The Mouse Hospital and Its Integration in Ultra-Precision Approaches to Cancer Care.

Front Oncol. 2018;8:340

Authors: Clohessy JG, Pandolfi PP

Abstract
Precision medicine holds real promise for the treatment of cancer. Adapting therapeutic strategies so patients receive individualized treatment protocols, will transform how diseases like cancer are managed. Already, molecular profiling technologies have provided unprecedented capacity to characterize tumors, yet the ability to translate this to actionable outcome in the clinic is limited. To enable real time translation of personalized therapeutic approaches to patient care in a co-clinical manner will require the adoption and integration of approaches that facilitate modeling of patient disease. The Mouse Hospital represents an approach that is ideally suited to pre- and co-clinical evaluation of novel therapeutic strategies for clinical care. Patient derived xenograft (PDX) technologies and in situ tumor modeling approaches using genetically engineered mouse models (GEMMs) already have a proven capacity to mimic human tumor responses, and their application can deliver invaluable insights into appropriate clinical approaches for individual patients by mirroring human clinical trials using a Co-Clinical Trial project and Mouse Hospital infrastructure. Additionally, the integration of the Mouse Hospital with other emerging technologies for the application of precision medicines, including organoid technologies, provides a platform that enables medical centers to truly reap the benefits that precision medicine has to offer.

PMID: 30211119 [PubMed]

User considerations in assessing pharmacogenomic tests and their clinical support tools.

NPJ Genom Med. 2018;3:26

Authors: Mukerjee G, Huston A, Kabakchiev B, Piquette-Miller M, van Schaik R, Dorfman R

Abstract
Pharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support. Demystifying an often confusing and variable PGx marketplace can lead to greater acceptance of PGx as a standard-of-care practice that improves drug outcomes and provides a lifetime value for patients. Here, we highlight the key underlying factors of a PGx test that should be considered, and discuss the current progress of PGx implementation.

PMID: 30210808 [PubMed]

American ginseng microbial metabolites attenuate DSS-induced colitis and abdominal pain.

Int Immunopharmacol. 2018 Sep 10;64:246-251

Authors: Wang CZ, Yao H, Zhang CF, Chen L, Wan JY, Huang WH, Zeng J, Zhang QH, Liu Z, Yuan J, Bi Y, Sava-Segal C, Du W, Xu M, Yuan CS

Abstract
Inflammatory bowel disease (IBD) is a significant public health problem in the United States. Abdominal pain is a major complaint among individuals with IBD. Successful IBD management not only controls enteric inflammation, but also reduces abdominal discomfort. Recently, increased attention has been focused on alternative strategies for IBD management. HPLC/Q-TOF-MS analysis was employed to evaluate the intestinal microbiome's biotransformation of parent American ginseng compounds into their metabolites. Using a DSS mouse model, the effects of American ginseng microbial metabolites on chemically induced colitis was investigated with disease activity index and histological assessment. Expressions of inflammatory cytokines were determined using real-time PCR and ELISA. Abdominal pain was evaluated using the von Frey filament test. After the gut microbiome's biotransformation, the major metabolites were found to be the compound K and ginsenoside Rg3. Compared with the DSS animal group, American ginseng treatment significantly attenuated experimental colitis, as supported by the histological assessment. The enteric microbiome-derived metabolites of ginseng significantly attenuated the abdominal pain. American ginseng treatment significantly reduced gut inflammation, consistent with pro-inflammatory cytokine level changes. The gut microbial metabolite compound K showed significant anti-inflammatory effects even at low concentrations, compared to its parent ginsenoside Rb1. American ginseng intestinal microbial metabolites significantly reduced chemically-induced colitis and abdominal pain, as mediated by the inhibition of pro-inflammatory cytokine expression. Intestinal microbial metabolism plays a critical role in American ginseng mediated colitis management.

PMID: 30212750 [PubMed - as supplied by publisher]

Optimization of the Cohesion Index in the SeDeM Diagram Expert System and application of SeDeM Diagram: An improved methodology to determine the Cohesion Index.

PLoS One. 2018;13(9):e0203846

Authors: Nofrerias I, Nardi A, Suñé-Pou M, Boeckmans J, Suñé-Negre JM, García-Montoya E, Pérez-Lozano P, Ticó-Grau JR, Miñarro-Carmona M

Abstract
In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density. Therefore, the resulting tablet will have a height within a defined range of heights where it has no critical effects on its hardness. Then, the impact of this optimization is shown in a formula development, one of the main SeDeM's applications. A mathematical equation was used to calculate the theoretical amount of excipient to formulate the API according to both methodologies. The compression results demonstrate that the characterization with the NM-Icd is more accurate than the previous one while preserving its simplicity.

PMID: 30212557 [PubMed - in process]

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia.

Radiol Oncol. 2018 Sep 11;52(3):296-306

Authors: Gasic V, Zukic B, Stankovic B, Janic D, Dokmanovic L, Lazic J, Krstovski N, Dolzan V, Jazbec J, Pavlovic S, Kotur N

Abstract
Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.

PMID: 30210047 [PubMed - in process]

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Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.

Psychol Med. 2018 Sep 12;:1-9

Authors: Sadeh N, Spielberg JM, Logue MW, Hayes JP, Wolf EJ, McGlinchey RE, Milberg WP, Schichman SA, Stone A, Miller MW

Abstract
BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.
METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.
RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.
CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

PMID: 30207258 [PubMed - as supplied by publisher]

Pharmacogenetic profile and major depressive and/or bipolar disorder treatment: a retrospective, cross-sectional study.

Pharmacogenomics. 2018 Sep 12;:

Authors: Tonozzi TR, Braunstein GD, Kammesheidt A, Curran C, Golshan S, Kelsoe J

Abstract
AIM: To compare pharmacogenetic test predictions with self-reported treatment experience and side effect tolerability among patients with depression taking psychotherapeutic medications.
METHODS: Subjects completed a survey recalling medication effectiveness and side effects and then underwent pharmacogenetic testing.
RESULTS: Our 15 gene pharmacogenetic panel predicted efficacy (p < 0.001) but did not predict side effect tolerability (p = 0.70) in a group of 352 patients. The pharmacogenetic panel and reported efficacy corresponded 60% of the time and medication tolerability agreed 71% of the time.
CONCLUSION: Pharmacogenetic testing may be a useful adjunct to predict efficacy of medications used to treat depression.

PMID: 30207201 [PubMed - as supplied by publisher]

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients.

Pharmacogenomics. 2018 Sep 12;:

Authors: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJ, Appel IM, Tamminga RY, Cessie SL, Swen JJ, der Straaten TV, Boer A, Maitland-van der Zee AH

Abstract
AIM: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm.
METHODS: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement.
RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement.
CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

PMID: 30207196 [PubMed - as supplied by publisher]

Weekly versus 3-weekly paclitaxel in combination with carboplatin in advanced ovarian cancer: which is the optimal adjuvant chemotherapy regimen?

J Gynecol Oncol. 2018 Nov;29(6):e96

Authors: Lee MX, Tan DS

Abstract
The 3-weekly regimen of carboplatin and paclitaxel is the backbone of first line adjuvant chemotherapy for advanced ovarian cancer. The landmark Japanese Gynaecologic Oncology Group (JGOG) 3016 study demonstrated significant improvements in progression-free survival and overall survival with dose dense weekly administration of paclitaxel in combination with 3-weekly carboplatin. However, efforts to replicate these benefits have failed in subsequent phase III trials. Weekly paclitaxel is purported to have enhanced antitumor activity, with stronger anti-angiogenic effects, and yet is better tolerated. In this review, we explore the rationale for dose dense weekly paclitaxel, and compare the relevant trials as well as quality of life considerations. Possible reasons for the difference in outcomes between the JGOG 3016 and other studies are reviewed, with a focus on how the addition of bevacizumab, the variations between histological and molecular subtypes of epithelial ovarian cancers, and ethnic pharmacogenetic differences may potentially affect the efficacy of dose dense paclitaxel.

PMID: 30207104 [PubMed - in process]

Concordance between glucose-6-phosphate dehydrogenase (G6PD) genotype and phenotype and rasburicase use in patients with hematologic malignancies.

Pharmacogenomics J. 2018 Sep 12;:

Authors: Robinson KM, Yang W, Haidar CE, Hankins JS, Jay DW, Kornegay N, Rubnitz JE, Broeckel U, Cheng C, Pui CH, Jeha S, Relling MV

Abstract
Phenotypic rather than genotypic tests remain the gold standard for diagnosing glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, with increasing use of genomic arrays and whole exome or genome sequencing, G6PD genetic data are increasingly available. We examined the utility of G6PD genetic data in patients with hematologic malignancies and the association of G6PD genotype and phenotype with rasburicase-induced methemoglobinemia. We analyzed G6PD activity for 990 patients. Genotype data were available from the Affymetrix DMET array (n = 379), whole exome sequencing (n = 374), and/or the Illumina exome array (n = 634) for 645 patients. Medical records of 341 patients with methemoglobin measures were assessed for the administration of rasburicase. We observed 5 non-synonymous SNPs, 4 of which were known to be associated with deficient G6PD activity (WHO Class I-III). Genotyping 367 males resulted in a positive predictive value of 81.8% (47.8-96.8%), and two males with a Class I-III allele having normal activity both received a red blood cell transfusion prior to the activity assay. However, genotyping males had only 39.1% (20.5-61.2%) sensitivity. Two of the 12 heterozygous females had deficient G6PD activity. Rasburicase-induced methemoglobinemia occurred in 6 patients, 5 of whom had at least one Class I-III allele, despite 2 of these having normal G6PD activity. We conclude that although an apparent nondeficient genotype does not necessarily imply a normal phenotype, a deficient genotype result indicates a deficient phenotype in those without transfusions, and may be a useful adjuct to phenotype to prevent adverse drug reactions.

PMID: 30206300 [PubMed - as supplied by publisher]

An optimized prediction framework to assess the functional impact of pharmacogenetic variants.

Pharmacogenomics J. 2018 Sep 12;:

Authors: Zhou Y, Mkrtchian S, Kumondai M, Hiratsuka M, Lauschke VM

Abstract
Prediction of phenotypic consequences of mutations constitutes an important aspect of precision medicine. Current computational tools mostly rely on evolutionary conservation and have been calibrated on variants associated with disease, which poses conceptual problems for assessment of variants in poorly conserved pharmacogenes. Here, we evaluated the performance of 18 current functionality prediction methods leveraging experimental high-quality activity data from 337 variants in genes involved in drug metabolism and transport and found that these models only achieved probabilities of 0.1-50.6% to make informed conclusions. We therefore developed a functionality prediction framework optimized for pharmacogenetic assessments that significantly outperformed current algorithms. Our model achieved 93% for both sensitivity and specificity for both loss-of-function and functionally neutral variants, and we confirmed its superior performance using cross validation analyses. This novel model holds promise to improve the translation of personal genetic information into biological conclusions and pharmacogenetic recommendations, thereby facilitating the implementation of Next-Generation Sequencing data into clinical diagnostics.

PMID: 30206299 [PubMed - as supplied by publisher]

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Pharmacogenomics J. 2018 Sep 12;:

Authors: Spear ML, Hu D, Pino-Yanes M, Huntsman S, Eng C, Levin AM, Ortega VE, White MJ, McGarry ME, Thakur N, Galanter J, Mak ACY, Oh SS, Ampleford E, Peters SP, Davis A, Kumar R, Farber HJ, Meade K, Avila PC, Serebrisky D, Lenoir MA, Brigino-Buenaventura E, Cintron WR, Thyne SM, Rodriguez-Santana JR, Ford JG, Chapela R, Estrada AM, Sandoval K, Seibold MA, Winkler CA, Bleecker ER, Myers DA, Williams LK, Hernandez RD, Torgerson DG, Burchard EG

Abstract
Short-acting β2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

PMID: 30206298 [PubMed - as supplied by publisher]

Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism.

Pharmacogenomics J. 2018 Sep 12;:

Authors: Yahouédéhou SCMA, Adorno EV, da Guarda CC, Ndidi US, Carvalho SP, Santiago RP, Aleluia MM, de Oliveira RM, Gonçalves MS

Abstract
Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.

PMID: 30206297 [PubMed - as supplied by publisher]

Cardioprotective effect of N-methylnicotinamide salt of pyruvate in experimental model of cardiac hypoxia.

Pharmacol Rep. 2018 Apr;70(2):378-384

Authors: Zabielska MA, Adamus J, Kowalski R, Gebicki J, Slominska EM, Khalpey Z, Smolenski RT

Abstract
BACKGROUND: Pyruvate improves contractility of normal, hypoxic, and post-ischemic myocardium. However, sodium overload is a major problem with its therapeutic application if sodium pyruvate is used. Development of alternative forms such as N-1-methylnicotinamide (MNA) pyruvate may help to overcome this problem. The aim of the study was to investigate the effect of MNA pyruvate in a murine model of cardiac ischemia.
METHODS: Seven month old male ApoE-/-LDLr-/- mice that develop myocardial infarction when exposed to hypoxic stress, were used in this study. Hypoxia (8% O2 in inspired air) was maintained for 8min and was followed by reoxygenation (21% O2 in inspired air). Four groups of mice were treated 10min before the hypoxic event by intravenous injection of MNA, MNA pyruvate, sodium pyruvate, and saline as control. The myocardial ischemia and damage was recorded by ECG. Four hours following the hypoxic episode serum troponin T and creatine kinase activity were measured.
RESULTS: Significant hypernatremia was found in the sodium pyruvate group. During hypoxia, control and MNA group developed profound STU depressions on ECG while no changes were observed in MNA pyruvate and sodium pyruvate group. Creatine kinase activity and troponin T content in the mice plasma were significantly higher in the control and MNA group as compared to the MNA pyruvate and sodium pyruvate group.
CONCLUSIONS: This study demonstrated that administration of MNA pyruvate prior to a hypoxia-induced cardiac event was cardioprotective. This intervention did not cause hypernatremia in contrast to sodium pyruvate.

PMID: 29477947 [PubMed - indexed for MEDLINE]

Pharmacogenetic Aspect of Intravitreal Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration: A Five-Year Follow-Up.

Ocul Immunol Inflamm. 2018;26(6):971-977

Authors: Sengul EA, Artunay O, Rasier R, Kockar A, Afacan C, Hancer VS, Yuzbasioglu E

Abstract
PURPOSE: This study aims to evaluate the role of complement factor H (CFH) in response to intravitreal ranibizumab (IVR) treatment, which is administered to patients with neovascular age-related macular degeneration (nAMD).
METHODS: In this retrospective study, 90 nAMD patients' 90 eyes were evaluated. IVR was injected once a month for three consecutive months, and then, patients were followed up for five years by using pro re nata method.
RESULTS: Average visual acuity (BCVA) values in TT group for the third, fourth and fifth years were found to be significantly higher than those in TC and CC groups, while average BCVA values in TC group were significantly higher than those in CC group (all p = .000 < .0167).
CONCLUSION: Patients with CFH TT genotype responded significantly better to treatment after third year, while patients with CC genotype had a poorer response to IVR.

PMID: 28471284 [PubMed - indexed for MEDLINE]

Genotype-guided Warfarin Dosing in Patients with Mechanical Valves: a Randomized Controlled Trial.

Ann Thorac Surg. 2018 Sep 08;:

Authors: Xu Z, Zhang SY, Huang M, Hu R, Li JL, Cen HJ, Wang ZP, Ou JS, Yin SL, Xu YQ, Wu ZK, Zhang X

Abstract
BACKGROUND: The clinical utility of genotype-guided warfarin dosing remains controversial. The objective of this trial was to evaluate the efficacy and safety of genotype-guided warfarin dosing in East Asians.
METHODS: A double-blind, randomized control trial was performed to compare a genotype-guided dosing algorithm (CYP2C9, VKORC1 and CYP4F2) with a clinical-guided one in the initiation treatment for patients with mechanical heart valves. The primary outcomes included the time to reach a stable dose and the percentage of time in the therapeutic range (TTR).
RESULTS: Two hundred and one patients were randomized, 101 to control and 100 to study. The major bleeding and thromboembolic event-free rate in the study group was 97.0% (95% Confidence Interval: 90.9%-99.2%). Compared with the control group, the study group shortened the time to reach a stable dose (mean: 42.09±23.655d versus 33.52±20.044d, P=0.009). The TTRs were 47.257% and 47.461% in the control and study group (P=0.941) respectively. Patients with the CYP2C9 *1/*3 had higher International Normalized Ratio (INR) variability than patients with the CYP2C9 *1/*1 (P=0.024). Compared with normal and sensitive responders, the highly sensitive ones were at increased risk of an INR≥4.0 (P<0.05).
CONCLUSIONS: The genotype-guided warfarin dosing was safe and might be more efficient with respect to the time to reach a stable dose. Pharmacogenomic testing might be beneficial to identify the patients with the CYP2C9 *1/*3 and the highly sensitive responders, who were high risk subgroup of patients with mechanical heart valves.An appropriately powered study is needed to further confirm the above findings.

PMID: 30205115 [PubMed - as supplied by publisher]

Using genomics to guide treatment for glioblastoma.

Pharmacogenomics. 2018 Sep 11;:

Authors: Young JS, Prados MD, Butowski N

Abstract
Glioblastoma has been shown to have many different genetic mutations found both within and between tumor samples. Molecular testing and genomic sequencing has helped to classify diagnoses and clarify difficult to interpret histopathological specimens. Genomic information also plays a critical role in prognostication for patients, with IDH mutations and MGMT methylation having significant impact of the response to chemotherapy and overall survival of patients. Unfortunately, personalized medicine and targeted therapy against specific mutations have not been shown to improve patient outcomes. As technology continues to improve, exome and RNA sequencing will play a role in the design of clinical trials, classification of patient subgroups and identification of rare mutations that can be targeted by small-molecule inhibitors and biologic agents.

PMID: 30203716 [PubMed - as supplied by publisher]

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

J Allergy Clin Immunol. 2018 Sep 07;:

Authors: Gignoux CR, Torgerson DG, Pino-Yanes M, Uricchio LH, Galanter J, Roth LA, Eng C, Hu D, Nguyen EA, Huntsman S, Mathias RA, Kumar R, Rodriguez-Santana J, Thakur N, Oh SS, McGarry M, Moreno-Estrada A, Sandoval K, Winkler CA, Seibold MA, Padhukasahasram B, Conti DV, Farber HJ, Avila P, Brigino-Buenaventura E, Lenoir M, Meade K, Serebrisky D, Borrell LN, Rodriguez-Cintron W, Thyne S, Joubert BR, Romieu I, Levin AM, Sienra-Monge JJ, Del Rio-Navarro BE, Gan W, Raby BA, Weiss ST, Bleecker E, Meyers DA, Martinez FJ, Gauderman WJ, Gilliland F, London SJ, Bustamante CD, Nicolae DL, Ober C, Sen S, Barnes K, Williams LK, Hernandez RD, Burchard EG

Abstract
BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.
OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.
METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.
RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.
CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

PMID: 30201514 [PubMed - as supplied by publisher]

Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation.

Biochem Pharmacol. 2018 Sep 07;:

Authors: Watanabe T, Saito T, Rico EMG, Hishinuma E, Kumondai M, Maekawa M, Oda A, Saigusa D, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

Abstract
Genetic variations within cytochrome P450 2B6 (CYP2B6) contribute to inter-individual variation in the metabolism of clinically important drugs, including cyclophosphamide, bupropion, methadone and efavirenz (EFZ). In this study, we performed an in vitro analysis of 40 CYP2B6 allelic variant proteins including seven novel variants identified in 1070 Japanese individuals. Wild-type and 39 variant proteins were heterologously expressed in 293FT cells to estimate the kinetic parameters (Km, Vmax, and CLint) of EFZ 8-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin (7-ETC) O-deethylation activities. The concentrations of CYP2B6 variant holo-enzymes were measured by using carbon monoxide (CO)-reduced difference spectroscopy, and the wild-type and 28 variants showed a peak at 450 nm. The kinetic parameters were measured for the wild-type and 24 variant proteins. The values for the remaining 15 variants could not be determined because the enzymatic activity was not detected at the highest substrate concentration used. Compared to wild-type, six variants showed significantly decreased EFZ 8-hydroxylation CLint values, while these values were significantly increased in another six variants, including CYP2B6.6. Although 7-ETC O-deethylation CLint values of CYP2B6 variants did not differ significantly from that of CYP2B6.1, the CLint ratios obtained for 7-ETC O-deethylation were highly correlated with EFZ 8-hydroxylation. Furthermore, three-dimensional structural modeling analysis was performed to elucidate the mechanism of changes in the kinetics of CYP2B6 variants. Our findings could provide evidence of the specific metabolic activities of the CYP2B6 proteins encoded by these variant alleles.

PMID: 30201214 [PubMed - as supplied by publisher]