Pharmacogenomics
The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy.
The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy.
Invest New Drugs. 2020 May 02;:
Authors: Zheng Y, Hou G, Zhang G, Lan T, Yuan J, Zhang L, Yan F, Wang F, Meng P, Dun X, Li X, Chen G, Zhu Z, Wei D, He W, Yuan J
Abstract
A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.
PMID: 32361788 [PubMed - as supplied by publisher]
Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease.
Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease.
J Antimicrob Chemother. 2020 May 03;:
Authors: Avataneo V, de Nicolò A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D'Avolio A
Abstract
BACKGROUND: Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.
OBJECTIVES: The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.
METHODS: Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.
RESULTS: Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.
CONCLUSIONS: This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.
PMID: 32361744 [PubMed - as supplied by publisher]
Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia.
Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia.
Int J Mol Sci. 2020 Apr 26;21(9):
Authors: Cacabelos R
Abstract
Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6-10 drugs/day with the consequent risk for drug-drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
PMID: 32357528 [PubMed - as supplied by publisher]
Super High-Flux Hemodialysis Provides Comparable Effectiveness with High-Volume Post-dilution Online Hemodiafiltration in Removing Protein-bound and Middle-molecule Uremic Toxins: A Prospective Cross-over Randomized Controlled Trial.
Super High-Flux Hemodialysis Provides Comparable Effectiveness with High-Volume Post-dilution Online Hemodiafiltration in Removing Protein-bound and Middle-molecule Uremic Toxins: A Prospective Cross-over Randomized Controlled Trial.
Ther Apher Dial. 2020 May 01;:
Authors: Thammathiwat T, Tiranathanagul K, Limjariyakul M, Chariyavilaskul P, Takkavatakarn K, Susantitaphong P, Meesangnin S, Wittayalertpanya S, Praditpornsilpa K, Eiam-Ong S
Abstract
Although high-volume post-dilution online hemodiafiltration (ol-HDF) is superior to high-flux hemodialysis (HD) in removing all kinds of uremic toxins and improving survival, this treatment is not available in most HD centers. The present study was conducted to compare the effectiveness in removals of protein-bound (indoxyl sulfate, IS), middle-molecule [beta-2 microglobulin (B2M) and alpha-1 microglobulin (A1MG)], and small-molecule uremic toxins between super high-flux HD (SHF-HD), HD with a novel SHF dialyzer and high-volume post-dilution ol-HDF in a non-inferiority fashion. Fifteen prevalent HD patients were randomly allocated into 2 sequences of 12-week treatment periods of SHF-HD treatment and later high-volume post-dilution ol-HDF period or vice versa. Each treatment period was divided by a wash out phase of 4-week high-flux HD. Twelve of fifteen patients could complete the study. When compared with high-volume post-dilution ol-HDF (convective volume of 24.4 ± 3.52 L), SHF-HD provided comparable RR values of IS, B2M, and A1MG with mean difference of 5.87 (95% CI,-1.63,13.37), 1.98 (95% CI,-0.21,4.18), and 22.96 (95%CI,-1.91,47.83), respectively. The spKt/Vurea was not different. The pre-dialysis levels of all uremic toxins at baseline and after 12-week treatment did not differ between both groups. Although albumin loss in dialysate in SHF-HD was greater than high-volume post-dilution ol-HDF, the serum albumin levels after 12-week SHF-HD treatment were significantly higher than baseline. In conclusion, SHF-HD provides non-inferior effectiveness to high-volume post-dilution ol-HDF in removing various uremic toxins with significantly increased serum albumin levels despite higher albumin loss. SHF-HD might be an effectively alternative treatment when high-volume post-dilution ol-HDF is not available.
PMID: 32356365 [PubMed - as supplied by publisher]
Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients.
Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients.
J Hum Genet. 2020 May 01;:
Authors: Cha PC, Satake W, Ando-Kanagawa Y, Yamamoto K, Murata M, Toda T
Abstract
Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (PAdjusted = 4.85 × 10-9). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10-7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.
PMID: 32355309 [PubMed - as supplied by publisher]
Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.
Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.
Haematologica. 2020 Apr 30;:
Authors: Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A
Abstract
Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.
PMID: 32354870 [PubMed - as supplied by publisher]
Identification of pharmacogenetic biomarkers for efficacy of cytoreductive surgery plus hyperthermic intraperitoneal mitomycin C in patients with colorectal peritoneal metastases.
Identification of pharmacogenetic biomarkers for efficacy of cytoreductive surgery plus hyperthermic intraperitoneal mitomycin C in patients with colorectal peritoneal metastases.
Eur J Surg Oncol. 2020 Apr 15;:
Authors: Hulshof EC, Lurvink RJ, Caserta N, de Hingh IHJT, van Wezel T, Böhringer S, Swen JJ, Gelderblom H, Guchelaar HJ, Deenen MJ
Abstract
INTRODUCTION: Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1∗2, NQO1∗3, and POR∗28 with the efficacy of CRS + HIPEC with MMC in patients with CPM.
METHOD: A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1∗2, NQO1∗3, and POR∗28 were tested for association.
RESULTS: A total of 253 patients were included. In NQO1∗3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1∗3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03-4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66-3.07]).
CONCLUSION: Carriership of the NQO1∗3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial.
PMID: 32354538 [PubMed - as supplied by publisher]
Response to "Dose rationale for favipiravir use in patients infected with SARS-CoV-2".
Response to "Dose rationale for favipiravir use in patients infected with SARS-CoV-2".
Clin Pharmacol Ther. 2020 Apr 30;:
Authors: Du YX, Chen XP
Abstract
We appreciate the letter by Eloy P., et al for their comments and complement regarding our review1-2 . Two independent in vitro studies indicated that favipiravir (T-705) inhibited SARS-CoV-2 replication in Vero E6 cells with EC50 values of 61.88 μM (9.4 μg/mL)3 and >100 μM (15.7 μg/mL)4 , respectively. Data from the authors' group suggests an EC50 value in the range 40-80 µg/mL (X. de Lamballerie & F. Touret, unpublished results). I agree with the authors' assumption that favipiravir shows similar EC50 against SARS-CoV-2 and EBOV. As favipiravir is a prodrug that requires metabolic activation through ribosylation and phosphorylation in the host cells to form its triphosphate form (favipiravir-RTP), we think that variation in favipiravir activation by the cultured cells may, at least partially, contribute to the difference in the in vitro EC50 among studies.
PMID: 32353191 [PubMed - as supplied by publisher]
Pharmacogenomics Biomarkers of Soft Tissue Sarcoma Therapies.
Pharmacogenomics Biomarkers of Soft Tissue Sarcoma Therapies.
Front Oncol. 2020;10:509
Authors: Caruso C, Garofalo C
Abstract
Soft tissue sarcomas (STS) are heterogeneous rare malignancies comprising ~1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Over the last two decades, the increased knowledge of the new molecular and genomic mechanisms of different STS histotypes allowed for a reclassification of these tumors and consequently to the development of novel chemotherapeutic agents. Generally, surgery, in combination with radiotherapy only in selected cases of localized disease, represents the most common treatment of primary STS, whereas the principal treatment modality for locally advanced or metastatic disease is first-line chemotherapy. The principal treatment for the preponderance of STS patients is usually an anthracycline (epirubicin and doxorubicin) in monotherapy or in combination with other drug novel chemotherapeutic agents. However, survival for treated patients with metastatic disease is poor, and a 2-years survival rate is about 30%. In this scenario, Pharmacogenomics (PGx) biomarkers that can predict drug response play an important role in the improvement of molecular diagnostics in clinical routines and contribute to elucidating the genetic basis for the differences in treatment efficacy and toxicity among STS patients. This review focuses on recent insight in the PGx biomarkers that have been described to modulate responsiveness and toxicity parameters of conventional and new chemotherapeutics drugs in several STS histotypes.
PMID: 32351891 [PubMed]
IL36 Cooperates With Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses.
IL36 Cooperates With Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses.
Front Immunol. 2020;11:634
Authors: Qu Q, Zhai Z, Xu J, Li S, Chen C, Lu B
Abstract
Despite the great impact on long-term survival of some cancer patients, the immune checkpoint blockade (ICB) therapy is limited by its low response rates for most cancers. There is a pressing need for novel combination immunotherapies that overcome the resistance to current ICB therapies. Cytokines play a pivotal role in tumor immunotherapy by helping initiating and driving antitumor immune responses. Here, we demonstrated that, besides conventional CD4+ and CD8+ T cells, IL36 surprisingly increased the number of tumor-infiltrating regulatory T (Treg) cells in vivo and enhanced proliferation of Tregs in vitro. Administration of CTLA-4 monoclonal antibodies (mAbs) strongly enhanced IL36-stimulated antitumor activities through depletion of Tregs. In addition, a cancer gene therapy using the IL36-loaded nanoparticles in combination with CTLA-4 mAbs additively reduced lung metastasis of breast tumor cells. We further showed that the combined therapy of CTLA-4 mAbs and IL36 led to an increase in proliferation and IFN-γ production by CD4+ and CD8+ T cells when compared to single therapy with CTLA-4 mAbs or IL36. Collectively, our findings demonstrated a new combination therapy that could improve the clinical response to ICB immunotherapy for cancer.
PMID: 32351508 [PubMed - in process]
Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.
Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.
Front Pharmacol. 2020;11:445
Authors: Al-Mahayri ZN, Patrinos GP, Ali BR
Abstract
Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determinants in chemotherapy response and the development of side effects. Some pharmacogenomic studies were designed to explore germline variants that can be used as biomarkers for predicting developing toxicity or adverse events during chemotherapy in BC. In this review, we reassess and summarize the major findings of pharmacogenomic studies of chemotherapy toxicity during BC management. In addition, deficiencies hampering utilizing these findings and the potential targets of future research are emphasized. Main insufficiencies in toxicity pharmacogenomics studies originate from study design, sample limitations, heterogeneity of selected genes, variants, and toxicity definitions. With the advent of high throughput genotyping techniques, researchers are expected to explore the identified as well as the potential genetic biomarkers of toxicity and efficacy to improve BC management. However, to achieve this, the limitations of previous work should be evaluated and avoided to reach more conclusive and translatable evidence for personalizing BC chemotherapy.
PMID: 32351390 [PubMed]
Antimicrobial potential, phytochemical profile, cytotoxic and genotoxic screening of Sedum praealtum A. DC. (balsam).
Antimicrobial potential, phytochemical profile, cytotoxic and genotoxic screening of Sedum praealtum A. DC. (balsam).
BMC Complement Med Ther. 2020 Apr 29;20(1):133
Authors: Boriollo MFG, Marques MB, da Silva TA, da Silva JJ, Dias RA, Silva Filho THN, Melo ILR, Dos Santos Dias CT, Bernardo WLC, de Mello Silva Oliveira N, Peters VM, Höfling JF, Spolidorio DMP
Abstract
BACKGROUND: Sedum praealtum has been used for a long time in traditional medicine as an analgesic and anti-inflammatory agent. Its beneficial effects have been known since ancient times, when Latinos used it to treat sore and swollen eyes. This research evaluated the antimicrobial potential, the cytotoxic and genotoxic effects, and some chromatographic profiles of the hydroethanolic extract of leaves, stems and roots of S. praealtum.
METHODS: The antimicrobial activities were carried out by broth microdilution and agar diffusion. In vitro cytotoxicity was evaluated by cell cultures of Aedes albopictus and the selectivity index (SI) was estimated: SI=CI50/MIC. Genotoxic and systemic toxic effects of S. praealtum leaves were analyzed by micronucleus assay in mice bone marrow. Chromatographic profiles and mass spectra were investigated by GC-MS.
RESULTS: Gram-positive (B. subtilis, B. cereus, M. luteus, E. faecalis and S. aureus) and gram-negative (E. coli, E. aerogenes, S. marcescens, P. aeruginosa, P. mirabilis and S. typhimurium) bacteria exhibited MICs ranging from 12.5-50 and 0-50 mg/ml, respectively. Sedum praealtum showed no efficacy against M. tuberculosis and M. bovis. Cytotoxicity (CI50) of S. praealtum was 4.22 and 5.96 mg/ml for leaves and stems, respectively, while its roots showed no cytotoxicity. Micronucleated polychromatic erythrocytes (MNPCEs) analyzes showed no differences between treatment doses (0.5-2 g/kg) and negative control (NaCl), but the PCE/NCE ratio (polychromatic erythrocyte/normochromatic erythrocyte) showed significant differences. Phytochemical screening identified thirteen compounds in the leaves, stems and roots of S. praealtum potentially associated with their biological activities.
CONCLUSIONS: This research comprises a first scientific study on genotoxicity, cytotoxicity and antimicrobial effects of S. praealtum (Balsam), and it provides an initial theoretical foundation for its comprehensive use. Results showed antibacterial action of S. praealtum against gram-positive bacteria and some gram-negative species (depending on the plant anatomical part), but ineffective antimycobacterial action. However, S. praealtum leaves and stems display potential cytotoxicity, contributing to the SI < 1 values. In addition, S. praealtum leaves exhibit no clastogenic and/or aneugenic effects, but it has systemic toxicity dose-independent.
PMID: 32349729 [PubMed - in process]
Gene-Wise Burden of Coding Variants Correlates to Noncoding Pharmacogenetic Risk Variants.
Gene-Wise Burden of Coding Variants Correlates to Noncoding Pharmacogenetic Risk Variants.
Int J Mol Sci. 2020 Apr 27;21(9):
Authors: Park J, Lee SY, Baik SY, Park CH, Yoon JH, Ryu BY, Kim JH
Abstract
Genetic variability can modulate individual drug responses. A significant portion of pharmacogenetic variants reside in the noncoding genome yet it is unclear if the noncoding variants directly influence protein function and expression or are present on a haplotype including a functionally relevant genetic variation (synthetic association). Gene-wise variant burden (GVB) is a gene-level measure of deleteriousness, reflecting the cumulative effects of deleterious coding variants, predicted in silico. To test potential associations between noncoding and coding pharmacogenetic variants, we computed a drug-level GVB for 5099 drugs from DrugBank for 2504 genomes of the 1000 Genomes Project and evaluated the correlation between the long-known noncoding variant-drug associations in PharmGKB, with functionally relevant rare and common coding variants aggregated into GVBs. We obtained the area under the receiver operating characteristics curve (AUC) by comparing the drug-level GVB ranks against the corresponding pharmacogenetic variants-drug associations in PharmGKB. We obtained high overall AUCs (0.710 ± 0.022-0.734 ± 0.018) for six different methods (i.e., SIFT, MutationTaster, Polyphen-2 HVAR, Polyphen-2 HDIV, phyloP, and GERP++), and further improved the ethnicity-specific validations (0.759 ± 0.066-0.791 ± 0.078). These results suggest that a significant portion of the long-known noncoding variant-drug associations can be explained as synthetic associations with rare and common coding variants burden of the corresponding pharmacogenes.
PMID: 32349395 [PubMed - in process]
Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib.
Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib.
Am Heart J. 2020 04;222:157-165
Authors: Tardif JC, Dubé MP, Pfeffer MA, Waters DD, Koenig W, Maggioni AP, McMurray JJV, Mooser V, White HD, Heinonen T, Black DM, Guertin MC, dal-GenE Investigators
Abstract
The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.
PMID: 32087417 [PubMed - indexed for MEDLINE]
Genetic polymorphisms of pharmacogenomic VIP variants in the Dai population from Yunnan province.
Genetic polymorphisms of pharmacogenomic VIP variants in the Dai population from Yunnan province.
Mol Genet Genomic Med. 2020 Apr 29;:e1231
Authors: Cheng Y, Dai R, Chen W, Li Q, Zhang C, Yang T
Abstract
BACKGROUND: Pharmacogenomics plays a crucial role in individualized therapy, but the variant information of pharmacogenomics in the Dai population is limited. We therefore aimed to screen very important pharmacogenetic (VIP) in the Dai population and compared differences between Dai and other 25 populations.
METHODS: In this study, we genotyped 73 VIP variants from the PharmGKB and compared genotype distribution of variants in Dai with other 25 populations by χ2 test. To assess the genetic relationship among 26 populations, we performed the structure analysis. In addition, pair-wise F-statistics (Fst) was calculated to measure the population differentiation.
RESULTS: We found 12, 10, 13, 17, 11, 39, 46, 46, 45, 43, 49, 46, 46, 46, 49, 45, 41, 42, 48, 53, 45, 50, 50, 51, 47, and 50 significantly different variants in Dai compared with other 25 populations. Genetic structure analysis showed Dai had close relationships with CDX (Chinese Dai in Xishuangbanna), CHB (Han Chinese in Beijing), JPT (Japanese in Tokyo), and KHV (Kinh in Ho Chi Minh City, Vietnam). Moreover, Dai is the most similar to KHV according to Fst analysis.
CONCLUSIONS: Our study complement the pharmacogenomics information of Dai population from Yunnan province and provide a theoretical basis for personalized medicine.
PMID: 32347657 [PubMed - as supplied by publisher]
Influence of metabolic profiles on the safety of drug therapy in routine care in Germany: protocol of the cohort study EMPAR.
Influence of metabolic profiles on the safety of drug therapy in routine care in Germany: protocol of the cohort study EMPAR.
BMJ Open. 2020 Apr 27;10(4):e032624
Authors: Huebner T, Steffens M, Linder R, Fracowiak J, Langner D, Garling M, Falkenberg F, Roethlein C, Gomm W, Haenisch B, Stingl J
Abstract
INTRODUCTION: Pre-emptive testing of pharmacogenetically relevant single-nucleotide polymorphisms can be an effective tool in the prevention of adverse drug reactions and therapy resistance. However, most of the tests are not used as standard in routine care in Germany because of lacking evidence for the clinical and economical benefit and their impact on the usage of healthcare services. We address this issue by investigating the influence of pharmacogenetic profiles on the use of healthcare services over an extended period of several years using routine care data from a statutory health insurance company. The goal is to provide clinical evidence whether pre-emptive pharmacogenetic testing of metabolic profiles in routine care in Germany is beneficial and cost-effective.
METHODS AND ANALYSIS: The EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung) study is a non-interventional cohort study conducted to analyse pharmacogenetic risk factors that are important for drug therapy by means of endpoints relevant for healthcare. The analysis is based on pharmacogenetic profiles and statutory health insurance data. We perform pharmacogenetic, pharmacoepidemiological and pharmacoeconomic analyses using health care utilisation scores and machine learning techniques. Therefore, we aim to include about 10 000 patients (≥18 years) insured by the health insurance provider Techniker Krankenkasse. The study focuses on patients with prescriptions of anticoagulants and prescriptions of cholesterol-lowering drugs. Also, a screening for special pharmacogenetic characteristics will be performed in patients with at least one Y57.9! diagnosis (Complication of medical and surgical care: drug or medicament, unspecified). Outcomes include the utilisation of health insurance services, the incidence of incapacity for work and costs for drugs and treatment.
ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committee of the Medical Faculty, University of Bonn (Lfd. Nr. 339/17). The results of this research project will be published in scientific open access journals and at conferences.
TRIAL REGISTRATION NUMBER: German Clinical Trials Register, DRKS00013909.
PMID: 32345696 [PubMed - in process]
The Role of Circulating Adiponectin and SNP276G>T at ADIPOQ Gene in BRCA-mutant Women.
The Role of Circulating Adiponectin and SNP276G>T at ADIPOQ Gene in BRCA-mutant Women.
Cancer Genomics Proteomics. 2020 May-Jun;17(3):301-307
Authors: Daniele A, Paradiso AV, Divella R, Digennaro M, Patruno M, Tommasi S, Pilato B, Tufaro A, Barone M, Minoia C, Colangelo D, Savino E, Casamassima P, Bruno E, Oliverio A, Pasanisi P
Abstract
BACKGROUND: Environmental factors may influence the lifetime risk of cancer (penetrance) in women with a BRCA mutation.
MATERIALS AND METHODS: In 89 BRCA-mutant women, affected or unaffected by breast/ovarian cancer, we explored serum levels of adipokines and their relation with the polymorphism SNP276G>T as modulators of BRCA penetrance.
RESULTS: Affected women had significantly lower adiponectin than healthy women. Affected women with rs1501299 TT had significantly lower adiponectin and higher leptin than GT and GG genotypes. GT genotype was significantly associated with the disease status [odds ratio (OR)=3.24, 95% confidence interval (95% CI)=1.03-10.17]. Women in the lower tertile of serum adiponectin had a RR of BRCA-associated cancer of 2.80, 95% CI=1.1-7.1 (p for trend=0.03) compared with women in the higher tertile.
CONCLUSION: In the SNP rs1501299 the T allele was significantly associated with lower serum levels of adiponectin in affected women, suggesting that the T allele might be related to cancer.
PMID: 32345671 [PubMed - in process]
Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.
Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.
BMC Neurol. 2020 Apr 28;20(1):159
Authors: Yi X, Zhou Q, Zhang Y, Zhou J, Lin J
Abstract
BACKGROUND: Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment.
METHODS: We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10 days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10 days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods.
RESULTS: Among the 375 patients, 95 (25.3%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C19*2 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P = 0.003).
CONCLUSIONS: END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes.
CLINICAL TRIAL REGISTRATION INFORMATION: The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.
PMID: 32345264 [PubMed - in process]
The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids-From Bench to Bedside.
The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids-From Bench to Bedside.
Int J Mol Sci. 2020 Apr 24;21(8):
Authors: Ciebiera M, Włodarczyk M, Zgliczyński S, Łoziński T, Walczak K, Czekierdowski A
Abstract
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30-40%, but may reach up to 70-80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major reason of the overall deterioration of the quality of life. The mechanisms leading to UFs formation and growth still remain poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is thought to be a starting point of all pathways leading to UF formation. Micro-ribonucleic acids (miRNAs) are non-coding single-stranded RNAs about 22 nucleotides in length, that regulate gene expression. One of recent advances in this field is the comprehension of the role of miRNAs in tumorigenesis. Alterations in the levels of miRNAs are related to the formation and growth of several tumors which show a distinct miRNA signature. The aim of this review is to summarize the current data about the role of miRNAs in the pathophysiology of UFs. We also discuss future directions in the miRNA research area with an emphasis on novel diagnostic opportunities or patient-tailored therapies. In our opinion data concerning the regulation of miRNA and its gene targets in the UFs are still insufficient in comparison with gynecological malignancies. The potential translational use of miRNA and derived technologies in the clinical care is at the early phase and needs far more evidence. However, it is one of the main areas of interest for the future as the use of miRNAs in the diagnostics and treatment of UFs is a new and exciting opportunity.
PMID: 32344726 [PubMed - in process]
Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment.
Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment.
Genes (Basel). 2020 Apr 24;11(4):
Authors: Kotur N, Lazic J, Ristivojevic B, Stankovic B, Gasic V, Dokmanovic L, Krstovski N, Milosevic G, Janic D, Zukic B, Pavlovic S
Abstract
Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
PMID: 32344632 [PubMed - in process]