Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer.

Pharmacogenomics J. 2016 Jul 5;

Authors: Musolino A, Naldi N, Dieci MV, Zanoni D, Rimanti A, Boggiani D, Sgargi P, Generali DG, Piacentini F, Ambroggi M, Cagossi K, Gianni L, Sarti S, Bisagni G, Ardizzoni A, Conte PF, Guarneri V

Abstract
Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.The Pharmacogenomics Journal advance online publication, 5 July 2016; doi:10.1038/tpj.2016.51.

PMID: 27378608 [PubMed - as supplied by publisher]

Pharmacogenomic and personalized approaches to tackle the nonalcoholic fatty liver disease.

Pharmacogenomics. 2016 Jul 5;

Authors: Lorbek G, Urlep Ž, Rozman D

Abstract
Nonalcoholic fatty liver disease (NAFLD) is a raising liver disease with increasing prevalence due to the epidemics of obesity and diabetes, with end points in cirrhosis or hepatocellular carcinoma. A multitude of genetic and metabolic perturbations, together with environmental factors, likely drive the disease. However, to date only a few genes, primarily PNPLA3 and TM6SF2, associate with NAFLD and there is no specific treatment. In this review we focus on the therapeutical aspects of NAFLD, taking into account drugs and lifestyle interventions. Sex also influences disease progression and treatment outcomes. Lastly, we discuss the present and potential future of personalized approaches to tackle NAFLD and how the known polymorphisms of NAFLD associated genes influence the choice and success of therapy.

PMID: 27377717 [PubMed - as supplied by publisher]

Developing Treatments for Stimulant Abuse: A Brief Overview.

East Asian Arch Psychiatry. 2016 Jun;26(2):52-9

Authors: Davidson C

Abstract
The abuse of stimulants such as cocaine, amphetamine, and methamphetamine is a huge problem in many parts of the world. Abuse of these drugs does not ruin just the user's life, but also adversely affects those around them. Despite many years of research, there are no approved medications for stimulant dependence, and treatment is focused on psychotherapy and abstinence. Over the last 10 to 20 years, there have been some major changes in approach to medication development for stimulant dependence. These include assessing ligands for non-dopaminergic sites, atypical dopamine transporter ligands, blocking long-term potentiation and / or memory reconsolidation, vaccines against the stimulant, and molecular approaches including pharmacogenomics and gene silencing. Also included in this overview are non-drug treatments such as deep brain stimulation and psychosurgery. This overview highlights recent preclinical and clinical studies of treatment development for stimulant dependence.

PMID: 27377486 [PubMed - as supplied by publisher]

Using systems biology to evaluate targets and mechanism of action of drugs for diabetes comorbidities.

Diabetologia. 2016 Jul 4;

Authors: Mayer B

Abstract
Medications approved for diabetes-associated renal and cardiovascular morbidities and candidate drugs currently in development are subject to substantial variability in drug response. Heterogeneity on a molecular phenotype level is not apparent at clinical presentation, which means that inter-individual differences in drug effect at the molecular level are masked. These findings identify the need for optimising patient phenotyping via use of molecular biomarkers for a personalised therapy approach. Molecular diversity may, on the one hand, result from the effect of genetic polymorphisms on drug transport, metabolism and effective target modulation. Equally relevant, differences may be due to molecular pathologies. The presence of distinct molecular phenotypes is suggested by classifiers aimed at modelling progressive disease. Such functions for prognosis incorporate a complex set of clinical variables or a multitude of molecular markers reflecting a diverse set of molecular disease mechanisms. This information on disease pathology and the mechanism of action of the drug needs to be systematically integrated with data on molecular biomarkers to develop an experimental tool for personalising medicine. The large amount of molecular data available for characterising diabetes-associated morbidities allows for elucidation of molecular process model representations of disease pathologies. Selecting biomarker candidates on such grounds and, in turn identifying their association with progressive disease allows for the identification of molecular processes associated with disease progression. The molecular effect of a drug can also be modelled at a molecular process level, and the integration of disease pathology and drug effect molecular models reveals candidate biomarkers for assessing drug response. Such tools serve as enrichment strategies aimed at adding precision to drug development and use.

PMID: 27376542 [PubMed - as supplied by publisher]

Commentary: A Novel Disease-Drug Database Demonstrating Applicability for Pharmacogenomic-Based Prescribing.

Clin Pharmacol Ther. 2016 Jul 1;

Authors: Whirl-Carrillo M, Sangkuhl K, Gong L, Klein TE

PMID: 27367543 [PubMed - as supplied by publisher]

Advocating for the Use of Pharmacogenomics: One Nurse's Story.

J Psychosoc Nurs Ment Health Serv. 2016 Jul 1;54(7):38-42

Authors: Pestka EL, Shea CE

Abstract
The current article describes the experiences of a motivated nurse who gained an understanding of pharmacogenomics and advocated for the use cytochrome P450 testing for patients in her clinical practice, her family members, herself, and for changing the health care delivery system to more readily recognize and address drug-metabolizing-enzyme abnormalities. Recommendations for nurses interested in promoting the use of pharmacogenomics include learning as much as possible about testing and implications, networking with other providers, identifying a knowledgeable pharmacist, assessing for a family history of problems with medication side effects or lack of efficacy, and keeping records of relevant medical and medication information to share with providers. [Journal of Psychosocial Nursing and Mental Health Services, 54(7), 38-42.].

PMID: 27362384 [PubMed - as supplied by publisher]

Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types.

BMC Genomics. 2016;17 Suppl 2:394

Authors: Chen T, Wang Z, Zhou W, Chong Z, Meric-Bernstam F, Mills GB, Chen K

Abstract
BACKGROUND: An important step towards personalizing cancer treatment is to integrate heterogeneous evidences to catalog mutational hotspots that are biologically and therapeutically relevant and thus represent where targeted therapy would likely be beneficial. However, existing methods do not sufficiently delineate varying functionality of individual mutations within the same genes.
RESULTS: We observed a large discordancy of mutation rates across different mutation subtypes and tumor types, and nominated 702 hotspot mutations in 549 genes in the Catalog of Somatic Mutations in Cancer (COSMIC) by considering context specific mutation characteristics such as genes, cancer types, mutation rates, mutation subtypes and sequence contexts. We observed that hotspot mutations were highly prevalent in Non CpG-island C/G transition and transversion sequence contexts in 10 tumor types, and specific insertion hotspot mutations were enriched in breast cancer and deletion hotspot mutations in colorectal cancer. We found that the hotspot mutations nominated by our approach were significantly more conserved than non-hotspot mutations in the corresponding cancer genes. We also examined the biological significance and pharmacogenomics properties of these hotspot mutations using data in the Cancer Genome Atlas (TCGA) and the Cancer Cell-Line Encyclopedia (CCLE), and found that 53 hotspot mutations are independently associated with diverse functional evidences in 1) mRNA and protein expression, 2) pathway activity, or 3) drug sensitivity and 82 were highly enriched in specific tumor types. We highlighted the distinct functional indications of hotspot mutations under different contexts and nominated novel hotspot mutations such as MAP3K4 A1199 deletion, NR1H2 Q175 insertion, and GATA3 P409 insertion as potential biomarkers or drug targets.
CONCLUSION: We identified a set of hotspot mutations across 17 tumor types by considering the background mutation rate variations among genes, tumor subtypes, mutation subtypes, and sequence contexts. We illustrated the common and distinct mutational signatures of hotspot mutations among different tumor types and investigated their variable functional relevance under different contexts, which could potentially serve as a resource for explicitly selecting targets for diagnosis, drug development, and patient management.

PMID: 27356755 [PubMed - in process]

Pharmacogenomics for infectious diseases in sub-Saharan Africa: Successes and opportunities.

Appl Transl Genom. 2016 Jun;9:3-5

Authors: Chaudhry M, Alessandrini M, Pepper MS

PMID: 27354934 [PubMed]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons.

Nutr Metab Cardiovasc Dis. 2016 May 30;

Authors: Yadav K, Sharma M, Ferdinand KC

Abstract
AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition.
BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality. However, 70% of events occur even in the presence of statins. This residual risk may be approached with additional LDL-C reduction. Statin intolerance is a common clinical concern affecting adherence and the benefit with statins. There is also significant variation of individual lipid-lowering. Following rapid development, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have progressed from genetic observations, to mechanistic studies, to closer realization of the goal of CVD risk reduction. This review discusses the science behind PCSK9 inhibition, evidence of trials involving efficacy and safety, and reflections of its present and future role in clinical care, especially in high-risk patients with ASCVD, persons with suboptimal responses to statins and familial hyperlipidemia. Monoclonal antibodies have demonstrated LDL-C lowering of up to 57% as monotherapy and up to 73% when added to statins. Statins have limited efficacy in reduction of LDL-C due to an increased number of LDL-receptors. Elevated lipoprotein (a) levels may also be significantly lowered by PCSK9i. The journey from discovery to PSCK9 target validation took less than five years, and development and approval of therapeutic modalities for PCSK9 inhibitors happened over the next seven. This review highlights the drug development and pharmacogenomics leading to the recent approval of two agents, alirocumab and evolocumab, with a third bococizumab, and other novel approaches to the pathway pending.
DATA SYNTHESIS: We searched MEDLINE database via Pubmed for reviews, research publications and relevant trials available on PCSK9 inhibition.
CONCLUSION: Despite decades of medical advances, ASCVD remains one of the major causes of morbidity and mortality worldwide. Statin use has multiplied since the validation of LDL hypothesis, however, it is undeniable a more effective and well-tolerated agent is needed in significant number or patients. With the arrival of the era of unprecedented CV protection with PCSK9 inhibition, this exciting new therapy holds a pivotal promise as the future of lipid management. The data available already indicate safety, tolerability and superb efficacy of these agents, which are already changing contemporary cholesterol management. The rapid translation of innovative basic science research into drug development may lead to CV outcomes reduction and confirm that this pathway will become prominently utilized.

PMID: 27352986 [PubMed - as supplied by publisher]

Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.

Eur J Cancer. 2016 Mar;55:27-37

Authors: Cresti N, Lee J, Rourke E, Televantou D, Jamieson D, Verrill M, Boddy AV

Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease.

PMID: 26773371 [PubMed - indexed for MEDLINE]

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.

BMC Cancer. 2015;15:718

Authors: Takahashi H, Kaniwa N, Saito Y, Sai K, Hamaguchi T, Shirao K, Shimada Y, Matsumura Y, Ohtsu A, Yoshino T, Doi T, Takahashi A, Odaka Y, Okuyama M, Sawada J, Sakamoto H, Yoshida T

Abstract
BACKGROUND: Variability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.
METHODS: We previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.
RESULTS: We identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10(-8) by Fisher's exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.
CONCLUSIONS: These results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.

PMID: 26475168 [PubMed - indexed for MEDLINE]

Pharmacogenomics and cardiology: improving treatment with existing drugs.

Pharmacogenomics. 2015;16(11):1223-6

Authors: Sorrentino MJ, O'Donnell PH

PMID: 26369612 [PubMed - indexed for MEDLINE]

Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score.

Pharmacogenomics. 2015;16(11):1277-86

Authors: Henricks LM, Lunenburg CA, Meulendijks D, Gelderblom H, Cats A, Swen JJ, Schellens JH, Guchelaar HJ

Abstract
The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.

PMID: 26265346 [PubMed - indexed for MEDLINE]

Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes.

Pharmacogenomics J. 2015 Oct;15(5):443-51

Authors: Altar CA, Carhart JM, Allen JD, Hall-Flavin DK, Dechairo BM, Winner JG

Abstract
In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGx™) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support.

PMID: 25686762 [PubMed - indexed for MEDLINE]

Where to now in cardiovascular disease prevention.

Atherosclerosis. 2016 Jun 18;

Authors: Najam O, Ray KK

Abstract
Clinical trials have been instrumental in reducing the morbidity and mortality associated with cardiovascular disease, especially in the developed world. Recently however this improvement has plateaued, highlighting the importance of optimising current strategies and considering alternative practises. Inequalities in global healthcare, the changing patient profile as a result of an obesity and diabetes epidemic, and inadequate utilisation of evidence-based treatments are partly responsible. Despite pharmacotherapies such as statins having substantial evidence for cardiovascular benefit, patient response may be variable with genetic factors thought to be partly responsible. Although randomised controlled trials remain the backbone of clinical research, they have limitations including time taken to complete a trial and the financial costs associated with it. In this opinion-based paper, we discuss some of the key considerations for the future of cardiovascular disease prevention.

PMID: 27350327 [PubMed - as supplied by publisher]

Antihypertensive therapy in pre-eclampsia: effects of plasma from nonresponsive patients on endothelial gene expression.

Pharmacogenomics. 2016 Jun 27;

Authors: Luizon MR, Caldeira-Dias M, Deffune E, Fernandes KS, Cavalli RC, Tanus-Santos JE, Sandrim VC

Abstract
AIM: Over 40% of patients with pre-eclampsia are nonresponsive to antihypertensive therapy, but the underlying mechanisms are unknown. We examined the effects of plasma from nonresponsive and responsive patients on endothelial gene expression.
PATIENTS & METHODS: PCR array was performed in human umbilical vein endothelial cells (HUVEC) incubated with plasma from nonresponsive (n = 4) and responsive (n = 4) patients. Gene networks and interactions with antihypertensive drugs used in pre-eclampsia were identified by Ingenuity Pathway Analysis.
RESULTS: Nifedipine and hydralazine act by upregulate or downregulate genes found to be downregulated or upregulated in HUVEC incubated with plasma from nonresponsive patients.
CONCLUSION: Our novel findings suggest that plasma from nonresponsive and responsive patients evoke different responses in HUVEC, and might advance the pharmacogenomics research in pre-eclampsia.

PMID: 27348131 [PubMed - as supplied by publisher]

Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes.

Int J Mol Sci. 2016;17(7)

Authors: Costa V, Federico A, Pollastro C, Ziviello C, Cataldi S, Formisano P, Ciccodicola A

Abstract
Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG). However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene-currently annotated as intronic-fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP), currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing.

PMID: 27347941 [PubMed - as supplied by publisher]

The potential of genetically guided treatment in Behçet's disease.

Pharmacogenomics. 2016 Jun 27;

Authors: Gheita TA, Gheita HA, Kenawy SA

Abstract
Continuous identification of specific targets and candidate genes together with novel approaches offers new promises for the future of gene therapy design in Behçet's disease (BD). Personalized medicine based on pharmacogenomics is being developed at the clinical stage to improve treatment response. Screening the whole gene and regulatory regions is important when searching for novel variants associated with such complex diseases. Different host genetic factors play significant roles in susceptibility to BD. Thus, identifying these genes responsible for susceptibility and resistance to BD may offer a notable contribution toward understanding its pathogenesis, and may lead to the development of novel prophylactic and treatment strategies. Evidenced-based treatment strategy is recommended for the management in BD patients. This review sheds light on the immunopathogenesis and pharmacogenetics of BD with special attention to the treatment targeting gene polymorphisms. In conclusion, the potential of genetically guided treatment in BD takes us back to the future for an accurate management strategy of this serious rheumatic disease. The ongoing discovery of pivotal genes related to the susceptibility, manifestations, disease activity and treatment options provide substantial hope to the reduced frequency of BD, effective control and improvement in the prognosis. Targeted gene therapy could be a leading option in the treatment armamentarium of BD.

PMID: 27347725 [PubMed - as supplied by publisher]

Understanding New Types of Evidence Ready for Translation into Nursing Informatics.

Stud Health Technol Inform. 2016;225:686-688

Authors: McCormick K

Abstract
Nurses are the primary deliverers of patient care and observers of patient side effects to medications. The primary objective of this tutorial is to bring the participants up to date in genomic applications for nursing from birth until death. A secondary objective is to define at least 17 pharmacogenomics evidence guidelines ready for implementation into the Electronic Health Record. The target audience are nurses in practice, implementers of EHRs, nursing in leadership and policy-making positions, those focused on defining new areas for nursing research, and educators who are in need of defining criteria for integrating genomics into nursing education.

PMID: 27332305 [PubMed - as supplied by publisher]

Network-based identification of microRNAs as potential pharmacogenomic biomarkers for anticancer drugs.

Oncotarget. 2016 Jun 14;

Authors: Li J, Lei K, Wu Z, Li W, Liu G, Liu J, Cheng F, Tang Y

Abstract
As the recent development of high-throughput technologies in cancer pharmacogenomics, there is an urgent need to develop new computational approaches for comprehensive identification of new pharmacogenomic biomarkers, such as microRNAs (miRNAs). In this study, a network-based framework, namely the SMiR-NBI model, was developed to prioritize miRNAs as potential biomarkers characterizing treatment responses of anticancer drugs on the basis of a heterogeneous network connecting drugs, miRNAs and genes. A high area under the receiver operating characteristic curve of 0.820 ± 0.013 was yielded during 10-fold cross validation. In addition, high performance was further validated in identifying new anticancer mechanism-of-action for natural products and non-steroidal anti-inflammatory drugs. Finally, the newly predicted miRNAs for tamoxifen and metformin were experimentally validated in MCF-7 and MDA-MB-231 breast cancer cell lines via qRT-PCR assays. High success rates of 60% and 65% were yielded for tamoxifen and metformin, respectively. Specifically, 11 oncomiRNAs (e.g. miR-20a-5p, miR-27a-3p, miR-29a-3p, and miR-146a-5p) from the top 20 predicted miRNAs were experimentally verified as new pharmacogenomic biomarkers for metformin in MCF-7 or MDA-MB-231 cell lines. In summary, the SMiR-NBI model would provide a powerful tool to identify potential pharmacogenomic biomarkers characterized by miRNAs in the emerging field of precision cancer medicine, which is available at http://lmmd.ecust.edu.cn/database/smir-nbi/.

PMID: 27329603 [PubMed - as supplied by publisher]