Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4α Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis.

Mol Cell Biol. 2018 04 01;38(7):

Authors: Bi Y, Shi X, Zhu J, Guan X, Garbacz WG, Huang Y, Gao L, Yan J, Xu M, Ren S, Ren S, Liu Y, Ma X, Li S, Xie W

Abstract
The cholesterol sulfotransferase SULT2B1b converts cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, downregulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4α upon fasting, and the Sult2B1b null (Sult2B1b-/-) mice showed increased gluconeogenic gene expression and an elevated fasting glucose level, suggesting that SULT2B1b also plays a restrictive role in HNF4α-mediated fasting-responsive gluconeogenesis. We also developed thiocholesterol, a hydrolysis-resistant derivative of CS, which showed superior activity to that of the native CS in inhibiting gluconeogenesis and improving insulin sensitivity in high-fat-diet-induced diabetic mice. We conclude that the HNF4α-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia.

PMID: 29378829 [PubMed - indexed for MEDLINE]

Population Pharmacogenomics for Precision Public Health in Colombia.

Front Genet. 2019;10:241

Authors: Nagar SD, Moreno AM, Norris ET, Rishishwar L, Conley AB, O'Neal KL, Vélez-Gómez S, Montes-Rodríguez C, Jaraba-Álvarez WV, Torres I, Medina-Rivas MA, Valderrama-Aguirre A, Jordan IK, Gallo JE

Abstract
While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1)∗5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.

PMID: 30967898 [PubMed]

Effects of RNA binding protein QKI on pancreatic cancer ductal epithelial cells and surrounding activation fibroblasts.

J Cell Biochem. 2019 Apr 10;:

Authors: Chu L, Hu Y, Jiang YH, Xu C, Liu WC, Lu ZF

Abstract
To determine the correlation between QKI and pancreatic cancer tissues, the QKI expression of pancreatic cancer cells and fibroblasts in the tumor-surrounding microenvironment were detected. Then, QKI overexpression and interference with QKI short hairpin RNA in LX-2 (a fibroblast cell line) were established in vitro. Meanwhile, to observe the cell proliferation, invasion, migration, and other changes, QKI, and related epithelial-mesenchymal transition (EMT) molecules were detected by a polymerase chain reaction and Western blot analysis. In addition, an in vivo tumorigenicity test in node mice was performed to confirm whether QKI expression can promote the proliferation, invasion, and metastasis of pancreatic cancer ductal epithelial cells. Finally, the autophagy levels of fibroblasts with QKI overexpression were observed by electron microscopy to further explore the QKI pathogenic mechanism. It was found that cell proliferation, invasion, migration, and EMT-related markers were increased in QKI-overexpressed fibroblasts LX-2. Furthermore, in vivo, liver and peritoneal metastasis decreased overall survival rate and increasing autophagy levels in QKI-overexpressing nude mice were observed. Meanwhile, knock down QKI with small interfering RNA can reverse all the above effects. QKI can promote the proliferation, metastasis, and invasion of pancreatic cancer through activating fibroblasts surrounding pancreatic cancer and accelerating EMT and increasing the autophagy in pancreatic cancer. QKI may become a potential target for the treatment of pancreatic cancer.

PMID: 30968977 [PubMed - as supplied by publisher]

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

Pharmacogenomics J. 2019 Apr 10;:

Authors: Johansson H, Aristarco V, Gandini S, Gjerde J, Macis D, Guerrieri-Gonzaga A, Serrano D, Lazzeroni M, Rajasekaran A, Williard CV, Mellgren G, DeCensi A, Bonanni B

Abstract
Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with "any event" was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592 .

PMID: 30967597 [PubMed - as supplied by publisher]

The Italian Rare Pancreatic Exocrine Cancer Initiative.

Tumori. 2019 Apr 09;:300891619839461

Authors: Brunetti O, Luchini C, Argentiero A, Tommasi S, Mangia A, Aprile G, Marchetti P, Vasile E, Casadei Gardini A, Scartozzi M, Barni S, Delfanti S, De Vita F, Di Costanzo F, Milella M, Cella CA, Berardi R, Cataldo I, Santini D, Doglioni C, Maiello E, Lawlor RT, Mazzaferro V, Lonardi S, Giuliante F, Brandi G, Scarpa A, Cascinu S, Silvestris N

Abstract
INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available.
METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays.
CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

PMID: 30967031 [PubMed - as supplied by publisher]

Functional Effects of let-7g Expression in Colon Cancer Metastasis.

Cancers (Basel). 2019 Apr 06;11(4):

Authors: Chang CM, Wong HS, Huang CY, Hsu WL, Maio ZF, Chiu SJ, Tsai YT, Chen BK, Wan YY, Wang JY, Chang WC

Abstract
MicroRNA regulation is crucial for gene expression and cell functions. It has been linked to tumorigenesis, development and metastasis in colorectal cancer (CRC). Recently, the let-7 family has been identified as a tumor suppressor in different types of cancers. However, the function of the let-7 family in CRC metastasis has not been fully investigated. Here, we focused on analyzing the role of let-7g in CRC. The Cancer Genome Atlas (TCGA) genomic datasets of CRC and detailed data from a Taiwanese CRC cohort were applied to study the expression pattern of let-7g. In addition, in vitro as well as in vivo studies have been performed to uncover the effects of let-7g on CRC. We found that the expression of let-7g was significantly lower in CRC specimens. Our results further supported the inhibitory effects of let-7g on CRC cell migration, invasion and extracellular calcium influx through store-operated calcium channels. We report a critical role for let-7g in the pathogenesis of CRC and suggest let-7g as a potential therapeutic target for CRC treatment.

PMID: 30959863 [PubMed]

Population Pharmacokinetics and dosing optimisation of Imipenem in Children with haematological malignancies.

Antimicrob Agents Chemother. 2019 Apr 08;:

Authors: Dong L, Zhai XY, Yang YL, Wang L, Zhou Y, Shi HY, Tang BH, Wu YE, Yang F, Wen L, Kong HX, Zhi LJ, Jacqz-Aigrain E, Zhao W

Abstract
Objectives: Imipenem is widely used for the treatment of children with serious infections. Currently, there is lack of pharmacokinetic studies of imipenem in children with hematological malignancies. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population based pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population.Methods: After treated with imipenem/cilastatin (IMP/CS), blood samples of children were collected and the concentration of imipenem were quantified using HPLC-UV. Then, population level pharmacokinetic analysis was conducted using NONMEM software.Results: Data from 56 children (age range: 2.03-11.82 years) with haematological malignancies were collected to conduct a population based pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be best suitable. The parameters of current weight, age and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1% and 67.1% of children reached the pharmacodynamic target (70% fT>MIC) against sensitive pathogens with an MIC of 0.5 mg/L at 15, 20 and 25 mg/kg q6h of imipenem, respectively. However, only 11.1% of children achieved the pharmacodynamic target against Pseudomonas aeruginosa with an MIC of 2 mg/L at a dose of 25 mg/kg q6h.Conclusion: Population pharmacokinetics of imipenem was assessed in children. The current dosage regimens of imipenem are underdose for resistant pathogens including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h.

PMID: 30962334 [PubMed - as supplied by publisher]

Implementation of genotype-guided dosing of warfarin with point-of-care genetic testing in three UK clinics: a matched cohort study.

BMC Med. 2019 Apr 08;17(1):76

Authors: Jorgensen AL, Prince C, Fitzgerald G, Hanson A, Downing J, Reynolds J, Zhang JE, Alfirevic A, Pirmohamed M

Abstract
BACKGROUND: Warfarin is a widely used oral anticoagulant. Determining the correct dose required to maintain the international normalised ratio (INR) within a therapeutic range can be challenging. In a previous trial, we showed that a dosing algorithm incorporating point-of-care genotyping information ('POCT-GGD' approach) led to improved anticoagulation control. To determine whether this approach could translate into clinical practice, we undertook an implementation project using a matched cohort design.
METHODS: At three clinics (implementation group; n = 119), initial doses were calculated using the POCT-GGD approach; at another three matched clinics (control group; n = 93), patients were dosed according to the clinic's routine practice. We also utilised data on 640 patients obtained from routinely collected data at comparable clinics. Primary outcome was percentage time in target INR range. Patients and staff from the implementation group also provided questionnaire feedback on POCT-GGD.
RESULTS: Mean percentage time in INR target range was 55.25% in the control group and 62.74% in the implementation group; therefore, 7.49% (95% CI 3.41-11.57%) higher in the implementation group (p = 0.0004). Overall, patients and staff viewed POCT-GGD positively, suggesting minor adjustments to allow smooth implementation into practice.
CONCLUSIONS: In the first demonstration of the implementation of genotype-guided dosing, we show that warfarin dosing determined using an algorithm incorporating genetic and clinical factors can be implemented smoothly into clinic, to ensure target INR range is reached sooner and maintained. The findings are like our previous randomised controlled trial, providing an alternative method for improving the risk-benefit of warfarin use in daily practice.

PMID: 30961588 [PubMed - in process]

Usefulness of COMT gene polymorphisms in North African populations.

Gene. 2019 May 15;696:186-196

Authors: Boussetta S, Cherni L, Pakstis AJ, Ben Salem N, Elkamel S, Khodjet-El-Khil H, Kidd KK, Elgaaied ABA

Abstract
The COMT gene encodes for catechol-O-methyl-transferase, an enzyme playing a major role in regulation of synaptic catecholamine neurotransmitters. Investigating 4 markers of the COMT gene (rs2020917, rs4818, rs4680, rs9332377) in 6 Tunisian populations and a pool of Libyans. Our objective was to determine the distribution of allelic, genotypic and haplotypic frequencies by comparison to other populations of the 1000 genomes project and 59 populations from the Kidd Lab dataset. The allelic frequencies established for these SNPs in the North African populations are similar to those of Europeans and South Asians. Linkage disequilibrium between these SNPs and haplotypes frequencies are different between populations whose clustering in principal components analysis (PCA) according to their geographic origin was more significant using haplotypic frequencies. COMT activity prediction by haplotypes genotyping could be limited to rs4818-rs4680 micro-haplotypes. The Low activity haplotype (CG) displays the highest frequency in African populations (55%), in the 59 Kidd Lab populations we found also that Sub-Saharan Africans, Native Americans, and some East Asian and Pacific Island populations all have frequencies in the 50-81% range for (CG) where as its lowest frequency was found in Europeans (10%), this results have been also confirmed for Southwest Asians. North Africans and South Asians with intermediate frequencies have approximately similar values (20% and 25%). Europeans show the highest frequencies of haplotypes with predicted High and Medium activity in contrast to Africans. North Africans and South Asians present similar results for all the category of the COMT activity prediction by haplotypes genotyping. The high level of genetic diversity of COMT haplotypes, not only allows distinction between populations according to their history settlement, origin and ethnicity, it constitutes a basis for studies of association of the COMT gene polymorphism with pathologies, drugs response and for forensic investigation in North African populations.

PMID: 30790653 [PubMed - indexed for MEDLINE]

Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients.

Am J Psychiatry. 2018 05 01;175(5):463-470

Authors: Jukić MM, Haslemo T, Molden E, Ingelman-Sundberg M

Abstract
OBJECTIVE: The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population.
METHOD: A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively.
RESULTS: Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively.
CONCLUSIONS: The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.

PMID: 29325448 [PubMed - indexed for MEDLINE]

3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism and toxicity: Emerging culture paradigms and applications.

Biotechnol J. 2019 Apr 08;:e1800347

Authors: Lauschke VM, Shafagh RZ, Hendriks DFG, Ingelman-Sundberg M

Abstract
Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo-like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips and plate-based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity and liver functionality have increased tremendously as compared to conventional in vitro models in which cells were cultured as two-dimensional monolayers. Here, we highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology and disease. This article is protected by copyright. All rights reserved.

PMID: 30957976 [PubMed - as supplied by publisher]

Risk of myocardial infarction associated with non-steroidal anti-inflammatory drugs: Impact of additional confounding control for variables collected from self-reported data.

J Clin Pharm Ther. 2019 Apr 07;:

Authors: Bakhriansyah M, Souverein PC, de Boer A, Klungel OH

Abstract
WHAT IS KNOWN AND OBJECTIVE: Important risk factors and over-the-counter (OTC) dispensing of non-steroidal anti-inflammatory drugs (NSAIDs) are often not routinely recorded in electronic health records. This study aimed to assess the impact of patient's reports on these factors on the risk of acute myocardial infarction (AMI) for NSAID use.
METHODS: A nested case-control study was conducted among adults in the Utrecht Cardiovascular Pharmacogenetics study. Cases were patients with a first diagnosis of AMI as a hospital discharge diagnosis and controls were those without AMI. NSAID exposure was either current use of selective COX-2 inhibitors or conventional NSAIDs. Information was collected from The Dutch PHARMO Database Network (pharmacy records of drug dispensing linked to hospitalization records) and the patient's questionnaire (lifestyle factors, body mass index and history of cardiovascular diseases). Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and to control for confounding factors.
RESULTS: We identified 970 AMI cases and 2974 controls. Among cases, 11 (1.1%) and 185 (19.1%) were exposed to selective COX-2 inhibitors and conventional NSAIDs, respectively. Compared to non-use, none of these drug classes were associated with an increased risk of AMI (adjusted OR 1.07, 95% CI: 0.52-2.18 and 0.93, 95% CI: 0.77-1.12, respectively). Additional adjustment for potential confounders from patient's reports did not change the risk estimates (adjusted OR 1.08, 95% CI: 0.53-2.22 and 0.89, 95% CI: 0.73-1.09, respectively).
WHAT IS NEW AND CONCLUSION: Additional confounding control for variables from self-reported data or considering self-reported OTC NSAID use did not change the risk estimates for the association between NSAIDs and AMI.

PMID: 30957267 [PubMed - as supplied by publisher]

Variability in analgesic response to non-steroidal anti-inflammatory drugs.

Prostaglandins Other Lipid Mediat. 2018 11;139:63-70

Authors: Theken KN

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used agents for the treatment of acute and chronic pain. However, it has long been recognized that there is substantial inter-individual variability in the analgesic response to NSAIDs, reflecting the complex interplay between mechanisms of pain, differences between distinct NSAIDs, and patient-specific factors such as genetic variation. This review summarizes the current knowledge regarding how these factors contribute to variability in the analgesic response to NSAIDs.

PMID: 30393163 [PubMed - indexed for MEDLINE]

Mitochondrial fission promotes cell migration by Ca2+ /CaMKII/ERK/FAK pathway in hepatocellular carcinoma.

Liver Int. 2018 07;38(7):1263-1272

Authors: Sun X, Cao H, Zhan L, Yin C, Wang G, Liang P, Li J, Wang Z, Liu B, Huang Q, Xing J

Abstract
BACKGROUND & AIMS: Mitochondrial dynamics of fission and fusion plays critical roles in a diverse range of important cellular functions, and its deregulation has been increasingly implicated in human diseases. Previous studies have shown that increased mitochondrial fission significantly promoted the proliferation of hepatocellular carcinoma (HCC) cells. However, how they influence the migration of tumour cells remained largely unknown.
METHODS: In the present study, we further investigated the effect of mitochondrial fission on the migration and metastasis of hepatocellular carcinoma cells. Moreover, the underlying molecular mechanisms and therapeutic application were explored.
RESULTS: Our data showed that dynamin-1-like protein expression was strongly increased in distant metastasis of hepatocellular carcinoma when compared to primary hepatocellular carcinoma. In contrast, the mitochondrial fusion protein mitofusin 1 showed an opposite trend. Moreover, the expression of dynamin-1-like protein and mitofusin 1 was significantly associated with the disease-free survival of hepatocellular carcinoma patients. In addition, our data further showed that mitochondrial fission significantly promoted the reprogramming of focal-adhesion dynamics and lamellipodia formation in hepatocellular carcinoma cells mainly by activating typical Ca2+ /CaMKII/ERK/FAK pathway. Importantly, treatment with mitochondrial division inhibitor-1 significantly decreased calcium signalling in hepatocellular carcinoma cells and had a potential treatment effect for hepatocellular carcinoma metastasis in vivo.
CONCLUSIONS: Taken together, our findings demonstrate that mitochondrial fission plays a critical role in the regulation of hepatocellular carcinoma cell migration, which provides strong evidence for this process as a drug target in hepatocellular carcinoma metastasis treatment.

PMID: 29210177 [PubMed - indexed for MEDLINE]

Genetic analysis of pharmacogenomic VIP variants in the Blang population from Yunnan Province of China.

Mol Genet Genomic Med. 2019 Apr 05;:e574

Authors: Zhang C, Guo W, Cheng Y, Li Q, Yang X, Dai R, Zhu L, Chen W

Abstract
BACKGROUND: Genetic polymorphisms in numerous pharmacogenetics studies were regarded as the essential factors involved in the response to or metabolism of drugs. These genetic variants called very important pharmacogenetic (VIP) variants played a role in drugs metabolism, which have been summarized in the PharmGKB database. In this study, we genotyped 80 VIP variants from the PharmGKB in 100 members of Blang volunteers from Yunnan province.
METHODS: Based on the PharmGKB database, we genotyped 80 VIP variants loci located in 47 genes. We used χ2 tests to evaluate the significant loci between Blang and the other populations, including ASW, CEU, CHB, CHD, GIH, JPT, LWK, MEX, MKK, TSI, and YRI. The global variation distribution of the significant variants was observed from the ALlele FREquency Database. And then, we used F-statistics (Fst), genetic structure, and phylogenetic tree analyses to ascertain the genetic affinity among 12 populations.
RESULTS: Comparing the Blang with the other 11 populations from the HapMap Project, the statistical results revealed that rs3814055 (NC_000003.12:g.119781188C>T) of nuclear receptor subfamily 1 group I member 2 (NR1I2, OMIM# 603,065) was the most significant variant, followed by rs1540339 (NC_000012.12:g.47863543C>T) of vitamin D receptor (VDR, OMIM#601,769). Furthermore, we found that genotype frequency of rs3814055 in the Blang was closer to the populations distributed in Miao. And genetic structure and F-statistics indicated that the Blangs had a relatively closer affinity with CHD, CHB, and JPT populations. In addition, the Han nationality in Shaanxi was closer to it.
CONCLUSIONS: Our results will complement the pharmacogenomics information of the Blang ethnic group and provide a theoretical basis for safer drug administration for Blang.

PMID: 30955239 [PubMed - as supplied by publisher]

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis. 2019 Apr 03;:

Authors: Guerreiro R, Escott-Price V, Hernandez DG, Kun-Rodrigues C, Ross OA, Orme T, Neto JL, Carmona S, Dehghani N, Eicher JD, Shepherd C, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Dawson T, Rosenthal L, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, International Parkinson's Disease Genomics Consortium, Stone DJ, Bras J

Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

PMID: 30953760 [PubMed - as supplied by publisher]

In vivo pharmacodynamic and pharmacokinetic effects of metformin mediated by the gut microbiota in rats.

Life Sci. 2019 Apr 03;:

Authors: Wu B, Chen M, Gao Y, Hu J, Liu M, Zhang W, Huang W

Abstract
AIMS: The gut microbiota plays a crucial role in the efficacy of metformin in T2DM treatment. We evaluated whether the pharmacodynamics and pharmacokinetics of metformin are mediated by gut microbiota.
MAIN METHODS: We used conventional diabetic and pseudo-germ-free rats. After 6 weeks of metformin treatment, pharmacodynamic indexes were determined. Metformin concentrations were measured with a validated HPLC-MS/MS method after the first oral administration.
KEY FINDINGS: Most endpoints were similar between vehicle-treated diabetic and vehicle-treated pseudo-germ-free diabetic rats. However, after 6 weeks of metformin treatment, compared with conventional diabetic rats, pseudo-germ-free diabetic rats exhibited significantly increased FBG, decreased oral glucose, reduced GSP, worsened insulin resistance, increased hyperlipidemia, and increased hepatic steatosis severity. Moreover, the Cmax of pseudo-germ-free rats increased significantly, while the t1/2α decreased significantly. These pharmacodynamic and pharmacokinetic changes were probably due to a decrease in Oct1 expression in the liver, resulting in altered hepatic uptake of metformin in vivo.
SIGNIFICANCE: These results implied that the gut microbiota may play an important role in the pharmacodynamics and pharmacokinetics of metformin and that the changes in these properties are probably due to Oct1 downregulation in the livers of pseudo-germ-free rats.

PMID: 30953641 [PubMed - as supplied by publisher]

Molecular typing of Bluetongue virus using the nCounter® Analysis System platform.

J Virol Methods. 2019 Apr 02;:

Authors: Curini V, Marcacci M, Tonelli A, Di Teodoro G, Di Domenico M, D'Alterio N, Portanti O, Ancora M, Savini G, Panfili M, Camma' C, Lorusso A

Abstract
Bluetongue virus (BTV) is a segmented double-stranded RNA virus, existing in multiple serotypes, belonging to the genus Orbivirus of the family Reoviridae. BTV causes Bluetongue (BT), a major OIE-listed disease of ruminants. Identification of BTV serotype is accomplished using multiple typing assays and tends to be executed based on the known epidemiological situation within a given country. Samples containing multiple serotypes, particularly those containing novel introductions, may therefore be missed. The aim of this work was to optimize the nCounter® Analysis System Microarray platform (NanoString technologies), that would simultaneously identify all BTV serotypes and co-infections in analyzed samples. Probes were designed according to all Seg-2 sequences, coding for VP2 proteins which determine serotype specificity, available on line. A specific BTV CodeSet of probes was optimized. Experiments were performed with 30 BTV isolates and with 46 field samples previously shown to be infected with BTV by classical molecular assays. All BTV isolates were correctly identified and the expected BTV serotype was recognized in 35 field samples with CT values between 22.0-33.0. In turn, it was unable to identify 11 samples with CT values between 29.0-38.0. Although specificity of the assay needs to be further investigated against a larger panel of BTV collected worldwide, RNA loads, which are normally detected in blood samples during the acute phase of infection, are within the range of CT values detectable by the BTV CodeSet. We propose the NanoString RNA microarray as a first-line molecular diagnostic tool for identification and typing of BTV. Once identification of the index cases is performed, diagnosis of the following samples may be performed by specific, more sensitive and cheaper PCR-based tools.

PMID: 30951789 [PubMed - as supplied by publisher]

Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants used in Atrial Fibrillation.

Expert Opin Drug Metab Toxicol. 2019 Apr 05;:

Authors: Fawzy AM, Lip GY

Abstract
INTRODUCTION: The availability of non-vitamin K antagonist oral anti-coagulants alongside vitamin K antagonists has offered a variety of options for anti-coagulation, but has also necessitated a good understanding of the pharmacological properties of each of these drugs prior to their use, to maximise the therapeutic benefit and minimise patient harm Areas covered: This review article outlines the pharmacokinetic and pharmacodynamic profiles of the currently licensed NOACs and VKAs that are most commonly used in clinical practice, with the aim of demonstrating how variations in these processes contribute to their use in clinical practice. A literature search was conducted on PubMed using keywords and relevant articles published by the 31st of December 2018 were included. Expert opinion: The effect of a drug is determined by a combination of elements which include patient characteristics and external influences, in addition to its pharmacokinetic and pharmacodynamic properties. A good understanding of this is essential. Despite the wealth of information available, particularly on VKAs, our knowledge on the pharmacology responsible for certain drug effects and inter-individual variations is still limited. Increasing efforts are being made to uncover these and includes focus on pharmacogenomics and drug transporter proteins.

PMID: 30951640 [PubMed - as supplied by publisher]

Pharmacogenomics of inhalational anesthetic agents.

Med Gas Res. 2019 Jan-Mar;9(1):52-53

Authors: Nair AS

PMID: 30950419 [PubMed - in process]