Complicated disease and response to initial therapy predicts early surgery in paediatric Crohn's disease: results from the Porto Group GROWTH study.

J Crohns Colitis. 2019 Jun 03;:

Authors: Levine A, Chanchlani N, Ziv-Baran T, Escher JC, Amil Dias J, Veres G, Koletzko S, Turner D, Kolho KL, Paerregaard A, Staiano A, Lionetti P, Nuti F, Sladek M, Shaoul R, Lazowska-Prezeorek I, de Carpi JM, Sigall Boneh R, Pfeffer Gik T, Cohen-Dolev N, Russell RK, Porto Group of ESPGHAN

Abstract
INTRODUCTION: The ability to predict risk for poor outcomes in Crohn's disease (CD) would enable early treatment intensification. We aimed to identify children with CD with complications at baseline and throughout the study period who are at risk for surgery two years from diagnosis.
MATERIAL AND METHODS: Newly diagnosed children with CD were enrolled into a prospective, multicentre inception cohort. Disease characteristics and serological markers were obtained at baseline and week 12 thereafter. Outcome data including disease activity, therapies, complications, and need for surgery were collected through 104 weeks. Chi-square automatic interaction detection (CHAID) algorithm was used to develop a prediction model for early surgery.
RESULTS: Of 285 children enrolled, 31(10.9%) required surgery within two years. Multivariate analysis identified stricturing disease at baseline (OR 5.26, 95% CI 2.02 - 13.67 (p=0.001)), and Paediatric Crohn's Disease Activity Index (PCDAI) >10 at week 12 (OR 1.06, 95% CI 1.02 - 1.10 (p=0.005) as key predictors for early surgery. CHAID demonstrated that absence of strictures at diagnosis (7.6%), corticosteroid-free remission at week 12 (4.1%), and early immunomodulator therapy (0.8%) were associated with the lowest risk of surgery, while stricturing disease at diagnosis (27.1%, P<0.001) or elevated PCDAI at week 12 (16.7%, p=0.014) had an increased risk of surgery at follow-up. Anti-OmpC status further stratified high-risk patients.
DISCUSSION: A risk algorithm using clinical and serological variables at diagnosis and week 12 can categorise patients into high- and low- risk groups from diagnosis.
FUNDING: A.L Thrasher foundation, Catherine McEwan foundation, and the Porto group of ESPGHAN.

PMID: 31162532 [PubMed - as supplied by publisher]

Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet. 2019 Jun 03;:

Authors: Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Taylor KD, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, Bis JC, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Björkegren JLM, Codoni V, Civelek M, Smith NL, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JMM, Kamatani Y, Debette S, Dichgans M

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31160810 [PubMed - as supplied by publisher]

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet. 2019 Jun 03;:

Authors: Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Di Angelantonio E, Drenos F, Du M, Dubé MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland Ø, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jørgensen ME, Jørgensen T, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikäinen LP, Männistö S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Loohuis LMO, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renström F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Edwards DRV, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Völker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhao W, Zhou W, Zondervan KT, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31160809 [PubMed - as supplied by publisher]

The Prevalence of DPYD*9A(c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis.

Clin Colorectal Cancer. 2019 May 03;:

Authors: Maharjan AS, McMillin GA, Patel GK, Awan S, Taylor WR, Pai S, Frankel AE, Nelson C, Wang B, Hosein PJ, Singh AP, Khushman M

Abstract
INTRODUCTION: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. In a cohort of 28 patients, DPYD*9A was the most commonly diagnosed variant (13 patients [46%]) and there was a noticeable genotype-phenotype correlation. In this study we genotyped a larger cohort of a mixed racial background to explore the prevalence of DPYD*9A variant and to confirm the genotype-phenotype correlation.
PATIENTS AND METHODS: Between 2011 and 2018, in addition to genotyping for high-risk DPYD variants (DPYD*2A, DPYD*13 and DPYD*9B), genotyping for DPYD*9A variant was performed on 113 patients with gastrointestinal malignancies treated with fluoropyrimidines. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Fisher exact test was used for statistical analysis.
RESULTS: Heterozygous and homozygous DPYD*9A genotypes were identified in 46 (41%) and 11 (10%) patients, respectively. Among patients with DPYD*9A genotypes (n = 57), men and women represented 30 (53%) and 27 (47%) patients, respectively. Caucasian, African American, and other ethnicities represented 29 (50.9%), 26 (45.6%), and 2 (3.5%) patients, respectively. Grade 3/4 toxicities were experienced in 26 patients with DPYD*9A genotype (3 patients had homozygous status) and in 20 patients with wild type DPYD*9A (P = .4405). In patients who received full-dose fluoropyrimidines (n = 85), Grade 3/4 toxicities were experienced in 22 patients with DPYD*9A genotype (2 patients had homozygous status), and in 17 patients with wild type DPYD (P = .8275).
CONCLUSION: In our updated analysis, the prevalence of heterozygous and homozygous DPYD*9A genotypes were 41% and 10%, respectively. The correlation between DPYD*9A genotype and DPD clinical phenotype was not reproduced. The noticeable correlation that we previously reported is likely because of small sample size and selection bias.

PMID: 31160238 [PubMed - as supplied by publisher]

Neuroimaging findings from an experimental pharmacology trial of naltrexone in heavy drinkers of East Asian descent.

Drug Alcohol Depend. 2019 May 09;:

Authors: Lim AC, Ghahremani DG, Grodin EN, Green R, Bujarski S, Hartwell EE, Courtney KE, Hutchison K, Miotto K, Ray LA

Abstract
BACKGROUND: Despite known genetic variation across races, studies examining pharmacogenetics of a single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) on clinical response to naltrexone have been conducted in predominantly Caucasian samples. Evidence is mixed for pharmacogenetic OPRM1 and naltrexone effects on neural responses to alcohol cues. The current study tests the pharmacogenetic effects of naltrexone and OPRM1 on neural responses to alcohol taste cues in heavy drinkers of East Asian descent.
METHODS: Participants (N = 41) completed two double-blinded and counterbalanced functional magnetic resonance imaging (fMRI) sessions: one after taking naltrexone (50 mg/day) for four days and one after taking placebo for four days. Following titration, participants completed an fMRI alcohol taste-cues task. Analyses tested effects of naltrexone, OPRM1, and their interaction in whole-brain and region of interest (ROI) analyses of functional activation and functional connectivity in response to alcohol versus water taste cues.
RESULTS: We found no effects of naltrexone orOPRM1 on neural activation in whole-brain and ROI analyses, which included left and right ventral striatum (VS), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Naltrexone increased functional connectivity between left VS and clusters in medial prefrontal cortex, posterior cingulate gyrus, as well as right VS and occipital cortex, compared to placebo.
CONCLUSIONS: Naltrexone treatment enhanced functional connectivity in a key reinforcement-related pathway during alcohol versus water taste cues, corroborating neuroimaging work with other substances. Null medication and pharmacogenetics effects on functional activation add to a mixed naltrexone literature and may underscore the modest size of these effects in East Asians.

PMID: 31160146 [PubMed - as supplied by publisher]

Targeted next generation sequencing as a tool for precision medicine.

BMC Med Genomics. 2019 Jun 03;12(1):81

Authors: Gulilat M, Lamb T, Teft WA, Wang J, Dron JS, Robinson JF, Tirona RG, Hegele RA, Kim RB, Schwarz UI

Abstract
BACKGROUND: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.
METHODS: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.
RESULTS: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.
CONCLUSIONS: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

PMID: 31159795 [PubMed - in process]

Systematic review and meta-analysis of genetic risk factors for neuropathic pain.

Pain. 2018 May;159(5):825-848

Authors: Veluchamy A, Hébert HL, Meng W, Palmer CNA, Smith BH

Abstract
Neuropathic pain (NP) is an increasingly common chronic pain state and a major health burden, affecting approximately 7% to 10% of the general population. Emerging evidence suggests that genetic factors could partially explain individual susceptibility to NP and the estimated heritability in twins is 37%. The aim of this study was to systematically review and summarize the studies in humans that have investigated the influence of genetic factors associated with NP. We conducted a comprehensive literature search and performed meta-analyses of all the potential genetic variants associated with NP. We reviewed 29 full-text articles and identified 28 genes that were significantly associated with NP, mainly involved in neurotransmission, immune response, and metabolism. Genetic variants in HLA genes, COMT, OPRM1, TNFA, IL6, and GCH1, were found to have an association with NP in more than one study. In the meta-analysis, polymorphisms in HLA-DRB1*13 (odds ratio [OR], 2.96; confidence interval [CI], 1.93-4.56), HLA-DRB1*04 (OR, 1.40; CI, 1.02-1.93), HLA-DQB1*03 (OR, 2.86; CI, 1.57-5.21), HLA-A*33 (OR, 2.32; CI, 1.42-3.80), and HLA-B*44 (OR, 3.17; CI, 2.22-4.55) were associated with significantly increased risk of developing NP, whereas HLA-A*02 (OR, 0.64; CI, 0.47-0.87) conferred reduced risk and neither rs1799971 in OPRM1 (OR, 0.55; CI, 0.27-1.11) nor rs4680 in COMT (OR, 0.95; CI, 0.81-1.13) were significantly associated with NP. These findings demonstrate an important and specific contribution of genetic factors to the risk of developing NP. However, large-scale replication studies are required to validate these candidate genes. Our review also highlights the need for genome-wide association studies with consistent case definition to elucidate the genetic architecture underpinning NP.

PMID: 29351172 [PubMed - indexed for MEDLINE]

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Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study.

Toxicol In Vitro. 2019 May 31;:

Authors: Bernasconi C, Pelkonen O, Andersson TB, Strickland J, Wilk-Zasadna I, Asturiol D, Cole T, Liska R, Worth A, Müller-Vieira U, Richert L, Chesne C, Coecke S

Abstract
CYP enzyme induction is a sensitive biomarker for phenotypic metabolic competence of in vitro test systems; it is a key event associated with thyroid disruption, and a biomarker for toxicologically relevant nuclear receptor-mediated pathways. This paper summarises the results of a multi-laboratory validation study of two in vitro methods that assess the potential of chemicals to induce cytochrome P450 (CYP) enzyme activity, in particular CYP1A2, CYP2B6, and CYP3A4. The methods are based on the use of cryopreserved primary human hepatocytes (PHH) and human HepaRG cells. The validation study was coordinated by the European Union Reference Laboratory for Alternatives to Animal Testing of the European Commission's Joint Research Centre and involved a ring trial among six laboratories. The reproducibility was assessed within and between laboratories using a validation set of 13 selected chemicals (known human inducers and non-inducers) tested under blind conditions. The ability of the two methods to predict human CYP induction potential was assessed. Chemical space analysis confirmed that the selected chemicals are broadly representative of a diverse range of chemicals. The two methods were found to be reliable and relevant in vitro tools for the assessment of human CYP induction, with the HepaRG method being better suited for routine testing. Recommendations for the practical application of the two methods are proposed.

PMID: 31158489 [PubMed - as supplied by publisher]

Placenta growth factor and sFlt-1 as biomarkers in ischemic heart disease and heart failure: a review.

Biomark Med. 2019 Jun 03;:

Authors: Draker N, Torry DS, Torry RJ

Abstract
Coronary heart disease (CHD) and heart failure (HF) produce significant morbidity/mortality but identifying new biomarkers could help in the management of each. In this article, we summarize the molecular regulation and biomarker potential of PIGF and sFlt-1 in CHD and HF. PlGF is elevated during ischemia and some studies have shown PlGF, sFlt-1 or PlGF:sFlt-1 ratio, when used in combination with standard biomarkers, strengthens predictions of outcomes. sFlt-1 and PlGF are elevated in HF with sFlt-1 as a stronger predictor of outcomes. Although promising, we discuss additional study criteria needed to confirm the clinical usefulness of PlGF or sFlt-1 in the detection and management of CHD or HF.

PMID: 31157982 [PubMed - as supplied by publisher]

The future of apolipoprotein E mimetic peptides in the prevention of cardiovascular disease.

Curr Opin Lipidol. 2019 May 30;:

Authors: Valanti EK, Chroni A, Sanoudou D

Abstract
PURPOSE OF REVIEW: This review aims to discuss the recent developments in the area of apolipoprotein E (apoE) mimetics and their therapeutic potential for treating cardiovascular disease, the leading cause of mortality worldwide.
RECENT FINDINGS: Ongoing research efforts target the development of novel therapies that would not only reduce circulating levels of atherogenic lipoproteins, but could also increase high density lipoprotein cholesterol (HDL-C) levels and/or improve HDL function. Among them, synthetic peptides that mimic the structure of natural human apoE, a component of triglyceride-rich lipoproteins and HDL, have been designed and proven to be functionally similar to apoE. In specific, apoE mimetic peptides mediate hepatic clearance of circulating atherogenic lipoproteins, dramatically reduce plasma cholesterol, and lead to attenuation of atherosclerosis development in vivo. These peptides also exhibit pleiotropic antiatherogenic properties, such as macrophage cholesterol efflux capacity, as well as anti-inflammatory and antioxidative functions.
SUMMARY: ApoE mimetics are undergoing preclinical and clinical evaluation with promising results to date that render them attractive candidates in cardiovascular disease prevention and treatment.

PMID: 31157629 [PubMed - as supplied by publisher]

Estimating the Effectiveness of DPYD Genotyping in Italian Individuals Suffering from Cancer Based on the Cost of Chemotherapy-Induced Toxicity.

Am J Hum Genet. 2019 May 18;:

Authors: Fragoulakis V, Roncato R, Fratte CD, Ecca F, Bartsakoulia M, Innocenti F, Toffoli G, Cecchin E, Patrinos GP, Mitropoulou C

Abstract
Fluoropyrimidines (FLs) have been widely used for more than 60 years against a range of solid tumors and still remains the cornerstone for the treatment of colorectal, gastric, and breast cancer. Here, we performed an economic analysis to estimate the cost of DPYD-guided toxicity management and the clinical benefit expressed as quality adjusted life years (QALYs) in a large group of 571 individuals of Italian origin suffering from cancer and treated with a fluoropyrimidines-based chemotherapy. Individuals suffering from cancer with a histologically confirmed diagnosis of cancer, who received a fluoropyrimidines-based treatment, were retrospectively genotyped in the DPYD gene. Effectiveness was measured as survival of individuals from chemotherapy, while study data on safety and efficacy as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. DPYD extensive metabolizers (528 individuals) had greater effectiveness and lesser cost, representing a cost-saving option over DPYD intermediate and poor metabolizers (43 individuals) with mean QALYs of 4.18 (95%CI: 3.16-5.55) versus 3.02 (95%CI: 1.94-4.25), respectively. Our economic analysis showed that there are some indications for differences in survival between the two groups (p > 0.05), while the cost of DPYD extensive metabolizers was significantly lower (p < 0.01) compared with those belonging to the group of intermediate/poor metabolizers. These findings suggest that DPYD-guided fluoropyrimidines treatment represent a cost-saving choice for individuals suffering from cancer in the Italian healthcare setting.

PMID: 31155283 [PubMed - as supplied by publisher]

New insights into tardive dyskinesia genetics: Implementation of whole-exome sequencing approach.

Prog Neuropsychopharmacol Biol Psychiatry. 2019 May 30;:109659

Authors: Alkelai A, Greenbaum L, Heinzen EL, Baugh EH, Teitelbaum A, Zhu X, Strous RD, Tatarskyy P, Zai CC, Tiwari AK, Tampakeras M, Freeman N, Müller DJ, Voineskos AN, Lieberman JA, Delaney SL, Meltzer HY, Remington G, Kennedy JL, Pulver AE, Peabody EP, Levy DL, Lerer B

Abstract
Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability. In order to identify TD risk genes, we performed whole-exome sequencing (WES) and gene-based collapsing analysis focusing on rare (allele frequency < 1%) and putatively deleterious variants (qualifying variants). 82 Jewish schizophrenia patients chronically treated with antipsychotics were included and classified as having severe TD or lack of any abnormal movements based on a rigorous definition of the TD phenotype. First, we performed a case-control, exome-wide collapsing analysis comparing 39 schizophrenia patients with severe TD to 3118 unrelated population controls. Then, we checked the potential top candidate genes among 43 patients without any TD manifestations. All the genes that were found to harbor one or more qualifying variants in patients without any TD features were excluded from the final list of candidate genes. Only one gene, regulating synaptic membrane exocytosis 2 (RIMS2), showed significant enrichment of qualifying variants in TD patients compared with unrelated population controls after correcting for multiple testing (Fisher's exact test p = 5.32E-08, logistic regression p = 2.50E-08). Enrichment was caused by a single variant (rs567070433) due to a frameshift in an alternative transcript of RIMS2. None of the TD negative patients had qualifying variants in this gene. In a validation cohort of 140 schizophrenia patients assessed for TD, the variant was also not detected in any individual. Some potentially suggestive TD genes were detected in the TD cohort and warrant follow-up in future studies. No significant enrichment in previously reported TD candidate genes was identified. To the best of our knowledge, this is the first WES study of TD, demonstrating the potential role of rare loss-of-function variant enrichment in this pharmacogenetic phenotype.

PMID: 31153890 [PubMed - as supplied by publisher]

A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice.

Lab Invest. 2019 May 31;:

Authors: Sueyoshi T, Sakuma T, Shindo S, Fashe M, Kanayama T, Ray M, Moore R, Negishi M

Abstract
Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRα knock-in mice (RxrαT167A) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues. RxrαT167A mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in the white adipose tissue (WAT) and ATP citrate lyase in the muscle. They also reduced gene expression for genes related to fatty acid catabolism and triglyceride synthesis in WAT and controlled heat factors such as adrenergic receptor β1 in muscles. In contrast, hepatic gluconeogenic pathways and synthetic pathways related to fatty acids remained unaffected by this mutation. Expression of multiple genes that were affected by the Thr 167 mutation in adipose tissue exhibited clear response to LG100268, a synthetic RXR agonist. Thus, the altered gene expression in mutant mice adipose appeared to be a direct effect of RXRα Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal in RxrαT167A during feeding, as observed with RXRα wild-type mice. However, RxrαT167A mice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRα phosphorylation at Thr 167. Thus, Thr 167 enabled RXRα to coordinate these three organs for regulation of energy metabolism and maintenance of glucose homeostasis.

PMID: 31152145 [PubMed - as supplied by publisher]

Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations.

Sci Immunol. 2019 May 31;4(35):

Authors: Dutton EE, Gajdasik DW, Willis C, Fiancette R, Bishop EL, Camelo A, Sleeman MA, Coccia M, Didierlaurent AM, Tomura M, Pilataxi F, Morehouse CA, Carlesso G, Withers DR

Abstract
Tissue residency is considered a defining feature of the innate lymphoid cell (ILC) populations located within mucosal and adipose tissues. ILCs are also present within all lymphoid tissues, but whether ILCs migrate between lymphoid and nonlymphoid sites and in what context is poorly understood. To determine whether migratory ILCs exist within peripheral lymph nodes (LNs), we labeled all cells within the brachial LN (bLN) of transgenic mice expressing a photoconvertible fluorescent protein by direct exposure to light. Tracking of cellular changes in the labeled LN revealed the gradual migration of new ILCs into the tissue, balanced by egress of ILCs dependent on sphingosine-1-phosphate receptors. Most of the migratory ILCs were ILC1s, entering LNs directly from the circulation in a CD62L- and CCR7-dependent manner and thus behaving like conventional natural killer (cNK) cells. Upon egress, both ILC1s and cNK cells were found to recirculate through peripheral LNs. A distinct population of migratory ILC2s were detected in the LN, but most of the ILC3s were tissue resident. Functionally, both migratory and resident ILC1s within LNs were able to rapidly produce IFN-γ to support the generation of robust TH1 T cell responses after immunization. Thus, migratory and resident ILC populations exist within peripheral LNs, with ILC1s, akin to cNK cells, able to traffic into these tissues where they can contribute to the initiation of adaptive immunity.

PMID: 31152090 [PubMed - in process]

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial.

Br J Cancer. 2018 04;118(8):1042-1050

Authors: Maitland ML, Piha-Paul S, Falchook G, Kurzrock R, Nguyen L, Janisch L, Karovic S, McKee M, Hoening E, Wong S, Munasinghe W, Palma J, Donawho C, Lian GK, Ansell P, Ratain MJ, Hong D

Abstract
BACKGROUND: Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib.
METHODS: Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle.
RESULTS: Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses.
CONCLUSIONS: In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue.
CLINICAL TRIAL REGISTRATION: NCT01110486.

PMID: 29551775 [PubMed - indexed for MEDLINE]

Personalizing dosing of risperidone, paliperidone and clozapine using therapeutic drug monitoring and pharmacogenetics.

Neuropharmacology. 2019 May 28;:

Authors: de Leon J

Abstract
By combining knowledge of pharmacogenetics, therapeutic drug monitoring (TDM) and drug-drug interactions (DDIs) the author developed a model for personalizing antipsychotic dosing, which is applied to risperidone, 9-hydroxyrisperidone or paliperidone, and clozapine. Drugs are approved using an average dose for an ideal average patient, but pharmacologists have described outliers: genetic poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Environmental and personal variables can also make patients behave as PMs or UMs. Drug clearance is represented by the concentration-to-dose (C/D) ratio under steady-state and trough conditions. A very low C/D ratio indicates a UM, while a very high C/D ratio indicates a PM. Total risperidone C/D ratio for the oral formulation is around 7 ng/ml per mg/day and can be influenced by CYP2D6 polymorphism, DDIs with inducers and inhibitors, and renal function. Oral paliperidone has low availability; its C/D ratio is around 4.1 ng/ml per mg/d and can be influenced by inducers and renal impairment. Once-a-month long-acting paliperidone provides a C/D ratio around 7.7 ng/ml per mg/day at steady state, which is expected to be in the 8th month (before the 9th injection). TDM is particularly important for long-acting paliperidone formulations that may accumulate once steady state is reached (after years for the 3- and 6-month formulations). In the US, clozapine C/D ratios typically range from 0.6 (male smokers) to 1.2 (female non-smokers) ng/ml per mg/day. East Asians' clozapine C/D ratios appear to be twice as high. Inhibitors (including fluvoxamine and oral contraceptives) and inflammation can also increase clozapine C/D ratios.

PMID: 31150659 [PubMed - as supplied by publisher]

Cytochrome P450 genotype and aggressive behavior on selective serotonin reuptake inhibitors.

Pharmacogenomics. 2018 09 01;19(14):1097-1099

Authors: Ekhart C, Matic M, Kant A, Elens L, Puijenbroek EV, Schaik RV

Abstract
Letter in reply to: Eikelenboom-Schieveld SJM, Fogleman JC. Letter to the Editor. Pharmcogenomics 19(14), 1095-1096 (2018) [ 1 ]. Regarding: Ekhart, Matic M, Kant A, van Puijenbroek E, van Schaik R. CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors. Phamacogenomics 18(7), 613-620 (2017) [ 2 ].

PMID: 30165797 [PubMed - indexed for MEDLINE]

Genetically Engineered Mouse Models of K-Ras-Driven Lung and Pancreatic Tumors: Validation of Therapeutic Targets.

Cold Spring Harb Perspect Med. 2018 05 01;8(5):

Authors: Drosten M, Guerra C, Barbacid M

Abstract
K-RAS signaling has been intensely studied for over 40 years. Yet, as of today, no drugs have been approved to treat K-RAS mutant cancers. Since the turn of the century, scientists have used genetically engineered mouse (GEM) models to reproduce K-RAS mutant cancers in a laboratory setting to elucidate those molecular events responsible for the onset and progression of these tumors and to identify suitable therapies. In this review, we outline a brief description of available GEM models for two tumor types known to be driven by K-RAS mutations: lung adenocarcinoma and pancreatic ductal adenocarcinoma. In addition, we summarize a series of studies that have used these GEM tumor models to validate, either by genetic or pharmacological approaches, the therapeutic potential of a variety of targets, with the ultimate goal of translating these results to the clinical setting.

PMID: 28778964 [PubMed - indexed for MEDLINE]

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