An Architecture for Genomics Analysis in a Clinical Setting Using Galaxy and Docker.

Gigascience. 2017 Oct 18;:

Authors: Digan W, Countouris H, Barritault M, Baudoin D, Laurent-Puig P, Blons H, Burgun A, Rance B

Abstract
Background: Next Generation Sequencing is used on a daily basis to perform molecular analysis to determine subtypes of disease (e.g., in cancer) and to assist in the selection of the optimal treatment. Clinical bioinformatics handles the manipulation of the data generated by the sequencer, from the generation to the analysis and interpretation. Reproducibility and traceability are crucial issues in a clinical setting.
Results: We have designed an approach based on the Docker container technology and Galaxy, the popular bioinformatics analysis support open-source software. Our solution simplifies the deployment of a small size analytical platform, and simplifies the process for the clinician. From the technical point of view, the tools embedded in the platform are isolated and versioned through docker images. Along the Galaxy platform, we also introduce the AnalysisManager, a solution allowing single-click analysis for the biologists and leveraging standardized bioinformatics APIs. We added a Shiny/R interactive environment to ease the visualization of the outputs.
Conclusions: The platform relies on containers and ensures the data traceability by recording analytical actions, and by associating inputs and outputs of the tools to the EDAM ontology through ReGaTe. The source code is freely available on Github at https://github.com/CARPEM/GalaxyDocker.

PMID: 29048555 [PubMed - as supplied by publisher]

Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

Exp Clin Psychopharmacol. 2017 Oct;25(5):353-362

Authors: Glatard A, Dobrinas M, Gholamrezaee M, Lubomirov R, Cornuz J, Csajka C, Eap CB

Abstract
Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly lower with varenicline for a partial decrease (HR = 0.33, 95% CI [0.12, 0.89] and HR = 0.20, 95% CI [0.04, 0.91], respectively) and nonsignificantly lower for a total cessation (HR = 0.45, 95% CI [0.20, 1.0] and HR = 0.38, 95% CI [0.14, 1.0]). When compared with the normal metabolizers determined by phenotyping, the hazard ratio for a partial decrease was similar in the normal metabolizers determined by genotyping (HR = 0.42, 95% CI [0.18, 0.94]) while it was significantly lower with varenicline for a total cessation (HR = 0.50, 95% CI [0.26, 0.98]). Women and normal nicotine metabolizers may benefit more from varenicline over nicotine replacement therapy. (PsycINFO Database Record

PMID: 29048184 [PubMed - in process]

Single nucleotide polymorphisms and microsatellites in the canine glutathione S-transferase pi 1 (GSTP1) gene promoter.

Canine Genet Epidemiol. 2017;4:9

Authors: Sacco J, Mann S, Toral K

Abstract
BACKGROUND: Genetic polymorphisms within the glutathione S-transferase P1 (GSTP1) gene affect the elimination of toxic xenobiotics by the GSTP1 enzyme. In dogs, exposure to environmental chemicals that may be GSTP1 substrates is associated with cancer. The objectives of this study were to investigate the genetic variability in the GSTP1 promoter in a diverse population of 278 purebred dogs, compare the incidence of any variants found between breeds, and predict their effects on gene expression. To provide information on ancestral alleles, a number of wolves, coyotes, and foxes were also sequenced.
RESULTS: Fifteen single nucleotide polymorphisms (SNPs) and two microsatellites were discovered. Three of these loci were only polymorphic in dogs while three other SNPs were unique to wolves and coyotes. The major allele at c.-46 is T in dogs but is C in the wild canids. The c.-185 delT variant was unique to dogs. The microsatellite located in the 5' untranslated region (5'UTR) was a highly polymorphic GCC tandem repeat, consisting of simple and compound alleles that varied in size from 10 to 22-repeat units. The most common alleles consisted of 11, 16, and 17-repeats. The 11-repeat allele was found in 10% of dogs but not in the other canids. Unequal recombination and replication slippage between similar and distinct alleles may be the mechanism for the multiple microsatellites observed. Twenty-eight haplotypes were constructed in the dog, and an additional 8 were observed in wolves and coyotes. While the most common haplotype acrossbreeds was the wild-type *1A(17), other prevalent haplotypes included *3A(11) in Greyhounds, *6A(16) in Labrador Retrievers, *9A(16) in Golden Retrievers, and *8A(19) in Standard Poodles. Boxers and Siberian Huskies exhibited minimal haplotypic diversity. Compared to the simple 16*1 allele, the compound 16*2 allele (found in 12% of dogs) may interfere with transcription factor binding and/or the stability of the GSTP1 transcript.
CONCLUSIONS: Dogs and other canids exhibit extensive variation in the GSTP1 promoter. Genetic polymorphisms within distinct haplotypes prevalent in certain breeds can affect GSTP1 expression and carcinogen detoxification, and thus may be useful as genetic markers for cancer in dogs.

PMID: 29046813 [PubMed]

Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer.

Mol Pharm. 2016 Jun 06;13(6):1996-2009

Authors: Patel NR, Piroyan A, Nack AH, Galati CA, McHugh M, Orosz S, Keeler AW, O'Neal S, Zamboni WC, Davis B, Coleman TP

Abstract
Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased in vitro potency. Pharmacokinetic studies show that the circulation time for all three difattyacid platins encapsulated in NE remained identical, thus indicating that chain length did not influence circulation time. A stable NMI-350 family of NEs were successfully designed, formulated, and characterized. The Pt-resistance in KBCR-1000 cells was reversed with the NMI-350 family. Dimyrisplatin loaded NE (NMI-350) was most potent in vitro. The NMI-350 family demonstrated identical pharmacokinetic profiles to one another and circulated much longer than cisplatin. These data indicate that NMI-350 warrants further preclinical and clinical development as a replacement for current Pt regimens especially for those afflicted with multi drug resistant cancers.

PMID: 27170232 [PubMed - indexed for MEDLINE]

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: Call for a drug label update.

Ann Oncol. 2017 Aug 02;:

Authors: Henricks LM, Opdam FL, Beijnen JH, Cats A, Schellens JHM

Abstract
The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States of America no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU.Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

PMID: 29045513 [PubMed - as supplied by publisher]

Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers.

PLoS One. 2017;12(10):e0185753

Authors: Hequet D, Callens C, Gentien D, Albaud B, Mouret-Reynier MA, Dubot C, Cottu P, Huchon C, Zilberman S, Berseneff H, Foa C, Salmon R, Roulot A, Lerebours F, Salomon A, Ghali N, Morel P, Li Q, Cayre A, Guinebretière JM, Hornberger J, Penault-Llorca F, Rouzier R

Abstract
PURPOSE: The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna's assay information on physicians' adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results.
METHODS: Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians' opinion on the test results and the patients' degree of anxiety, difficulties with therapy and quality of life.
RESULTS: Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher's exact test). Prosigna test results also decreased patients' anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty.
CONCLUSIONS: The results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

PMID: 29045452 [PubMed - in process]

Activation of Parvalbumin Neurons in the Rostro-Dorsal Sector of the Thalamic Reticular Nucleus Promotes Sensitivity to Pain in Mice.

Neuroscience. 2017 Oct 14;:

Authors: Liu J, Zhang MQ, Wu X, Lazarus M, Cherasse Y, Yuan MY, Huang ZL, Li RX

Abstract
The calcium-binding protein, parvalbumin (PV), is highly expressed in thalamic reticular nucleus (TRN) GABAergic neurons, which receive input from the cerebral cortex and thalamus and send inhibitory output to the thalamic relay nucleus. Previous studies suggest that the TRN is involved in pain regulation as an important relay nucleus of the ascending pain pathway. However, little is known about its functional role in pain regulation and interconnectivity. In our study, the role of rostro-dorsal sector of TRN (TRNrd) PV-positive neurons in pain regulation was studied using chemogenetics based on designer receptors exclusively activated by designer drugs (DREADD). Then, projections from the TRNrd PV-positive neurons were explored using PV-Cre transgenic mice, conditional anterograde axonal tract tracing, and optogenetics, combined with immunohistochemistry and electrophysiology. The results showed that activation of PV-positive neurons in the TRNrd decreased the mechanical threshold and thermal latency of behaving mice during the light period when neuronal activity was low. Furthermore, the anterodorsal and paratenial thalamic nucleus received innervation from PV-positive neurons in the TRNrd. They were specifically inhibited by GABA, which is released from local axonal endings of PV neurons. These findings indicate that activation of PV neurons in the TRNrd increases pain sensitivity in PV-Cre transgenic mice.

PMID: 29042322 [PubMed - as supplied by publisher]

Myeloid cells contribute indirectly to VEGF expression upon hypoxia via activation of Müller cells.

Exp Eye Res. 2017 Oct 14;:

Authors: Nürnberg C, Kociok N, Brockmann C, Lischke T, Crespo-Garcia S, Reichhart N, Wolf S, Baumgrass R, Eming SA, Beer-Hammer S, Joussen AM

Abstract
Anti-VEGF-directed therapies have been a milestone for treating retinal vascular diseases. Depletion of monocyte lineage cells suppresses pathological neovascularization in the oxygen-induced retinopathy mouse model. However, the question whether myeloid-derived VEGF-A expression is responsible for the pathogenesis in oxygen-induced retinopathy remained unknown. We analyzed LysMCre-driven myeloid cell-specific VEGF-A knockout mice as well as mice with complete depletion of circulating macrophages through clodronate-liposome treatment in the oxygen-induced retinopathy model by immunohistochemistry, qPCR, and flow cytometry. Furthermore, we analyzed VEGF-A mRNA expression in MIO-M1 cells alone and in co-culture with BV-2 cells in vitro. The myeloid cell-specific VEGF-A knockout did not change relative retinal VEGF-A mRNA levels, the relative avascular area or macrophage/granulocyte numbers in oxygen-induced retinopathy and under normoxic conditions. We observed an insignificantly attenuated pathology in systemically clodronate-liposome treated knockouts but evident VEGF-A expression in activated Müller cells on immunohistochemically stained sections. MIO-M1 cells had significantly higher expression levels of VEGF-A in co-culture with BV-2 cells compared to cultivating MIO-M1 cells alone. Our data show that myeloid-derived cells contribute to pathological neovascularization in oxygen-induced retinopathy through activation of VEGF-A expression in Müller cells.

PMID: 29042140 [PubMed - as supplied by publisher]

Pharmacogenetics: a general review on progress to date.

Br Med Bull. 2017 Oct 11;:1-15

Authors: Daly AK

Abstract
Background: Pharmacogenetics is not a new subject area but its relevance to drug prescribing has become clearer in recent years due to developments in gene cloning and DNA genotyping and sequencing.
Sources of data: There is a very extensive published literature concerned with a variety of different genes and drugs.
Areas of agreement: There is general agreement that pharmacogenetic testing is essential for the safe use of drugs such as the thiopurines and abacavir.
Areas of controversy: Whether pharmacogenetic testing should be applied more widely including to the prescription of certain drugs such as warfarin and clopidogrel where the overall benefit is less clear remains controversial.
Growing points: Personal genotype information is increasingly being made available directly to the consumer. This is likely to increase demand for personalized prescription and mean that prescribers need to take pharmacogenetic information into account. Projects such as 100 000 genomes are providing complete genome sequences that can form part of a patient medical record. This information will be of great value in personalized prescribing.
Areas timely for developing research: Development of new drugs targeting particular genetic risk factors for disease. These could be prescribed to those with an at risk genotype.

PMID: 29040422 [PubMed - as supplied by publisher]

Store-operated Ca(2+) Entry Facilitates the Lipopolysaccharide-induced Cyclooxygenase-2 Expression in Gastric Cancer Cells.

Sci Rep. 2017 Oct 16;7(1):12813

Authors: Wong JH, Ho KH, Nam S, Hsu WL, Lin CH, Chang CM, Wang JY, Chang WC

Abstract
Helicobacter pylori has been identified as one of the major causes of chronic gastritis, gastric and duodenal ulcers, and gastric cancer. Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria, and H. pylori LPS might play an exclusively important role in activating inflammatory pathways in monocytes and macrophages. To study the role of LPS in the underlying mechanism of inflammatory responses, we established an in vitro model using the human AGS gastric cancer cell line. We found that LPS mediates inflammation through setting off a cascade of events: activation of the store-operated calcium (SOC) channel, initiation of downstream NF-κB signaling, and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Phosphorylated ERK1/2 promotes the nuclear translocation of NF-κB, and eventually elevates the expression level of COX-2, a major inflammatory gene.

PMID: 29038542 [PubMed - in process]

Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.

Diabetes Care. 2016 Nov;39(11):1915-1924

Authors: Shah HS, Gao H, Morieri ML, Skupien J, Marvel S, Paré G, Mannino GC, Buranasupkajorn P, Mendonca C, Hastings T, Marcovina SM, Sigal RJ, Gerstein HC, Wagner MJ, Motsinger-Reif AA, Buse JB, Kraft P, Mychaleckyj JC, Doria A

Abstract
OBJECTIVE: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
RESEARCH DESIGN AND METHODS: A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality.
RESULTS: Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10(-9) and P = 2 × 10(-8), respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029).
CONCLUSIONS: Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.

PMID: 27527847 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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15 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 2017/10/17

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.

Toxic Metals Increase Serum Tumor Necrosis Factor-α Levels, Modified by Essential Elements and Different Types of Tumor Necrosis Factor-α Promoter Single-nucleotide Polymorphisms.

Epidemiology. 2017 Oct;28 Suppl 1:S113-S120

Authors: Huang YC, Chang WC, Shan YH, Lin CY, Wang CL, Dai CY, Ho CK, Wu MT, Chuang HY

Abstract
BACKGROUND: Lead (Pb), cadmium (Cd), and arsenic (As) could cause health issues through oxidative stress that is indicated in the elevated tumor necrosis factor-alpha (TNF-α). However, some of the essential elements-selenium (Se), zinc (Zn), cobalt (Co), and copper (Cu)-are cofactors or structural components of antioxidant enzymes. It is suggested that single-nucleotide polymorphisms (SNPs) in the TNF-α gene have different TNF-α responses. This study aims to evaluate the effect of serum TNF-α levels through the interactions between toxic metals and essential elements and how the interactions between the toxic metals and TNF-α SNPs (-1031 T > C, -863 C > A, -857 C > T, -308 G > A, -238 G > A) influence serum TNF-α levels.
METHODS: Blood samples were collected from 455 workers who carried out annual health examinations and multielements determined by inductively coupled plasma mass spectrometry (ICP-MS). TNF-α levels were detected by enzyme-linked immunosorbent assay (ELISA). TNF-α promoter SNPs were analyzed by specific primer probes using real-time polymerase chain reaction (PCR) methods.
RESULTS: Increasing blood Pb, Cd, and As levels were associated with elevated TNF-α levels. The interaction between Pb and Cu decreased TNF-α levels and so did the interaction between Cd and Se. In the interaction between Pb and SNPs, individuals with AA/AG (-308 G > A) and AA/AG (-238 G > A) had higher serum TNF-α levels. However, lower TNF-α levels were noted in those individuals with AA/CA (-863 C > A). In the interaction between As and SNPs, workers with AA/AG (-238 G > A) had synergic effect with As and induced higher serum TNF-α levels.
CONCLUSIONS: Blood Cu and Se were antagonists of toxic metals (Pb, As, and Cd) through lower serum TNF-α levels. Variant types of TNF-α SNPs (-308 G > A, -238 G > A) and wild type of -863 CC would be more susceptible to toxic metals.

PMID: 29028684 [PubMed - in process]

Correction to: Role of intestinal microbiome in American ginseng-mediated colon cancer prevention in high fat diet-fed AOM/DSS mice.

Clin Transl Oncol. 2017 Oct 13;:

Authors: Wang CZ, Huang WH, Zhang CF, Wan JY, Wang Y, Yu C, Williams S, He TC, Du W, Musch MW, Chang EB, Yuan CS

Abstract
This article was originally published with the wrong title.

PMID: 29027650 [PubMed - as supplied by publisher]

Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki Disease.

Circ Cardiovasc Genet. 2017 Oct;10(5):

Authors: Kuo HC, Wong HS, Chang WP, Chen BK, Wu MS, Yang KD, Hsieh KS, Hsu YW, Liu SF, Liu X, Chang WC

Abstract
BACKGROUND: Intravenous immunoglobulin (IVIG) is the treatment of choice in Kawasaki disease (KD). IVIG is used to prevent cardiovascular complications related to KD. However, a proportion of KD patients have persistent fever after IVIG treatment and are defined as IVIG resistant.
METHODS AND RESULTS: To develop a risk scoring system based on genetic markers to predict IVIG responsiveness in KD patients, a total of 150 KD patients (126 IVIG responders and 24 IVIG nonresponders) were recruited for this study. A genome-wide association analysis was performed to compare the 2 groups and identified risk alleles for IVIG resistance. A weighted genetic risk score was calculated by the natural log of the odds ratio multiplied by the number of risk alleles. Eleven single-nucleotide polymorphisms were identified by genome-wide association study. The KD patients were categorized into 3 groups based on their calculated weighted genetic risk score. Results indicated a significant association between weighted genetic risk score (groups 3 and 4 versus group 1) and the response to IVIG (Fisher's exact P value 4.518×10(-)(03) and 8.224×10(-)(10), respectively).
CONCLUSIONS: This is the first weighted genetic risk score study based on a genome-wide association study in KD. The predictive model integrated the additive effects of all 11 single-nucleotide polymorphisms to provide a prediction of the responsiveness to IVIG.

PMID: 29025760 [PubMed - in process]

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

Expert Opin Drug Saf. 2017 Oct 12;:1-13

Authors: Seripa D, Lozupone M, Stella E, Paroni G, Bisceglia P, La Montagna M, D'onofrio G, Gravina C, Urbano M, Priore MG, Lamanna A, Daniele A, Bellomo A, Logroscino G, Greco A, Panza F

Abstract
INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

PMID: 29025271 [PubMed - as supplied by publisher]

Cancer Stem Cell Hypothesis for Therapeutic Innovation in Clinical Oncology? Taking the Root Out, Not Chopping the Leaf.

OMICS. 2016 Dec;20(12):681-691

Authors: Dzobo K, Senthebane DA, Rowe A, Thomford NE, Mwapagha LM, Al-Awwad N, Dandara C, Parker MI

Abstract
Clinical oncology is in need of therapeutic innovation. New hypotheses and concepts for translation of basic research to novel diagnostics and therapeutics are called for. In this context, the cancer stem cell (CSC) hypothesis rests on the premise that tumors comprise tumor cells and a subset of tumor-initiating cells, CSCs, in a quiescent state characterized by slow cell cycling and expression of specific stem cell surface markers with the capability to maintain a tumor in vivo. The CSCs have unlimited self-renewal abilities and propagate tumors through division into asymmetric daughter cells. This differentiation is induced by both genetic and environmental factors. Another characteristic of CSCs is their therapeutic resistance, which is due to their quiescent state and slow dividing. Notably, the CSC phenotype differs greatly between patients and different cancer types. The CSCs may differ genetically and phenotypically and may include primary CSCs and metastatic stem cells circulating within the blood system. Targeting CSCs will require the knowledge of distinct stem cells within the tumor. CSCs can differentiate into nontumorigenic cells and this has been touted as the source of heterogeneity observed in many solid tumors. The latter cannot be fully explained by epigenetic regulation or by the clonal evolution theory. This heterogeneity markedly influences how tumors respond to therapy and prognosis. The present expert review offers an analysis and synthesis of the latest research and concepts on CSCs, with a view to truly disruptive innovation for future diagnostics and therapeutics in clinical oncology.

PMID: 27930094 [PubMed - indexed for MEDLINE]

Dental health care providers' views on child physical abuse in Malaysia.

Eur Arch Paediatr Dent. 2016 Oct;17(5):387-395

Authors: Hussein AS, Ahmad R, Ibrahim N, Yusoff A, Ahmad D

Abstract
AIMS: To assess the knowledge, attitudes and experience of a group of Malaysian dental health care providers regarding child physical abuse (CPA) cases in terms of frequency of occurrence, diagnosis, risk factors and reporting.
METHODS: A questionnaire was distributed to all dental health care providers attending a national paediatric dentistry conference in Kuantan, Malaysia, and demographical variables, knowledge, attitudes and experience about CPA, risk factors and the reasons for not reporting abuse cases were collected. Descriptive statistics and bivariance analysis were performed. A 5 % level of statistical significance was applied for the analyses (p ≤ 0.05).
RESULTS: The response rate was 74.7 %. Half of the respondents (52.8 %) stated that the frequency of occurrence of CPA is common in Malaysia. Full agreement between dental health care providers was not determined concerning the identification of signs of CPA and its risk factors. Although 83.3 % were aware that reporting CPA is a legal requirement in Malaysia, only 14.8 % have reported such cases. Lack of adequate history was the main reason for not reporting. Virtually two-thirds of the respondents (62 %) indicated that they had not received sufficient information about CPA and were willing to be educated on how to diagnose and report child abuse cases (81.5, 78.7 %, respectively).
CONCLUSIONS: There were considerable disparities in respondents' knowledge and attitudes regarding the occurrence, signs of suspected cases, risk factors and reporting of CPA. Despite being aware of such cases, only a handful was reported. Enhancement in the education of Malaysian dental health care providers on recognising and reporting CPA is recommended.

PMID: 27421713 [PubMed - indexed for MEDLINE]

11 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 2017/10/13

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.