Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity.

Mol Ther. 2017 Apr 24;:

Authors: Xie J, Mao Q, Tai PWL, He R, Ai J, Su Q, Zhu Y, Ma H, Li J, Gong S, Wang D, Gao Z, Li M, Zhong L, Zhou H, Gao G

Abstract
Short hairpin (sh)RNAs delivered by recombinant adeno-associated viruses (rAAVs) are valuable tools to study gene function in vivo and a promising gene therapy platform. Our data show that incorporation of shRNA transgenes into rAAV constructs reduces vector yield and produces a population of truncated and defective genomes. We demonstrate that sequences with hairpins or hairpin-like structures drive the generation of truncated AAV genomes through a polymerase redirection mechanism during viral genome replication. Our findings reveal the importance of genomic secondary structure when optimizing viral vector designs. We also discovered that shDNAs could be adapted to act as surrogate mutant inverted terminal repeats (mTRs), sequences that were previously thought to be required for functional self-complementary AAV vectors. The use of shDNAs as artificial mTRs opens the door to engineering a new generation of AAV vectors with improved potency, genetic stability, and safety for both preclinical studies and human gene therapy.

PMID: 28462820 [PubMed - as supplied by publisher]

Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD.

Mol Psychiatry. 2017 May 02;:

Authors: da Silva BS, Cupertino RB, Rovaris DL, Schuch JB, Kappel DB, Müller D, Bandeira CE, Victor MM, Karam RG, Mota NR, Rohde LA, Contini V, Grevet EH, Bau CHD

Abstract
Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.Molecular Psychiatry advance online publication, 2 May 2017; doi:10.1038/mp.2017.90.

PMID: 28461697 [PubMed - as supplied by publisher]

Development and validation of UHPLC-MS/MS methods for the quantification of colistin in plasma and dried plasma spots.

J Pharm Biomed Anal. 2016 Sep 10;129:551-7

Authors: Cangemi G, Barco S, Castagnola E, Tripodi G, Favata F, D'Avolio A

Abstract
Quantification of colistin in plasma samples may be very useful in optimizing therapy especially in special patients' population. Nevertheless, therapeutic drug monitoring of colistin is still limited probably for the low number of laboratories which perform this analysis and for high shipment costs. We developed and validated new UHPLC-MS/MS methods to quantify colistin in plasma and in dried plasma spots (DPS) collected on dried sample spots devices (DSSD). Colistin A, Colistin B and polimixin B, used as internal standard, were detected using multiple reaction monitoring (MRM) of the following specific transitions: 585.5→534.9; 576, 578.5→527.9; 568.9 and 602.5→100.9, 551.9, 592.8, respectively. Colistin A and B were extracted from plasma using protein precipitation and from DSSD using an extraction basic solution. Both methods were validated, and the mean intra and inter-day accuracies and precisions were in accordance with FDA and EMA guidelines. Colistin in DPS was found to be stable for at least one week at room temperature (20-25°C). A statistically significant linear correlation was found between colistin extracted from plasma and from DPS [r(2) 0.9864 (P<0.0001, 95% CI 0.9699-0.9939) for colistin A and 0.9695 (P<0.0001, 95% CI 0.9310-0.9866) for colistin B, respectively]. DPS on DSSD represents a safe and cheap strategy to store and ship at room temperature plasma samples. Thus, it is suited for pharmacokinetic studies and therapeutic drug monitoring of colistin.

PMID: 27505127 [PubMed - indexed for MEDLINE]

An American Thoracic Society/National Heart, Lung, and Blood Institute Workshop Report: Addressing Respiratory Health Equality in the United States.

Ann Am Thorac Soc. 2017 May;14(5):814-826

Authors: Celedón JC, Burchard EG, Schraufnagel D, Castillo-Salgado C, Schenker M, Balmes J, Neptune E, Cummings KJ, Holguin F, Riekert KA, Wisnivesky JP, Garcia JGN, Roman J, Kittles R, Ortega VE, Redline S, Mathias R, Thomas A, Samet J, Ford JG, American Thoracic Society and the National Heart, Lung, and Blood Institute

Abstract
Health disparities related to race, ethnicity, and socioeconomic status persist and are commonly encountered by practitioners of pediatric and adult pulmonary, critical care, and sleep medicine in the United States. To address such disparities and thus progress toward equality in respiratory health, the American Thoracic Society and the National Heart, Lung, and Blood Institute convened a workshop in May of 2015. The workshop participants addressed health disparities by focusing on six topics, each of which concluded with a panel discussion that proposed recommendations for research on racial, ethnic, and socioeconomic disparities in pulmonary, critical care, and sleep medicine. Such recommendations address best practices to advance research on respiratory health disparities (e.g., characterize broad ethnic groups into subgroups known to differ with regard to a disease of interest), risk factors for respiratory health disparities (e.g., study the impact of new tobacco or nicotine products on respiratory diseases in minority populations), addressing equity in access to healthcare and quality of care (e.g., conduct longitudinal studies of the impact of the Affordable Care Act on respiratory and sleep disorders), the impact of personalized medicine on disparities research (e.g., implement large studies of pharmacogenetics in minority populations), improving design and methodology for research studies in respiratory health disparities (e.g., use study designs that reduce participants' burden and foster trust by engaging participants as decision-makers), and achieving equity in the pulmonary, critical care, and sleep medicine workforce (e.g., develop and maintain robust mentoring programs for junior faculty, including local and external mentors). Addressing these research needs should advance efforts to reduce, and potentially eliminate, respiratory, sleep, and critical care disparities in the United States.

PMID: 28459618 [PubMed - in process]

Pharmacogenetic testing revisited: 5' nuclease real-time polymerase chain reaction test panels for genotyping CYP2D6 and CYP2C19.

Pharmgenomics Pers Med. 2017;10:115-128

Authors: Larsen JB, Rasmussen JB

Abstract
Due to their involvement in the metabolization of commonly prescribed psychopharmaceutical drugs, the cytochrome oxidase genes CYP2D6 and CYP2C19 are extensive targets for pharmacogenetic testing. The existence of common allelic variants allows the prediction of a metabolic phenotype based on a genotype result, hereby supplying a clinical tool for optimizing prescription and minimizing adverse effects. In this study, we present the development of two 5' nuclease real-time polymerase chain reaction (PCR) test panels, capable of detecting eight of the most clinically relevant alleles of the CYP2D6 gene (*2, *3, *4, *6, *9, *10, 17, *41) and the three most common nonfunctional alleles of CYP2C19 (*2, *3, *4). The assays have been thoroughly validated using a large collection of reference samples, by parallel testing and by DNA sequencing. The reanalysis of reference samples provided the calculation of the frequency of the CYP2D6*4K allele in a population, not previously reported. Furthermore, original test results from CYP2D6*41, generated based on the presence of the 2850T and the lack of the -1584G single-nucleotide polymorphism (SNP), were compared with genotyping based on the current acknowledged founder SNP 2988G of this allele. These results indicate that up to 17.7% of the patients originally tested as carriers of the CYP2D6*41 allele may have had an incorrect phenotypic result assigned. The two 5' nuclease real-time PCR test panels have subsequently been optimized for use in the clinical laboratory, using a standard real-time PCR instrument and software.

PMID: 28458572 [PubMed - in process]

Antidepressant Pharmacogenetics.

Am J Psychiatry. 2017 May 01;174(5):417-418

Authors: Singh AB, Bousman CA

PMID: 28457163 [PubMed - in process]

Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism.

Mol Pharmacol. 2017 Mar;91(3):167-177

Authors: Audet-Delage Y, Rouleau M, Rouleau M, Roberge J, Miard S, Picard F, Têtu B, Guillemette C

Abstract
Alternative splicing at the human glucuronosyltransferase 1 gene locus (UGT1) produces alternate isoforms UGT1A_i2s that control glucuronidation activity through protein-protein interactions. Here, we hypothesized that UGT1A_i2s function as a complex protein network connecting other metabolic pathways with an influence on cancer cell metabolism. This is based on a pathway enrichment analysis of proteomic data that identified several high-confidence candidate interaction proteins of UGT1A_i2 proteins in human tissues-namely, the rate-limiting enzyme of glycolysis pyruvate kinase (PKM), which plays a critical role in cancer cell metabolism and tumor growth. The partnership of UGT1A_i2 and PKM2 was confirmed by coimmunoprecipitation in the HT115 colon cancer cells and was supported by a partial colocalization of these two proteins. In support of a functional role for this partnership, depletion of UGT1A_i2 proteins in HT115 cells enforced the Warburg effect, with a higher glycolytic rate at the expense of mitochondrial respiration, and led to lactate accumulation. Untargeted metabolomics further revealed a significantly altered cellular content of 58 metabolites, including many intermediates derived from the glycolysis and tricarboxylic acid cycle pathways. These metabolic changes were associated with a greater migration potential. The potential relevance of our observations is supported by the down-regulation of UGT1A_i2 mRNA in colon tumors compared with normal tissues. Alternate UGT1A variants may thus be part of the expanding compendium of metabolic pathways involved in cancer biology directly contributing to the oncogenic phenotype of colon cancer cells. Findings uncover new aspects of UGT functions diverging from their transferase activity.

PMID: 28049773 [PubMed - indexed for MEDLINE]

Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

Pharmacogenet Genomics. 2016 Dec;26(12):547-557

Authors: Vandenberghe F, Saigí-Morgui N, Delacrétaz A, Quteineh L, Crettol S, Ansermot N, Gholam-Rezaee M, von Gunten A, Conus P, Eap CB

Abstract
BACKGROUND: Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors.
AIM: The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment.
METHODS: Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients.
RESULTS: Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001).
CONCLUSION: These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG.

PMID: 27741037 [PubMed - indexed for MEDLINE]

Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients.

Pharmacogenet Genomics. 2016 Oct;26(10):462-72

Authors: Genvigir FD, Salgado PC, Felipe CR, Luo EY, Alves C, Cerda A, Tedesco-Silva H, Medina-Pestana JO, Oliveira N, Rodrigues AC, Doi SQ, Hirata MH, Hirata RD

Abstract
BACKGROUND: Polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.
OBJECTIVE: The aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.
MATERIAL AND METHODS: Brazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.
RESULTS: Frequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).
CONCLUSION: The results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.

PMID: 27434656 [PubMed - indexed for MEDLINE]

Rapid evidence review of the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.

Psychopharmacology (Berl). 2017 Apr 29;:

Authors: Peterson K, Dieperink E, Anderson J, Boundy E, Ferguson L, Helfand M

Abstract
OBJECTIVE: This study aims to conduct an evidence review of the effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment for major depressive disorder.
METHODS: We searched MEDLINE®, the Cochrane Central Registry of Controlled Trials, and PsycINFO through February 2017. We used prespecified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO number CRD42016036358).
RESULTS: We included two randomized trials (RCT), five controlled cohort studies, and six modeling studies of mostly women in their mid-40s with few comorbidities. CNSDose (ABCB1, ABCC1, CYP2C19, CYP2D6, UGT1A1) is the only pharmacogenomics test that significantly improved remission (one additional remitting patient in 12 weeks per three genotyped, 95% CI 1.7 to 3.5) and reduced intolerability in an RCT. ABCB1 genotyping leads to one additional remitting patient in 5 weeks per three genotyped (95% CI 3 to 20), but tolerability was not reported. In an RCT, GeneSight (CYP2D6, CYPC19, CYP1A2, SLC6A4, HTR2A) did not statistically significantly improve remission, and evidence is inconclusive about its tolerability. Evidence is generally low strength because RCTs were few and underpowered. Cost-effectiveness is unclear due to lack of directly observed cost-effectiveness outcomes. We found no studies that evaluated whether pharmacogenomics shortens time to optimal treatment, whether improvements were due to switches to genetically congruent medication, or whether effectiveness varies based on test and patient characteristics.
CONCLUSIONS: Certain pharmacogenomics tools show promise of improving short-term remission rates in women in their mid-40s with few comorbidities. But, important evidence limitations preclude recommending their widespread use and indicate a need for further research.

PMID: 28456840 [PubMed - as supplied by publisher]

Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 26;:

Authors: Gassó P, Rodríguez N, Boloc D, Blázquez A, Torres T, Gortat A, Plana MT, Lafuente A, Mas S, Lázaro L

Abstract
Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

PMID: 28456685 [PubMed - as supplied by publisher]

Novel Oxytocin Receptor Variants in Laboring Women Requiring High Doses of Oxytocin.

Am J Obstet Gynecol. 2017 Apr 26;:

Authors: Reinl EL, Goodwin ZA, Raghuraman N, Lee GY, Jo EY, Gezahegn BM, Pillai MK, Cahill AG, de Guzman Strong C, England SK

Abstract
BACKGROUND: Although oxytocin is commonly used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly amongst women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene.
OBJECTIVES: This work aims to identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements.
STUDY DESIGN: Term, nulliparous women requiring oxytocin doses of ≤4 milliunits/minute (low-dose requiring, n=83) or ≥20 milliunits/minute (high-dose requiring, n=104) for labor augmentation or induction were consented to a post-partum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage > 30X) with Illumina MiSeq was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. Fisher's exact or chi-squared tests were used for categorical variables, and Student t-tests or Wilcoxon rank sum tests were used for continuous variables. A P-value < 0.05 was considered statistically significant.
RESULTS: The high-dose-requiring women had higher rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean for first stage arrest and less likely to undergo cesarean for non-reassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n=187) revealed 30 distinct coding variants: 17 non-synonymous, 11 synonymous, and two small structural variations. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine non-synonymous variants were unique to the high-dose-requiring group. These included three known variants (R151C, G221S, and W228C) and six novel variants not found in Ensembl or ExAC (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and non-synonymous substitutions in the patient groups.
CONCLUSIONS: Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. Additionally, we found three oxytocin receptor variants (two novel, one known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women.

PMID: 28456503 [PubMed - as supplied by publisher]

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Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer.

JAMA Oncol. 2017 Apr 27;:

Authors: Drögemöller BI, Monzon JG, Bhavsar AP, Borrie AE, Brooks B, Wright GEB, Liu G, Renouf DJ, Kollmannsberger CK, Bedard PL, Aminkeng F, Amstutz U, Hildebrand CA, Gunaretnam EP, Critchley C, Chen Z, Brunham LR, Hayden MR, Ross CJD, Gelmon KA, Carleton BC

Abstract
Importance: Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects.
Objective: To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients.
Design, Setting, and Participants: This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays.
Exposures: Cisplatin-based chemotherapy.
Main Outcomes and Measures: Cisplatin-induced ototoxic effects.
Results: After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10-7). Functional validation of this transporter gene revealed that in vitro SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing.
Conclusions and Relevance: This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

PMID: 28448657 [PubMed - as supplied by publisher]

Together into the future...Pharmacogenomics and documentation.

Nurs Manage. 2017 May;48(5):32-40

Authors: McCormick KA

Abstract
New partnerships target optimal care quality and outcomes.

PMID: 28448287 [PubMed - in process]

Together into the future... Pharmacogenomics and documentation.

Nurs Manage. 2017 May;48(5):1

Authors:

PMID: 28448279 [PubMed - in process]

Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese.

Cancer Chemother Pharmacol. 2017 Apr 26;:

Authors: Tanabe Y, Shimizu C, Hamada A, Hashimoto K, Ikeda K, Nishizawa D, Hasegawa J, Shimomura A, Ozaki Y, Tamura N, Yamamoto H, Yunokawa M, Yonemori K, Takano T, Kawabata H, Tamura K, Fujiwara Y

Abstract
PURPOSE: Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer.
METHODS: Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN.
RESULTS: Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively).
CONCLUSIONS: ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

PMID: 28447211 [PubMed - as supplied by publisher]

STAT3 regulates glycolysis via targeting hexokinase 2 in hepatocellular carcinoma cells.

Oncotarget. 2017 Apr 11;8(15):24777-24784

Authors: Li M, Jin R, Wang W, Zhang T, Sang J, Li N, Han Q, Zhao W, Li C, Liu Z

Abstract
Signal transducer and activator of transcription 3 (STAT3) and hexokinase 2 (HK2) are involved in hepatocellular carcinoma (HCC). Deregulation of cellular energetics involving an increase in glycolysis is a characteristic of HCC. This study examined whether STAT3 regulates HCC glycolysis through the HK2 pathway in HCC cells. Human HCC cell lines HepG2 and Hep3B cells were transfected with pcDNA3.1(+)-EGFP-STAT3, STAT3 siRNA and HK2 siRNA, respectively, or treated with rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), and the effects on STAT3 and HK2 expression and cell glycolysis were determined. STAT3 and HK2 expressions were evaluated by real-time polymerase chain reaction and Western blotting. The level of glycolysis metabolism was assessed by the determination of glucose consumption and lactate production.The results showed that transfection of HepG2 and Hep3B cells with pcDNA3.1(+)-EGFP-STAT3 significantly increased STAT3 mRNA and protein expression, glucose consumption and lactate production, and HK2 mRNA and protein expression. However, transfection of HepG2 and Hep3B cells with STAT3 siRNA significantly decreased glucose consumption and lactate production and HK2 mRNA and protein expression. Transfection of HepG2 and Hep3B cells with HK2 siRNA significantly decreased glucose consumption and lactate production. Treatment of HepG2 and Hep3B cells with rapamycin significantly reduced HK2 mRNA and protein expression and glucose consumption and lactate production. These results suggest that mTOR-STAT3-HK2 pathway is involved in the glycolysis of HCC cells and STAT3 may regulate HCC glycolysis through HK2 pathway, providing potential multiple therapeutic targets through intervention of glycolysis for the treatment of HCC.

PMID: 28445971 [PubMed - in process]

From genetic single candidate gene studies to complex genomics of GvHD.

Br J Haematol. 2017 Apr 26;:

Authors: Bogunia-Kubik K, Łacina P

Abstract
Graft-versus-host disease (GvHD) is a serious complication affecting the recipients of allogeneic haematopoietic stem cells. In this present review we attempt to summarize the current knowledge on the effect of the donor and recipient genotypes on GvHD, starting from human leucocyte antigen (HLA) matching for an optimal donor selection, typing of non-classical HLA and minor histocompatibility antigens through the polymorphic variations in genes coding for non-HLA proteins contributing to the development of GvHD and response to treatment. The results of recent Candidate Gene Studies (CGS) and Genome-Wide Association Studies (GWAS) are presented and discussed.

PMID: 28444735 [PubMed - as supplied by publisher]

Confused reference in the article entitle: pharmacogenomics of platinum-based chemotherapy in non-small cell lung cancer-focusing on DNA repair systems.

Med Oncol. 2017 Jun;34(6):106

Authors: Wang BY, Zhang QS, Luo Y

PMID: 28444625 [PubMed - in process]