Targeting gap junction in epilepsy: Perspectives and challenges.

Biomed Pharmacother. 2019 Jan;109:57-65

Authors: Li Q, Li QQ, Jia JN, Liu ZQ, Zhou HH, Mao XY

Abstract
Gap junctions (GJs) are multiple cellular intercellular connections that allow ions to pass directly into the cytoplasm of neighboring cells. Electrical coupling mediated by GJs plays a role in the generation of highly synchronous electrical activity. Accumulative investigations show that GJs in the brain are involved in the generation, synchronization and maintenance of seizure events. At the same time, GJ blockers exert potent curative potential on epilepsy in vivo or in vitro. This review aims to shed light on the role of GJs in epileptogenesis. Targeting GJs is likely to be served as a novel therapeutic approach on epileptic patients.

PMID: 30396092 [PubMed - indexed for MEDLINE]

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data.

Circ Genom Precis Med. 2019 Mar 21;:

Authors: Patel RS, Schmidt AF, Tragante V, McCubrey RO, Holmes MV, Howe LJ, Direk K, Åkerblom A, Leander K, Virani SS, Kaminski KA, Muehlschlegel JD, Dubé MP, Allayee H, Almgren P, Alver M, Baranova EV, Behlouli H, Boeckx B, Braund PS, Breitling LP, Delgado G, Duarte NE, Dufresne L, Eriksson N, Foco L, Gijsberts CM, Gong Y, Hartiala J, Heydarpour M, Hubacek JA, Kleber M, Kofink D, Kuukasjärvi P, Lee VV, Leiherer A, Lenzini PA, Levin D, Lyytikäinen LP, Martinelli N, Mons U, Nelson CP, Nikus K, Pilbrow AP, Ploski R, Sun YV, Tanck MWT, Tang WHW, Trompet S, van der Laan SW, Van Setten J, Vilmundarson RO, Viviani Anselmi C, Vlachopoulou E, Boerwinkle E, Briguori C, Carlquist JF, Carruthers KF, Casu G, Deanfield J, Deloukas P, Dudbridge F, Fitzpatrick N, Gigante B, James S, Lokki ML, Lotufo PA, Marziliano N, Mordi IR, Muhlestein JB, Newton-Cheh C, Pitha J, Saely CH, Samman-Tahhan A, Sandesara PB, Teren A, Timmis A, Van de Werf F, Wauters E, Wilde AAM, Ford I, Stott DJ, Algra A, Andreassi MG, Ardissino D, Arsenault BJ, Ballantyne CM, Bergmeijer TO, Bezzina CR, Body SC, Bogaty P, de Borst GJ, Brenner H, Burkhardt R, Carpeggiani C, Condorelli G, Cooper-DeHoff RM, Cresci S, de Faire U, Doughty RN, Drexel H, Engert JC, Fox KAA, Girelli D, Hagström E, Hazen SL, Held C, Hemingway H, Hoefer IE, Hovingh GK, Johnson JA, de Jong PA, Jukema JW, Kaczor MP, Kähönen M, Kettner J, Kiliszek M, Klungel OH, Lagerqvist B, Lambrechts D, Laurikka JO, Lehtimäki T, Lindholm D, Mahmoodi BK, Maitland-van der Zee AH, McPherson R, Melander O, Metspalu A, Pepinski W, Olivieri O, Opolski G, Palmer CN, Pasterkamp G, Pepine CJ, Pereira AC, Pilote L, Quyyumi AA, Richards AM, Sanak M, Scholz M, Siegbahn A, Sinisalo J, Smith JG, Spertus JA, Stewart AFR, Szczeklik W, Szpakowicz A, Ten Berg JM, Thanassoulis G, Thiery J, van der Graaf Y, Visseren FLJ, Waltenberger J, Van der Harst P, Tardif JC, Sattar N, Lang CC, Paré G, Brophy JM, Anderson JL, März W, Wallentin L, Cameron VA, Horne BD, Samani NJ, Hingorani AD, Asselbergs FW

Abstract
BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.
METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD.
RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

PMID: 30897348 [PubMed - as supplied by publisher]

Hyperprogression-Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer.

JAMA Oncol. 2019 Mar 21;:

Authors: Pearson AT, Sweis RF

PMID: 30896751 [PubMed - as supplied by publisher]

Subsequent Event Risk in Individuals with Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium.

Circ Genom Precis Med. 2019 Mar 21;:

Authors: Patel R, Tragante V, Schmidt AF, McCubrey RO, Holmes MV, Howe LJ, Direk K, Åkerblom A, Leander K, Virani SS, Kaminski KA, Muehlschlegel JD, Allayee H, Almgren P, Alver M, Baranova EV, Behlouli H, Boeckx B, Braund PS, Breitling LP, Delgado G, Duarte NE, Dubé MP, Dufresne L, Eriksson N, Foco L, Scholz M, Gijsberts CM, Glinge C, Gong Y, Hartiala J, Heydarpour M, Hubacek JA, Kleber M, Kofink D, Kotti S, Kuukasjärvi P, Lee VV, Leiherer A, Lenzini PA, Levin D, Lyytikäinen LP, Martinelli N, Mons U, Nelson CP, Nikus K, Pilbrow AP, Ploski R, Sun YV, Tanck MWT, Tang WHW, Trompet S, van der Laan SW, Van Setten J, Vilmundarson RO, Viviani Anselmi C, Vlachopoulou E, Al Ali L, Boerwinkle E, Briguori C, Carlquist JF, Carruthers KF, Casu G, Deanfield J, Deloukas P, Dudbridge F, Engström T, Fitzpatrick N, Fox K, Gigante B, James S, Lokki ML, Lotufo PA, Marziliano N, Mordi IR, Muhlestein JB, Newton-Cheh C, Pitha J, Saely CH, Samman-Tahhan A, Sandesara PB, Teren A, Timmis A, Van de Werf F, Wauters E, Wilde AAM, Ford I, Stott DJ, Algra A, Andreassi MG, Ardissino D, Arsenault BJ, Ballantyne CM, Bergmeijer TO, Bezzina CR, Body SC, Boersma EH, Bogaty P, Bots M, Brenner H, Brugts JJ, Burkhardt R, Carpeggiani C, Condorelli G, Cooper-DeHoff RM, Cresci S, Danchin N, de Faire U, Doughty RN, Drexel H, Engert JC, Fox KAA, Girelli D, Grobbee DE, Hagström E, Hazen SL, Held C, Hemingway H, Hoefer IE, Hovingh GK, Jabbari R, Johnson JA, Jukema JW, Kaczor MP, Kähönen M, Kettner J, Kiliszek M, Klungel OH, Lagerqvist B, Lambrechts D, Laurikka JO, Lehtimäki T, Lindholm D, Mahmoodi BK, Maitland-van der Zee AH, McPherson R, Melander O, Metspalu A, Niemcunowicz-Janica A, Olivieri O, Opolski G, Palmer CN, Pasterkamp G, Pepine CJ, Pereira AC, Pilote L, Quyyumi AA, Richards AM, Sanak M, Siegbahn A, Simon T, Sinisalo J, Smith JG, Spertus JA, Stender S, Stewart AFR, Szczeklik W, Szpakowicz A, Tardif JC, Ten Berg JM, Tfelt-Hansen J, Thanassoulis G, Thiery J, Torp-Pedersen C, van der Graaf Y, Visseren FLJ, Waltenberger J, Weeke PE, Van der Harst P, Lang CC, Sattar N, Cameron VA, Anderson JL, Brophy JM, Paré G, Horne BD, März W, Wallentin L, Samani NJ, Hingorani AD, Asselbergs FW

Abstract
BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.
METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.
RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints.
CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

PMID: 30896328 [PubMed - as supplied by publisher]

IGNITE network: Response of patients to genomic medicine interventions.

Mol Genet Genomic Med. 2019 Mar 20;:e636

Authors: Orlando LA, Voils C, Horowitz CR, Myers RA, Arwood MJ, Cicali EJ, McDonough CW, Pollin TI, Guan Y, Levy KD, Ramirez A, Quittner A, Madden EB

Abstract
BACKGROUND: The IGNITE network funds six genomic medicine projects. Though interventions varied, we hypothesized that synergies across projects could be leveraged to better understand the participant experiences with genomic medicine interventions. Therefore, we performed cross-network analyses to identify associations between participant demographics and attitudes toward the intervention (attitude), plan to share results (share), and quality of life (QOL).
METHODS: Data collection for demographics, attitude, share, and QOL surveys were standardized across projects. Recruitment and survey administration varied by each project's protocol.
RESULTS: Participants (N = 6,817) were 67.2% (N = 4,584) female, and 37.4% (N = 3,544) were minority. Mean age = 54.0 (sd 14.a). Younger participants were as follows: (1) more positive in attitude pre-intervention (1.15-fold decrease/10-year age increase (OR)) and more negative after (1.14-fold increase OR); (2) higher in QOL pre-intervention (1.07-fold increase OR) and postintervention; (3) more likely to share results (1.12-fold increase OR). Race was significant when sharing results (white participants increased OR = 1.88), but not for change in QOL pre-postintervention or attitude.
CONCLUSION: Our findings demonstrate the feasibility of this approach and identified a few key themes which are as follows: age was consistently significant across the three outcomes, whereas race had less of an impact than expected. However, these are only associations and thus warrant further study.

PMID: 30895746 [PubMed - as supplied by publisher]

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med. 2019 Mar 21;:

Authors: Cavallari LH, Van Driest SL, Prows CA, Bishop JR, Limdi NA, Pratt VM, Ramsey LB, Smith DM, Tuteja S, Duong BQ, Hicks JK, Lee JC, Obeng AO, Beitelshees AL, Bell GC, Blake K, Crona DJ, Dressler L, Gregg RA, Hines LJ, Scott SA, Shelton RC, Weitzel KW, Johnson JA, Peterson JF, Empey PE, Skaar TC, IGNITE Network

Abstract
PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.
METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.
RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.
CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

PMID: 30894703 [PubMed - as supplied by publisher]

Extensive epigenetic and transcriptomic variability between genetically identical human B-lymphoblastoid cells with implications in pharmacogenomics research.

Sci Rep. 2019 Mar 20;9(1):4889

Authors: Ozgyin L, Horvath A, Hevessy Z, Balint BL

Abstract
Genotyped human B-lymphoblastoid cell lines (LCLs) are widely used models in mapping quantitative trait loci for chromatin features, gene expression, and drug response. The extent of genotype-independent functional genomic variability of the LCL model, although largely overlooked, may inform association study design. In this study, we use flow cytometry, chromatin immunoprecipitation sequencing and mRNA sequencing to study surface marker patterns, quantify genome-wide chromatin changes (H3K27ac) and transcriptome variability, respectively, among five isogenic LCLs derived from the same individual. Most of the studied LCLs were non-monoclonal and had mature B cell phenotypes. Strikingly, nearly one-fourth of active gene regulatory regions showed significantly variable H3K27ac levels, especially enhancers, among which several were classified as clustered enhancers. Large, contiguous genomic regions showed signs of coordinated activity change. Regulatory differences were mirrored by mRNA expression changes, preferentially affecting hundreds of genes involved in specialized cellular processes including immune and drug response pathways. Differential expression of DPYD, an enzyme involved in 5-fluorouracil (5-FU) catabolism, was associated with variable LCL growth inhibition mediated by 5-FU. The extent of genotype-independent functional genomic variability might highlight the need to revisit study design strategies for LCLs in pharmacogenomics.

PMID: 30894562 [PubMed - in process]

XPO5 genetic polymorphisms in cancer risk and prognosis.

Pharmacogenomics. 2018 06 01;19(9):799-808

Authors: Patrão AS, Dias F, Teixeira AL, Maurício J, Medeiros R

Abstract
miRNAs are small noncoding RNA molecules that have a very important role in gene expression regulation and, therefore, in cell homeostasis. SNPs in certain miRNA-related genes have been shown to influence cancer risk and prognosis. miRNA cellular processing is complex and involves multiple proteins. XPO5 is a key factor in this process as it is responsible for the nuclear export of the precursor pre-miRNA to the cytoplasm, where it will be further processed to its final miRNA conformation in order to be loaded to RNA inducing silencing complex to exert its regulatory effect. SNPs in miRNA machinery related genes have previously been shown to influence carcinogenesis, but the role of XPO5 SNPs in its expression and function is not yet fully understood. In our review, we elaborate comprehensively on the role of XPO5 and how polymorphisms have been shown to influence cancer risk and prognosis to date.

PMID: 29790454 [PubMed - indexed for MEDLINE]

RICTOR gene amplification is correlated with metastasis and therapeutic resistance in triple-negative breast cancer.

Pharmacogenomics. 2018 06 01;19(9):757-760

Authors: El Shamieh S, Saleh F, Moussa S, Kattan J, Farhat F

Abstract
Triple-negative breast cancer (TNBC) is characterized by its aggressive behavior, metastasis and lack of targeted therapies. Herein, we discuss the clinical, histopathological and genetic profile of a woman diagnosed with TNBC. Since the patient had no durable response to chemotherapy, a genetic profiling was carried out. Next-generation sequencing analysis of 592 genes showed a missense mutation, p.E545A in PIK3CA, thus the patient was started on the mTOR inhibitor everolimus, in combination with exemestane, which controlled her pain; however, the disease progressed aggressively. More importantly, next-generation sequencing analysis showed a RICTOR gene amplification (eight copies) suggesting that RICTOR promotes the genesis of TNBC. We conclude that determining regulators of RICTOR and furthermore, their inhibitors might decrease cancer cells proliferation rate in patients with TNBC.

PMID: 29790419 [PubMed - indexed for MEDLINE]

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11.

Int J Cancer. 2019 Mar 19;:

Authors: Ungaro F, Colombo P, Massimino L, Ugolini GS, Correale C, Rasponi M, Garlatti V, Rubbino F, Tacconi C, Spaggiari P, Spinelli A, Carvello M, Sacchi M, Spanò S, Vetrano S, Malesci A, Peyrin-Biroulet L, Danese S, D'Alessio S

Abstract
Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix (ECM). Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC-associated human intestinal lymphatic endothelial cells (HILEC) regulate tumor cell growth via Growth Differentiation Factor 11 (GDF11), a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis. This article is protected by copyright. All rights reserved.

PMID: 30889293 [PubMed - as supplied by publisher]

Precision medicine in Thailand.

Am J Med Genet C Semin Med Genet. 2019 Mar 19;:

Authors: Shotelersuk V, Tongsima S, Pithukpakorn M, Eu-Ahsunthornwattana J, Mahasirimongkol S

Abstract
Extraordinary advances in high throughput next generation sequencing (NGS) technology and bioinformatics are the main thrust that transforms the current state of healthcare into the era of precision medicine where clinical practice takes individual variability into account. Here, we summarize the current status of the infrastructure we have and the adoption of precision medicine in Thailand in four spheres: rare diseases, oncology, pharmacogenomics, and noncommunicable diseases. Moreover, we provide our perspectives to the future of precision medicine in Thailand, especially the manpower and ethical, legal, and social issues. We believe that with decreasing costs of NGS, increasing ability to interpret the genomic data, a greater number of actionable and available treatments, implementation of precision medicine at the public health level is not a matter of if but when.

PMID: 30888117 [PubMed - as supplied by publisher]

Expanding Pharmacist and Student Pharmacist Access to Genetics/Genomics/Pharmacogenomics Competency Education.

J Med Educ Curric Dev. 2019 Jan-Dec;6:2382120519834325

Authors: Kisor DF, Farrell CL

Abstract
Background: As pharmacogenomics (PGx), a component of genetics/genomics and precision medicine, gains traction in the clinical setting, education of health care providers and health professions students must be made broadly available to improve accessibility of such services to patients. As medication experts with education in pharmacology, pharmacokinetics, and pharmacodynamics, pharmacists must further their education to include pharmacogenomics. Currently, few opportunities exist to gain this type of education, and therefore, these services are not yet broadly available to the public.
Objective: The specific goal of this study was to evaluate pharmacists' and student pharmacists' self-assessed perception of competence related to genetics, genomics, and pharmacogenomics as presented via an online "pharmacogenomics certification program" (PGx program).
Design: The PGx program was delivered online with the content consisting of 3 background lessons and 8 specific drug-gene lessons presented in the context of pharmacist competency statements. In addition, 11 "video modules" with competency-related PGx content were included to provide a comprehensive program. A pre- and post-course survey instrument was used to evaluate the participants' self-assessed perception of competence related to each of 16 statements.
Results: One hundred thirty-seven (137) individuals enrolled in and completed the pharmacogenomics certification program. Overall, participants reported self-perceived improved competency as evidenced by the pre-course survey as compared with the post-course survey for each of the 16 competency statements related to genetics/genomics, including pharmacogenomics. Similar results were observed for the subgroups of student pharmacists (n = 63) and pharmacists (n = 74).
Future direction: This study showed that dissemination of genetics/genomics/pharmacogenomics competency statements education can be accomplished via online delivery. This delivery approach can expand genetics/genomics/pharmacogenomics content dissemination. The intent is to reach a broader population of pharmacy students, pharmacists, and other health care providers and health professions students to potentially advance the availability of such services, which can improve the safety and efficacy of medication use for patients.

PMID: 30886894 [PubMed]

Genetic Association of Olanzapine Treatment Response in Han Chinese Schizophrenia Patients.

Front Pharmacol. 2019;10:177

Authors: Zhou W, Xu Y, Lv Q, Sheng YH, Chen L, Li M, Shen L, Huai C, Yi Z, Cui D, Qin S

Abstract
Olanzapine, a second-generation antipsychotic medication, plays a critical role in current treatment of schizophrenia (SCZ). It has been observed that the olanzapine responses in schizophrenia treatment are different across individuals. However, prediction of this individual-specific olanzapine response requires in-depth knowledge of biomarkers of drug response. Here, we performed an integrative investigation on 238 Han Chinese SCZ patients to identify predictive biomarkers that were associated with the efficacy of olanzapine treatment. This study applied HaloPlex technology to sequence 143 genes from 79 Han Chinese SCZ patients. Our result suggested that there were 12 single nucleotide polymorphisms (SNPs) had significant association with olanzapine response in Han Chinese SCZ patients. Using MassARRAY platform, we tested that if these 12 SNPs were also statistically significant in 159 other SCZ patients (independent cohort) and the combined 238 SCZ patients (composed of two tested cohorts). The result of this analysis showed that 2 SNPs were significantly associated with the olanzapine response in both independent cohorts (rs324026, P = 0.023; rs12610827, P = 0.043) and combined SCZ patient population (rs324026, adjust P = 0.014; rs12610827, adjust P = 0.012). Our study provides systematic analyses of genetic variants associated with olanzapine responses of Han Chinese SCZ patients. The discovery of these novel biomarkers of olanzapine-response will facilitate to advance future olanzapine treatment specific for Han Chinese SCZ patients.

PMID: 30886581 [PubMed]

Personalized medicine in functional gastrointestinal disorders: Understanding pathogenesis to increase diagnostic and treatment efficacy.

World J Gastroenterol. 2019 Mar 14;25(10):1185-1196

Authors: Wang XJ, Camilleri M

Abstract
There is overwhelming evidence that functional gastrointestinal disorders (FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms (UGI Sx). Among patients with UGI Sx, approximately equal proportions (25%) of patients have delayed gastric emptying (GE), reduced gastric accommodation (GA), both impaired GE and GA, or neither, presumably due to increased gastric or duodenal sensitivity. Treatments targeted to the underlying pathophysiology utilize prokinetics, gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia (with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome (IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2D6, 2C19 and 3A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here; pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.

PMID: 30886502 [PubMed - in process]

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

Cardiovasc Diabetol. 2019 Mar 18;18(1):35

Authors: Duflot T, Moreau-Grangé L, Roche C, Iacob M, Wils J, Rémy-Jouet I, Cailleux AF, Leuillier M, Renet S, Li D, Morisseau C, Lamoureux F, Richard V, Prévost G, Joannidès R, Bellien J

Abstract
BACKGROUND: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.
METHODS AND RESULTS: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.
CONCLUSIONS: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

PMID: 30885203 [PubMed - in process]

The small molecule Bcl-2/Mcl-1 inhibitor TW-37 shows single-agent cytotoxicity in neuroblastoma cell lines.

BMC Cancer. 2019 Mar 18;19(1):243

Authors: Klenke S, Akdeli N, Stelmach P, Heukamp L, Schulte JH, Bachmann HS

Abstract
BACKGROUND: High-risk neuroblastoma with N-Myc amplification remains a therapeutic challenge in paediatric oncology. Antagonism of pro-death Bcl-2 homology (BH) proteins to pro-survival BH members such as Mcl-1 and Bcl-2 has become a treatment approach, but previous studies suggest that a combined inhibition of Bcl-2 and Mcl-1 is necessary. TW-37 inhibits Mcl-1 and Bcl-2 with almost the same affinity. However, single-agent cytotoxicity of TW-37 in neuroblastoma cell lines has not been investigated.
METHODS: Cell viability, apoptosis, proliferation and changes in growth properties were determined in SKNAS, IMR-5, SY5Y and Kelly cells after treatment with TW-37. After transfection with Mcl-1 or Bcl-2 siRNA, apoptosis and proliferation were investigated in Kelly cells. Mice with Kelly cell line xenografts were treated with TW-37 and tumor growth, survival and apoptosis were determined.
RESULTS: Cell lines with N-Myc amplification were more sensitive to TW-37 treatment, IC50 values for IMR-5 and Kelly cells being 0.28 μM and 0.22 μM, compared to SY5Y cells and SKNAS cells (IC50 0.96 μM and 0.83 μM). Treatment with TW-37 resulted in increased apoptosis and reduced proliferation rates, especially in IMR5 and Kelly cells. Bcl-2 as well as Mcl-1 knockdown induced apoptosis in Kelly cells. TW-37 led to a decrease in tumor growth and a favorable survival (p = 0.0379) in a Kelly neuroblastoma xenografts mouse model.
CONCLUSION: TW-37 has strong single-agent cytotoxicity in vitro and in vivo. Therefore, combined inhibition of Bcl-2/Mcl-1 by TW-37 in N-Myc amplified neuroblastoma may represent an interesting therapeutic strategy.

PMID: 30885150 [PubMed - in process]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/03/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Human Endothelial Colony Forming Cells Express Intracellular CD133 that Modulates their Vasculogenic Properties.

Stem Cell Rev. 2019 Mar 16;:

Authors: Rossi E, Poirault-Chassac S, Bieche I, Chocron R, Schnitzler A, Lokajczyk A, Bourdoncle P, Dizier B, Bacha NC, Gendron N, Blandinieres A, Guerin CL, Gaussem P, Smadja DM

Abstract
Stem cells at the origin of endothelial progenitor cells and in particular endothelial colony forming cells (ECFCs) subtype have been largely supposed to be positive for the CD133 antigen, even though no clear correlation has been established between its expression and function in ECFCs. We postulated that CD133 in ECFCs might be expressed intracellularly, and could participate to vasculogenic properties. ECFCs extracted from cord blood were used either fresh (n = 4) or frozen (n = 4), at culture days <30, to investigate the intracellular presence of CD133 by flow cytometry and confocal analysis. Comparison with HUVEC and HAEC mature endothelial cells was carried out. Then, CD133 was silenced in ECFCs using specific siRNA (siCD133-ECFCs) or scramble siRNA (siCtrl-ECFCs). siCD133-ECFCs (n = 12), siCtrl-ECFCs (n = 12) or PBS (n = 12) were injected in a hind-limb ischemia nude mouse model and vascularization was quantified at day 14 with H&E staining and immunohistochemistry for CD31. Results of flow cytometry and confocal microscopy evidenced the positivity of CD133 in ECFCs after permeabilization compared with not permeabilized ECFCs (p < 0.001) and mature endothelial cells (p < 0.03). In the model of mouse hind-limb ischemia, silencing of CD133 in ECFCs significantly abolished post-ischemic revascularization induced by siCtrl-ECFCs; indeed, a significant reduction in cutaneous blood flows (p = 0.03), capillary density (CD31) (p = 0.01) and myofiber regeneration (p = 0.04) was observed. Also, a significant necrosis (p = 0.02) was observed in mice receiving siCD133-ECFCs compared to those treated with siCtrl-ECFCs. In conclusion, our work describes for the first time the intracellular expression of the stemness marker CD133 in ECFCs. This feature could resume the discrepancies found in the literature concerning CD133 positivity and ontogeny in endothelial progenitors.

PMID: 30879244 [PubMed - as supplied by publisher]