Pharmacogenetic guidelines and decision support tools for depression treatment: application to late-life.

Pharmacogenomics. 2018 Nov;19(16):1269-1284

Authors: Chang DD, Eyreeuro HA, Abbott R, Coudreaut M, Baune BT, Shaman JA, Lavretsky H, Lenze EJ, Merrill DA, Singh AB, Mulsant BH, Reynolds CF, Müller DJ, Bousman C

Abstract
Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.

PMID: 30422065 [PubMed - in process]

Prolonged central apnoea after intravenous morphine administration in a 12-year-old male with a UGT1A1 loss-of-function polymorphism.

Br J Clin Pharmacol. 2018 Nov 12;:

Authors: Toce MS, Kim H, Chung S, Krauss BS

Abstract
ADVERSE EVENT: Repeated and prolonged episodes of central apnoea and hypoxia after receiving intravenous morphine for analgesia and ketamine for sedation.
DRUG IMPLICATED: Intravenous morphine sulfate.
THE PATIENT: Previously healthy 12-year-old male with no history of sleep apnoea who presented with distal tibia and fibula fracture.
EVIDENCE THAT LINKS DRUG TO EVENT: Pharmacogenomic testing revealed that the patient was homozygous for the T allele at the rs887829 SNP in UGT1A1, an enzyme involved in the metabolism of morphine. This polymorphism is a loss-of-function variant, leading to impaired metabolism of morphine.
MECHANISM: Morphine is metabolized by UDP-glucuronosyltransferase (UGT)-2B7 and UGT1A1 to form its major metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Our patient was a poor metabolizer through UGT1A1, likely leading to increased respiratory depression as morphine has greater respiratory depressant effects compared to its metabolites.
IMPLICATIONS: When appropriate, physicians should enquire about prior receipt of opioids, in both the patient and family, to be better prepared for potential adverse reactions. In the patient with excessive sedation or respiratory depression to standard doses of morphine, genetic testing may be warranted, especially if there is a family or past history that supports a metabolic defect in morphine metabolism and/or excretion.

PMID: 30421550 [PubMed - as supplied by publisher]

Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records.

Eur J Hum Genet. 2018 Nov 12;:

Authors: Tasa T, Krebs K, Kals M, Mägi R, Lauschke VM, Haller T, Puurand T, Remm M, Esko T, Metspalu A, Vilo J, Milani L

Abstract
Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel loss-of-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

PMID: 30420678 [PubMed - as supplied by publisher]

Age-Related Changes in Expression and Activity of Human Hepatic Mitochondrial Glutathione Transferase Zeta1.

Drug Metab Dispos. 2018 08;46(8):1118-1128

Authors: Zhong G, James MO, Smeltz MG, Jahn SC, Langaee T, Simpson P, Stacpoole PW

Abstract
Glutathione transferase zeta1 (GSTZ1) catalyzes glutathione (GSH)-dependent dechlorination of dichloroacetate (DCA), an investigational drug with therapeutic potential in metabolic disorders and cancer. GSTZ1 is expressed in both hepatic cytosol and mitochondria. Here, we examined the ontogeny and characterized the properties of human mitochondrial GSTZ1. GSTZ1 expression and activity with DCA were determined in 103 human hepatic mitochondrial samples prepared from livers of donors aged 1 day to 84 years. DNA from each sample was genotyped for three common GSTZ1 functional single nucleotide polymorphisms. Expression of mitochondrial GSTZ1 protein increased in an age-dependent manner to a plateau after age 21 years. Activity with DCA correlated with expression, after taking into account the somewhat higher activity of samples that were homo- or heterozygous for GSTZ1A. In samples from livers with the GSTZ1C variant, apparent enzyme kinetic constants for DCA and GSH were similar for mitochondria and cytosol after correcting for the loss of GSH observed in mitochondrial incubations. In the presence of 38 mM chloride, mitochondrial GSTZ1 exhibited shorter half-lives of inactivation compared with the cytosolic enzyme (P = 0.017). GSTZ1 protein isolated from mitochondria was shown by mass spectrometry to be identical to cytosolic GSTZ1 protein in the covered primary protein sequence. In summary, we report age-related development in the expression and activity of human hepatic mitochondrial GSTZ1 does not have the same pattern as that reported for cytosolic GSTZ1. Some properties of cytosolic and mitochondrial GSTZ1 differed, but these were not related to differences in amino acid sequence or post-translationally modified residues.

PMID: 29853471 [PubMed - indexed for MEDLINE]

Polymorphisms in Genes Involved in the Leptin-Melanocortin Pathway are Associated with Obesity-Related Cardiometabolic Alterations in a Southern Chilean Population.

Mol Diagn Ther. 2018 02;22(1):101-113

Authors: Manriquez V, Aviles J, Salazar L, Saavedra N, Seron P, Lanas F, Fajardo CM, Hirata MH, Hirata RDC, Cerda A

Abstract
BACKGROUND: Polymorphisms in genes encoding proteins of the leptin-melanocortin pathway have been associated with obesity. The involvement of these polymorphisms with changes in body mass index (BMI) and anthropometric measures could also imply a contribution to the risk of metabolic syndrome (MetS) and metabolic alterations. We evaluated the relationship of leptin-melanocortin system polymorphisms with obesity, MetS, and other metabolic alterations in Southern Chilean individuals.
METHODS: Two-hundred individuals were grouped as normoweight (BMI 18.0-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI ≥ 30 kg/m2) or according to MetS status. Anthropometric measures (BMI, abdominal circumference, waist-to-hip ratio [WHR]) and biochemical parameters (glycemia and lipid profile) were evaluated. Polymorphisms LEP rs7799039, LEPR rs1137101, MC3R rs3746619 and rs3827103, and MC4R rs17782313 were evaluated by real-time PCR using allelic discrimination assays.
RESULTS: LEPR rs1137101 GG genotype was related to reduced risk of obesity (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.08-0.79; p = 0.018) and MetS (OR 0.36, 95% CI 0.15-0.88; p = 0.024), but it was not significant after Bonferroni correction for multiple tests as compared to the AA genotype (p > 0.01). Moreover, LEPR rs1137101 allele G (AG + GG) was related to lower BMI and WHR (p < 0.01). Further multiple linear regression analysis demonstrated that this genotype was also responsible for reduced BMI in 2.44 kg/m2 and WHR in 0.033 units. MC4R rs17782313 allele C (TC + CC) was slightly associated with diminished risk of MetS (OR 0.48, 95% CI 0.23-0.98; p = 0.040) and reduced BMI values in 1.95 kg/m2 (p < 0.05). Regarding lipid profile, LEPR rs1137101 allele G carriers had lower triglycerides and very-low-density lipoprotein (VLDL) cholesterol, whereas individuals carrying the MC4R rs17782313 allele C had higher high-density lipoprotein (HDL) cholesterol (p < 0.01). LEP rs7799039 allele A (GA + AA) was slightly associated with reduced total and low-density lipoprotein (LDL) cholesterol (p < 0.05).
CONCLUSIONS: These results suggest that polymorphisms at LEP, LEPR, and MC4R may be useful biomarkers of obesity-related cardiometabolic alterations in our population.

PMID: 28975585 [PubMed - indexed for MEDLINE]

Effectiveness of genetically-guided treatment in first-episode schizophrenia.

Schizophr Res. 2018 03;193:441-442

Authors: Luck M, Turner M, Shad MU

PMID: 28679479 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial.

Lancet Respir Med. 2018 Nov 08;:

Authors: Busse WW, Bleecker ER, FitzGerald JM, Ferguson GT, Barker P, Sproule S, Olsson RF, Martin UJ, Goldman M, BORA study investigators

Abstract
BACKGROUND: Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma.
METHODS: We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542).
FINDINGS: Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA).
INTERPRETATION: The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year.
FUNDING: AstraZeneca and Kyowa Hakko Kirin.

PMID: 30416083 [PubMed - as supplied by publisher]

A transnational collaborative network dedicated to the study and applications of the vascular endothelial growth factor-A in medical practice: the VEGF Consortium.

Clin Chem Lab Med. 2018 03 28;56(4):83-86

Authors: Stathopoulou MG, Xie T, Ruggiero D, Chatelin J, Rancier M, Weryha G, Kurth MJ, Aldasoro Arguinano AA, Gorenjak V, Petrelis AM, Dagher G, Dedoussis G, Deloukas P, Lamont J, Marc J, Simmaco M, Schaik RHNV, Innocenti F, Merlin JL, Schneider J, Alizadeh BZ, Ciullo M, Seshadri S, Visvikis-Siest S, VEGF Consortium

PMID: 29087954 [PubMed - indexed for MEDLINE]

Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation.

Clin Pharmacokinet. 2018 Nov 10;:

Authors: Tron C, Lemaitre F, Verstuyft C, Petitcollin A, Verdier MC, Bellissant E

Abstract
Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of membrane transporters that may be involved in the interindividual variability of the response to tacrolimus. Several genetic variants in genes coding for influx or efflux membrane transporters (e.g. ABCB1, ABCC2, ABCC8, SLC30A8, SLCO1B1/3, SLC28A1, SLC22A11, and SLC28A3) have been associated with tacrolimus pharmacokinetics variability or the occurrence of toxicity; however, there is still a degree of controversy as to the impact of these variants in vivo and further investigations are needed to confirm these results in larger cohorts and to validate the relevance of such genetic biomarkers for personalization of immunosuppressive therapy in solid organ transplantations. The relationship between transporter polymorphisms and the intracellular concentration of tacrolimus should also be further investigated. Finally, the main challenge could be elucidation of the interplay of biological mechanisms underlying genetic variations that alter the drug concentration or its clinical effect.

PMID: 30415459 [PubMed - as supplied by publisher]

The Role of MicroRNAs in Patients with Amyotrophic Lateral Sclerosis.

J Mol Neurosci. 2018 Nov 10;:

Authors: Dardiotis E, Aloizou AM, Siokas V, Patrinos GP, Deretzi G, Mitsias P, Aschner M, Tsatsakis A

Abstract
Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that affects motor neurons and leads to death within 2 to 3 years after the first symptoms manifest. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in fundamental cellular processes and, post-transcriptionally, the translation levels of target mRNA transcripts. We searched PubMed for studies that examined miRNAs in ALS patients and attempted to group the results in order to find the strongest miRNA candidate for servings as an ALS biomarker. The studies on humans so far have been diverse, yielding considerably heterogeneous results, as they were performed on a wide variety of tissues and subjects. Among the miRNAs that were found consistently deregulated are miR-206, miR-133, miR-149, and miR-338-3p. Additively, the deregulation of some specific miRNAs seems to compose a miRNA expression profile that is specific for ALS. More research is required in order for the scientific community to reach a consensus.

PMID: 30415446 [PubMed - as supplied by publisher]

Pharmacogenetic considerations of anticoagulant medication.

J Physiol Pharmacol. 2018 Aug;69(4):

Authors: Miklosz J, Kalaska B, Mogielnicki A

Abstract
Predicting the clinical consequences of anticoagulant therapy by identifying gene variants could help in the risk assessment of thrombosis or bleeding before and after surgery and may result in choosing more beneficial therapy. This work provides an overview of pharmacogenetic data of commonly used anticoagulant medication. The review focuses on polymorphisms influencing the efficacy and safety of the parenteral and oral anticoagulants. There is evidence that heparin resistance and heparin-induced thrombocytopenia could be genetically determined but it does not mean that the risk of bleeding or thromboembolism is related to mutations in general. CYP2C9 and VKORC1 polymorphisms are essential determinants in the genotype-guided dosing of warfarin and may distinguish patients who would benefit from switching to direct oral anticoagulants (DOACs). Further multi-ethnic studies associating genes of enzymes metabolizing DOACs with primary clinical endpoints are necessary. Pharmacogenetics-based dosing of anticoagulant medication should point towards the subpopulation of patients.

PMID: 30415235 [PubMed - in process]

Integration of Tumor Genomic Data with Cell Lines Using Multi-dimensional Network Modules Improves Cancer Pharmacogenomics.

Cell Syst. 2018 Oct 31;:

Authors: Webber JT, Kaushik S, Bandyopadhyay S

Abstract
Leveraging insights from genomic studies of patient tumors is limited by the discordance between these tumors and the cell line models used for functional studies. We integrate omics datasets using functional networks to identify gene modules reflecting variation between tumors and show that the structure of these modules can be evaluated in cell lines to discover clinically relevant biomarkers of therapeutic responses. Applied to breast cancer, we identify 219 gene modules that capture recurrent alterations and subtype patients and quantitate various cell types within the tumor microenvironment. Comparison of modules between tumors and cell lines reveals that many modules composed primarily of gene expression and methylation are poorly preserved. In contrast, preserved modules are highly predictive of drug responses in a manner that is robust and clinically relevant. This work addresses a fundamental challenge in pharmacogenomics that can only be overcome by the joint analysis of patient and cell line data.

PMID: 30414925 [PubMed - as supplied by publisher]

Emergency Medical Services Administration of Systemic Corticosteroids for Pediatric Asthma: A Statewide Study of Emergency Department Outcomes.

Acad Emerg Med. 2018 Nov 10;:

Authors: Fishe JN, Gautam S, Hendry P, Blake KV, Hendeles L

Abstract
BACKGROUND: For children with an asthma exacerbation, systemic corticosteroids (CS) administered in the emergency department (ED) decrease hospital admission rates and ED length-of-stay (LOS).1-4 Time-dependent effects favor earlier CS administration, ideally within the first hour of ED arrival.2,3 Only one pediatric study has examined if earlier, EMS administration of CS improves patient outcomes.5 That study found decreased hospital admission rates and ED LOS after adding dexamethasone to intravenous (IV) methylprednisolone as options for pediatric asthma. However, the study was of a single EMS agency and overall EMS CS use was low (<20%).5 To date, no large study has examined pediatric asthma outcomes after EMS treatment. This study's objective was to examine a statewide population of pediatric asthma patients to determine the effects of EMS administration of CS on ED outcomes. This article is protected by copyright. All rights reserved.

PMID: 30414344 [PubMed - as supplied by publisher]

Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk Mitigation Measure.

Pharmacotherapy. 2018 Nov 10;:

Authors: Stainsby CM, Perger TM, Vannappagari V, Mounzer KC, Hsu RK, Henegar CE, Oyee J, Urbaityte R, Lane CE, Carter LM, Pakes GE, Shaefer MS

Abstract
INTRODUCTION: HLA-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and HIV treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4% to 8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, observational (OPERA) cohort, and spontaneous reporting data.
METHODS: A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007 to September 22, 2015. Potential cases were identified using pre-specified MedDRA preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999 to January 1, 2016 were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016.
RESULTS: Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE).
CONCLUSIONS: Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment. This article is protected by copyright. All rights reserved.

PMID: 30414209 [PubMed - as supplied by publisher]

Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity.

Nat Protoc. 2018 Nov 09;:

Authors: Sharma A, McKeithan WL, Serrano R, Kitani T, Burridge PW, Del Álamo JC, Mercola M, Wu JC

Abstract
Cardiotoxicity has historically been a major cause of drug removal from the pharmaceutical market. Several chemotherapeutic compounds have been noted for their propensities to induce dangerous cardiac-specific side effects such as arrhythmias or cardiomyocyte apoptosis. However, improved preclinical screening methodologies have enabled cardiotoxic compounds to be identified earlier in the drug development pipeline. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to screen for drug-induced alterations in cardiac cellular contractility, electrophysiology, and viability. We previously established a novel 'cardiac safety index' (CSI) as a metric that can evaluate potential cardiotoxic drugs via high-throughput screening of hiPSC-CMs. This metric quantitatively examines drug-induced alterations in CM function, using several in vitro readouts, and normalizes the resulting toxicity values to the in vivo maximum drug blood plasma concentration seen in preclinical or clinical pharmacokinetic models. In this ~1-month-long protocol, we describe how to differentiate hiPSCs into hiPSC-CMs and subsequently implement contractility and cytotoxicity assays that can evaluate drug-induced cardiotoxicity in hiPSC-CMs. We also describe how to carry out the calculations needed to generate the CSI metric from these quantitative toxicity measurements.

PMID: 30413796 [PubMed - as supplied by publisher]

Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8.

J Alzheimers Dis. 2018 Nov 05;:

Authors: Bagallab I, Mauricio Reyes-Ruiz J, Abulnaja K, Huwait E, Glabe C

Abstract
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.

PMID: 30412489 [PubMed - as supplied by publisher]

CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines.

Breast Cancer Res Treat. 2018 Nov 08;:

Authors: Drögemöller BI, Wright GEB, Shih J, Monzon JG, Gelmon KA, Ross CJD, Amstutz U, Carleton BC, CPNDS Clinical Recommendations Group

Abstract
PURPOSE: Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic.
METHODS: A systematic literature review was conducted to identify studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment. Critical appraisal of the retrieved scientific evidence was performed, and recommendations were developed for CYP2D6 genetic testing in the context of tamoxifen therapy.
RESULTS: Although conflicting literature exists, the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment. Of note, review of the CYP2D6 genotyping assays used in each of the studies revealed the importance of comprehensive genotyping strategies to accurately predict CYP2D6 metabolizer phenotypes.
CONCLUSIONS AND RECOMMENDATIONS: Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER-positive breast cancer patients. Based on this information, it is recommended that alternatives to standard tamoxifen treatments may be considered in CYP2D6 poor or intermediate metabolizers.

PMID: 30411242 [PubMed - as supplied by publisher]

Gastric Cancer Cell Lines Have Different MYC-Regulated Expression Patterns but Share a Common Core of Altered Genes.

Can J Gastroenterol Hepatol. 2018;2018:5804376

Authors: Maués JHDS, Ribeiro HF, Pinto GR, Lopes LO, Lamarão LM, Pessoa CMF, Moreira-Nunes CFA, de Carvalho RM, Assumpção PP, Rey JA, Burbano RMR

Abstract
MYC is an oncogene responsible for excessive cell growth in cancer, enabling transcriptional activation of genes involved in cell cycle regulation, metabolism, and apoptosis, and is usually overexpressed in gastric cancer (GC). By using siRNA and Next-Generation Sequencing (NGS), we identified MYC-regulated differentially expressed Genes (DEGs) in three Brazilian gastric cancer cell lines representing the histological subtypes of GC (diffuse, intestinal, and metastasis). The DEGs were picked using Sailfish software, followed by Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using KEGG. We found 11 significantly enriched gene sets by using enrichment score (ES), False Discovery Rate (FDR), and nominal P-values. We identified a total of 5.471 DEGs with correlation over (80%). In diffuse-type and in metastatic GC cell lines, MYC-silencing caused DEGs downregulation, while the intestinal-type GC cells presented overall DEGs upregulation after MYC siRNA depletion. We were able to detect 11 significant gene sets when comparing our samples to the hallmark collection of gene expression, enriched mostly for the following hallmarks: proliferation, pathway, signaling, metabolic, and DNA damage response. When we analyzed our DEGs considering KEGG metabolic pathways, we found 12 common branches covering a wide range of biological functions, and three of them were common to all three cell lines: ubiquitin-mediated proteolysis, ribosomes, and system and epithelial cell signaling in Helicobacter pylori infection. The GC cell lines used in this study share 14 MYC-regulated genes, but their gene expression profile is different for each histological subtype of GC. Our results present a computational analysis of MYC-related signatures in GC, and we present evidence that GC cell lines representing distinct histological subtypes of this disease have different MYC-regulated expression profiles but share a common core of altered genes. This is an important step towards the understanding of MYC's role in gastric carcinogenesis and an indication of probable new drug targets in stomach cancer.

PMID: 30410872 [PubMed - in process]

Creating and validating a warfarin pharmacogenetic dosing algorithm for Colombian patients.

Pharmgenomics Pers Med. 2018;11:169-178

Authors: Galvez JM, Restrepo CM, Contreras NC, Alvarado C, Calderón-Ospina CA, Peña N, Cifuentes RA, Duarte D, Laissue P, Fonseca DJ

Abstract
Purpose: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter- and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. CYP2C9 and VKORC1 gene polymorphisms affect warfarin metabolism and dosage. Due to the central role of populations' ethnical and genetic origin on warfarin dosage variability, novel algorithms for Latin American subgroups are necessary to establish safe anticoagulation therapy.
Patients and methods: We genotyped CYP2C9*2 (c.430C > T), CYP2C9*3 (c.1075A > C), CYP4F2 (c.1297G > A), and VKORC1 (-1639 G > A) polymorphisms in 152 Colombian patients who received warfarin. We evaluated the impact on the variability of patients' warfarin dose requirements. Multiple linear regression analysis, using genetic and non-genetic variables, was used for creating an algorithm for optimal warfarin maintenance dose.
Results: Median weekly prescribed warfarin dosage was significantly lower in patients having the VKORC1-1639 AA genotype and poor CYP2C9*2/*2,*2/*3 metabolizers than their wild-type counterparts. We found a 2.3-fold increase in mean dose for normal sensitivity patients (wild-type VKORC1/CYP2C9 genotypes) compared to the other groups (moderate and high sensitivity); 31.5% of the patients in our study group had warfarin sensitivity-related genotypes. The estimated regression equation accounted for 44.4% of overall variability in regard to warfarin maintenance dose. The algorithm was validated, giving 45.9% correlation (R 2=0.459).
Conclusion: Our results describe and validate the first algorithm for predicting warfarin maintenance in a Colombian mestizo population and have contributed toward the understanding of pharmacogenetics in a Latin American population subgroup.

PMID: 30410385 [PubMed]

Genome-scale analysis identifies SERPINE1 and SPARC as diagnostic and prognostic biomarkers in gastric cancer.

Onco Targets Ther. 2018;11:6969-6980

Authors: Liao P, Li W, Liu R, Teer JK, Xu B, Zhang W, Li X, Mcleod HL, He Y

Abstract
Background: Gastric cancer (GC) is one of the most common types of malignancy and is associated with high morbidity and mortality rates around the world. With poor clinical outcomes, potential biomarkers for diagnosis and prognosis are important to investigate.
Objective: The aim of this study is to investigate the gene expression module of GC and to identify potential diagnostic and prognostic biomarkers.
Method: Microarray data (GSE13911, GSE29272, GSE54129, and GSE79973), including 293 stomach tumor tissues and 196 normal tissues, were analyzed to identify differentially expressed genes (DEGs). DEGs were identified in four profiles by intersecting four overlapping subsets, including 90 downregulated and 45 upregulated DEGs in common. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses have been showed that extracellular matrix was the most enriched signal pathway. Furthermore, hub genes were analyzed by protein-protein interaction network and clinical outcomes were assessed by Kaplan-Meier survival analysis. Two independent datasets were used to validate the differential expression of two hub genes: Serpin Family E Member 1 (SERPINE1) and Secreted Protein Acidic and Cysteine Rich (SPARC).
Results: Validation of independent datasets indicated that SERPINE1 and SPARC expression were drastically increased in gastric tumor tissues and associated with poor outcomes in GC patients. The expression of SERPINE1 was related to race (Asian and White) (P< 0.05).
Conclusion: SERPINE1 and SPARC were significantly upregulated in gastric tissues and associated with poor outcomes. The investigations of SERPINE1 and SPARC may promote their predictive and prognostic value in GC.

PMID: 30410354 [PubMed]