Development of a Korean-specific virtual population for physiologically-based pharmacokinetic modeling and simulation.

Biopharm Drug Dispos. 2019 Mar 28;:

Authors: Kim Y, Hatley O, Rhee SJ, Yi S, Lee HA, Yoon S, Chung JY, Yu KS, Lee H

Abstract
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms, and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam, and rosuvastatin) of five major DMEs and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a <2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the pharmacokinetics of a drug, particularly in various stages of drug development.

PMID: 30921829 [PubMed - as supplied by publisher]

Collateral sensitivity of drug-resistant ABCB5- and mutation-activated EGFR overexpressing cells towards resveratrol due to modulation of SIRT1 expression.

Phytomedicine. 2019 Mar 14;59:152890

Authors: Saeed MEM, Rahama M, Kuete V, Dawood M, Elbadawi M, Sugimoto Y, Efferth T

Abstract
BACKGROUND: In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells.
PURPOSE: In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells.
METHODS: Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay.
RESULTS: Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity.
CONCLUSION: The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.

PMID: 30921566 [PubMed - as supplied by publisher]

Personal genome testing on physicians improves attitudes on pharmacogenomic approaches.

PLoS One. 2019;14(3):e0213860

Authors: Lee KH, Min BJ, Kim JH

Abstract
In this era of clinical genomics, the accumulation of knowledge of pharmacogenomics (PGx) is rising dramatically and attempts to utilize it in clinical practice are also increasing. However, this advanced knowledge and information have not yet been sufficiently utilized in the clinical field due to various barriers including physician factors. This study was conducted to evaluate the attitudes of physicians to PGx services by providing them their own genomic data analysis report focusing on PGx. We also tried to evaluate the clinical applicability of whole exome sequencing (WES)-based functional PGx test. In total 88 physicians participated in the study from September 2015 to August 2016. Physicians who agreed to participate in the study were asked to complete a pre-test survey evaluating their knowledge of and attitude toward clinical genomics including PGx. Only those who completed the pre-test survey proceeded to WES and were provided with a personal PGx analysis report in an offline group meeting. Physicians who received these PGx reports were asked to complete a follow-up survey within two weeks. We then analyzed changes in their knowledge and attitude after reviewing their own PGx analysis results through differences in their pre-test and post-test survey responses. In total, 70 physicians (79.5%) completed the pre-test and post-test surveys and attended an off-line seminar to review their personal PGx reports. After physicians reviewed the report, their perception of and attitude towards the PGx domain and genomics significantly changed. Physician' awareness of the likelihood of occurrence of adverse drug reactions and genetic contribution was also changed significantly. Overall, physicians were very positive about the value and potential of the PGx test but maintained a conservative stance on its actual clinical use. Results revealed that physicians' perception and attitude to the utility of PGx testing was significantly changed after reviewing their own WES results.

PMID: 30921347 [PubMed - in process]

Interferon-regulated suprabasin is essential for stress-induced stem-like cell conversion and therapy resistance of human malignancies.

Mol Oncol. 2019 Mar 27;:

Authors: Hubackova S, Pribyl M, Kyjacova L, Moudra A, Dzijak R, Salovska B, Hynek S, Tambor V, Imrichova T, Svec J, Vodicka P, Vaclavikova R, Rob L, Bartek J, Hodny Z

Abstract
Radiation and chemotherapy represent standard-of-care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio- and chemo-therapy, we exposed human cancer cell lines (HeLa, MCF-7, and DU145) to clinically-relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low-adherent stem-like cells. Stress-mobilized low-adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in the development of a heterogeneous, low-adherent fraction comprised of not only apoptotic/necrotic cells, but also live cells exhibiting active Notch signalling and expressing stem-cell markers. Chemical inhibition of MEK or siRNA-mediated knockdown of Erk1/2 and IRF1 prevented mobilization of the surviving low-adherent population, indicating that interferon-gamma-mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF1. Notably, a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low-adherent cancer cells induced by 5-azacytidine or irradiation. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN suppressed the low-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively, implicating SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.

PMID: 30919591 [PubMed - as supplied by publisher]

Comparison between MassARRAY and Pyrosequencing for CYP2C19 and ABCB1 Gene Variants of Clopidogrel Efficiency Genotyping.

Mol Membr Biol. 2019 Mar 27;:1-18

Authors: Liu J, Xu Z, Li Y, Dai S, Liu J, Pan J, Jiang Y

Abstract
Clopidogrel is one of the most frequently used drugs in patients to reduce cardiovascular events. Since patients with different genetic variations respond quite differently to clopidogrel therapy, the related genetic testing plays a vital role in its dosage and genetic testing related to clopidogrel therapy is currently considered as routine test worldwide. In this study, we aim to use two different methods MALDI-TOF mass spectrometry and pyrosequencing to detect gene variant of CYP2C19 and ABCB1. Six single nucleotides polymorphisms (SNP) within CYP2C19 (*2, *3, *4, *5, *17) and ABCB1 C3435T in 458 Chinese Han patients were determined using both MassARRAY and Pyrosequencing. Sanger sequencing was used for verification. Results of both methods were analyzed and compared. Allele frequencies of each SNP and distribution of different genotypes were calculated based on the MassARRAY and Sanger sequencing results. Both methods provided 100% call rates for gene variants, while results of 6 samples were different with two methods. With Sanger sequencing as the reference results, MassARRAY generated all the same results. The minor allele frequencies of the above six SNPs were 27.1% (CYP2C19*), 5.9% (CYP2C19*3), 0% (CYP2C19*4), 0% (CYP2C19*5), 1.1% (CYP2C19*17), 40.9% (ABCB1), respectively. MassARRAY provides accurate clopidogrel related genotyping with relatively high cost-efficiency, throughput and short time when compared with pyrosequencing.

PMID: 30916611 [PubMed - as supplied by publisher]

The role of pharmacogenomics in adverse drug reactions.

Expert Rev Clin Pharmacol. 2019 Mar 27;:

Authors: Cacabelos R, Cacabelos N, Carril JC

Abstract
INTRODUCTION: Adverse drug reactions (ADRs) are a major health concern worldwide. There are multiple causes of ADRs, some of which are preventable. Pharmacogenomics accounts for ≈80% variability in drug efficacy and safety. Over 400 genes are clinically relevant in drug metabolism, and ≈200 pharmagenes are associated with ADRs. The condition of extensive metabolizer in the Caucasian population is lower than 20%, and about 60% of patients are exposed to potential ADRs. Areas covered: Important topics related to pharmacogenomics in drug efficacy and safety are covered, including: (i) major components of the pharmacogenomic machinery; (ii) epigenetic regulation of pharmagene expression; and (iii) pharmacogenomics-related ADRs of different drug categories. Expert commentary: The Regulatory Agencies should make recommendations to the pharmaceutical industry in favor of the introduction of pharmacogenomics in drug development and the inclusion of pharmacogenomic information on drug labels, with specific warnings for the population at risk. Educational programs are fundamental for drug prescribers to become familiar with personalized treatments. Pharmacogenetic testing should be gradually introduced into medical practice. ADRs can be reduced not only by adherence to prescribing guidelines, suitable monitoring and regular medication review, but also by the implementation of pharmacogenomic procedures in the clinical setting.

PMID: 30916581 [PubMed - as supplied by publisher]

Renal impairment and analgesia: From effectiveness to adverse effects.

J Cell Physiol. 2019 Mar 27;:

Authors: Alizadeh R, Aghsaie Fard Z

Abstract
Kidney pain is one of the clinically significant features of renal dysfunction. Mild to severe pain is seen in the lower back area. Painkillers are mostly recommended in these cases to relieve the symptom. Yet, several analgesics are associated with side effects that can worsen the state of the disease. This review is based on the studies conducted in these aspects analgesics used to treat kidney pain and their effectiveness, renal consequences of postoperative analgesia, and pharmacogenetics of these palliatives are briefly summarized in this paper.

PMID: 30916404 [PubMed - as supplied by publisher]

Clinical Studies on Drug-Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls and Interpretation.

Clin Pharmacol Ther. 2019 Mar 27;:

Authors: Tornio A, Filppula AM, Niemi M, Backman JT

Abstract
Many drug-drug interactions (DDIs) are based on alterations of the plasma concentrations of a victim drug due to another drug causing inhibition and/or induction of the metabolism or transporter-mediated disposition of the victim drug. In the worst case, such interactions cause more than tenfold increases or decreases in victim drug exposure, with potentially life-threatening consequences. There has been tremendous progress in the predictability and modeling of DDIs. Accordingly, the combination of modeling approaches and clinical studies is the current mainstay in evaluation of the pharmacokinetic DDI risks of drugs. In this article, we focus on the methodology of clinical studies on DDIs involving drug metabolism or transport. We specifically present considerations related to general DDI study designs, recommended enzyme and transporter index substrates and inhibitors, pharmacogenetic perspectives, index drug cocktails, endogenous substrates, limited sampling strategies, physiologically-based pharmacokinetic modeling, complex DDIs, methodological pitfalls, and interpretation of DDI information. This article is protected by copyright. All rights reserved.

PMID: 30916389 [PubMed - as supplied by publisher]

Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children.

Front Pediatr. 2019;7:63

Authors: Smigoc Schweiger D, Goricar K, Hovnik T, Mendez A, Bratina N, Brecelj J, Vidan-Jeras B, Battelino T, Dolzan V

Abstract
Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation.

PMID: 30915320 [PubMed]

Rare Dihydropyrimidine Dehydrogenase Variants and Toxicity by Floropyrimidines: A Case Report.

Front Oncol. 2019;9:139

Authors: Palmirotta R, Lovero D, Delacour H, Le Roy A, Cremades S, Silvestris F

Abstract
Variations in the activity, up to absolute deficiency, of the enzyme dihydropyrimidine dehydrogenase (DPD), result in the occurrence of adverse reactions to chemotherapy, and have been included among the pharmacogenetic factors underlying inter-individual variability in response to fluoropyrimidines. The study of single-nucleotide polymorphisms of the DPYD gene, which encodes the DPD enzyme, is one of the main parameters capable of predicting reduced enzymatic activity and the consequent influence on fluoropyrimidine treatment, in terms of reduction of both adverse reactions and therapeutic efficacy in disease control. In this paper, we describe a patient with metastatic breast cancer showing signs of increased toxicity following capecitabine therapy. The DPD enzyme activity analysis revealed a partial deficiency. The study of the most frequent polymorphisms of the DPYD gene suggested a wild-type genotype but indicated a novel variant c.1903A>G (p.Asn635Asp), not previously described, proximal to the splice donor site of exon 14. After excluding the potential pathogenic feature of the newly-identified variant, we performed cDNA sequencing of the entire DPYD coding sequence. This analysis identified the variants c.85T>C and c.496A>G, which were previously described as pivotal components of the haplotype associated with decreased enzyme activity and suggested that both variant alleles are related to DPD deficiency. The clinical case findings described in this study emphasize the importance of performing complete genetic analysis of the DPYD gene in order to identify rare and low frequency variants potentially responsible for toxic reactions to fluoropyrimidine treatment.

PMID: 30915274 [PubMed]

Association Study Among Candidate Genetic Polymorphisms and Chemotherapy-Related Severe Toxicity in Testicular Cancer Patients.

Front Pharmacol. 2019;10:206

Authors: Lavanderos MA, Cayún JP, Roco Á, Sandoval C, Cerpa L, Rubilar JC, Cerro R, Molina-Mellico S, Celedón C, Cerda B, García-Martín E, Agúndez JAG, Acevedo C, Peña K, Cáceres DD, Varela NM, Quiñones LA

Abstract
Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan ®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III-IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III-IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy.

PMID: 30914949 [PubMed]

Encircling the regions of the pharmacogenomic landscape that determine drug response.

Genome Med. 2019 Mar 26;11(1):17

Authors: Fernández-Torras A, Duran-Frigola M, Aloy P

Abstract
BACKGROUND: The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize drug combinations, and point to new therapeutic biomarkers. However, the inherent complexity of transcriptional signatures, with thousands of differentially expressed genes, makes them hard to interpret, thus giving poor mechanistic insights and hampering translation to clinics.
METHODS: To simplify drug signatures, we have developed a network-based methodology to identify functionally coherent gene modules. Our strategy starts with the calculation of drug-gene correlations and is followed by a pathway-oriented filtering and a network-diffusion analysis across the interactome.
RESULTS: We apply our approach to 189 drugs tested in 671 cancer cell lines and observe a connection between gene expression levels of the modules and mechanisms of action of the drugs. Further, we characterize multiple aspects of the modules, including their functional categories, tissue-specificity, and prevalence in clinics. Finally, we prove the predictive capability of the modules and demonstrate how they can be used as gene sets in conventional enrichment analyses.
CONCLUSIONS: Network biology strategies like module detection are able to digest the outcome of large-scale pharmacogenomic initiatives, thereby contributing to their interpretability and improving the characterization of the drugs screened.

PMID: 30914058 [PubMed - in process]

The effect of Cistus incanus herbal tea supplementation on oxidative stress markers and lipid profile in healthy adults.

Cardiol J. 2019 Mar 26;:

Authors: Kuchta A, Konopacka A, Waleron K, Viapiana A, Wesołowski M, Dąbkowski K, Ćwiklińska A, Mickiewicz A, Śledzińska A, Wieczorek E, Gliwińska A, Kortas-Stempak B, Jankowski M

Abstract
BACKGROUND: Oxidative stress and dyslipidemia play a critical role in the development of cardiovascular disease. Regular intake of polyphenol-rich diets is associated with a reduced risk of cardiovascular diseases.
METHODS: The present study was a pilot study with 24 healthy volunteers and was designed to determine if a 12-week administration of Cistus incanus herbal tea, containing phenolic acids and flavonoids, reduces cardiovascular risk factors including oxidative stress and dyslipidemia in healthy adults. Phenolic compounds profile and antibacterial activity of Cistus incanus infusion were also measured.
RESULTS: Herbal infusion led to improvement in lipid profile by increase (D4%, p = 0.033) high-density lipoprotein cholesterol concentration and decrease triglyceride (D14%, p = 0.013) concentrations. In addition, the Cistus incanus diet was associated with decreased serum concentrations of malondialdehyde (D16%, p < 0.01) and advanced oxidation protein products (D18%, p < 0.001).
CONCLUSIONS: Cistus incanus administration decreases cardiovascular risk factors including oxidative stress and dyslipidemia and this action supports the idea of using Cistus incanus tea on a daily basis as an effective dietary component for prevention of atherosclerotic cardiovascular disease.

PMID: 30912576 [PubMed - as supplied by publisher]

Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs.

J Pharmacokinet Pharmacodyn. 2019 Mar 25;:

Authors: Benet LZ, Bowman CM, Koleske ML, Rinaldi CL, Sodhi JK

Abstract
Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interaction or pharmacogenomic variant studies to be utilized to characterize whether a drug is low versus high hepatic extraction ratio, even without intravenous dosing. The characteristics of drugs based on the ratios of area under the curve, maximum concentration and half-life are identified with recognition that volume of distribution is essentially unchanged for drug interaction and pharmacogenomic variant studies where only metabolic outcomes are changed and transporters are not significantly involved. Comparison of maximum concentration changes following single dose interaction and pharmacogenomic variance studies may also identify the significance of intestinal first pass changes. The irrelevance of protein binding changes on pharmacodynamic outcomes following oral and intravenous dosing of low hepatic extraction ratio drugs, versus its relevance for high hepatic extraction ratio drugs is re-emphasized.

PMID: 30911879 [PubMed - as supplied by publisher]

Downregulation of DANCR acts as a potential biomarker for papillary thyroid cancer diagnosis.

Biosci Rep. 2019 Mar 25;:

Authors: Zhang K, Lv J, Peng XW, Liu JQ, Li CL, Li J, Yin NW, Li H, Li Z

Abstract
Long non-coding RNAs (lncRNAs) have been reported dysregulated and play crucial role in the progression of cancer. LncRNA DANCR has recently been revealed that involved in tumorigenesis of numerous types of cancer, including osteosarcoma, gastric cancer, breast cancer, hepatocellular carcinoma and colorectal cancer. However, the expression profiles and biological relevance of DANCR in papillary thyroid cancer (PTC) have not yet been reported. In the present study, the expression level of DANCR in PTC tissues and adjacent normal tissues was detected by reverse transcription-quantitative polymerase chain reaction in papillary thyroid cancer patients, then we analyzed the association with clinical pathological characteristics of patients and DANCR expressions. These results demonstrated that the expression of DANCR was notably decreased in tumor tissues in comparison with adjacent normal tissues (P<0.001). Furthermore, the present study found DANCR expression level was correlated to T grade (P<0.01) and TNM stage (P=0.017). The present study demonstrated that DANCR was associated with PTC aggressive clinical features and may serve as a diagnostic biomarker for detecting PTC patients.

PMID: 30910839 [PubMed - as supplied by publisher]

Quantification of Panax notoginseng saponins metabolites in rat plasma with in vivo gut microbiota-mediated biotransformation by HPLC-MS/MS.

Chin J Nat Med. 2019 Mar;17(3):231-240

Authors: Guo YP, Chen MY, Shao L, Zhang W, Rao T, Zhou HH, Huang WH

Abstract
Panax notoginseng saponins (PNS) are the major components of Panax notoginseng, with multiple pharmacological activities but poor oral bioavailability. PNS could be metabolized by gut microbiota in vitro, while the exact role of gut microbiota of PNS metabolism in vivo remains poorly understood. In this study, pseudo germ-free rat models were constructed by using broad-spectrum antibiotics to validate the gut microbiota-mediated transformation of PNS in vivo. Moreover, a high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was developed for quantitative analysis of four metabolites of PNS, including ginsenoside F1 (GF1), ginsenoside Rh2 (GRh2), ginsenoside compound K (GCK) and protopanaxatriol (PPT). The results showed that the four metabolites could be detected in the control rat plasma, while they could not be determined in pseudo germ-free rat plasma. The results implied that PNS could not be biotransformed effectively when gut microbiota was disrupted. In conclusion, gut microbiota plays an important role in biotransformation of PNS into metabolites in vivo.

PMID: 30910060 [PubMed - in process]

Neuropsychiatric manifestations among HIV-1 infected African patients receiving efavirenz-based cART with or without tuberculosis treatment containing rifampicin.

Eur J Clin Pharmacol. 2018 Nov;74(11):1405-1415

Authors: Mugusi S, Ngaimisi E, Janabi M, Mugusi F, Minzi O, Aris E, Bakari M, Bertilsson L, Burhenne J, Sandstrom E, Aklillu E

Abstract
PURPOSE: Efavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti-tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations.
METHODS: Prospective cohort study of cART naïve HIV patients with or without tuberculosis (HIV-TB) co-infection treated with efavirenz-based cART. Rifampicin-based anti-tuberculosis therapy was initiated 4 weeks prior to efavirenz-based cART in HIV-TB patients. Data on demographic, clinical, laboratory, and a 29-item questionnaire on neuropsychiatric manifestations were collected for 16 weeks after cART initiation. Genotyping for CYP2B6, CYP3A5, SLCO1B1, and ABCB1 and quantification of efavirenz plasma concentration were done on the 4th and 16th week.
RESULTS: Data from 458 patients (243 HIV-only and 215 HIV-TB) were analyzed. Overall incidence of neuropsychiatric manifestations was 57.6% being higher in HIV-only (66.7%) compared to HIV-TB patients (47.4%) (p < 0.01). HIV-only patients were more symptomatic, with proportionately higher grades of manifestations compared to HIV-TB patients. Median time to manifestations was 1 week after cART initiation in HIV-only and 6 weeks after anti-TB (i.e., 2 weeks after cART initiation) in HIV-TB patients. HIV-only patients had significantly higher efavirenz plasma concentrations at 4 weeks after cART compared to HIV-TB patients. No association of sex or genotype was seen in relation to neuropsychiatric manifestations. Risk for neuropsychiatric manifestations was three times more in HIV-only patients compared to HIV-TB (p < 0.01).
CONCLUSIONS: Incidence of neuropsychiatric manifestations during early initiation of efavirenz-based cART is high in Tanzanian HIV patients. Risk of neuropsychiatric manifestations is lower in HIV patients co-treated with rifampicin containing anti-TB compared to those treated with efavirenz-based cART only.

PMID: 30003275 [PubMed - indexed for MEDLINE]

Epidemiology of Childhood Hyperthyroidism in France: A Nationwide Population-Based Study.

J Clin Endocrinol Metab. 2018 08 01;103(8):2980-2987

Authors: Simon M, Rigou A, Le Moal J, Zeghnoun A, Le Tertre A, De Crouy-Chanel P, Kaguelidou F, Leger J

Abstract
Context: Hyperthyroidism affects all age groups, but epidemiological data for children are scarce.
Objective: To perform a nationwide epidemiological survey of hyperthyroidism in children and adolescents.
Design: A cross-sectional descriptive study.
Setting: Identification of entries corresponding to reimbursements for antithyroid drugs in the French national insurance database.
Participants: All cases of childhood hyperthyroidism (6 months to 17 years of age) in 2015.
Main Outcome Measures: National incidence rate estimated with a nonlinear Poisson model and spatial distribution of cases.
Results: A total of 670 cases of childhood hyperthyroidism were identified. Twenty patients (3%) had associated autoimmune or genetic disease, with type 1 diabetes and Down syndrome the most frequent. The annual incidence for 2015 was 4.58/100,000 person-years (95% CI 3.00 to 6.99/100,000). Incidence increased with age, in both sexes. This increase accelerated after the age of 8 in girls and 10 in boys and was stronger in girls. About 10% of patients were affected before the age of 5 years (sex ratio 1.43). There was an interaction between age and sex, the effect of being female increasing with age: girls were 3.2 times more likely to be affected than boys in the 10 to 14 years age group and 5.7 times more likely to be affected in the 15 to 17 years age group. No conclusions about spatial pattern emerged.
Conclusion: These findings shed light on the incidence of hyperthyroidism and the impact of sex on this incidence during childhood and adolescence. The observed incidence was higher than expected from the results published for earlier studies in Northern European countries.

PMID: 29846622 [PubMed - indexed for MEDLINE]

Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study.

Br J Clin Pharmacol. 2019 Mar 25;:

Authors: Victorri-Vigneau C, Verstuyft C, Bouquié R, Laforgue EJ, Hardouin JB, Leboucher J, Le Geay B, Dano C, Challet-Bouju G, Grall-Bronnec M

Abstract
Our study aimed to evaluate the impacts of the CYP2B6 G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. OPAL was a clinical survey of sociodemographic characteristics, history and consequences of pathology, response to treatment, current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. When comparing the three CYP2B6 genotype groups, both methadone (R) and (S)-enantiomers concentration/dose were different (p=0.029, p=0.0019). The CYP2D6 phenotypes seemed to be not relevant with regards to methadone levels. By multivariate analysis, neither CYP2B6 genotype nor the CYP2D6 phenotype explained (i) the (R)-methadone concentration/dose values (p=0.92; p=0.86), (ii) the (S)-methadone concentration/dose values (p=0.052; p=0.95), nevertheless there was a difference between TT group and GT and GG groups (p=0.019), (iii) the opiate cessation (p=0.12; p=0.90). Genotyping of the CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

PMID: 30907440 [PubMed - as supplied by publisher]

ABCB1 2677G>T single nucleotide polymorphism influences warfarin dose requirement for warfarin maintenance therapy.

Br J Biomed Sci. 2019 Mar 25;

Authors: Gopisankar MG, Hemachandren M, Surendiran A

Abstract
This work represents an advance in biomedical science because it shows, in a singlecentre study of 210 patients, an association between ABCB1 2677 G>T genetic polymorphism and the maintenance dose requirement of warfarin for patients who have achieved a stable INR. Hence incorporation of this polymorphism to algorithms for dose prediction of warfarin may improve the accuracy of dose prediction.

PMID: 30907254 [PubMed - as supplied by publisher]