Endocytosis-dependent lysosomal degradation of Src induced by protease-activated receptor 1.

FEBS Lett. 2019 Feb 13;:

Authors: Tsai CC, Kuo FT, Lee SB, Chang YT, Fu HW

Abstract
Src plays a critical role in regulating cellular responses induced by protease-activated receptor 1 (PAR1). Here, we found that PAR1 activation induces lysosomal degradation of Src. Src is associated and trafficked together with activated PAR1 to early endosomes and then sorted to lysosomes for degradation. Blocking agonist-induced endocytosis of PAR1 by inhibition of dynamin activity suppresses PAR1-induced degradation of Src. However, Src activity is not required for agonist-induced PAR1 internalization; nor is it required for Src degradation upon PAR1 activation. We show that PAR1 activation triggers endocytosis-dependent lysosomal degradation of Src in both human embryonic kidney 293 and human umbilical vein endothelial cells. Our finding provides a new paradigm for how an irreversibly activated receptor regulates its downstream signaling. This article is protected by copyright. All rights reserved.

PMID: 30758841 [PubMed - as supplied by publisher]

Development and Cross-Validation of High-Resolution Melting Analysis-Based Cardiovascular Pharmacogenetics Genotyping Panel.

Genet Test Mol Biomarkers. 2019 Feb 13;:

Authors: Langaee T, El Rouby N, Stauffer L, Galloway C, Cavallari LH

Abstract
AIMS: This study was designed to develop a high-resolution melting (HRM) analysis-based cardiovascular (CV) pharmacogenetics (PGx) genotyping panel for the Canon DNA Genetic Analyzer multiplex genotyping platform and cross-validate its performance with the TaqMan®-based OpenArray® method.
METHODS: The CV PGx genotyping panel containing 17 single nucleotide polymorphisms (SNPs) selected from 5 genes (CYP2C9, CYP2C19, CYP4F2, SLCO1B1, and VKORC1) and the CYP2C cluster was used to compare genotyping results between analysis methods. Genomic DNA from 223 clinical samples was used to genotype the 17 SNPs on the Canon DNA Genetic Analyzer and TaqMan OpenArray Quant Studio Real-Time PCR (polymerase chain reaction) System.
RESULTS: The concordance between the Canon DNA analyzer and TaqMan-based OpenArray genotyping results for the 17 SNPs ranged from 99.10% to 100% where SNPs (rs4244285, rs12248560, rs4986893, rs72552267, rs28399504, rs4149056, rs28371686, rs9332131, rs72558189, rs9923231, rs12777823), (rs41291556, rs1799853, rs7900194, rs28371685, rs2108622), and (rs1057910) showed 100%, 99.60%, and 99.10% concordance, respectively.
CONCLUSION: These results show that the HRM analysis-based CV PGx genotyping panel performed well when compared with TaqMan-based OpenArray. The multiple genetic variant testing capability, efficient turnaround time and reproducibility of both assays formats suggest that the PGx panel with the DNA analyzer or other real-time PCR instruments with HRM assay analysis capability can be used for PGx testing in both research and clinical practice settings.

PMID: 30758238 [PubMed - as supplied by publisher]

Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure.

J Cardiovasc Transl Res. 2019 Feb 12;:

Authors: Luzum JA, English JD, Ahmad US, Sun JW, Canan BD, Sadee W, Kitzmiller JP, Binkley PF

Abstract
Two common genetic polymorphisms in the beta-1 adrenergic receptor (ADRB1 Ser49Gly [rs1801252] and Arg389Gly [rs1801253]) significantly affect receptor function in vitro. The objective of this study was to determine whether ADRB1 Ser49Gly and Arg389Gly are associated with recovery of left ventricular ejection fraction (LVEF) in patients with heart failure. Patients with heart failure and baseline LVEF ≤ 40% were genotyped (n = 98), and retrospective chart review assessed the primary outcome of LVEF recovery to ≥ 40%. Un/adjusted logistic regression models revealed that Ser49Gly, but not Arg389Gly, was significantly associated with LVEF recovery in a dominant genetic model. The adjusted odds ratio for Ser49 was 8.2 (95% CI = 2.1-32.9; p = 0.003), and it was the strongest predictor of LVEF recovery among multiple clinical variables. In conclusion, patients with heart failure and reduced ejection fraction that are homozygous for ADRB1 Ser49 were significantly more likely to experience LVEF recovery than Gly49 carriers.

PMID: 30756358 [PubMed - as supplied by publisher]

Inhibitory effects of Kampo medicines, Keishibukuryogan and Shakuyakukanzoto, on the substrate uptake activities of solute carrier organic anion transporters.

J Pharmacol Sci. 2018 Dec;138(4):279-283

Authors: Lee HS, Shin HJ, Cho M, Lee SH, Oh DS

Abstract
The aim of this study was to assess the effects of Keishibukuryogan (K-06) and Shakuyakukanzoto (TJ-68), commercial herbal medicines, on the substrate uptake activities of renal organic anion transporters. We performed transporter uptake and cell viability assays in Xenopus oocytes and HEK293 human kidney embryonic cells treated with K-06 or TJ-68. K-06 and TJ-68 markedly inhibited the substrate uptake activities of URAT1, OAT1, and OAT3, while they did not exhibit non-cytotoxic effects. Our findings demonstrated that K-06 and TJ-68 inhibited the substrate uptake activities of renal transporters, suggesting their mechanism of action as nephroprotective agents.

PMID: 30424926 [PubMed - indexed for MEDLINE]

Allelic frequencies of 60 pharmacogene variants assessed within a Burmese population residing in northeast Indiana, USA.

Pharmacogenomics. 2018 04;19(5):393-399

Authors: Hoefer CC, Brick EJ, Savariar A, Kisor DF, Dawson A, Khatri A, Henriksen B

Abstract
AIM: The aim of this study was to investigate 60 SNPs pertaining to drug metabolism and pharmacodynamics in the Burmese refugee population in the Fort Wayne, Indiana area to better inform patient care.
MATERIALS & METHODS: Sixty-two self-identified Burmese refugees were genotyped for 60 common SNPs pertaining to pharmacokinetic and pharmacodynamic pharmacogenes. The resulting allelic frequencies were compared with Ensembl's database for surrounding populations to Myanmar and America.
RESULTS: The frequency of OPRM1, CYP2D6, SLCO1B1, MTHFR and VKORC1 were approximately 20% different in the Burmese refugee population as compared with the Ensembl populations.
CONCLUSION: Our study demonstrates that genetic differences are expected to affect drug efficacy in patients with a Burmese background.

PMID: 29517466 [PubMed - indexed for MEDLINE]

SNPs affecting the clinical outcomes of regularly used immunosuppressants.

Pharmacogenomics. 2018 04;19(5):495-511

Authors: Meng HY, Luo ZH, Hu B, Jin WL, Yan CK, Li ZB, Xue YY, Liu Y, Luo YE, Xu LQ, Yang H

Abstract
Recent studies have suggested that genomic diversity may play a key role in different clinical outcomes, and the importance of SNPs is becoming increasingly clear. In this article, we summarize the bioactivity of SNPs that may affect the sensitivity to or possibility of drug reactions that occur among the signaling pathways of regularly used immunosuppressants, such as glucocorticoids, azathioprine, tacrolimus, mycophenolate mofetil, cyclophosphamide and methotrexate. The development of bioinformatics, including machine learning models, has enabled prediction of the proper immunosuppressant dosage with minimal adverse drug reactions for patients after organ transplantation or for those with autoimmune diseases. This article provides a theoretical basis for the personalized use of immunosuppressants in the future.

PMID: 29517418 [PubMed - indexed for MEDLINE]

Genetic predictors of efficacy and toxicity of iguratimod in patients with rheumatoid arthritis.

Pharmacogenomics. 2018 04;19(5):383-392

Authors: Xiao W, Guo JP, Li C, Ye H, Wei W, Zou Y, Dai L, Li Z, Zhang M, Li X, Cai X, Zhao J, Wang Y, Tao Y, Liu D, Li Y, Wu M, Sun E, Wu L, Luo L, Mu R, Li Z

Abstract
Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety.
AIM: The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA.
MATERIALS & METHODS: Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2 rs4244285 A carriers had higher risk for IGU-induced toxicity compared to the GG carriers.
CONCLUSION: Our study suggests that the polymorphisms of ABCG2 (rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA.

PMID: 29517409 [PubMed - indexed for MEDLINE]

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

pharmacogenomics

These pubmed results were generated on 2019/02/13

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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

These pubmed results were generated on 2019/02/13

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.

Empirical evaluation of variant calling accuracy using ultra-deep whole-genome sequencing data.

Sci Rep. 2019 Feb 11;9(1):1784

Authors: Kishikawa T, Momozawa Y, Ozeki T, Mushiroda T, Inohara H, Kamatani Y, Kubo M, Okada Y

Abstract
In the design of whole-genome sequencing (WGS) studies, sequencing depth is a crucial parameter to define variant calling accuracy and study cost, with no standard recommendations having been established. We empirically evaluated the variant calling accuracy of the WGS pipeline using ultra-deep WGS data (approximately 410×). We randomly sampled sequence reads and constructed a series of simulation WGS datasets with a variety of gradual depths (n = 54; from 0.05× to 410×). Next, we evaluated the genotype concordances of the WGS data with those in the SNP microarray data or the WGS data using all the sequence reads. In addition, we assessed the accuracy of HLA allele genotyping using the WGS data with multiple software tools (PHLAT, HLA-VBseq, HLA-HD, and SNP2HLA). The WGS data with higher depths showed higher concordance rates, and >13.7× depth achieved as high as >99% of concordance. Comparisons with the WGS data using all the sequence reads showed that SNVs achieved >95% of concordance at 17.6× depth, whereas indels showed only 60% concordance. For the accuracy of HLA allele genotyping using the WGS data, 13.7× depth showed sufficient accuracy while performance heterogeneity among the software tools was observed (the highest concordance of 96.9% was observed with HLA-HD). Improvement in HLA genotyping accuracy by further increasing the depths was limited. These results suggest a medium degree of the WGS depth setting (approximately 15×) to achieve both accurate SNV calling and cost-effectiveness, whereas relatively higher depths are required for accurate indel calling.

PMID: 30741997 [PubMed - in process]

Genetic risk factors and gene-environment interactions in adult and childhood attention-deficit/hyperactivity disorder.

Psychiatr Genet. 2019 Feb 06;:

Authors: Palladino VS, McNeill R, Reif A, Kittel-Schneider S

Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the 'missing heritability' of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene-environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene-environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.

PMID: 30741787 [PubMed - as supplied by publisher]

Severe toxicity in adult patients with lung cancer under treatment with pemetrexed: a prospective cohort study.

J Chemother. 2019 Feb 10;:1-10

Authors: Vázquez C, Orlova M, Verzura MA, Minatta JN, Scibona P, Jáuregui EG, Díaz de Arce H, Pallotta MG, Belloso WH

Abstract
Pemetrexed is an antimetabolite approved for treatment of non-small cell lung cancer. Harbouring interindividual variability in both the pharmacokinetic and pharmacogenetic profiles may lead to life-threatening toxicities. A prospective cohort study of adult patients initiating treatment with pemetrexed in combination with platinum between 2013 and 2015 were follow up. Primary exposure were the methylenetetrahydrofolate reductase (MTHFR) single base polymorphisms in exon 4 and 7 and 5'-UTR- thymidylate synthase (TYMS) VNTR genotypes, in addition to baseline clinical and demographic variables. We used a Cox regression model to evaluate patient's survival and toxicity experience and its association with both baseline characteristics, and a-priori determined genetic polymorphisms. Seventy two patients were included, 52.7% developed severe hematologic toxicity during follow-up. None of the tested genotypes were significantly associated with the main outcome on multivariate analysis, nor other basal clinical variables. Overall survival between patients experiencing the outcome was not different from those without it, but hospital admissions were more frequent. MTHFR and 5'-UTR-TYMS genotypes were not useful for predicting high grade toxicity events in patients under treatment with pemetrexed.

PMID: 30739598 [PubMed - as supplied by publisher]

Are lithium effects dependent on genetic/epigenetic architecture?

Neuropsychopharmacology. 2019 01;44(1):228

Authors: Walss-Bass C, Fries GR

Abstract

PMID: 30194423 [PubMed - indexed for MEDLINE]

The use of mechanistic evidence in drug approval.

J Eval Clin Pract. 2018 10;24(5):1166-1176

Authors: Aronson JK, La Caze A, Kelly MP, Parkkinen VP, Williamson J

Abstract
The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.

PMID: 29888417 [PubMed - indexed for MEDLINE]

An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance.

Cell. 2018 04 19;173(3):649-664.e20

Authors: Bester AC, Lee JD, Chavez A, Lee YR, Nachmani D, Vora S, Victor J, Sauvageau M, Monteleone E, Rinn JL, Provero P, Church GM, Clohessy JG, Pandolfi PP

Abstract
Resistance to chemotherapy plays a significant role in cancer mortality. To identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for acute myeloid leukemia (AML), we developed a comprehensive and integrated genome-wide platform based on a dual protein-coding and non-coding integrated CRISPRa screening (DICaS). Putative resistance genes were initially identified using pharmacogenetic data from 760 human pan-cancer cell lines. Subsequently, genome scale functional characterization of both coding and long non-coding RNA (lncRNA) genes by CRISPR activation was performed. For lncRNA functional assessment, we developed a CRISPR activation of lncRNA (CaLR) strategy, targeting 14,701 lncRNA genes. Computational and functional analysis identified novel cell-cycle, survival/apoptosis, and cancer signaling genes. Furthermore, transcriptional activation of the GAS6-AS2 lncRNA, identified in our analysis, leads to hyperactivation of the GAS6/TAM pathway, a resistance mechanism in multiple cancers including AML. Thus, DICaS represents a novel and powerful approach to identify integrated coding and non-coding pathways of therapeutic relevance.

PMID: 29677511 [PubMed - indexed for MEDLINE]

Setting our AdipoSIGHTS on Stem Cells in Pharmacogenomics.

Cell Stem Cell. 2019 Feb 07;24(2):206-207

Authors: Kovacs P

Abstract
In a recent study published in Cell Stem Cell, Hu et al. (2019) used human adipose stem cell-derived adipocytes to demonstrate that genetic variation predicts anti-diabetic response to thiazolidinediones (TZDs) by modulating PPARγ binding.

PMID: 30735647 [PubMed - in process]

Unraveling Difficult Answers: From Genotype to Phenotype in Coronary Artery Disease.

Cell Stem Cell. 2019 Feb 07;24(2):203-205

Authors: Magdy T, Burridge PW

Abstract
Genome-wide association studies (GWASs) have robustly found a correlation between coronary artery disease (CAD) and an intergenic region at locus 9p21.3. However, the mechanistic implication of this association is unknown. Recently in Cell, Lo Sardo et al. used hiPSC genome editing to demonstrate how this locus contributes to CAD predisposition.

PMID: 30735646 [PubMed - in process]

Low diagnostic accuracy of fragile X tremor/ataxia syndrome diagnostic criteria in late onset ataxia.

Mov Disord. 2019 Feb 08;:

Authors: Dávila-Ortiz de Montellano DJ, Jara-Prado A, Rodríguez-Violante M, Camacho-Molina A, Carnevale A, Fresán-Orellana A, Camarena-Medellín B, Sánchez-García D, Sotelo J

PMID: 30735585 [PubMed - as supplied by publisher]

Association between SLCO1B1 rs4149056 and tegafur-uracil-induced hepatic dysfunction in breast cancer.

Pharmacogenomics. 2019 Feb 08;:

Authors: Kamio H, Uchiyama T, Kanno H, Onoe Y, Saito K, Kameoka S, Kamio T, Okamoto T

Abstract
AIM: The aim of this study was to identify pharmacogenomic biomarkers to predict tegafur-uracil (UFT)-induced liver dysfunction.
PATIENTS & METHODS:  A total of 68 patients, who were administered UFT, were evaluated using a two-step pharmacogenomics analysis.
RESULTS: The first screening revealed the association between five SNPs and UFT-induced hepatic dysfunction. In the second step, SLCO1B1 (rs4149056) was found to be the only SNP associated with UFT treatment-related elevation of aspartate aminotransferase (odds ratio: C/C vs T/T = 7.8, C/T vs T/T = 5.7; p = 0.037) and alanine transaminase (odds ratio: C/C vs T/T = 12.2, C/T vs T/T = 4.1; p = 0.034) levels.
CONCLUSION:  The SLCO1B1 polymorphisms are possible predictors of UFT treatment-related hepatic dysfunction.

PMID: 30734632 [PubMed - as supplied by publisher]

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

Breast Cancer. 2019 Feb 07;:

Authors: Ishiguro H, Ohno S, Yamamoto Y, Takao S, Sato N, Fujisawa T, Kadoya T, Kuroi K, Bando H, Teramura Y, Iwata H, Tanaka S, Toi M

Abstract
BACKGROUND: An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.
METHODS: The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.
RESULTS: Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.
CONCLUSION: TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

PMID: 30734152 [PubMed - as supplied by publisher]