Reference values assessment in a Mediterranean population for small dense low-density lipoprotein concentration isolated by an optimized precipitation method.

Vasc Health Risk Manag. 2017;13:201-207

Authors: Fernández-Cidón B, Padró-Miquel A, Alía-Ramos P, Castro-Castro MJ, Fanlo-Maresma M, Dot-Bach D, Valero-Politi J, Pintó-Sala X, Candás-Estébanez B

Abstract
BACKGROUND: High serum concentrations of small dense low-density lipoprotein cholesterol (sd-LDL-c) particles are associated with risk of cardiovascular disease (CVD). Their clinical application has been hindered as a consequence of the laborious current method used for their quantification.
OBJECTIVE: Optimize a simple and fast precipitation method to isolate sd-LDL particles and establish a reference interval in a Mediterranean population.
MATERIALS AND METHODS: Forty-five serum samples were collected, and sd-LDL particles were isolated using a modified heparin-Mg(2+) precipitation method. sd-LDL-c concentration was calculated by subtracting high-density lipoprotein cholesterol (HDL-c) from the total cholesterol measured in the supernatant. This method was compared with the reference method (ultracentrifugation). Reference values were estimated according to the Clinical and Laboratory Standards Institute and The International Federation of Clinical Chemistry and Laboratory Medicine recommendations. sd-LDL-c concentration was measured in serums from 79 subjects with no lipid metabolism abnormalities.
RESULTS: The Passing-Bablok regression equation is y = 1.52 (0.72 to 1.73) + 0.07x (-0.1 to 0.13), demonstrating no significant statistical differences between the modified precipitation method and the ultracentrifugation reference method. Similarly, no differences were detected when considering only sd-LDL-c from dyslipidemic patients, since the modifications added to the precipitation method facilitated the proper sedimentation of triglycerides and other lipoproteins. The reference interval for sd-LDL-c concentration estimated in a Mediterranean population was 0.04-0.47 mmol/L.
CONCLUSION: An optimization of the heparin-Mg(2+) precipitation method for sd-LDL particle isolation was performed, and reference intervals were established in a Spanish Mediterranean population. Measured values were equivalent to those obtained with the reference method, assuring its clinical application when tested in both normolipidemic and dyslipidemic subjects.

PMID: 28652759 [PubMed - indexed for MEDLINE]

Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics.

FASEB J. 2017 Jun;31(6):2696-2708

Authors: Vorrink SU, Ullah S, Schmidt S, Nandania J, Velagapudi V, Beck O, Ingelman-Sundberg M, Lauschke VM

Abstract
Adverse reactions or lack of response to medications are important concerns for drug development programs. However, faithful predictions of drug metabolism and toxicity are difficult because animal models show only limited translatability to humans. Furthermore, current in vitro systems, such as hepatic cell lines or primary human hepatocyte (PHH) 2-dimensional (2D) monolayer cultures, can be used only for acute toxicity tests because of their immature phenotypes and inherent instability. Therefore, the migration to novel phenotypically stable models is of prime importance for the pharmaceutical industry. Novel 3-dimensional (3D) culture systems have been shown to accurately mimic in vivo hepatic phenotypes on transcriptomic and proteomic level, but information about their metabolic stability is lacking. Using a combination of targeted and untargeted high-resolution mass spectrometry, we found that PHHs in 3D spheroid cultures remained metabolically stable for multiple weeks, whereas metabolic patterns of PHHs from the same donors cultured as conventional 2D monolayers rapidly deteriorated. Furthermore, pharmacokinetic differences between donors were maintained in 3D spheroid cultures, enabling studies of interindividual variability in drug metabolism and toxicity. We conclude that the 3D spheroid system is metabolically stable and constitutes a suitable model for in vitro studies of long-term drug metabolism and pharmacokinetics.-Vorrink, S. U., Ullah, S., Schmid, S., Nandania, J., Velagapudi, V., Beck, O., Ingelman-Sundberg, M., Lauschke, V. M. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics.

PMID: 28264975 [PubMed - indexed for MEDLINE]

Establishing Genotypic Cutoff Values To Measure Antimicrobial Resistance in Salmonella.

Antimicrob Agents Chemother. 2017 Mar;61(3):

Authors: Tyson GH, Zhao S, Li C, Ayers S, Sabo JL, Lam C, Miller RA, McDermott PF

Abstract
Whole-genome sequencing (WGS) has transformed our understanding of antimicrobial resistance, helping us to better identify and track the genetic mechanisms underlying phenotypic resistance. Previous studies have demonstrated high correlations between phenotypic resistance and the presence of known resistance determinants. However, there has never been a large-scale assessment of how well resistance genotypes correspond to specific MICs. We performed antimicrobial susceptibility testing and WGS of 1,738 nontyphoidal Salmonella strains to correlate over 20,000 MICs with resistance determinants. Using these data, we established what we term genotypic cutoff values (GCVs) for 13 antimicrobials against Salmonella For the drugs we tested, we define a GCV as the highest MIC of isolates in a population devoid of known acquired resistance mechanisms. This definition of GCV is distinct from epidemiological cutoff values (ECVs or ECOFFs), which currently differentiate wild-type from non-wild-type strains based on MIC distributions alone without regard to genetic information. Due to the large number of isolates involved, we observed distinct MIC distributions for isolates with different resistance gene alleles, including for ciprofloxacin and tetracycline, suggesting the potential to predict MICs based on WGS data alone.

PMID: 27993845 [PubMed - indexed for MEDLINE]

Viruses in pulp and periapical inflammation: a review.

Odontology. 2016 May;104(2):184-91

Authors: Hernández Vigueras S, Donoso Zúñiga M, Jané-Salas E, Salazar Navarrete L, Segura-Egea JJ, Velasco-Ortega E, López-López J

Abstract
The presence of viruses in endodontic disease has been studied in the last decade. Their presence is associated with periapical radiolucency and with clinical findings, such as pain. The aim of this review is to analyze the scientific evidence currently published about viruses in pulp and periapical inflammation, and its possible clinical implications. A literature review was carried out using the Medline/Pubmed database. The search was performed, in English and Spanish, using the following keyword combinations: virus AND endodontic; virus AND periapical; virus AND pulpitis; herpesvirus AND periapical; papillomavirus AND periapical. We subsequently selected the most relevant studies, which complied with the search criterion. A total of 21 articles were included, of which 18 detected the present of viruses in the samples. In 3 of the studies, viral presence was not found in the samples studied. The Epstein-Barr virus was found in about 41 % of cases compared to controls, in which it was present in about 2 %. The main association between viruses and endodontic pathosis is between Cytomegalovirus and Epstein-Barr virus; these are found in 114 of the 406 samples of different endodontic pathosis. Some evidence supports that the Epstein-Barr virus is present in a significant number of endodontic diseases, without exact knowledge of their action in these diseases.

PMID: 25796386 [PubMed - indexed for MEDLINE]

Mechanisms underlying metabolic disturbances associated with psychosis and antipsychotic drug treatment.

J Psychopharmacol. 2017 Aug 01;:269881117722987

Authors: Reynolds GP, McGowan OO

Abstract
The increase in cardiovascular disease and reduced life expectancy in schizophrenia likely relate to an increased prevalence of metabolic disturbances. Such metabolic risk factors in schizophrenia may result from both symptom-related effects and aetiological factors. However, a major contributory factor is that of treatment with antipsychotic drugs. These drugs differ in effects on body weight; the underlying mechanisms are not fully understood and may vary between drugs, but may include actions at receptors associated with the hypothalamic control of food intake. Evidence supports 5-hydroxytryptamine receptor 1C and dopamine D2 receptor antagonism as well as antagonism at histamine H1 and muscarinic M3 receptors. These M3 receptors may also mediate the effects of some drugs on glucose regulation. Several antipsychotics showing little propensity for weight gain, such as aripiprazole, have protective pharmacological mechanisms, rather than just the absence of a hyperphagic effect. In addition to drug differences, there is large individual variation in antipsychotic drug-induced weight gain. This pharmacogenetic association reflects genetic variation in several drug targets, including the 5-hydroxytryptamine receptor 1C, as well as genes involved in obesity and metabolic disturbances. Thus predictive genetic testing for drug-induced weight gain would represents a first step towards personalised medicine addressing this severe and problematic iatrogenic disease.

PMID: 28892404 [PubMed - as supplied by publisher]

Pharmacogenetics of opioid analgesics in dogs.

J Vet Pharmacol Ther. 2017 Sep 11;:

Authors: Kongara K

Abstract
Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs.

PMID: 28892154 [PubMed - as supplied by publisher]

Role of pharmacogenomics in antiepileptic drug therapy: current status and future perspectives.

Curr Pharm Des. 2017 Sep 10;:

Authors: Gambardella A, Labate A, Mumoli L, Lopes-Cendes I, Cendes F

Abstract
BACKGROUND: Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine.
OBJECTIVE: In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future.
METHODS: We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs.
RESULTS: Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity.
CONCLUSION: To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis.

PMID: 28891449 [PubMed - as supplied by publisher]

Validation Study of a Predictive Algorithm to Evaluate Opioid Use Disorder in a Primary Care Setting.

Health Serv Res Manag Epidemiol. 2017 Jan-Dec;4:2333392817717411

Authors: Sharma M, Lee C, Kantorovich S, Tedtaotao M, Smith GA, Brenton A

Abstract
BACKGROUND: Opioid abuse in chronic pain patients is a major public health issue. Primary care providers are frequently the first to prescribe opioids to patients suffering from pain, yet do not always have the time or resources to adequately evaluate the risk of opioid use disorder (OUD).
PURPOSE: This study seeks to determine the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm ("profile") incorporating phenotypic and, more uniquely, genotypic risk factors.
METHODS AND RESULTS: In a validation study with 452 participants diagnosed with OUD and 1237 controls, the algorithm successfully categorized patients at high and moderate risk of OUD with 91.8% sensitivity. Regardless of changes in the prevalence of OUD, sensitivity of the algorithm remained >90%.
CONCLUSION: The algorithm correctly stratifies primary care patients into low-, moderate-, and high-risk categories to appropriately identify patients in need for additional guidance, monitoring, or treatment changes.

PMID: 28890908 [PubMed]

Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.

J Clin Endocrinol Metab. 2017 Jun 01;102(6):1908-1916

Authors: Wang Y, Wactawski-Wende J, Sucheston-Campbell LE, Preus L, Hovey KM, Nie J, Jackson RD, Handelman SK, Nassir R, Crandall CJ, Ochs-Balcom HM

Abstract
Context: Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.
Objective: The objective was to test an interaction between genetic susceptibility and HT on fracture risk.
Design: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also used the case-only approach to test for a multiplicative interaction.
Setting: Forty US clinical centers.
Participants: A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.
Main Outcome Measures: Adjudicated fracture incidence.
Results: Both GRSs were associated with fracture risk per 1-unit increment in GRS (hazard ratio, 1.04 [95% confidence interval, 1.02 to 1.06] for Fx-GRS and hazard ratio, 1.03 [95% confidence interval,1.02-1.04] for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a substantial additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS P for RERI = 0.047, BMD-GRS P for RERI = 0.046.
Conclusions: These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.

PMID: 28324062 [PubMed - indexed for MEDLINE]

Blistering eruptions in childhood Henoch-Schönlein syndrome: systematic review of the literature.

Eur J Pediatr. 2017 Apr;176(4):487-492

Authors: Ramelli V, Lava SA, Simonetti GD, Bianchetti MG, Ramelli GP, Milani GP

Abstract
The occurrence of blistering eruptions in childhood Henoch-Schönlein syndrome has been so far addressed exclusively in individual case reports. To describe epidemiology, clinical presentation, and therapeutic options in Henoch-Schönlein patients ≤18 years of age with blistering eruptions, we completed a systematic literature search. For the final analysis, we retained 39 reports. Ten children with blisters were found in 7 (1.5%) case series containing a total of 666 unselected pediatric Henoch-Schönlein cases. We also found 41 individually documented cases of Henoch-Schönlein syndrome with blistering eruptions. Blistering eruptions and purpura were distributed very similarly, blisters developed concomitantly with palpable purpura or with a latency of ≤14 days, and 80% of the cases remitted within 4 weeks with a similar course in children managed expectantly and in those managed with steroids.
CONCLUSION: Blistering eruptions are rare in Henoch-Schönlein syndrome. They can be a source of diagnostic dilemma but do not have any prognostic value since they almost always spontaneously subside within 4 weeks. What is known: • Textbooks and reviews marginally refer to the occurrence of blistering eruptions in children with Henoch-Schönlein syndrome. What is new • Blistering eruptions occur in <2% of cases. • Blisters and purpura are distributed similarly, blisters develop concomitantly with purpura or with a latency of ≤14 days. • Almost all cases remit within 4 weeks with a similar course in children managed expectantly and in those managed with systemic steroids.

PMID: 28161822 [PubMed - indexed for MEDLINE]

Deficiency of N-Acetyltransferase Increases the Interactions of Isoniazid with Endobiotics in mouse Liver.

Biochem Pharmacol. 2017 Sep 06;:

Authors: Wang P, Shehu AI, Lu J, Joshi RH, Venkataramanan R, Sugamori KS, Grant DM, Zhong XB, Ma X

Abstract
Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.

PMID: 28888949 [PubMed - as supplied by publisher]

Germline Genetic Variants with Implications for Disease Risk and Therapeutic Outcomes.

Physiol Genomics. 2017 Sep 08;:physiolgenomics.00035.2017

Authors: Pasternak AL, Ward KM, Luzum JA, Ellingrod VL, Hertz DL

Abstract
Genetic testing has multiple clinical applications including disease risk assessment, diagnosis and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care.

PMID: 28887371 [PubMed - as supplied by publisher]

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

Eur J Pharm Sci. 2017 Sep 05;:

Authors: Giletti A, Vital M, Lorenzo M, Cardozo P, Borelli G, Gabus R, Martínez L, Díaz L, Assar R, Rodriguez MN, Esperón P

Abstract
BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid.
METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated.
RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found.
CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

PMID: 28887233 [PubMed - as supplied by publisher]

Dapsone-induced severe cutaneous adverse drug reactions are strongly linked with HLA-B*13: 01 allele in the Thai population.

Pharmacogenet Genomics. 2017 Sep 06;:

Authors: Tempark T, Satapornpong P, Rerknimitr P, Nakkam N, Saksit N, Wattanakrai P, Jantararoungtong T, Koomdee N, Mahakkanukrauh A, Tassaneeyakul W, Suttisai S, Pratoomwun J, Klaewsongkram J, Rerkpattanapipat T, Sukasem C

Abstract
OBJECTIVES: A previous publication in Chinese leprosy patients showed that the HLA-B*13:01 allele is a strong genetic marker for dapsone-induced drug hypersensitivity reactions, however there are no data describing whether HLA-B*13:01 is a valid marker for prediction of dapsone-induced drug hypersensitivity reactions in other ethnicities or nonleprosy patients. The aim of this study is to investigate whether there is an association between HLA genotypes and dapsone-induced severe cutaneous adverse reactions (SCARs) in nonleprosy patients.
PATIENTS AND METHODS: HLA-B genotypes of 15 patients with dapsone-induced SCARs (11 drug reaction with eosinophilia and systemic symptoms, four Stevens-Johnson syndrome/toxic epidermal necrolysis), 29 control patients, and 986 people from the general Thai population were determined by the reverse PCR sequence-specific oligonucleotides probe.
RESULTS: The HLA-B*13:01 allele was significantly associated with dapsone-induced SCARs compared with dapsone-tolerant controls (odds ratio: 54.00, 95% confidence interval: 7.96-366.16, P=0.0001) and the general population (odds ratio: 26.11, 95% confidence interval: 7.27-93.75, P=0.0001). In addition, HLA-B*13:01 associated with dapsone-induced SJS-TEN (OR: 40.50, 95% confidence interval: 2.78-591.01, P=0.0070) and DRESS (OR: 60.75, 95% confidence interval: 7.44-496.18, P=0.0001).
CONCLUSION: This study demonstrated an association between HLA-B*13:01 and dapsone-induced SCARs including Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms in nonleprosy patients. Moreover, these results suggest that the HLA-B*13:01 allele may be a useful genetic marker for prediction of dapsone-induced SCARs in Thai and Han-Chinese populations.

PMID: 28885988 [PubMed - as supplied by publisher]

Association Between CYP2C19*17 Alleles and pH Probe Testing Outcomes in Children With Symptomatic Gastroesophageal Reflux.

J Clin Pharmacol. 2017 Sep 08;:

Authors: Franciosi JP, Mougey EB, Williams A, Gomez-Suarez RA, Thomas C, Creech CL, George K, Corao D, Lima JJ

Abstract
Esophageal pH monitoring remains a primary diagnostic tool for detecting gastroesophageal reflux disease (GERD). GERD that is refractory to proton pump inhibitor (PPI) medications may be related to CYP2C19 variants. Current PPI dosing practices in children do not take into account CYP2C19 allelic variants, which may lead to underdosing and subsequently to a misperception of PPI therapy failure. We hypothesized that pH probe acid exposure outcomes associate with CYP2C19*17 alleles among children with clinical concern for GERD. We identified a retrospective cohort of 74 children (age range 0.71-17.1 years, mean 8.5, SD 4.6) with stored endoscopic tissue samples and who had also undergone esophageal pH testing while on PPI therapy. These individuals were genotyped for common CYP2C19 alleles and were dichotomized to either CYP2C19*17 allelic carriers without corresponding loss of function alleles as cases vs controls. Associations between pH probe acid exposure outcomes and CYP2C19*17 alleles were investigated. Compared to controls, children who carry CYP2C19*17 alleles without corresponding loss-of-function alleles demonstrated statistically significant longer times with pH < 4 (76.46 vs 33.47 minutes, P = .03); and higher percent of time with pH < 4.0 (5.71 vs 2.67 minutes, P = .04). These findings remained statistically significant using multiple-regression modeling with test duration, PPI dose, and race as confounding variables. PPI therapy in children with *17 alleles may be better optimized with CYP2C19 genotype-guided dosing prior to pH probe testing.

PMID: 28884817 [PubMed - as supplied by publisher]

Epigenetic regulation of inflammation in localized aggressive periodontitis.

Clin Epigenetics. 2017;9:94

Authors: Shaddox LM, Mullersman AF, Huang H, Wallet SM, Langaee T, Aukhil I

Abstract
BACKGROUND: We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 μl (100 ng/μl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2).
RESULTS: Significant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients.
CONCLUSIONS: Our findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes.
TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01330719.

PMID: 28883894 [PubMed - in process]

ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels.

Arterioscler Thromb Vasc Biol. 2017 Sep 07;:

Authors: Trigueros-Motos L, van Capelleveen JC, Torta F, Castaño D, Zhang LH, Chai C, Kang M, Dimova LG, Schimmel AWM, Tietjen I, Radomski C, Tan LJ, Hwee TC, Narayanaswamy P, Wu D, Dorninger F, Yakala GK, Barhdadi A, Angeli V, Dubé MP, Berger J, Dallinga-Thie GM, Tietge UJF, Wenk MR, Hayden MR, Hovingh GK, Singaraja RR

Abstract
OBJECTIVE: High-density lipoproteins (HDL) are considered to protect against atherosclerosis in part by facilitating the removal of cholesterol from peripheral tissues. However, factors regulating lipid efflux are incompletely understood. We previously identified a variant in adenosine triphosphate-binding cassette transporter A8 (ABCA8) in an individual with low HDL cholesterol (HDLc). Here, we investigate the role of ABCA8 in cholesterol efflux and in regulating HDLc levels.
APPROACH AND RESULTS: We sequenced ABCA8 in individuals with low and high HDLc and identified, exclusively in low HDLc probands, 3 predicted deleterious heterozygous ABCA8 mutations (p.Pro609Arg [P609R], IVS17-2 A>G and p.Thr741Stop [T741X]). HDLc levels were lower in heterozygous mutation carriers compared with first-degree family controls (0.86±0.34 versus 1.17±0.26 mmol/L; P=0.005). HDLc levels were significantly decreased by 29% (P=0.01) in Abca8b(-/-) mice on a high-cholesterol diet compared with wild-type mice, whereas hepatic overexpression of human ABCA8 in mice resulted in significant increases in plasma HDLc and the first steps of macrophage-to-feces reverse cholesterol transport. Overexpression of wild-type but not mutant ABCA8 resulted in a significant increase (1.8-fold; P=0.01) of cholesterol efflux to apolipoprotein AI in vitro. ABCA8 colocalizes and interacts with adenosine triphosphate-binding cassette transporters A1 and further potentiates adenosine triphosphate-binding cassette transporters A1-mediated cholesterol efflux.
CONCLUSIONS: ABCA8 facilitates cholesterol efflux and modulates HDLc levels in humans and mice.

PMID: 28882873 [PubMed - as supplied by publisher]

Bevacizumab-induced hypertension: Clinical presentation and molecular understanding.

Pharmacol Ther. 2017 Sep 04;:

Authors: Li M, Kroetz DL

Abstract
Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity.

PMID: 28882537 [PubMed - as supplied by publisher]

Associations of genetic variants of endothelin with cardiovascular complications in patients with renal failure.

BMC Nephrol. 2017 Sep 07;18(1):291

Authors: Kao CC, Cheng SY, Wu MY, Chien SC, Lu HF, Hsu YW, Zhang YF, Wu MS, Chang WC

Abstract
BACKGROUND: Cardiovascular (CV) complications are the main cause of death in end-stage renal disease (ESRD) patients. The high CV risks are attributable to the additive effects of multiple factors. Endothelin (EDN) is a potent vasoconstrictor and plays a role in regulating vascular homeostasis. However, whether variants of the EDN gene are associated with risks of CV events is not known. We conducted a study to investigate associations of variants of the EDN gene with CV events in ESRD patients.
METHODS: A cohort of 190 ESRD patients was recruited, and 19 tagged single-nucleotide polymorphisms within the EDN gene family were selected for genotyping through a TaqMan assay. Data on clinical characteristics and hospitalizations for CV events were collected. Associations of genetic variants of the EDN gene with CV events were analyzed.
RESULTS: In this cohort, 62% (n = 118) of patients were hospitalized for a CV event. The EDN1 rs4714384 (CC/TC vs. TT) polymorphism was associated with an increased risk of a CV event after multiple testing (p < 0.001). Further functional exploration showed that it was a quantitative trait locus which may significantly alter gene expression in the tibial artery.
CONCLUSIONS: EDN1 rs4714384 is very likely an important biomarker of CV events in ESRD patients.

PMID: 28882114 [PubMed - in process]

Advances in single-cell RNA sequencing and its applications in cancer research.

Oncotarget. 2017 Aug 08;8(32):53763-53779

Authors: Zhu S, Qing T, Zheng Y, Jin L, Shi L

Abstract
Unlike population-level approaches, single-cell RNA sequencing enables transcriptomic analysis of an individual cell. Through the combination of high-throughput sequencing and bioinformatic tools, single-cell RNA-seq can detect more than 10,000 transcripts in one cell to distinguish cell subsets and dynamic cellular changes. After several years' development, single-cell RNA-seq can now achieve massively parallel, full-length mRNA sequencing as well as in situ sequencing and even has potential for multi-omic detection. One appealing area of single-cell RNA-seq is cancer research, and it is regarded as a promising way to enhance prognosis and provide more precise target therapy by identifying druggable subclones. Indeed, progresses have been made regarding solid tumor analysis to reveal intratumoral heterogeneity, correlations between signaling pathways, stemness, drug resistance, and tumor architecture shaping the microenvironment. Furthermore, through investigation into circulating tumor cells, many genes have been shown to promote a propensity toward stemness and the epithelial-mesenchymal transition, to enhance anchoring and adhesion, and to be involved in mechanisms of anoikis resistance and drug resistance. This review focuses on advances and progresses of single-cell RNA-seq with regard to the following aspects: 1. Methodologies of single-cell RNA-seq 2. Single-cell isolation techniques 3. Single-cell RNA-seq in solid tumor research 4. Single-cell RNA-seq in circulating tumor cell research 5.
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PMID: 28881849 [PubMed - in process]