GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications.

Pharmacogenomics. 2019 07;20(10):765-780

Authors: Cruz D, Pinto R, Freitas-Silva M, Nunes JP, Medeiros R

Abstract
Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

PMID: 31368859 [PubMed - indexed for MEDLINE]

Resequencing CYP2D6 gene in Indian population: CYP2D6*41 identified as the major reduced function allele.

Pharmacogenomics. 2019 07;20(10):719-729

Authors: Manoharan A, Shewade DG, Ravindranath PA, Rajkumar RP, Ramprasad VL, Adithan S, Damodaran SE

Abstract
Aim: The CYP2D6 gene is highly polymorphic and harbors population specific alleles that define its predominant metabolizer phenotype. This study aimed to identify polymorphisms in Indian population owing to scarcity of CYP2D6 data in this population. Materials & methods: The CYP2D6 gene was resequenced in 105 south Indians using next generation sequencing technology and haplotypes were reconstructed. Results & conclusion: Four novel missense variants have been designated as CYP2D6*110, *111, *112 and *113. The most common alleles were CYP2D6*1 (42%), *2 (32%), and *41 (12.3%) and diplotypes were CYP2D6*1/*2 (26%), *1/*1 (11%), *2/*41 (10%) and *1/*41 (7%) accounting for high incidence of extensive metabolizers in Indians.

PMID: 31368850 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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

pharmacogenomics

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

Association between the -2548G/A polymorphism of the leptin gene and antipsychotic-induced weight gain: Analysis of the CATIE sample and meta-analysis.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 23;:109952

Authors: Yoshida K, Maciukiewicz M, Zai CC, Gonçalves VF, Brandl EJ, Lieberman JA, Meltzer HY, Tiwari AK, Kennedy JL, Müller DJ

Abstract
BACKGROUND: Antipsychotics, especially most of the second-generation antipsychotics, have a high risk for metabolic syndrome and antipsychotic-induced weight gain (AIWG). A promoter variant of the leptin (LEP) gene, -2548G/A (rs7799039), has been associated with AIWG in several studies. The aim of this study was to evaluate this association in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sample, followed by meta-analysis.
METHODS: We investigated the association between rs7799039 and AIWG in a sub-sample of European (N = 164) individuals from the CATIE study. Body mass index (BMI) change and weight gain (presence or absence) was analyzed using ANCOVA and logistic regression, respectively. For the meta-analysis, a literature search was conducted using MEDLINE, Embase, and PsycINFO up to October 2019. The pooled odds ratio was calculated for presence or absence of weight gain (≥7% weight change) using a random effects model.
RESULTS: We did not detect an association between rs7799039 and BMI change or weight gain (presence or absence) in the CATIE sample. As for the meta-analysis, we included 12 studies. No significant associations between the LEP rs7799039 polymorphism and AIWG were observed under the allelic genetic model (allele A vs. allele G) (OR = 1.10 [0.71, 1.70], p = .68). In the subgroup analyses of first-episode schizophrenia patients, a significant association between the A-allele and weight gain was observed, respectively (OR = 2.32 [1.41, 3.82], p = .0009).
CONCLUSIONS: The present meta-analysis showed no significant effect of rs7799039 on AIWG. However, this variant may influence AIWG in first-episode schizophrenia patients. Further investigation of a larger and more homogenous sample is required to elucidate the role of the LEP gene in AIWG.

PMID: 32335267 [PubMed - as supplied by publisher]

miR-103/107 regulates left-right asymmetry in zebrafish by modulating Kupffer's vesicle development and ciliogenesis.

Biochem Biophys Res Commun. 2020 Apr 22;:

Authors: Heigwer J, Kutzner J, Haeussler M, Burkhalter MD, Draebing T, Juergensen L, Katus HA, Philipp M, Westhoff JH, Hassel D

Abstract
In zebrafish, cilia movement within the Kupffer's vesicle (KV) generates a fluid flow responsible for accumulating nodal signals exclusively in the left lateral plate mesoderm, thereby initiating left-right patterning (LRP). Defects in LRP cause devastating congenital disorders including congenital heart malformations due to organ mis-positioning. We identified the miR-103/107 family to be involved in regulating LRP. Depletion of miR-103/107 in zebrafish embryos resulted in malpositioned and malformed visceral organs and hearts due to disturbed LRP gene expression, indicating early defects in LRP. Additionally, loss of miR-103/107 affected KV morphogenesis and cilia formation without disturbing endoderm development. Human fibroblasts depleted of miR-103a/107 often failed to extend cilia or developed shorter cilia, indicating functional conservation between species. We identified arl6, araf and foxH1 as direct targets of miR-103/107 providing a mechanistic link to cilia development and nodal signal titration. We describe a new microRNA family controlling KV development and hence influencing establishment of internal organ asymmetry.

PMID: 32334837 [PubMed - as supplied by publisher]

Understanding the Pathogenesis, Therapeutic Targets/Drug Action and Pharmacogenetics of Type 2 Diabetes: Is there a Future for Personalised Medicine?

Endocr Metab Immune Disord Drug Targets. 2020 Apr 25;:

Authors: Engwa GA, Nweke FN, Karngong GN, Afiukwa CA, Nwagu KE

Abstract
Type 2 diabetes (T2D) is a chronic non-communicable disease that is of major health concern with a steadily rising prevalence across the globe. It is a metabolic disorder characterized by high blood glucose level either as a result of impaired insulin secretion and/or insulin action usually termed insulin resistance. This disease is influenced by lifestyle/feeding habit changes and genetic factors which causes physiological changes in glucose and lipid metabolism. As such, antidiabetic treatments have targeted specific enzymes, receptors, transport proteins, hormones, transcription factors etc. that are related to glucose metabolism, fat metabolism, insulin secretion and insulin signalization. Genetic variations due to mutations in certain target genes have been shown to influence the pathogenesis of T2D but also these polymorphisms have been observed to alter the therapeutic efficacy of drugs as well as their safety. Pharmacogenetic studies have been able to identify specific genetic variants of target genes that affect the metabolism, therapeutic response and adverse effects of antidiabetic drugs with the aim to translate the research findings to clinical practice. However, pharmacogenetic studies have not fully been able to identify distinct genetic markers that can serve as biomarkers for genetic screening, thus, limiting personalised medicine. As we advocate personalise medicine for the management of T2D in the future, pharmacogenetic studies should lay emphasis in addressing challenges of genetic screening and its translation to personalised therapy.

PMID: 32334506 [PubMed - as supplied by publisher]

137 CME on Pharmacogenomics Testing Improves Knowledge, Competence, and Confidence Related to Implementing Testing in Practice.

CNS Spectr. 2020 Apr;25(2):287

Authors: Lucero KS, Chatterjee-Shin P, Dermer SJ

Abstract
STUDY OBJECTIVE(S): Pharmacogenomics (PGx) testing, in particular combinatorial PGx testing, represents a potential means for delivering personalized treatment selection for patients with psychiatric disorders. The goal of this educational intervention was to educate clinicians about the role of PGx testing in neuropsychiatric conditions such as MDD, how these novel tests may be implemented into clinical practice, and how results may be used to inform decision-making.
METHOD: Psychiatrists (n=830) participated in an online enduring CME activity on PGx testing in psychiatric disorders •The format was a 30-minute 2-person discussion (launched December 7, 2018)•Data from this activity were collected for 30 days after launch•Effectiveness of education for the CME activities was analyzed using 3 multiple-choice and 1 self-efficacy question (5-point Likert-type scale), presented as pre-/post-CME repeated pairs•A paired samples t-test was conducted to examine improvements in mean confidence pre and postParticipant knowledge, competence, and confidence change in pre- to post-CME responses were calculated.
RESULTS: Overall, 72% of psychiatrists (n=830) had knowledge or competence that was reinforced or improved as a result of education.
FOLLOWING EDUCATION: *56% and 12% of psychiatrists had reinforcement and improvement, respectively, in knowledge related to the clinical benefits of PGx-guided treatment strategies•61% and 8% of psychiatrists had reinforcement and improvement, respectively, in competence related to interpreting PGx tests for patients with neuropsychiatric disorders•Within the group of psychiatrists with reinforced and improved knowledge/competence, there was a 30% increase in their confidence using PGx tests to help guide treatment decisions for patients with major depressive disorder (MDD) (M pre=2.14, post=2.77, scale 1 to 5)•Confidence in the use of PGx testing was correlated with likelihood of considering PGx testing for patients with MDD.
CONCLUSIONS: Online CME aided in psychiatrists' knowledge, competence, and confidence in using pharmacogenomics testing in patients with psychiatric disorders.
FUNDING ACKNOWLEDGEMENTS: Supported by an independent educational grant from Myriad Neuroscience, formerly Assurex Health.

PMID: 32331080 [PubMed - as supplied by publisher]

150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression.

CNS Spectr. 2020 Apr;25(2):295-296

Authors: Dunlop BW, Parikh SV, Patel M, Rothschild AJ, Thase ME, DeBattista C, Conway CR, Forester BP, Shelton RC, Macaluso M, Li J, Brown K, Brown L, Jablonski MR, Greden JF

Abstract
BACKGROUND: The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
METHODS: Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: 'use as directed', 'moderate gene-drug interactions', or 'significant gene-drug interactions.' Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
RESULTS: At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
CONCLUSIONS: Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
FUNDING ACKNOWLEDGEMENTS: Assurex Health, Inc.

PMID: 32331038 [PubMed - as supplied by publisher]

110 Implementation of Personalized Medicine in a Community Psychiatry Practice.

CNS Spectr. 2020 Apr;25(2):271

Authors: Umbreit A, Sinha S, Holm E

Abstract
OBJECTIVE: To describe the initial results of implementing pharmacogenomics testing in a community-based psychiatry practice and potential impacts on medication management.
METHOD: Retrospective chart review of prospectively maintained medical records of all adult patients with pharmacogenomics results from 9/01/2017 to 6/30/2019 under the care of psychiatrist and clinical pharmacist.
RESULTS: A total of 51 patients met inclusion criteria. A total of 7 pharmacokinetic genes and, due to changes in the test report over time, a range of 6-10 pharmacodynamic genes relevant to psychotropic medications were evaluated per patient. Every patient had genetic variations, with an average of 6.1 per patient (range 3-9; SD= 1.5). Patients were taking an average of 3.6 (range 1-8; SD=1.7) psychiatric medications at the time of the genetic test, to treat an average of 5 psychiatric conditions (range 1-9; SD=2.2). An average of 1.2 (range 0-4; SD=1.0) gene-drug interactions were uncovered per patient. Following review by psychiatrist and pharmacist, medication adjustments resulted in patients remaining on an average of 3.6 psychiatric medications, but decreasing the average number of gene-drug interactions per patient to 0.8 (range 0-3, SD=0.8).
DISCUSSION: The large number of genetic variations observed per patient is consistent with previous findings 1-2. The decrease in number of gene-drug interactions following testing demonstrates the practical utility of pharmacogenomics information to guide medication therapy. This study did not examine outcomes such as improvement in psychiatric condition or reduction in medication adverse effects; however, these endpoints have been evaluated in other trials 3-4.
CONCLUSIONS: Pharmacogenomics testing presents an opportunity for a personalized medicine approach in a community-based psychiatry practice.

PMID: 32331002 [PubMed - as supplied by publisher]

Nutrigenetics and nutrigenomics: ready for clinical use or still a way to go?

Per Med. 2020 Apr 24;:

Authors: Koromina M, Konstantinidou V, Georgaka M, Innocenti F, Patrinos GP

Abstract
Nutritional Genomics or nutrigenetics/nutrigenomics is an emerging area of research aiming to delineate the interplay between nutrients intake and the reciprocal pathologies with the human genome. Coupled with other omics disciplines, such as metabolomics, proteomics and transcriptomics, nutrigenomics aspires to individualize nutrition, reminiscent of pharmacogenomics and the individualization of drug use. Here, we provide an overview of a session focused on nutrigenomics, organized in conjunction with the Panhellenic Bioscientists Association during the First Greek National Personalised Medicine Conference in Athens, Greece on 15 December 2019.

PMID: 32329405 [PubMed - as supplied by publisher]

Screening Circular RNAs Related to Acquired Gefitinib Resistance in Non-small Cell Lung Cancer Cell Lines.

J Cancer. 2020;11(13):3816-3826

Authors: Wen C, Xu G, He S, Huang Y, Shi J, Wu L, Zhou H

Abstract
Background: Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used to treat EGFR mutation-positive patients with non-small cell lung cancer (NSCLC). However, the efficacy of gefitinib is limited by the development of acquired resistance. Studies have shown that circular RNAs (circRNAs) are involved in the acquired resistance to many anticancer agents. However, the expression profiles and functions of circRNAs in gefitinib resistance in NSCLC are poorly understood so far. Methods: In this study, circRNA expression profiling was explored in two gefitinib-resistant NSCLC cell lines (HCC827/GR and PC9/GR) and their parental sensitive cells (HCC827 and PC9) using high-throughput RNA sequencing. Quantitative real-time PCR (qRT-PCR) was used to confirm the expression of selected differentially expressed circRNAs. Bioinformatic tools including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), network analysis, and Kaplan-Meier plotter database were used to predict the functions and pathways of these differentially expressed circRNAs. Results: We identified 46 and 56 differentially expressed circRNAs in HCC827/GR and PC9/GR cell lines, respectively, compared with those in their parental cell lines. Gene ontology and KEGG pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions. We found that hsa_circ_0000567 was consistently up-regulated, and hsa_circ_0006867 was consistently down-regulated in two resistant cell lines. We further used hsa_circ_0000567 and hsa_circ_0006867 as key circRNAs to construct circRNA-miRNA-mRNA networks. Several target mRNAs of these two circRNAs had been shown to significantly associate with the overall survival of patients with lung cancer. Conclusions: In this study, we generated the comprehensive expression and functional profiles of the differentially expressed circRNAs between gefitinib-resistant and -sensitive NSCLC cells, and showed that dysregulation of circRNAs might play an important role in the development of acquired resistance to gefitinib in NSCLC.

PMID: 32328186 [PubMed]

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study.

Front Pharmacol. 2020;11:325

Authors: Roco A, Nieto E, Suárez M, Rojo M, Bertoglia MP, Verón G, Tamayo F, Arredondo A, Cruz D, Muñoz J, Bravo G, Salas P, Mejías F, Godoy G, Véliz P, Quiñones LA

Abstract
Background: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables.
Objective: The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients.
Methodology: DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0-3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910).
Results: The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability.
Conclusion: We developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.

PMID: 32327994 [PubMed]

Amino Acid Deletions in p6Gag Domain of HIV-1 CRF07_BC Ameliorate Galectin-3 Mediated Enhancement in Viral Budding.

Int J Mol Sci. 2020 Apr 21;21(8):

Authors: Wang WH, Yeh CS, Lin CY, Yuan RY, Urbina AN, Lu PL, Chen YH, Chen YA, Liu FT, Wang SF

Abstract
HIV-1 CRF07_BC is a recombinant virus with amino acid (a.a.) deletions in p6Gag, which are overlapped with the Alix-binding domain. Galectin-3 (Gal3), a β-galactose binding lectin, has been reported to interact with Alix and regulate HIV-1 subtype B budding. This study aims to evaluate the role of Gal3 in HIV-1 CRF07_BC infection and the potential effect of a.a. deletions on Gal3-mediated regulation. A total of 38 HIV-1+ injecting drug users (IDUs) were enrolled in the study. Viral characterization and correlation of Gal3 were validated. CRF07_BC containing 7 a.a. deletions and wild-type in the p6Gag (CRF07_BC-7d and -wt) were isolated and infectious clones were generated. Viral growth kinetic and budding assays using Jurkat-CCR5/Jurkat-CCR5-Gal3 cells infected with CRF07_BC were performed. Results indicate that 69.4% (25/38) of the recruited patients were identified as CRF07_BC, and CRF07_BC-7d was predominant. Slow disease progression and significantly higher plasma Gal3 were noted in CRF07_BC patients (p < 0.01). Results revealed that CRF07_BC infection resulted in Gal3 expression, which was induced by Tat. Growth dynamic and budding assays indicated that Gal3 expression in Jurkat-CCR5 cells significantly enhanced CRF07_BC-wt replication and budding (p < 0.05), while the promoting effect was ameliorated in CRF07_BC-7d. Co-immunoprecipitation found that deletions in the p6Gag reduced Gal-3-mediated enhancement of the Alix-Gag interaction.

PMID: 32326345 [PubMed - in process]

Role of Genetic Variations in the Hepatic Handling of Drugs.

Int J Mol Sci. 2020 Apr 20;21(8):

Authors: Marin JJG, Serrano MA, Monte MJ, Sanchez-Martin A, Temprano AG, Briz O, Romero MR

Abstract
The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

PMID: 32326111 [PubMed - in process]

Ser100-Phosphorylated RORα Orchestrates CAR and HNF4α to Form Active Chromatin Complex in Response to Phenobarbital to Regulate Induction of CYP2B6.

Mol Pharmacol. 2020 03;97(3):191-201

Authors: Fashe M, Hashiguchi T, Negishi M, Sueyoshi T

Abstract
We have previously shown that the retinoid-related orphan receptor alpha (RORα) phosphorylation plays a pivotal role in sulfotransferase 1E1 gene regulation within mouse liver. Here, we found serine 100-phosphorylated RORα orchestrates constitutive androstane receptor (CAR) and hepatocyte nuclear factor 4 alpha (HNF4α) to induce CYP2B6 by phenobarbital (PB) in human primary hepatocytes (HPHs). RORα knockdown using small interfering RNAs suppressed CYP2B6 mRNAs in HPH, whereas transient expression of RORα in COS-1 cells activated CYP2B6 promoter activity in reporter assays. Through chromatin immunoprecipitation (IP) and gel shift assays, we found that RORα in the form of phosphorylated (p-) S100 directly bound to a newly identified RORα response element (RORα response element on CYP2B6 promoter, -660/-649) within the CYP2B6 promoter in untreated or treated HPH. In PB-treated HPH, p-Ser100 RORα was both enriched in the distal phenobarbital response element module (PBREM) and the proximal okadaic acid response element (OARE), a known HNF4α binding site. Chromatin conformation capture assay revealed direct contact between the PBREM and OARE only in PB-treated HPH. Moreover, CAR preferably interacted with phosphomimetically mutated RORα at Ser100 residue in co-IP assay. A gel shift assay with a radiolabeled OARE module and nuclear extracts prepared from PB-treated mouse liver confirmed that HNF4α formed a complex with Ser 100-phosphorylated RORα, as shown by supershifted complexes with anti-p-Ser100 RORα and anti-HNF4α antibodies. Altogether, the results established that p-Ser100 RORα bridging the PBREM and OARE orchestrates CAR and HNF4α to form active chromatin complex during PB-induced CYP2B6 expression in human primary hepatocytes. SIGNIFICANCE STATEMENT: CYP2B6 is a vital enzyme for the metabolic elimination of xenobiotics, and it is prone to induction by xenobiotics, including phenobarbital via constitutive androstane receptor (CAR) and hepatocyte nuclear factor 4 alpha (HNF4α). Here, we show that retinoid-related orphan receptor alpha (RORα), through phosphorylated S100 residue, orchestrated CAR-HNF4α interaction on the CYP2B6 promoter in human primary hepatocyte cultures. These results signify not only the role of RORα in the molecular process of CYP2B6 induction, but it also reveals the importance of conserved phosphorylation sites within the DNA-binding domain of the receptor.

PMID: 31924695 [PubMed - indexed for MEDLINE]

The role of phase I and II genetic polymorphisms, smoking, alcohol and cancer family history, in the risk of developing testicular cancer.

Pharmacogenet Genomics. 2019 09;29(7):159-166

Authors: Roco A, Lavanderos A, Cayún JP, Acevedo C, Celedón C, Rubilar JC, Sandoval C, Cerpa L, García-Martín E, Agúndez JA, Esguevillas G, Amo G, Canepa A, Cerda B, Peña K, Cáceres DD, Varela NM, Quiñones LA

Abstract
BACKGROUND: Testicular cancer (TCa) is a malignant tumor with highest incidence and mortality rates in Chile. The genes coding for cytochrome P450, glutathione-S-transferases (GSTs), and UDP glucuronyl transferases (UGT) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes have been associated with a high incidence of various types of cancer and an increased risk of presenting adverse reactions to drugs.
OBJECTIVE: The aim of this study was to relate the presence of genetic polymorphisms in cytochrome P450 1A1 (CYP1A1), CYP3A4, GSTM1, GSTP1, GSTT1, and UGT1A1 genes and nongenetic factors with the risk of developing TCa.
METHODS: A total of 276 volunteers from the Chilean general population and 251 Chilean TCa patients were recruited for the study. Genotypic analyses were performed using qPCR and PCR-RFLP.
RESULTS: Variant alleles found to increase the risk of developing TCa were CYP1A1*2C (rs1048943), GSTP1 (rs1695), and GSTT1null, especially when in conjunction with a cancer family history and/or a smoking habit. The results of the multivariate analysis showed that the presence of variant alleles of GSTP1 (rs1695) together with a smoking habit and a family history of cancer accounted for a 15.9% risk of developing TCa in the Chilean population. CYP1A1*2C, GSTM1null, GSTT1null, and GSTP1 (rs1695) are statistically related to the risk of appearance of TCa, alone or associated with nongenetic factors.
CONCLUSION: Therefore, phase I and II variant alleles might be useful in evaluating susceptibility to TCa in the studied population.

PMID: 31107374 [PubMed - indexed for MEDLINE]

Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors.

Eur J Med Chem. 2020 Apr 06;196:112291

Authors: Nepali K, Chang TY, Lai MJ, Hsu KC, Yen Y, Lin TE, Lee SB, Liou JP

Abstract
This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.

PMID: 32325365 [PubMed - as supplied by publisher]

Incidence of Adverse Drug Reactions in COVID-19 patients in China: an active monitoring study by Hospital Pharmacovigilance System.

Clin Pharmacol Ther. 2020 Apr 23;:

Authors: Sun J, Deng X, Chen X, Huang J, Huang S, Li Y, Feng J, Liu J, He G

Abstract
To evaluate the incidence, type and risk factors associated with adverse drug reactions (ADRs) among COVID-19 patients by Hospital Pharmacovigilance System (CHPS). A retrospective analysis was performed on 217 COVID-19 patients admitted to the First Hospital of Changsha in China, from January 17, 2020 to February 29, 2020. The active monitoring model in CHPS was used to detect ADR signals of hospital information system. The risk factors for the ADRs were classified using the WHO-UMC system. Univariate and multivariate logistic regression was carried out to analyze the risk factors of ADRs. Our results showed that the prevalence of ADRs was 37.8% in the patients, which was predominated by drug-induced gastrointestinal disorders and liver system disorders (23.0% vs. 13.8% ). The ADR could be explained by the use of lopinavir/ ritonavir and umifenovir by 63.8% and 18.1%, respectively. 96.8% of ADRs occurred within 14 days of hospitalization. Multivariable analysis showed that length of stay (OR: 2.02, [95% CI: 1.03-3.96], P=0.04), number of drugs used in hospital (OR: 3.17, [95%CI: 1.60-6.27], P=0.001) and underlying basic diseases (OR:2.07, [95%CI: 1.02-4.23], P = 0.04) were independent risk factor for ADRs in the patients. Together, the incidence of ADRs was significantly high during the treatment period. Moreover, the active monitoring of the CHPS system reflected ADRs during COVID-19 treatment in the real world, which provided reference for safe medication in clinic.

PMID: 32324898 [PubMed - as supplied by publisher]

Ketamine Treatment in Depression: A Systematic Review of Clinical Characteristics Predicting Symptom Improvement.

Curr Top Med Chem. 2020 Apr 22;:

Authors: Lowe DJE, Müller DJ, George TP

Abstract
Ketamine has been shown to be efficacious for the treatment of depression, specifically among individuals who do not responded to first-line treatments. There is still, however, a lack of clarity surrounding the clinical features and response periods across samples that respond to ketamine. This paper systematically reviews published randomized, controlled trials that investigate ketamine as an antidepressant intervention in both unipolar and bipolar depression to determine the specific clinical features of the samples across different efficacy periods. Moreover, similarities and differences in clinical characteristics associated with acute versus longer-term drug response are discussed. Similarities across all samples suggest that the population that responds to ketamine's antidepressant effect have experienced chronic, long-term depression, approaching ketamine treatment as a "last resort". Moreover, differences between these groups suggest future research to investigate the potential of stronger efficacy towards depression in the context of bipolar disorder compared to major depression, and in participants who undergo antidepressant washout before ketamine administration. From these findings, suggestions for the future direction of ketamine research for depression are formed.

PMID: 32324515 [PubMed - as supplied by publisher]