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Galen E B Wright, Ursula Amstutz, Britt I Drögemöller, Joanne Shih, Shahrad R Rassekh, Michael R Hayden, Bruce C Carleton, Colin J D Ross
Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently-identified risk variant, CEP72 rs924607 and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients...
July 12, 2018: Clinical Pharmacology and Therapeutics
Moh'd Khushman, Girijesh Kumar Patel, Peter Joel Hosein, Javier Ariel Laurini, Daniel Cameron, David Roland Clarkson, Thomas Wayne Butler, Carole Wiseman Norden, Wilma Baliem, Vanessa Jones, Sanjyot Bhadkamkar, Cindy Nelson, Frances Lee, Ajay P Singh, William R Taylor
Background: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines...
June 2018: Journal of Gastrointestinal Oncology
Vinko Palada, Mari A Kaunisto, Eija Kalso
PURPOSE OF REVIEW: The review describes recent advances in genetics and genomics of postoperative pain, the association between genetic variants and the efficacy of analgesics, and the role of pharmacogenomics in the selection of appropriate analgesic treatments for postoperative pain. RECENT FINDINGS: Recent genetic studies have reported associations of genetic variants in catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), voltage-gated channel alpha subunit 11 (SCN11A) and μ-opioid receptor (OPRM1) genes with postoperative pain...
July 9, 2018: Current Opinion in Anaesthesiology
Arjun P Athreya, Alan J Gaglio, Junmei Cairns, Krishna R Kalari, Richard M Weinshilboum, Liewei Wang, Zbigniew T Kalbarczyk, Ravishankar K Iyer
This paper demonstrates the ability of machine learning approaches to identify a few genes among the 23; 398 genes of the human genome to experiment on in the laboratory to establish new drug mechanisms. As a case study, this work uses MDA-MB-231 breast cancer single-cells treated with the antidiabetic drug metformin. We show that mixture-model based unsupervised methods with validation from hierarchical clustering can identify single-cell subpopulations (clusters). These clusters are characterized by a small set of genes (1% of the genome) that have significant differential expression across the clusters and are also highly correlated with pathways with anticancer effects driven by metformin...
July 2, 2018: IEEE Transactions on Nanobioscience
Zexian Zeng, Yu Deng, Xiaoyu Li, Tristan Naumann, Yuan Luo
This article reviews recent advances in applying natural language processing (NLP) to Electronic Health Records (EHRs) for computational phenotyping. NLP-based computational phenotyping has numerous applications including diagnosis categorization, novel phenotype discovery, clinical trial screening, pharmacogenomics, drug-drug interaction (DDI) and adverse drug event (ADE) detection, as well as genome-wide and phenome-wide association studies. Significant progress has been made in algorithm development and resource construction for computational phenotyping...
June 25, 2018: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Javad Akhtari, Alireza Tafazoli, Hassan Mehrad-Majd, Abdolkarim Mahrooz
RNA interference (RNAi) is a process for regulating the gene expression in which small interfering RNAs (siRNAs) silence target genes. siRNA-based therapy as a new molecular treatment approach, offers therapeutic prospects for many common diseases such as cancer and cardiovascular disorders. Nevertheless, the efficacy of siRNA delivery has, so far, remained a challenging issue. This is due to their easy degradation through the circulation system and the difficulties in the intracellular delivery to specific tissues where they silence the target genes...
July 9, 2018: Current Clinical Pharmacology
Ingrid A Holm, Pankaj B Agrawal, Ozge Ceyhan-Birsoy, Kurt D Christensen, Shawn Fayer, Leslie A Frankel, Casie A Genetti, Joel B Krier, Rebecca C LaMay, Harvey L Levy, Amy L McGuire, Richard B Parad, Peter J Park, Stacey Pereira, Heidi L Rehm, Talia S Schwartz, Susan E Waisbren, Timothy W Yu, Robert C Green, Alan H Beggs
BACKGROUND: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. METHODS: Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants...
July 9, 2018: BMC Pediatrics
Kevin J Li, Haley V Solomon, Lynn E DeLisi
PURPOSE OF REVIEW: To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis. RECENT FINDINGS: Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5-rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1...
July 4, 2018: Current Opinion in Psychiatry
Edith Pascale Mofo Mato, Magellan Guewo-Fokeng, M Faadiel Essop, Peter Mark Oroma Owira
BACKGROUND: Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele...
July 2018: Medicine (Baltimore)
Jayne E Hewitt
Since the human genome was successfully mapped much academic attention has been given to ethical, legal and regulatory issues associated with the integration and application of genomics in health care. In line with the recent political commitment to promoting precision medicine that relies heavily on omic knowledge, it is timely to review the issues that this body of literature has addressed. Focusing on pharmacogenomics, this review quantifies the issues identified in this body of academic work. It reveals that, after nearly two decades, interest in the regulatory and legal issues associated with pharmacogenomics continues to generate significant attention...
April 2018: Journal of Law and Medicine
Allan E Rettie, Stephen B Liggett
No abstract text is available yet for this article.
July 4, 2018: Journal of Personalized Medicine
L E Crowley, M Mekki, S Chand
This review is focused on present and future biomarkers, along with pharmacogenomics used in clinical practice for kidney transplantation. It aims to highlight biomarkers that could potentially be used to improve kidney transplant early and long-term graft survival, but also potentially patient co-morbidity. Future directions for improving outcomes are discussed, which include immune tolerance and personalising immunosuppression regimens.
July 4, 2018: Molecular Diagnosis & Therapy
Henk-Jan Guchelaar
No abstract text is available yet for this article.
July 2, 2018: European Journal of Human Genetics: EJHG
François Danion, Vincent Jullien, Claire Rouzaud, Manal Abdel Fattah, Simona Lapusan, Romain Guéry, Naïke Bigé, Marjolaine Morgand, Nicolas Pallet, Fanny Lanternier, Olivier Lortholary
Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring for optimizing therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations of CYP2C19 that were partially responsible for therapeutic failure of voriconazole. We suggest systematic voriconazole pharmacogenomic investigation in cerebral aspergillosis to avoid effective therapy delay in this life-threatening disease...
July 2, 2018: Antimicrobial Agents and Chemotherapy
Samuele Naviglio, Paolo Giuffrida, Gabriele Stocco, Marco Vincenzo Lenti, Alessandro Ventura, Gino Roberto Corazza, Antonio Di Sabatino
Anti-tumour necrosis factor (TNF) agents have changed the therapeutic approach to inflammatory bowel disease. However, a considerable proportion of patients either does not primarily respond or lose response to treatment. Despite the longstanding experience in the use of these drugs, still there is the need of identifying possible predictors of efficacy. Areas covered: We critically review the current knowledge on predictors of response to anti-TNF therapy, both those available in clinical practice and those still under investigation...
June 29, 2018: Expert Review of Gastroenterology & Hepatology
Shuhui Meng, Shuyu Chen, Ailin Tao
Asthma is a heterogeneous disease that consists of different phenotypes and endotypes, driven by different mechanistic pathways. An increasing number of genetic loci and single-nucleotide polymorphisms have been associated with therapeutic responses to asthma drugs. The purpose of this review is to focus on certain susceptibility genes, gene variants and typical therapeutic drugs of the glucocorticoid, leukotriene, histamine, and β2-adrenergic receptor pathways related to asthma. Pharmacogenomics can help us better understand the genetic basis of drug responses and better define new therapeutic targets to improve treatment effectiveness...
June 28, 2018: Current Drug Metabolism
Yaowaluck Hongkaew, Sadeep Medhasi, Ekawat Pasomsub, Nattawat Ngamsamut, Apichaya Puangpetch, Natchaya Vanwong, Monpat Chamnanphon, Penkhae Limsila, Chuthamanee Suthisisang, Bob Wilffert, Chonlaphat Sukasem
The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level...
June 29, 2018: Pharmacogenomics Journal
Raffaele Hellweg, Ashley Mooneyham, Zenas Chang, Mihir Shetty, Edith Emmings, Yoshie Iizuka, Christopher Clark, Timothy Starr, Juan H Abrahante, Florian Schütz, Gottfried Konecny, Peter Argenta, Martina Bazzaro
Despite advances in surgical technique and adjuvant treatment, endometrial cancer has recently seen an increase in incidence and mortality in the USA. The majority of endometrial cancers can be cured by surgery alone or in combination with adjuvant chemo- or radiotherapy; however, a subset of patients experience recurrence for reasons that remain unclear. Recurrence is associated with chemoresistance to carboplatin and paclitaxel and consequentially, high mortality. Understanding the pathways involved in endometrial cancer chemoresistance is paramount for the identification of biomarkers and novel molecular targets for this disease...
June 27, 2018: Hormones & Cancer
Marinka Zitnik, Monica Agrawal, Jure Leskovec
Motivation: The use of drug combinations, termed polypharmacy, is common to treat patients with complex diseases or co-existing conditions. However, a major consequence of polypharmacy is a much higher risk of adverse side effects for the patient. Polypharmacy side effects emerge because of drug-drug interactions, in which activity of one drug may change, favorably or unfavorably, if taken with another drug. The knowledge of drug interactions is often limited because these complex relationships are rare, and are usually not observed in relatively small clinical testing...
July 1, 2018: Bioinformatics
Amir Mehrvarz Sarshekeh, Henry Q Xiong, Kenzo Iizuka, Howard S Hochster, Scott Kopetz
Background DFP-10917 is a cytotoxic deoxycytidine analogue that causes DNA fragmentation, G2 /M-phase arrest, and apoptosis. This agent has been shown to have antitumor activity against colorectal cancer (CRC) in preclinical studies and to be tolerable in patients. The purpose of our phase II trial was to evaluate the safety, efficacy and pharmacogenomics of DFP-10917 as well as DNA damage studies in patients with advanced CRC refractory to cytotoxic chemotherapy. Methods In this single-arm, Simon two-stage, phase II trial, patients with chemotherapy-refractory advanced CRC received 2...
June 13, 2018: Investigational New Drugs
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