Risk of acute myocardial infarction after discontinuation of antihypertensive agents: a case-control study.

J Hum Hypertens. 2017 Mar 23;:

Authors: Alharbi FF, Souverein PC, de Groot MC, Maitland-van der Zee AH, de Boer A, Klungel OH

Abstract
We performed a nested case-control study in a cohort of antihypertensive drug users to assess the association between discontinuation of different antihypertensive agents and the risk of acute myocardial infarction (AMI). Cases and controls were drawn from the Utrecht Cardiovascular Pharmacogenetics database. Patients who were hospitalised for their first AMI were considered cases and controls were not hospitalised for AMI. Antihypertensive users were defined as current users if the index date (date of AMI) fell within the prescribed duration or as discontinuers if this date fell outside the prescribed duration. According to the recency of discontinuation, discontinuers were divided into the following: recent discontinuers (⩽90 days), intermediate-term discontinuers (91-180 days) and long-term discontinuers (>180 days). We found that the risk of AMI was significantly increased in discontinuers, regardless of time since discontinuation, of beta-blockers (adjusted odds ratio (OR) 1.54; 95% confidence interval (CI; 1.25-1.91), P-value<0.0005), calcium channel blockers (CCBs; adjusted OR 2.25; 95% CI (1.53-3.30), P-value<0.0005) and diuretics (adjusted OR 1.76; 95% CI (1.24-2.48), P-value=0.002) compared to current users of these drugs. Moreover, the risk of AMI was significantly increased in long-term discontinuers (beta-blockers, CCBs, angiotensin-converting enzyme inhibitors and diuretics) and intermediate-term discontinuers (beta-blockers and CCBs) versus current users of these drugs. There was no difference in AMI risk between recent discontinuers of antihypertensive drugs versus current users of these drugs. In conclusion, discontinuation of antihypertensive drugs increases the risk of AMI after >90 days of discontinuation. This further underlines the importance of persistence to antihypertensive drug therapy to reduce the risk of AMI in patients with hypertension.Journal of Human Hypertension advance online publication, 23 March 2017; doi:10.1038/jhh.2017.1.

PMID: 28332511 [PubMed - as supplied by publisher]

Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.

Biomed Res Int. 2017;2017:4189678

Authors: Tang YJ, Hu K, Huang WH, Wang CZ, Liu Z, Chen Y, Ouyang DS, Tan ZR, Zhou HH, Yuan CS

Abstract
Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D' = 0.977, r(2) = 0.944). The mean values of Cmax, AUC0-24, and AUC0-∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.

PMID: 28331852 [PubMed - in process]

Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.

Clin Genitourin Cancer. 2017 Feb 27;:

Authors: Motzer RJ, Figlin RA, Martini JF, Hariharan S, Agarwal N, Li CX, Williams JA, Hutson TE

Abstract
BACKGROUND: Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule.
PATIENTS AND METHODS: Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial. Associations between 9 SNP variants (CXCL8, LOXL2, CCDC26, SH3GL2, CLLU1, IL2RA, AURKB, and 2 SNPs on Chromosomes 7 and 12) and progression-free survival (PFS), objective response rate, and overall survival were assessed using Kaplan-Meier analysis, Cox proportional hazard model, and the Fisher exact test.
RESULTS: CXCL8 rs1126647 A/A versus A/T (P = .004) or T/T (P < .0001) and SH3GL2 rs10963287 C/C versus C/T (P = .005) or T/T (P = .018) were associated with improved overall survival in all patients. CLLU1 rs525810 A/A genotype versus A/G (P = .014) or G/G (P = .048) was associated with improved PFS in the continuous daily dosing arm. IL2RA rs7893467 T/G versus T/T was associated with improved PFS (P = .034) in the 4-weeks-on/2-weeks-off arm and objective response rate (P = .034) in all patients. No significant associations between improved efficacy and genotype were found for other SNPs.
CONCLUSION: Germline variants in CLLU1, IL2RA, CXCL8, and SH3GL2 warrant further retrospective study in independent cohorts of patients with metastatic RCC treated with vascular endothelial growth factor-class inhibitors, to test their biological significance and potential clinical fitness as biomarkers to guide treatment.

PMID: 28330808 [PubMed - as supplied by publisher]

Influence of MDR1 CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia.

Pharmacol Res. 2017 Mar 18;:

Authors: Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, Gogia A, Shastri SS, Biswas NR, Gupta YK

Abstract
Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95%CI(1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95%CI(1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95%CI(1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95%CI(1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95%CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95%CI(0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95%CI(0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.

PMID: 28330783 [PubMed - as supplied by publisher]

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

Int J Mol Sci. 2016 Aug 30;17(9):

Authors: Lv QL, Hu L, Chen SH, Sun B, Fu ML, Qin CZ, Qu Q, Wang GH, He CJ, Zhou HH

Abstract
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

PMID: 27589728 [PubMed - indexed for MEDLINE]

Is deafness mutation screening required in cystic fibrosis patients?

Paediatr Respir Rev. 2016 Aug;20 Suppl:24-6

Authors: Abusamra R, McShane D

Abstract
Aminoglycosides are widely used in cystic fibrosis management. The m.1555A>G mutation predisposes to aminoglycoside ototoxicity. It may cause later onset hearing loss in the absence of aminoglycosides use and gradual hearing loss may be an inevitable consequence of the mutation. Given that aminoglycoside therapy forms the backbone of IV protocols in CF, this article recommends screening for this mutation to allow informed decision-making prior to aminoglycoside administration, to avoid preventable deafness.

PMID: 27427311 [PubMed - indexed for MEDLINE]

Polyphenols from Chilean Propolis and Pinocembrin Reduce MMP-9 Gene Expression and Activity in Activated Macrophages.

Biomed Res Int. 2016;2016:6505383

Authors: Saavedra N, Cuevas A, Cavalcante MF, Dörr FA, Saavedra K, Zambrano T, Abdalla DS, Salazar LA

Abstract
Polyphenols from diverse sources have shown anti-inflammatory activity. In the context of atherosclerosis, macrophages play important roles including matrix metalloproteinases synthesis involved in degradation of matrix extracellular components affecting the atherosclerotic plaque stability. We prepared a propolis extract and pinocembrin in ethanol solution. Propolis extract was chemically characterized using LC-MS. The effect of treatments on gene expression and proteolytic activity was measured in vitro using murine macrophages activated with LPS. Cellular toxicity associated with both treatments and the vehicle was determined using MTT and apoptosis/necrosis detection assays. MMP-9 gene expression and proteolytic activity were measured using qPCR and zymography, respectively. Thirty-two compounds were identified in the propolis extract, including pinocembrin among its major components. Treatment with either ethanolic extract of propolis or pinocembrin inhibits MMP-9 gene expression in a dose-dependent manner. Similarly, an inhibitory effect was observed in proteolytic activity. However, the effect showed by ethanolic extract of propolis was higher than the effect of pinocembrin, suggesting that MMP-9 inhibition results from a joint contribution between the components of the extract. These data suggest a potential role of polyphenols from Chilean propolis in the control of extracellular matrix degradation in atherosclerotic plaques.

PMID: 27119082 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/03/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/03/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Clinical Impact of Pharmacogenetic-Guided Treatment for Patients Exhibiting Neuropsychiatric Disorders: A Randomized Controlled Trial.

Prim Care Companion CNS Disord. 2017 Mar 16;19(2):

Authors: Olson MC, Maciel A, Gariepy JF, Cullors A, Saldivar JS, Taylor D, Centeno J, Garces JA, Vaishnavi S

Abstract
Objective: Pharmacogenetic testing holds promise as a personalized medicine tool by permitting individualization of pharmacotherapy in accordance with genes influencing therapeutic response, side effects, and adverse events. The authors evaluated the effect on outcomes for patients diagnosed with neuropsychiatric disorders of pharmacogenetics (PGx)-guided treatment compared to usual standard of care.
Methods: This was a prospective, randomized study of 237 patients at an outpatient community-based psychiatric practice conducted between April 2015 and October 2015. Baseline patient assessments and a buccal swab were collected for pharmacogenetic testing at study initiation. For the experimental group, PGx results were provided to the clinicians as guides to treatment. Control subjects were treated according to the usual standard of care with no clinician reference to their PGx results. Neuropsychiatric Questionnaire (NPQ) and Symbol Digit Coding Test (SDC) scores and adverse drug events, hospitalizations, and medication information were collected at 30, 60, and 90 days.
Results: More than half (53%) of patients in the control group reported at least 1 adverse drug event compared to 28% of patients with PGx-guided medication management (P = .001). NPQ and SDC scores improved for both groups, but no statistical difference in efficacy as measured by these assessments was observed within the 90-day observation period.
Conclusions: Pharmacogenetic testing may facilitate psychiatric drug therapy with greater tolerability and similar efficacy compared to standard of care.
Trial Registration: ClinicalTrials.gov Identifier: NCT02411123​​.

PMID: 28314093 [PubMed - in process]

Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections.

Pharmacogenet Genomics. 2017 Mar 16;:

Authors: Hamadeh IS, Klinker KP, Borgert SJ, Richards AI, Li W, Mangal N, Hiemenz JW, Schmidt S, Langaee TY, Peloquin CA, Johnson JA, Cavallari LH

Abstract
OBJECTIVES: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.
PATIENT AND METHODS: Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations.
RESULTS: Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044).
CONCLUSION: Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

PMID: 28306618 [PubMed - as supplied by publisher]

[Genetic tests for controlling treatment with antidepressants].

Nervenarzt. 2017 Mar 16;:

Authors: Bschor T, Baethge C, Hiemke C, Müller-Oerlinghausen B

Abstract
In clinical practice, there is a need for a more individualized selection of antidepressants and adequate dosage. The investigation of pharmacokinetically relevant genes is a promising approach to assist this selection. In the past 2 years, two commercially available tests have been subject of advertisement, a test from Stada, which analyses variants of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 and a test from HMNC Brain Health, which analyses variants of the ABCB1 gene. The costs for both kits are not covered by the statutory health insurance and it is therefore proposed that the patients are invoiced directly in the form of individual healthcare payment. The companies claim that by applying the tests antidepressant treatment failure can be avoided and that patients will respond faster to the antidepressant used. These claims are not based on appropriate clinical trials, which are either lacking or reveal conflicting results. Hence, the routine use of these tests is not recommended. In accordance with the German S3 Guideline for unipolar depression, therapeutic drug monitoring (TDM) of serum levels should be carried out in cases of non-response to an antidepressant with adequate dosage and duration. As a rule the costs for TDM are covered by the statutory health insurance. Cytochrome P450 genotyping is only indicated when the serum level is not within the expected range and other reasons to explain this discrepancy are excluded. Many laboratories provide these analyses and in individual cases the costs are reimbursed by the statutory health insurance. Further research should be carried out to investigate the importance of the ABCB1 gene for the treatment with antidepressants.

PMID: 28303314 [PubMed - as supplied by publisher]

A prospective study to assess the association between genotype, phenotype and Prakriti in individuals on phenytoin monotherapy.

J Ayurveda Integr Med. 2017 Mar 14;:

Authors: Thaker SJ, Gandhe PP, Godbole CJ, Bendkhale SR, Mali NB, Thatte UM, Gogtay NJ

Abstract
BACKGROUND: Genetic polymorphisms in drug metabolizing enzymes (DMEs) impart distinct drug metabolizing capacity and a unique phenotype to an individual. Phenytoin has large inter-individual variability in metabolism due to polymorphisms in CYP2C9 and CYP2C19. As per Ayurveda, Prakriti imparts a unique phenotype to an individual.
OBJECTIVE: To assess whether Prakriti can substitute phenotyping [therapeutic drug monitoring (TDM)] and genotyping in individualizing therapy with phenytoin in epilepsy patients.
METHODS AND MATERIALS: This was a cross-sectional study conducted over a period of three years. Prakriti was assessed using standardized and validated software. Polymorphisms in CYP2C9 and CYP2C19 were assessed using Polymerase Chain Reaction (PCR)-Restriction fragment length polymorphism (PCR-RFLP). Plasma concentrations of phenytoin (phenotype) were determined using reverse phase-high performance liquid chromatography (RF-HPLC).
RESULTS: Total 351 patients were enrolled for the study. Kapha vata (KV) (39%) was the predominantly observed Prakriti followed by vata kapha (VK) (20.8%) and vata pitta (VP) (8.83%) among the patients. The CYP2C9 and CYP2C19 genotype distributions were in accordance with Hardy-Weinberg equilibrium. There was no association between Prakriti and genotypes and Prakriti and phenotype (p > 0.05 each). Patients with CYP2C9 *1/*3 genotype were thrice more likely to have toxic plasma concentrations of phenytoin as compared to those with wild-type genotype (*1/*1) (Adjusted odds ratio - 3.36; 95% C.I. 1.61, 7.01). However, no such association was observed between polymorphisms of CYP2C19 and phenotype.
CONCLUSIONS: We did not find any association between Prakriti and either phenotype or genotypes suggesting that Prakriti assessment would be of limited utility in individualizing phenytoin therapy in epilepsy patients.

PMID: 28302415 [PubMed - as supplied by publisher]

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools.

Curr Drug Metab. 2017 Mar 15;:

Authors: Issa NT, Wathieu H, Ojo A, Byers SW, Dakshanamurthy S

Abstract
Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes. Computational workflows that assess drug metabolism and its toxicological and pharmacokinetic effects, such as by applying the adverse outcome pathway framework for risk assessment, may improve the efficiency and speed of preclinical drug development.

PMID: 28302026 [PubMed - as supplied by publisher]

A possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients.

Drug Metab Pharmacokinet. 2016 Dec;31(6):467-470

Authors: Sai K, Kajinami K, Akao H, Iwadare M, Sato-Ishida R, Kawai Y, Takeda K, Tanimoto T, Yamano T, Akasaka T, Ishida T, Hirata KI, Saku K, Yagi S, Soeki T, Sata M, Ueno M, Miyazaki S, Shiraki A, Oyama JI, Node K, Sugamura K, Ogawa H, Kurose K, Maekawa K, Matsuzawa Y, Imatoh T, Hasegawa R, Japanese Pharmacogenomics Data Science Consortium, Saito Y

Abstract
Statin-related myopathy (SRM) is a clinically important adverse reaction. Recent pharmacogenetic research, mainly in non-Asian populations, have indicated clinical relevance of some of genetic biomarkers to SRM, but predictive markers for SRM in Asian populations including Japanese has not yet been established. This study was aimed to identify clinically important genetic markers associated with SRM in Japanese patients. Allele frequencies of the three reported candidate markers - SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 - and carrier frequencies of HLA types were compared between patients with SRM patients (n = 52) and healthy Japanese subjects (n = 2878 or 86 (for rs9806699) as controls). No significant association of RYR2, SLCO1B1, and GATM variants with SRM were observed in our Japanese patients, but a significant association was detected for HLA-DRB1*04:06 with SRM (odds ratio: 3.19; 95% confidence interval: 1.53-6.66). This study suggested that HLA-DRB1*04:06 might be associated with SRM onset in a Japanese population. Further studies are required to validate these results.

PMID: 27839692 [PubMed - indexed for MEDLINE]

Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population.

Drug Metab Pharmacokinet. 2016 Dec;31(6):433-444

Authors: He H, Nie YL, Li JF, Meng XG, Yang WH, Chen YL, Wang SJ, Ma X, Kan QC, Zhang LR

Abstract
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.

PMID: 27727071 [PubMed - indexed for MEDLINE]

Targeting DNA Damage Response in the Radio(Chemo)therapy of Non-Small Cell Lung Cancer.

Int J Mol Sci. 2016 May 31;17(6):

Authors: Li L, Zhu T, Gao YF, Zheng W, Wang CJ, Xiao L, Huang MS, Yin JY, Zhou HH, Liu ZQ

Abstract
Lung cancer is the leading cause of cancer death worldwide due to its high incidence and mortality. As the most common lung cancer, non-small cell lung cancer (NSCLC) is a terrible threat to human health. Despite improvements in diagnosis and combined treatments including surgical resection, radiotherapy and chemotherapy, the overall survival for NSCLC patients still remains poor. DNA damage is considered to be the primary cause of lung cancer development and is normally recognized and repaired by the intrinsic DNA damage response machinery. The role of DNA repair pathways in radio(chemo)therapy-resistant cancers has become an area of significant interest in the clinical setting. Meanwhile, some studies have proved that genetic and epigenetic factors can alter the DNA damage response and repair, which results in changes of the radiation and chemotherapy curative effect in NSCLC. In this review, we focus on the effect of genetic polymorphisms and epigenetic factors such as miRNA regulation and lncRNA regulation participating in DNA damage repair in response to radio(chemo)therapy in NSCLC. These may provide novel information on the radio(chemo)therapy of NSCLC based on the individual DNA damage response.

PMID: 27258253 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/03/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/03/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Risk for molecular contamination of tissue samples evaluated for targeted anti-cancer therapy.

PLoS One. 2017;12(3):e0173760

Authors: Asor E, Stav MY, Simon E, Fahoum I, Sabo E, Ben-Izhak O, Hershkovitz D

Abstract
With the increasing usage of sensitive PCR technology for pharmacogenetics, cross contamination becomes a significant concern. Researchers employed techniques which basically include replacing laboratory equipment after each sample preparation; however, there are no recommended guidelines. In the present work we wanted to evaluate the risk of cross contamination during tissue processing using the routine precaution measures. Twenty-one surgical samples of lung adenocarcinoma were used, of which 7 contained EGFR exon 19 mutation, 7 contained EGFR exon 21 mutation (p.L858R) and 7 were EGFR wild-type. The samples were ordered by alternating the mutation group to maximize the potential for cross contamination and underwent tissue sectioning and de-paraffinization. The entire process was performed using the same tools. Following DNA extraction all samples underwent PCR amplification and were scrutinized for small fractions of EGFR mutation using deep sequencing with the Ion torrent PGM technology. Twenty samples yielded results. The fraction of mutated copies was 41 ± 23% (range 11-66) for the cases with known exon 19 mutation and 48±24% (range 0-65) for the cases with known exon 21 mutations. No in-frame exon 19 deletion mutations were identified in the wild-type (WT) and exon 21 groups. The fraction of EGFR exon 21 (codon 858) mutations was 0.018±0.014% (range 0-0.05%) in the WT and exon 19 groups, which was not statistically different than the background sequencing artifact noise for the same base-pair alteration (p = 0.21). Our results suggest that standard precautions are sufficient for molecular pathology diagnosis of surgical samples and are not associated with increased risk of cross contamination.

PMID: 28288198 [PubMed - in process]