effect of genomic counseling on physician-patient communication, as Intention to Treat (ITT) and Per Protocol (PP), adjusted for physician educational intervention. Counselees in the active arm had more physician-patient communications than control subjects (ITT, OR: 3.76 (95% CI: 1.38 - 10.22, P < 0.0094); PP, OR: 5.53 (95% CI: 2.20 - 13.90, P = 0.0017). In conclusion, genomic counseling appreciably affected physician-patient communication following receipt of potentially actionable genomic risk information.

PMID: 27322592 [PubMed - as supplied by publisher]

Integrating heterogeneous drug sensitivity data from cancer pharmacogenomic studies.

Oncotarget. 2016 Jun 14;

Authors: Pozdeyev N, Yoo M, Mackie R, Schweppe RE, Tan AC, Haugen BR

Abstract
The consistency of in vitro drug sensitivity data is of key importance for cancer pharmacogenomics. Previous attempts to correlate drug sensitivities from the large pharmacogenomics databases, such as the Cancer Cell Line Encyclopedia (CCLE) and the Genomics of Drug Sensitivity in Cancer (GDSC), have produced discordant results. We developed a new drug sensitivity metric, the area under the dose response curve adjusted for the range of tested drug concentrations, which allows integration of heterogeneous drug sensitivity data from the CCLE, the GDSC, and the Cancer Therapeutics Response Portal (CTRP). We show that there is moderate to good agreement of drug sensitivity data for many targeted therapies, particularly kinase inhibitors. The results of this largest cancer cell line drug sensitivity data analysis to date are accessible through the online portal, which serves as a platform for high power pharmacogenomics analysis.

PMID: 27322211 [PubMed - as supplied by publisher]

Pre-Examination Factors Affecting Molecular Diagnostic Test Results and Interpretation: a Case-Based Approach.

Clin Chim Acta. 2016 Jun 16;

Authors: Payne DA, Baluchova K, Peoc'h KH, van Schaik RH, Chan KC, Maekawa M, Mamotte C, Russomando G, Rousseau F, Ahmad-Nejad P, IFCC Committee for Molecular Diagnostics (C-MD)

Abstract
BACKGROUND: Multiple organizations produce guidance documents that provide opportunities to harmonize quality practices for diagnostic testing. The International Organization for Standardization ISO 15189 standard addresses requirements for quality in management and technical aspects of the clinical laboratory. One technical aspect addresses the complexities of the pre-examination phase prior to diagnostic testing.
METHODS: The Committee for Molecular Diagnostics of the International Federation for Clinical Chemistry and Laboratory Medicine (also known as, IFCC C-MD) conducted a survey of international molecular laboratories and determined ISO 15189 to be the most referenced guidance document. In this review, the IFCC C-MD provides case-based examples illustrating the value of select pre-examination processes as these processes relate to molecular diagnostic testing. Case-based examples in infectious disease, oncology, inherited disease and pharmacogenomics address the utility of: 1) providing information to patients and users, 2) designing requisition forms, 3) obtaining informed consent and 4) maintaining sample integrity prior to testing.
CONCLUSIONS: The pre-examination phase requires extensive and consistent communication between the laboratory, the healthcare provider and the end user. The clinical vignettes presented in this paper illustrate the value of applying select ISO 15189 recommendations for general laboratory to the more specialized area of Molecular Diagnostics.

PMID: 27321365 [PubMed - as supplied by publisher]

Recent advance in the pharmacogenomics of human Solute Carrier Transporters (SLCs) in drug disposition.

Adv Drug Deliv Rev. 2016 Jun 16;

Authors: Zhou F, Zhu L, Wang K, Murray M

Abstract
Drug pharmacokinetics is influenced by the function of metabolising enzymes and influx/efflux transporters. Genetic variability of these genes is known to impact on clinical therapies. Solute carrier transporters (SLCs) are the primary influx transporters responsible for the cellular uptake of drug molecules, which consequently, impact on drug efficacy and toxicity. The Organic anion transporting polypeptides (OATPs), Organic anion transporters (OATs) and Organic cation transporters (OCTs/OCTNs) are the most important SLCs involved in drug disposition. The information regarding the influence of SLC polymorphisms on drug pharmacokinetics is limited and remains a hot topic of pharmaceutical research. This review summarises the recent advance in the pharmacogenomics of SLCs with an emphasis on human OATPs, OATs and OCTs/OCTNs. Our current appreciation of the degree of variability in these transporters may contribute to better understanding the inter-patient variation of therapies and thus, guide the optimisation of clinical treatments.

PMID: 27320645 [PubMed - as supplied by publisher]

FDA drug labeling: rich resources to facilitate precision medicine, drug safety, and regulatory science.

Drug Discov Today. 2016 Jun 15;

Authors: Fang H, Harris SC, Liu Z, Zhou G, Zhang G, Xu J, Rosario L, Howard P, Tong W

Abstract
Here, we provide a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug-drug interactions, adverse drug reactions (ADRs), and more. Labeling data have been collected over several decades by the FDA and are an important resource for regulatory research and decision making. However, navigating through these data is challenging. To aid such navigation, the FDALabel database was developed, which contains a set of approximately 80000 labeling data. The full-text searching capability of FDALabel and querying based on any combination of specific sections, document types, market categories, market date, and other labeling information makes it a powerful and attractive tool for a variety of applications. Here, we illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.

PMID: 27319291 [PubMed - as supplied by publisher]

Mass Spectrometry in Precision Medicine: Phenotypic Measurements Alongside Pharmacogenomics.

Clin Chem. 2016 Jan;62(1):70-6

Authors: Clarke NJ

Abstract
BACKGROUND: Precision medicine is becoming a major topic within the medical community and is gaining traction as a standard approach in many disciplines. This approach typically revolves around the use of a patient's genetic makeup to allow the physician to choose the appropriate course of treatment. In many cases the genetic information directs the drug to be used to treat the patient. In other cases the genetic markers associated with enzyme function may inform dosage recommendations. However there is a second way in which precision medicine can be practiced-that is, by therapeutic drug monitoring (TDM).
CONTENT: A review of the use of mass spectrometry for TDM in the arena of precision medicine is undertaken. Because the measurement of a drug or its metabolites provides the physician with a snapshot of the therapeutic exposure the patient is undergoing, these concentrations can be thought of as an actual phenotype measurement based around the patient's genetics coupled with all of the environmental, pharmacological, and nutritional variables. The outcome of a TDM measurement by mass spectrometry provides the patient's current phenotype vs the potential phenotype imputed by the genetics.
SUMMARY: The use of mass spectrometry can provide an understanding of how a drug is interacting with the patient, and is orthoganol to the information provided by pharmacogenomic assays. Further, the speed and relatively low expense of drug monitoring by mass spectrometry makes it an ideal test for precision medicine patient management.

PMID: 26555454 [PubMed - indexed for MEDLINE]

Using Literature-Based Discovery to Explain Adverse Drug Effects.

J Med Syst. 2016 Aug;40(8):185

Authors: Hristovski D, Kastrin A, Dinevski D, Burgun A, Žiberna L, Rindflesch TC

Abstract
We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects.

PMID: 27318993 [PubMed - as supplied by publisher]

The ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24-25, 2015. Workshop Report.

Clin Sarcoma Res. 2016;6:3

Authors: Kager L, Whelan J, Dirksen U, Hassan B, Anninga J, Bennister L, Bovée JV, Brennan B, Broto JM, Brugières L, Cleton-Jansen AM, Copland C, Dutour A, Fagioli F, Ferrari S, Fiocco M, Fleuren E, Gaspar N, Gelderblom H, Gerrand C, Gerß J, Gonzato O, van der Graaf W, Hecker-Nolting S, Herrero-Martín D, Klco-Brosius S, Kovar H, Ladenstein R, Lancia C, LeDeley MC, McCabe MG, Metzler M, Myklebost O, Nathrath M, Picci P, Potratz J, Redini F, Richter GH, Reinke D, Rutkowski P, Scotlandi K, Strauss S, Thomas D, Tirado OM, Tirode F, Vassal G, Bielack SS

Abstract
This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

PMID: 27315524 [PubMed - as supplied by publisher]

CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients.

Clin Transplant. 2016 Jun 17;

Authors: Deininger KM, Vu A, Page RL, Ambardekar AV, Lindenfeld J, Aquilante CL

Abstract
BACKGROUND: Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A4*22 and CYP3A5*3 variants on tacrolimus drug disposition in adult heart transplant recipients.
METHODS: The retrospective study included n=76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A4*22 and CYP3A5*3, and combined genotypes were classified as: extensive metabolizers (EM, CYP3A4*1/*1+CYP3A5*1 carriers); intermediate metabolizers (IM, CYP3A4*1/*1+CYP3A5*3/*3, or CYP3A4*22 carriers+CYP3A5*1 carriers), and poor metabolizers (PM, CYP3A4*22 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/ml per mg/day).
RESULTS: In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (p<0.001) in CYP3A5 expressers versus nonexpressers. When combined CYP3A genotype was evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs versus IMs (p<0.001) and EMs versus PMs (p=0.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs versus PMs.
CONCLUSION: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A5*3. These data suggest that CYP3A4*22 and combined CYP3A genotype are unlikely to provide additional information beyond CYP3A5 genotype. This article is protected by copyright. All rights reserved.

PMID: 27314545 [PubMed - as supplied by publisher]

Implementation of Clinical Pharmacogenomics within a Large Health System: From Electronic Health Record Decision Support to Consultation Services.

Pharmacotherapy. 2016 Jun 17;

Authors: Hicks JK, Stowe D, Willner MA, Wai M, Daly T, Gordon SM, Lashner BA, Parikh S, White R, Teng K, Moss T, Erwin A, Chalmers J, Eng C, Knoer S

Abstract
The number of clinically relevant, gene-based guidelines and recommendations pertaining to drug prescribing continues to grow. Incorporating gene-drug interaction information into the drug prescribing process can help optimize pharmacotherapy outcomes and improve patient safety. However, pharmacogenomic implementation barriers exist such as integration of pharmacogenomic results into electronic health records (EHRs), development and deployment of pharmacogenomic decision-support tools to EHRs, and feasible models for establishing ambulatory pharmacogenomic clinics. We describe the development of pharmacist-managed pharmacogenomic services within a large health system. The Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B*57:01-abacavir, HLA-B*15:02-carbamazepine, and TPMT-thiopurines (i.e., azathioprine, mercaptopurine, and thioguanine) were systematically integrated into patient care. Sixty-three custom rules and alerts (20 for TPMT-thiopurines, 8 for HLA-B*57:01-abacavir, and 35 for HLA-B*15:02-anticonvulsants) were developed and deployed to the EHR for the purpose of providing point-of-care pharmacogenomic decision support. In addition, a pharmacist and physician-geneticist collaboration established a pharmacogenomics ambulatory clinic. This clinic provides genetic testing when warranted, result interpretation along with pharmacotherapy recommendations, and patient education. Our processes for developing these pharmacogenomic services and solutions for addressing implementation barriers are presented. This article is protected by copyright. All rights reserved.

PMID: 27312955 [PubMed - as supplied by publisher]

Association between Prolonged Neutropenia and Reduced Relapse Risk in Pediatric AML: A Report from the Children's Oncology Group.

Int J Cancer. 2016 Jun 16;

Authors: Sung L, Aplenc R, Alonzo TA, Gerbing RB, Wang YC, Meshinchi S, Gamis AS

Abstract
Objective was to describe the relationship between the number of sterile site infections and duration of neutropenia during the first four cycles of chemotherapy and the risk of recurrence and overall survival. AAML0531 was a Children's Oncology Group (COG) randomized phase 3 clinical trial that included 1022 children with de novo AML. For this analysis, we focused on non-Down syndrome favorable and standard risk patients who completed at least 4 cycles of chemotherapy without recurrence or withdrawal during protocol therapy. Those receiving hematopoietic stem cell transplantation in first remission were excluded. 569 patients were included; 274 (48.2%) were favorable risk. The median cumulative time with neutropenia between Induction II to completion of Intensification II was 96 (range 54-204) days. Number of sterile site infections did not influence the risk of relapse or overall survival. However, longer duration of neutropenia was associated with a lower risk of relapse (hazard ratio 0.81 per 20 days neutropenia, P=0.007). Longer duration of neutropenia was associated with a reduced risk of relapse for children with favorable and standard risk AML. Toxicity may be influenced by pharmacogenomics suggesting that individualized chemotherapy dosing may be an effective strategy. This article is protected by copyright. All rights reserved.

PMID: 27312107 [PubMed - as supplied by publisher]

MicroRNA hsa-miR-25-3p suppresses the expression and drug induction of CYP2B6 in human hepatocytes.

Biochem Pharmacol. 2016 Jun 13;

Authors: Jin Y, Yu D, Tolleson WH, Knox B, Wang Y, Chen S, Ren Z, Deng H, Guo Y, Ning B

Abstract
Cytochrome P450 2B6 (CYP2B6), mainly expressed in the liver and brain, is important for processing a number of widely used drugs. Variations in CYP2B6 expression are associated with decreased drug efficacy or adverse effects in some patients. Although CYP2B6 genetic variants are associated with its differential expression, epigenetic mechanisms affecting CYP2B6 gene regulation have not been established. Sequence analysis identified 29 domains in the CYP2B6 mRNA transcript that could be subject to regulation by microRNAs. Inverse correlations were found in human hepatocytes for the levels of the microRNAs hsa-miR-504-5p and hsa-miR-25-3p compared with CYP2B6 mRNA. Reporter gene assays showed that hsa-miR-25-3p suppresses CYP2B6 expression by targeting a specific sequence in the 3'-untranslated region of the mRNA transcript. Electrophoretic mobility shift assays confirmed that hsa-miR-25-3p forms stable complexes with its cognate mRNA sequence and that it recruits cellular factors, including Ago-4. Transfection of HepaRG cells with hsa-miR-25-3p mimics inhibited expression of the endogenous CYP2B6 gene and it also decreased rifampicin-dependent induction of CYP2B6 at the mRNA and protein levels. In summary, in sillico and in vitro analyses show that hsa-miR-25-3p suppresses CYP2B6 expression in human liver cells via an epigenetic mechanism.

PMID: 27311985 [PubMed - as supplied by publisher]

Comparison of genome sequencing and clinical genotyping for pharmacogenes.

Clin Pharmacol Ther. 2016 Jun 17;

Authors: Yang W, Wu G, Broeckel U, Smith CA, Turner V, Haidar CE, Wang S, Carter R, Karol SE, Neale G, Crews K, Yang JJ, Mullighan CG, Downing JR, Evans WE, Relling MV

Abstract
We compared whole exome sequencing (WES, n=176 patients) and whole genome sequencing (WGS, n=68) and clinical genotyping (DMET array-based approach) for interrogating thirteen genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. We focused on 127 CPIC important variants: 103 single nucleotide variations (SNV), 21 insertion/deletions (Indel), HLA-B alleles, and two CYP2D6 structural variations. WES and WGS provided interrogation of non-overlapping sets of 115 SNV/Indels with call rate >98%. Among 68 loci interrogated by both WES and DMET, 64 loci (94.1%, CI:85.6-98.4%) showed no discrepant genotyping calls. Among 66 loci interrogated by both WGS and DMET, 63 loci (95.5%, CI:87.2-99.0%) showed no discrepant genotyping calls. In conclusion, even without optimization to interrogate pharmacogenetic variants, WES and WGS displayed potential to provide reliable interrogation of most pharmacogenes and further validation of genome sequencing in a clinical lab setting is warranted. This article is protected by copyright. All rights reserved.

PMID: 27311679 [PubMed - as supplied by publisher]

Progress and prospects in pharmacogenetics of antidepressant drugs.

Expert Opin Drug Metab Toxicol. 2016 Jun 16;

Authors: Fabbri C, Crisafulli C, Calabrò M, Spina E, Serretti A

Abstract
INTRODUCTION: Depression is responsible for the most part of the personal and socio-economic burden due to psychiatric disorders. Since antidepressant response clusters in families, pharmacogenetics represents a meaningful tool to provide tailored treatments and improve the prognosis of depression.
AREAS COVERED: This review aims to summarize and discuss the pharmacogenetics of antidepressant drugs in major depressive disorder, with a focus on the most replicated genes, genome-wide association studies (GWAS), but also on the findings provided by new and promising analysis methods. In particular, multimarker tests such as pathway analysis and polygenic risk scores increase the power of detecting associations compared to the analysis of individual polymorphisms. Since genetic variants are not necessarily associated with a change in protein level, gene expression studies may provide complementary information to genetic studies. Finally, the pharmacogenetic tests that have been investigated for clinical application are discussed.
EXPERT OPINION: Despite the lack of widespread clinical applications, preliminary results suggest that pharmacogenetics may be useful to guide antidepressant treatment. The US Food and Drug Administration included pharmacogenetic indications in the labeling of several antidepressants. This represented an important official recognition of the clinical relevance of genetic polymorphisms in antidepressant treatment.

PMID: 27310483 [PubMed - as supplied by publisher]