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Pharmacogenomics Journal

Rosario López-Rodríguez, Aida Ferreiro-Iglesias, Aurea Lima, Miguel Bernardes, Andrzej Pawlik, Agnieszka Paradowska-Gorycka, Jerzy Świerkot, Ryszard Slezak, Isidoro Gonzalez-Alvaro, Javier Narvaez, Eva Pérez-Pampín, Antonio Mera-Varela, Laura Vidal-Bralo, José Gorgonio Acuña-Ochoa, Carmen Conde, Antonio Gonzalez
Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit...
March 8, 2018: Pharmacogenomics Journal
Yu Wu, Yilun Zhou, Yuesong Pan, Xingquan Zhao, Liping Liu, David Wang, Chunxue Wang, Hao Li, S Claiborne Johnston, Xia Meng, Yilong Wang, Yongjun Wang
Clopidogrel resistance is prevalent in chronic kidney disease (CKD) patients. Genetic polymorphism is considered to be the most important factor that influences clopidogrel resistance. Limited data exist as to the role of pharmacogenetics in prognosis of stroke patients with impaired renal function on clopidogrel. We sought to explore whether decreased kidney function alters the association between CYP2C19 genetic variants and clinical outcome in patients with minor stroke or transient ischemic attack (TIA) receiving clopidogrel therapy...
March 8, 2018: Pharmacogenomics Journal
Prema S Rao, Ryan Endicott, Randy Mullins, U Subrahmanyeswara Rao
Comparison of human genome sequences from different individuals has unraveled that genes involved in the drug efficacy and metabolism are polymorphic, harboring mutations, splicing variations and other alterations. These data provide a reasonable explanation for the inter-individual variations observed in drug therapy. Thus, a detailed molecular analysis and an in-depth knowledge of these genes is a prerequisite to practice pharmacogenomics-based medicine. We have introduced a 6-week laboratory research rotation to train students in the expression analysis of different pharmacogenes combined with bioinformatics tools...
March 8, 2018: Pharmacogenomics Journal
K Tryfonidis, C Papadaki, S Assele, E Lagoudaki, J Menis, A Koutsopoulos, M Trypaki, E Tsakalaki, M Sfakianaki, B Hasan, E Stathopoulos, V Georgoulias, J Souglakos
Differences in gene expression levels between the primary tumors (PTs) and matched regional lymph nodal metastases (LNs) in patients with totally excised non-small cell lung cancer (NSCLC) were explored. Microdissected formalin-fixed paraffin-embedded (FFPE) samples from (PT) and their matched infiltrated LNs, from 239 patients [183 (with matched PT and LNs samples)-case and 56 PT only samples-control cohorts] were analyzed for BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression by quantitative real-time polymerase-chain reaction (PCR)...
February 22, 2018: Pharmacogenomics Journal
Takahiro Mimori, Jun Yasuda, Yoko Kuroki, Tomoko F Shibata, Fumiki Katsuoka, Sakae Saito, Naoki Nariai, Akira Ono, Naomi Nakai-Inagaki, Kazuharu Misawa, Keiko Tateno, Yosuke Kawai, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Kichiya Suzuki, Kengo Kinoshita, Masao Nagasaki, Masayuki Yamamoto
Human leukocyte antigen (HLA) is a gene complex known for its exceptional diversity across populations, importance in organ and blood stem cell transplantation, and associations of specific alleles with various diseases. We constructed a Japanese reference panel of class I HLA genes (ToMMo HLA panel), comprising a distinct set of HLA-A, HLA-B, HLA-C, and HLA-H alleles, by single-molecule, real-time (SMRT) sequencing of 208 individuals included in the 1070 whole-genome Japanese reference panel (1KJPN). For high-quality allele reconstruction, we developed a novel pipeline, Primer-Separation Assembly and Refinement Pipeline (PSARP), in which the SMRT sequencing and additional short-read data were used...
January 19, 2018: Pharmacogenomics Journal
Emma K Erickson, Sean P Farris, Yuri A Blednov, R Dayne Mayfield, R Adron Harris
Astrocytes play critical roles in central nervous system (CNS) homeostasis and are implicated in the pathogenesis of neurological and psychiatric conditions, including drug dependence. Little is known about the effects of chronic ethanol consumption on astrocyte gene expression. To address this gap in knowledge, we performed transcriptome-wide RNA sequencing of astrocytes isolated from the prefrontal cortex (PFC) of mice following chronic ethanol consumption. Differential expression analysis revealed ethanol-induced changes unique to astrocytes that were not identified in total homogenate preparations...
January 5, 2018: Pharmacogenomics Journal
Ismat Khatri, Christian Alexander, Klaus Brandenburg, Zhiqi Chen, Adrian Heini, Didier Heumann, Jean-Pierre Mach, Vienna Mazzoli, Ernst Rietschel, Alexey Tersikh, Artur Ulmer, Kai Yu, Ulrich Zähringer, Reginald Gorczynski
Injections of a crude fetal sheep liver extract (FSLE) containing fetal hemoglobin, MPLA, and glutathione (GSSH) reversed cytokine changes in aged mice. To investigate the role of fetal hemoglobin we derived mice with homzygous deletions for either of the two major βchains, HgbβmaKO or HgbβmiKO. Hgbβmi is the most prominent fetal Hgbβ chain, with Hgbβma more prominent in adult mice. Mice lacking another fetal Hgb chain, HgbεKO, died in utero. CHO cells transfected with cloned Hgb chains were used to produce proteins for preparation of rabbit heteroantibodes...
January 4, 2018: Pharmacogenomics Journal
Amber Dahlin, Weiliang Qiu, Augusto A Litonjua, John J Lima, Mayumi Tamari, Michiaki Kubo, Charles G Irvin, Stephen P Peters, Ann C Wu, Scott T Weiss, Kelan G Tantisira
Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control)...
January 3, 2018: Pharmacogenomics Journal
Payman Shahabi, Félix Lamothe, Stéphanie Dumas, Étienne Rouleau-Mailloux, Yassamin Feroz Zada, Sylvie Provost, Geraldine Asselin, Ian Mongrain, Diane Valois, Marie-Josée Gaulin Marion, Louis-Philippe Lemieux Perreault, Sylvie Perreault, Marie-Pierre Dubé
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2...
January 3, 2018: Pharmacogenomics Journal
François R Girardin, Antoine Poncet, Arnaud Perrier, Nathalie Vernaz, Mark Pletscher, Caroline F Samer, Jeffrey A Lieberman, Jean Villard
Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA...
January 3, 2018: Pharmacogenomics Journal
Núria Saigi-Morgui, Lina Quteineh, Pierre-Yves Bochud, Severine Crettol, Zoltán Kutalik, Nicolas J Mueller, Isabelle Binet, Christian Van Delden, Jürg Steiger, Paul Mohacsi, Jean-Francois Dufour, Paola M Soccal, Manuel Pascual, Chin B Eap
New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain : 1...
December 27, 2017: Pharmacogenomics Journal
Ángela Gutierrez-Camino, Maitane Umerez, Idoia Martin-Guerrero, Nagore García de Andoin, Borja Santos, Ana Sastre, Aizpea Echebarria-Barona, Itziar Astigarraga, Aurora Navajas, Africa Garcia-Orad
Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function...
December 27, 2017: Pharmacogenomics Journal
Nut Koonrungsesomboon, Rapheephorn Khatsri, Penwisa Wongchompoo, Supanimit Teekachunhatean
A large interindividual variation in the activity of cytochrome P450 1A2 (CYP1A2) raises concern about therapeutic failure or toxicity when medical professionals prescribe drugs extensively metabolized by CYP1A2. To date, a number of studies have assessed the association between genetic polymorphisms and CYP1A2 activity; however, there are controversies as to the functional importance of CYP1A2 polymorphisms on the metabolism of CYP1A2 substrates. This systematic review and meta-analysis assessed the effects of genetic polymorphisms on CYP1A2 activity, as measured by caffeine metabolism, in a total of 3570 individual subjects...
December 27, 2017: Pharmacogenomics Journal
Pau Riera, Anna C Virgili, Juliana Salazar, Ana Sebio, María Tobeña, Ivana Sullivan, David Páez
The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0...
December 27, 2017: Pharmacogenomics Journal
Maria Plesa, Vincent Gagné, Sanja Glisovic, Melissa Younan, Bahram Sharif-Askari, Caroline Laverdière, Nathalie Alos, Jean-Marie Leclerc, Stephen E Sallan, Donna Neuberg, Jeffery L Kutok, Lewis B Silverman, Daniel Sinnett, Maja Krajinovic
Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols...
December 27, 2017: Pharmacogenomics Journal
T M Linares-Pineda, M Cañadas-Garre, A Sánchez-Pozo, M Á Calleja-Hernández
Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment...
January 2018: Pharmacogenomics Journal
L Colàs-Campàs, J L Royo, M V Montserrat, C Marzo, J Molina-Seguín, I Benabdelhak, S Cambray, F Purroy
Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS...
December 22, 2017: Pharmacogenomics Journal
D I Staquicini, S D'Angelo, F Ferrara, K Karjalainen, G Sharma, T L Smith, C A Tarleton, D E Jaalouk, A Kuniyasu, W B Baze, B K Chaffee, P W Hanley, K F Barnhart, E Koivunen, S Marchiò, R L Sidman, J E Cortes, H M Kantarjian, W Arap, R Pasqualini
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents...
December 5, 2017: Pharmacogenomics Journal
W C Tan-Koi, P C Leow, Y Y Teo
With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents...
December 5, 2017: Pharmacogenomics Journal
J Jack, G W Small, C C Brown, T M Havener, H L McLeod, A A Motsinger-Reif, K L Richards
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells...
December 5, 2017: Pharmacogenomics Journal
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