A pilot fMRI study of lithium response in bipolar disorder.

Psychiatry Res Neuroimaging. 2019 Feb 21;286:1-3

Authors: Rootes-Murdy K, Glazer K, Mondimore FM, Goes FS, Pharmacogenomics of Bipolar Disorder (PGBD) Study, Zandi PP, Bakker A, DePaulo JR, Mahon PB

PMID: 30822677 [PubMed - as supplied by publisher]

Current understanding of pharmacogenetic implications of DNA damaging drugs used in osteosarcoma treatment.

Expert Opin Drug Metab Toxicol. 2019 Mar 01;:

Authors: Hattinger CM, Patrizio MP, Luppi S, Magagnoli F, Picci P, Serra M

Abstract
INTRODUCTION: DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients. Area covered. In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed. Expert Opinion. Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.

PMID: 30822170 [PubMed - as supplied by publisher]

Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases.

Expert Opin Drug Metab Toxicol. 2019 Mar 01;:

Authors: Barbosa ACS, Feng Y, Yu C, Huang M, Xie W

Abstract
INTRODUCTION: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury. Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases. Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.

PMID: 30822161 [PubMed - as supplied by publisher]

Determinants of CYP2D6 mRNA levels in healthy human liver tissue.

Clin Transl Sci. 2019 Mar 01;:

Authors: Ning M, Duarte JD, Stevison F, Isoherranen N, Rubin LH, Jeong H

Abstract
Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme that exhibits large interindividual variability. Recent studies suggest that differential transcriptional regulation of CYP2D6 may be in part responsible for the variability. In this study, we characterized potential determinants of CYP2D6 transcript levels in healthy human liver tissue samples (n=115) including genetic polymorphisms in CYP2D6 and the genes encoding transcription regulators for CYP2D6 expression; mRNA expression of the transcription factors and their known target gene; and hepatic levels of bile acid and retinoid, agents that modulate the expression/activity of the transcription factors. Their associations with CYP2D6 mRNA levels in the tissues were examined. Results from multivariable linear regression analysis revealed CYP8B1 mRNA level and rs3892097, the SNP defining the nonfunctional CYP2D6*4 allele, as the two most significant predictors of CYP2D6 mRNA levels in the liver tissue samples, explaining 30% of the variability. This article is protected by copyright. All rights reserved.

PMID: 30821899 [PubMed - as supplied by publisher]

Factors Affecting Interindividual Variability of Hepatic UGT2B17 Protein Expression Examined Using a Novel Specific Monoclonal Antibody.

Drug Metab Dispos. 2019 Feb 28;:

Authors: Emond JP, Labriet A, Desjardins S, Rouleau M, Villeneuve L, Hovington H, Brisson H, Lacombe L, Simonyan D, Caron P, Perigny M, Tetu B, Fallon JK, Klein K, Smith PC, Zanger U, Guillemette C, Levesque E

Abstract
The accurate quantification of the metabolic enzyme UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers reveals a strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification (r = 0.93) and three major expression patterns (absent, low or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, which is located in the binding site for the transcription factor Forkhead Box A1 (FOXA1) of the UGT2B17 promoter. The highest expression was observed for individuals carrying at least one rs59678213 A allele. A multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213 and reached 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize UGT2B17 level in various disease states and establish more precisely the UGT2B17 enzyme contribution to drug and hormone metabolism.

PMID: 30819787 [PubMed - as supplied by publisher]

Insomnia and depressive symptoms in relation to unhealthy eating behaviors in bariatric surgery candidates.

BMC Psychiatry. 2018 05 29;18(1):153

Authors: Wrzosek M, Wojnar M, Sawicka A, Tałałaj M, Nowicka G

Abstract
BACKGROUND: Alongside obesity, insomnia and depression are common public health problems. Sleep problems are currently believed to be associated with excessive food intake and metabolic disturbances. Therefore, we aimed to explore a relationship between insomnia, depressive symptoms and eating habits as well as metabolic parameters in bariatric surgery candidates.
METHODS: A total of 361 unrelated obese subjects were included in this study. Severity of sleep problems was measured with Athens Insomnia Scale (AIS) and the severity of depressive symptoms was assessed with the Beck Depression Inventory (BDI-II). Obstructive sleep apnea (OSA) was assessed by the Apnea Hypopnoea Index (AHI). Information was obtained about demographics, eating habits and lifestyle. Blood samples were collected to measure concentration of lipids (cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol), and glucose.
RESULTS: The median (interquartile range) score for AIS in the study participants was 5 (3-8) with a range of 0-24 and 47% (171) participants scored ≥6 (met criteria for diagnosis of insomnia). Statistically significant correlations were found between the AIS scores and serum triglycerides and glucose concentrations, and BDI-II total scores. The highest scores on AIS and BDI-II were found in participants with high frequency of snack food consumption, in physically inactive individuals as well as in those who self-reported eating at night or who declared more than 3 intense emotions associated with a desire-to-eat. Adjusted multivariate logistic regression analysis revealed that clinical insomnia was most strongly associated with daily consumption of snack foods, with the odds ratio of 3.26 (95% CI: 1.74-6.11), while depressive symptoms were strongly associated with both eating in response to ≥3 specific emotions with OR = 2.93 (95% CI: 1.26-6.78) as well as with daily consumption of snack foods with OR = 2.87 (95% CI: 1.16-5.14).
CONCLUSIONS: The results indicate that insomnia and depression in obese individuals are associated with eating habits, and suggest that in some patients these associations appears as major factors affecting obesity development.

PMID: 29843671 [PubMed - indexed for MEDLINE]

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept.

PLoS One. 2019;14(2):e0213073

Authors: Ferreiro-Iglesias A, Montes A, Perez-Pampin E, Cañete JD, Raya E, Magro-Checa C, Vasilopoulos Y, Caliz R, Ferrer MA, Joven B, Carreira P, Balsa A, Pascual-Salcedo D, Blanco FJ, Moreno-Ramos MJ, Manrique-Arija S, Ordoñez MDC, Alegre-Sancho JJ, Narvaez J, Navarro-Sarabia F, Moreira V, Valor L, Garcia-Portales R, Marquez A, Gomez-Reino JJ, Martin J, Gonzalez A

Abstract
Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

PMID: 30818333 [PubMed - in process]

Cytochrome P450 CYP2B6*6 distribution among Congolese individuals with HIV, Tuberculosis and Malaria infection.

Int J Infect Dis. 2019 Feb 25;:

Authors: Peko SM, Gampio Gueye NS, Vouvoungui C, Koukouikila Koussounda F, Kobawila SC, Nderu D, Velavan TP, Ntoumi F

Abstract
BACKGROUND: The cytochrome P450 CYP2B6*6 (CYP2B6 c.516G > T; rs3745274) is one of the genetic factor that alters the drug metabolism in antimalarial, antiretroviral and TB first-line drugs. In Central African populations, the distribution of the CYP2B6*6 variant is poorly documented. This study investigated on the distribution of CYP2B6 c.516G> T variant among Congolese individuals.
METHODS: A total of 418 patients with HIV-1 mono-infection, HIV-1 and Tuberculosis coinfection and symptomatic P. falciparum malaria were genotyped for the CYP2B6 c.516G> T SNP using Restriction Fragment Length Polymorphism (RFLP). The allele frequencies and genotype distributions were determined.
RESULTS: The CYP2B6 c.516G> T was successfully analysed in 69% (288/418) of the study participants. Among the investigated individuals, the distribution of the major allele CYP2B6*G was 45% and the minor CYP2B6*T allele was 55%. Significant differences in genotype distribution was also observed among the studied individuals. The CYP2B6*GG (rapid metabolizer) genotype was observed in 17% (49/288) followed by CYP2B6*GT (intermediate metabolizer 55% (159/288) and CYP2B6*TT (poor metabolizers) 28% (80/288).
CONCLUSION: This study contributes to increase understanding on population pharmacogenetics and may help policy makers regulate treatment guidelines in the Congolese population with a high burden of HIV, Malaria and TB.

PMID: 30818046 [PubMed - as supplied by publisher]

Reproducibility of pharmacogenetics findings for paclitaxel in a heterogeneous population of patients with lung cancer.

PLoS One. 2019;14(2):e0212097

Authors: Sissung TM, Rajan A, Blumenthal GM, Liewehr DJ, Steinberg SM, Berman A, Giaccone G, Figg WD

Abstract
Pharmacogenetics studies have identified several allelic variants with the potential to reduce toxicity and improve treatment outcome. The present study was designed to determine if such findings are reproducible in a heterogenous population of patients with lung cancer undergoing therapy with paclitaxel. We designed a prospective multi-institutional study that recruited n = 103 patients receiving paclitaxel therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Progression-free survival (PFS) of paclitaxel therapy and clinically-significant paclitaxel toxicities were classified and compared according to genotype. Initial screening revealed eleven variants that are associated with PFS. Of these, seven variants in ABCB11 (rs4148768), ABCC3 (rs1051640), ABCG1 (rs1541290), CYP8B1 (rs735320), NR3C1 (rs6169), FMO6P (rs7889839), and GSTM3 (rs7483) were associated with paclitaxel PFS in a multivariate analysis accounting for clinical covariates. Multivariate analysis revealed four SNPs in VKORC1 (rs2884737), SLC22A14 (rs4679028), GSTA2 (rs6577), and DCK (rs4643786) were associated with paclitaxel toxicities. With the exception of a variant in VKORC1, the present study did not find the same genetic outcome associations of other published research on pharmacogenetics variants that affect paclitaxel outcomes. This finding suggests that prior pharmacogenomics research findings may not be reproduced in the most frequently-diagnosed malignancy, lung cancer.

PMID: 30817750 [PubMed - in process]

Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity.

Addict Biol. 2019 Feb 27;:

Authors: El-Boraie A, Taghavi T, Chenoweth MJ, Fukunaga K, Mushiroda T, Kubo M, Lerman C, Nollen NL, Benowitz NL, Tyndale RF

Abstract
The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.

PMID: 30815984 [PubMed - as supplied by publisher]

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations.

Clin Pharmacokinet. 2019 Feb 28;:

Authors: Ohara M, Suzuki Y, Shinohara S, Gong IY, Schmerk CL, Tirona RG, Schwarz UI, Wen MS, Lee MTM, Mihara K, Nutescu EA, Perera MA, Cavallari LH, Kim RB, Takahashi H

Abstract
BACKGROUND: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown.
METHODS: Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients.
RESULTS: Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 μg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 -1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 -1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4.
CONCLUSIONS: Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

PMID: 30815847 [PubMed - as supplied by publisher]

HIV Universal Vaccine.

Mol Cell Ther. 2018 Apr;6(1):

Authors: Malecki M, Saetre B

Abstract
Background: For many deadly viruses, there are no preventive and / or therapeutic vaccines approved by health authorities World-wide (e.g., HIV, Ebola, Dengue, and many others). Although, for some viruses, prophylactic vaccines are very effective (e.g., HBV, and many others).In this realm, we design, manufacture, test, and streamline into the clinics novel viral universal vaccines (VUV). VUV have such unique features, that medical vaccination or natural infection induced immunity against some viruses (e.g., HBV) upon the VUV's administration to the infected with other, different viruses patients, is redirected against these other, newly infecting viruses (e.g., HIV).
Specific Aim: The specific aim of this work was biomolecular engineering of the HIV universal vaccine comprising the two main functional domains: CD4 or anti-gp120 - as the HIV tagging domain and HBsAg - as the immune response eliciting domain, so that upon its administration the HBV medical immunization or natural infection induced immunity would be redirected, accelerated, and amplified to fight the HIV infection.
Healthy Donors and Patients: Per the Institutional Review Board approval and in compliance with the Declaration of Helsinki, all healthy donors and patients were presented with the Patients' Bill of Rights and provided Patient Informed Consent. All the procedures were pursued by the licensed medical doctors.
Methods & Results: We have biomolecularly engineered HIV universal vaccine (HIVUV) comprising human CD4 or anti-gp120 and HBsAg of HBV. By immunoblotting and magnetic activated molecular sorting, we have demonstrated high specificity of this vaccine in binding HIV. By flow cytometry and nuclear magnetic resonance, we have demonstrated high efficacy of these vaccines to engage HBV immunized patients' immune system against HIV. Administration of HIVUV to blood or lymph of the HIV+ patients resulted in rapid reduction of the HIV viremia down to undetectable. It also resulted in protection of populations of CD4+ cells against HIV caused decline.
Conclusions: We have demonstrated the proof of concept for high efficacy of VUV, specifically HIVUV, in annihilating HIV. Nevertheless, the same compositions, processes, and methods, for persons skilled in biotechnology, pharmacogenomics, and molecular medicine, are adaptable for other deadly viral infections, which we vigorously pursue.

PMID: 30815266 [PubMed]

More accurate semiparametric regression in pharmacogenomics.

Stat Interface. 2018;11(4):573-580

Authors: Rong Y, Zhao SD, Zhu J, Yuan W, Cheng W, Li Y

Abstract
A key step in pharmacogenomic studies is the development of accurate prediction models for drug response based on individuals' genomic information. Recent interest has centered on semiparametric models based on kernel machine regression, which can flexibly model the complex relationships between gene expression and drug response. However, performance suffers if irrelevant covariates are unknowingly included when training the model. We propose a new semiparametric regression procedure, based on a novel penalized garrotized kernel machine (PGKM), which can better adapt to the presence of irrelevant covariates while still allowing for a complex nonlinear model and gene-gene interactions. We study the performance of our approach in simulations and in a pharmacogenomic study of the renal carcinoma drug temsirolimus. Our method predicts plasma concentration of temsirolimus as well as standard kernel machine regression when no irrelevant covariates are included in training, but has much higher prediction accuracy when the truly important covariates are not known in advance. Supplemental materials, including R code used in this manuscript, are available online.

PMID: 30815051 [PubMed]

Combined extract of Moringa oleifera and Centella asiatica modulates oxidative stress and senescence in hydrogen peroxide-induced human dermal fibroblasts.

Turk J Biol. 2018;42(1):33-44

Authors: Abdul Hisam EE, Rofiee MS, Khalid AM, Jalaluddin AF, Mohamad Yusof MI, Idris MH, Ramli S, James RJ, Jack Yoeng W, Lay Kek T, Salleh MZ

Abstract
Moringa oleifera Lam. and Centella asiatica (L.) Urb. leaves have been previously reported to exhibit antioxidant activity. The objective of the present study is to determine the in vitro antioxidant activity of the combined extracts of M. oleifera and C. asiatica (TGT-PRIMAAGE) and its effect on hydrogen peroxide (H 2O2)-induced oxidative stress in human dermal fibroblasts. TGTPRIMAAGE acted on the mechanism of hydrogen transfer as it showed scavenging activity in the DPPH assay. This is due to the presence of phenolics and flavonoids in TGT-PRIMAAGE. TGT-PRIMAAGE effectively reduced cellular generation of reactive oxygen species induced by H O2. The activities of superoxide dismutase and catalase were also increased in cells treated with TGT-PRIMAAGE. 2 Treatment with TGT-PRIMAAGE showed significant reduction (P < 0.05) in the number of senescent cells. Significant reduction (P < 0.05) of malondialdehyde was also seen in cells treated with TGT-PRIMAAGE. The p53 protein level was reduced in TGT-PRIMAAGEtreated cells, which indicates its potential in protecting the cells from oxidative stress induced by H2O2.

PMID: 30814868 [PubMed]

Genetic variability of inflammation and oxidative stress genes does not play a major role in the occurrence of adverse events of dopaminergic treatment in Parkinson's disease.

J Neuroinflammation. 2019 Feb 27;16(1):50

Authors: Redenšek S, Flisar D, Kojović M, Kramberger MG, Georgiev D, Pirtošek Z, Trošt M, Dolžan V

Abstract
BACKGROUND: Inflammation and oxidative stress are recognized as important contributors to Parkinson's disease pathogenesis. As such, genetic variability in these pathways could have a role in susceptibility for the disease as well as in the treatment outcome. Dopaminergic treatment is effective in management of motor symptoms, but poses a risk for motor and non-motor adverse events. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on Parkinson's disease susceptibility and the occurrence of adverse events of dopaminergic treatment.
METHODS: In total, 224 patients were enrolled, and their demographic and clinical data on the disease course were collected. Furthermore, a control group of 146 healthy Slovenian blood donors were included for Parkinson's disease' risk evaluation. Peripheral blood was obtained for DNA isolation. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1β rs16944, IL1β rs1143623, IL6 rs1800795, CAT rs1001179, CAT rs10836235, SOD2 rs4880, NOS1 rs2293054, NOS1 rs2682826, TNF-α rs1800629, and GPX1 rs1050450. Logistic regression was used for analysis of possible associations.
RESULTS: We observed a nominally significant association of the IL1β rs1143623 C allele with the risk for Parkinson's disease (OR = 0.59; 95%CI = 0.38-0.92, p = 0.021). CAT rs1001179 A allele was significantly associated with peripheral edema (OR = 0.32; 95%CI = 0.15-0.68; p = 0.003). Other associations observed were only nominally significant after adjustments: NOS1 rs2682826 A allele and excessive daytime sleepiness and sleep attacks (OR = 1.75; 95%CI = 1.00-3.06, p = 0.048), SOD2 rs4880 T allele and nausea/vomiting (OR = 0.49, 95%CI = 0.25-0.94; p = 0.031), IL1β rs1143623 C allele and orthostatic hypotension (OR = 0.57, 95%CI = 0.32-1.00, p = 0.050), and NOS1 rs2682826 A allele and impulse control disorders (OR = 2.59; 95%CI = 1.09-6.19; p = 0.032). We did not find any associations between selected polymorphisms and motor adverse events.
CONCLUSIONS: Apart from some nominally significant associations, one significant association between CAT genetic variability and peripheral edema was observed as well. Therefore, the results of our study suggest some links between genetic variability in inflammation- and oxidative stress-related pathways and non-motor adverse events of dopaminergic treatment. However, the investigated polymorphisms do not play a major role in the occurrence of the disease and the adverse events of dopaminergic treatment.

PMID: 30813952 [PubMed - in process]

IPCT: Integrated Pharmacogenomic Platform of Human Cancer Cell Lines and Tissues.

Genes (Basel). 2019 Feb 22;10(2):

Authors: Shoaib M, Ansari AA, Haq F, Ahn SM

Abstract
: (1) Motivation: The exponential increase in multilayered data, including omics, pathways, chemicals, and experimental models, requires innovative strategies to identify new linkages between drug response information and omics features. Despite the availability of databases such as the Cancer Cell Line Encyclopedia (CCLE), the Cancer Therapeutics Response Portal (CTRP), and The Cancer Genome Atlas (TCGA), it is still challenging for biologists to explore the relationship between drug response and underlying genomic features due to the heterogeneity of the data. In light of this, the Integrated Pharmacogenomic Database of Cancer Cell Lines and Tissues (IPCT) has been developed as a user-friendly way to identify new linkages between drug responses and genomic features, as these findings can lead not only to new biological discoveries but also to new clinical trials. (2) Results: The IPCT allows biologists to compare the genomic features of sensitive cell lines or small molecules with the genomic features of tumor tissues by integrating the CTRP and CCLE databases with the REACTOME, cBioPortal, and Expression Atlas databases. The input consists of a list of small molecules, cell lines, or genes, and the output is a graph containing data entities connected with the queried input. Users can apply filters to the databases, pathways, and genes as well as select computed sensitivity values and mutation frequency scores to generate a relevant graph. Different objects are differentiated based on the background color of the nodes. Moreover, when multiple small molecules, cell lines, or genes are input, users can see their shared connections to explore the data entities common between them. Finally, users can view the resulting graphs in the online interface or download them in multiple image or graph formats. (3) Availability and Implementation: The IPCT is available as a web application with an integrated MySQL database. The web application was developed using Java and deployed on the Tomcat server. The user interface was developed using HTML5, JQuery v.3.1.0 , and the Cytoscape Graph API v.1.0.4. The IPCT can be accessed at http://ipct.ewostech.net. The source code is available at https://github.com/muhammadshoaib/ipct.

PMID: 30813377 [PubMed]

Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.

PLoS One. 2019;14(2):e0211568

Authors: Muise ES, Guan HP, Liu J, Nawrocki AR, Yang X, Wang C, Rodríguez CG, Zhou D, Gorski JN, Kurtz MM, Feng D, Leavitt KJ, Wei L, Wilkening RR, Apgar JM, Xu S, Lu K, Feng W, Li Y, He H, Previs SF, Shen X, van Heek M, Souza SC, Rosenbach MJ, Biftu T, Erion MD, Kelley DE, Kemp DM, Myers RW, Sebhat IK

Abstract
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

PMID: 30811418 [PubMed - in process]

Early Lessons from the Implementation of Genomic Medicine Programs.

Annu Rev Genomics Hum Genet. 2019 Feb 27;:

Authors: Williams MS

Abstract
Massively parallel sequencing is emerging from research settings into clinical practice, helping the vision of precision medicine to become a reality. The most successful applications are using the tools of implementation science within the framework of the learning health-care system. This article examines the application of massively parallel sequencing to four clinical scenarios: pharmacogenomics, diagnostic testing, somatic testing for molecular tumor characterization, and population screening. For each application, it highlights an exemplar program to illustrate the enablers and challenges of implementation. International examples are also presented. These early lessons will allow other programs to account for these factors, helping to accelerate the implementation of precision medicine and health. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 30811224 [PubMed - as supplied by publisher]

37PGenomics and pharmacogenomics analyses of cancer cell lines using the CellMinerCDB and CellMiner web-applications.

Ann Oncol. 2019 Feb 01;30(Supplement_1):

Authors: Reinhold W, Pommier Y

PMID: 30810190 [PubMed - in process]

Pharmacogenetic variants in Bipolar Disorder with elevated treatment resistance and intolerance: towards a personalised pattern of care.

Bipolar Disord. 2019 Feb 27;:

Authors: Casetta C, Montrasio C, Cheli S, Baldelli S, Bianchi I, Clementi E, Gambini O, D'Agostino A

Abstract
BACKGROUND: Clinical psychiatry has recently begun to promote a personalised approach to care that can offer the best patient-tailored treatment in terms of efficacy and tolerability. Although still in its infancy, pharmacogenetic profiling is one of the most promising tools in a comprehensive, individualized assessment of the patient.
CASE REPORT: We present the case of a woman with treatment-resistant Bipolar Disorder, whose life has been ravaged by continuous hospitalizations for severe manic and depressive episodes. Numerous treatment attempts have been made but side effects occurred with almost all the medications administered, even the lowest doses. A retrospective pharmacogenetic analysis showed a rare pattern of expression for many of the CYP450 enzymes that are involved in the hepatic metabolism of the main compounds available for Bipolar Disorder. Several aspects of the patient's complex response to medication can be explained by a rare combination of CYP3A4/5, CYP2C19, CYP1A2 and, possibly, ABCB1 polymorphisms.
CONCLUSIONS: Although far from a widespread application, pharmacogenetics might represent an extremely useful tool to aim for an individualized therapy, especially in treatment-refractory cases. This article is protected by copyright. All rights reserved.

PMID: 30809922 [PubMed - as supplied by publisher]