The influence of SLC22A1 rs622342 and ABCC8 rs757110 genetic variants on the efficacy of metformin and glimepiride combination therapy in Egyptian patients with type 2 diabetes.

J Drug Assess. 2019;8(1):115-121

Authors: Ebid AIM, Ehab M, Ismail A, Soror S, Mahmoud MA

Abstract
Background: The incidence of Type 2 Diabetes Mellitus (T2DM) in Egypt is considered one of the highest in the world. Metformin and Sulfonylureas are usually prescribed together due to their efficacy and their relatively low cost. Organic cation transport 1, encoded by SLC22A1 gene, is the main transporter of metformin into hepatocytes, which is considered metformin site of action. Sulfonylureas enhance insulin release from pancreatic B-cells through binding to sulfonylurea receptor 1, encoded by ABCC8 gene. Single nucleotide polymorphisms in the SLC22A1 and ABCC8 genes might affect the response of each drug. Aims: To investigate the influence of SLC22A1 rs622342 (A>C) and ABCC8 rs757110 (A>C) genetic variants on the efficacy of metformin and glimepiride combination therapy in Egyptian T2DM patients. Methods: Observational cross-sectional study in which patients receiving metformin and glimepiride combination therapy for at least 6 months were included for genotyping and classified into either responders or non-responders, based on their HbA1C level. Results: A total of 127 patients were included and genotyped. They were divided into 93 responders (HbA1C<7%) and 34 non-responders (HbA1C≥7%). Minor allele frequencies for rs622342 and rs757110 were 0.189 and 0.271, respectively. Only SLC22A1 rs622342 variant was found to be associated with the response of combination therapy, in which AA alleles carriers were 2.7-times more responsive to metformin than C allele carriers (Recessive model, odds ratio = 2.718, p = 0.025, 95% CI = 1.112-6.385). Conclusion: Genotyping of rs622342 can be useful in predicting the response to metformin in combination therapy in Egyptian T2DM patients.

PMID: 31231590 [PubMed]

Baicalein Exerts Neuroprotective Effects in FeCl3-Induced Posttraumatic Epileptic Seizures via Suppressing Ferroptosis.

Front Pharmacol. 2019;10:638

Authors: Li Q, Li QQ, Jia JN, Sun QY, Zhou HH, Jin WL, Mao XY

Abstract
Posttraumatic epilepsy (PTE) is a prevalent type of acquired epilepsy secondary to traumatic brain injury, and is characterized by repeated seizures. Traditional antiepileptic drugs have minimal response in preventing posttraumatic epileptic seizures. It is essential for the development of new therapeutic strategy. Our previous work disclosed a potent neuroprotective role of baicalein, a flavonoid extracted from Scutellaria baicalensis Georgi, against inherited epilepsy in rats. Whether baicalein has protective potential in posttraumatic epileptic seizures and the possible molecular mechanism remain elusive. Additionally, the brain is vulnerable to lipid peroxidation-induced damage due to high consumption of oxygen and abundant polyunsaturated fatty acids in neuronal membranes. Our present investigation aimed to elucidate whether baicalein exerts neuroprotective effects on posttraumatic epileptic seizures by inhibiting ferroptosis, a newly discovered lipid peroxidation-dependent cell death modality. We found that baicalein significantly reduced seizure score, number of seizures, and average seizure duration in an iron chloride (FeCl3)-induced PTE mouse model. The neuroprotective effect of baicalein was also validated in a ferric ammonium citrate (FAC)-induced HT22 hippocampal neuron damage model. Moreover, in vitro, baicalein could remarkably decrease ferroptotic indices (lipid reactive oxygen species, 4-hydroxynonenal, and prostaglandin endoperoxide synthase 2) and inhibit the expression of 12/15-lipoxygenase (12/15-LOX) in an iron-induced HT22 cell damage model. These findings were also validated in a mouse PTE model. It was concluded that baicalein exerted neuroprotective effects against posttraumatic epileptic seizures via suppressing ferroptosis and 12/15-LOX was likely to be involved in baicalein's neuroprotection.

PMID: 31231224 [PubMed]

Metabolome analysis for investigating host-gut microbiota interactions.

J Formos Med Assoc. 2019 Mar;118 Suppl 1:S10-S22

Authors: Chen MX, Wang SY, Kuo CH, Tsai IL

Abstract
Dysbiosis of the gut microbiome is associated with host health conditions. Many diseases have shown to have correlations with imbalanced microbiota, including obesity, inflammatory bowel disease, cancer, and even neurodegeneration disorders. Metabolomics studies targeting small molecule metabolites that impact the host metabolome and their biochemical functions have shown promise for studying host-gut microbiota interactions. Metabolome analysis determines the metabolites being discussed for their biological implications in host-gut microbiota interactions. To facilitate understanding the critical aspects of metabolome analysis, this article reviewed (1) the sample types used in host-gut microbiome studies; (2) mass spectrometry (MS)-based analytical methods and (3) useful tools for MS-based data processing/analysis. In addition to the most frequently used sample type, feces, we also discussed others biosamples, such as urine, plasma/serum, saliva, cerebrospinal fluid, exhaled breaths, and tissues, to better understand gut metabolite systemic effects on the whole organism. Gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and capillary electrophoresis-mass spectrometry (CE-MS), three powerful tools that can be utilized to study host-gut microbiota interactions, are included with examples of their applications. After obtaining big data from MS-based instruments, noise removal, peak detection, missing value imputation, and data analysis are all important steps for acquiring valid results in host-gut microbiome research. The information provided in this review will help new researchers aiming to join this field by providing a global view of the analytical aspects involved in gut microbiota-related metabolomics studies.

PMID: 30269936 [PubMed - indexed for MEDLINE]

Tiled array-based sequencing identifies enrichment of loss-of-function variants in the highly homologous filaggrin gene in African-American children with severe atopic dermatitis.

Exp Dermatol. 2018 09;27(9):989-992

Authors: Mathyer ME, Quiggle AM, Wong XFCC, Denil SLIJ, Kumar MG, Ciliberto HM, Bayliss SJ, Common JE, de Guzman Strong C

Abstract
Filaggrin (FLG) loss-of-function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population-specific. African-American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short-read alignment to FLG's high homology repeat variation. Here, we employed an array-based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well-characterized cohort of AA children with moderate-to-severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10-4 ) and ESP (1.7%; P = 3.5 × 10-5 ) suggesting a disease-enrichment effect for FLG LOF. Our results demonstrate the utility of array-based sequencing in discovering FLG LOF, including novel and population-specific, which are of higher prevalence in our AA severe AD group than previously reported.

PMID: 29791750 [PubMed - indexed for MEDLINE]

Nuclear Receptor CAR Suppresses GADD45B-p38 MAPK Signaling to Promote Phenobarbital-induced Proliferation in Mouse Liver.

Mol Cancer Res. 2018 08;16(8):1309-1318

Authors: Hori T, Saito K, Moore R, Flake GP, Negishi M

Abstract
Phenobarbital, a nongenotoxic hepatocarcinogen, induces hepatic proliferation and promotes development of hepatocellular carcinoma (HCC) in rodents. Nuclear receptor constitutive active/androstane receptor (NR1I3/CAR) regulates the induction and promotion activities of phenobarbital. Here, it is demonstrated that phenobarbital treatment results in dephosphorylation of a tumor suppressor p38 MAPK in the liver of C57BL/6 and C3H/HeNCrlBR mice. The molecular mechanism entails CAR binding and inhibition of the growth arrest and DNA-damage-inducible 45 beta (GADD45B)-MAPK kinase 6 (MKK6) scaffold to repress phosphorylation of p38 MAPK. Phenobarbital-induced hepatocyte proliferation, as determined by BrdUrd incorporation, was significantly reduced in both male and female livers of GADD45B knockout (KO) mice compared with the wild-type mice. The phenobarbital-induced proliferation continued until 48 hours after phenobarbital injection in only the C57BL/6 males, but neither in males of GADD45B KO mice nor in females of C57BL/6 and GADD45B KO mice. Thus, these data reveal nuclear receptor CAR interacts with GADD45B to repress p38 MAPK signaling and elicit hepatocyte proliferation in male mice.Implications: This GADD45B-regulated male-predominant proliferation can be expanded as a phenobarbital promotion signal of HCC development in future studies.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/8/1309/F1.large.jpg Mol Cancer Res; 16(8); 1309-18. ©2018 AACR.

PMID: 29716964 [PubMed - indexed for MEDLINE]

Physiologically-based pharmacokinetic modelling of a CYP2C19 substrate, BMS-823778, utilizing pharmacogenetic data.

Br J Clin Pharmacol. 2018 06;84(6):1335-1345

Authors: Gong J, Iacono L, Iyer RA, Humphreys WG, Zheng M

Abstract
AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically-based pharmacokinetic (PBPK) model for BMS-823778 and use the model to predict PK and drug-drug interaction (DDI) in virtual populations with multiple polymorphic genes.
METHODS: The PBPK model was built and verified using existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes.
RESULTS: The verified PBPK model of BMS-823778 accurately recovered observed PK in different populations. In addition, the model was able to capture the exposure differences between subjects with different CYP2C19 genotypes. PK simulation indicated higher exposures of BMS-823778 in CYP2C19 poor metabolizers who were also devoid of UGT1A4 activity, compared to those with normal UGT1A4 functionality. Moderate DDI with itraconazole was predicted in subjects with wild-type CYP2C19 or UGT1A4. However, in subjects without CYP2C19 or UGT1A4 functionality, significant DDI was predicted when BMS-823778 was coadministered with itraconazole.
CONCLUSIONS: A PBPK model was developed using clinical data that accurately predicted human PK in different population with various CYP2C19 phenotypes. Simulations with the verified PBPK model indicated that UGT1A4 was probably an important clearance pathway in CYP2C19 poor metabolizers. DDI with itraconazole is likely to be dependent on the genotypes of CYP2C19 and UGT1A4.

PMID: 29469197 [PubMed - indexed for MEDLINE]

Knowledge and understanding of pharmacogenomic testing among patients and health care professionals: A scoping review.

Patient Educ Couns. 2019 Jun 15;:

Authors: Veilleux S, Bouffard M

Abstract
OBJECTIVE: To support the introduction of pharmacogenomic tests in current practice, this study identifies the factors associated with a better understanding of the information related to genetic, genomic and/or pharmacogenomic tests by patients and health care professionals.
METHODS: Following a scoping review methodology, a search for literature was conducted with keywords related to health literacy and knowledge translation in the context of pharmacogenomic tests. Since only 6 articles were identified, the context of genetic or genomic testing were added to the inclusion criteria, leading to 24 articles.
RESULTS: Fourteen of the studies analyzed focused on genetic predictive, diagnostic or carrier tests, or concerned genetics in general, while ten addressed or included the use of pharmacogenomic tests. Demographic, individual, experiential and contextual factors were associated with a better understanding of the information related to genetic, genomic and/or pharmacogenomic tests among the targeted populations.
RESEARCH IMPLICATIONS: Our review shows that there is currently little empirical research available to identify the factors to consider in order to develop educational tools and resources specific to pharmacogenomics.
CONCLUSION: Expanding our review to include genetic and genomic testing factors can serve as a starting point for the evidence to be validated in future empirical research.

PMID: 31229328 [PubMed - as supplied by publisher]

Differences in presentation and survival of Asians compared to Caucasians with ovarian cancer: An NRG Oncology/GOG Ancillary study of 7914 patients.

Gynecol Oncol. 2019 Jun 19;:

Authors: Fuh KC, Java JJ, Chan JK, Kapp DS, Monk BJ, Burger RA, Young RC, Alberts DS, McGuire WP, Markman M, Bell J, Ozols RF, Armstrong DK, Aghajanian C, Bookman MA, Mannel RS

Abstract
PURPOSE: To compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer.
METHODS: Ancillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed.
RESULTS: Of 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p < 0.001), and were more likely to be of clear cell (15.8% vs. 6.2%, p < 0.001) and mucinous (3.3% vs. 1.9%, p < 0.001) histology. Asians had an improved 5-year disease-specific survival of 54.1% compared to 46.1% for Caucasians, p = 0.001. In multivariate analysis, the Asian race remained a significant prognostic factor for all-cause survival (HR: 0.84; 95% CI: 0.72-0.99; p = 0.04). Other factors predictive of improved survival included younger age, better performance status, optimal cytoreduction, earlier stage, non-clear cell histology, and lower grade tumors.
CONCLUSION: Asians enrolled into phase III ovarian cancer clinical trials were younger, with better performance status, earlier-stage of disease, and have a greater number of clear cell and mucinous tumors. After adjusting for these prognostic factors, Asians have a better survival compared to Caucasians.

PMID: 31229298 [PubMed - as supplied by publisher]

A new population pharmacokinetic model for vancomycin in patients with variable renal function: Therapeutic drug monitoring based on extended covariate model using CKD-EPI estimation.

J Clin Pharm Ther. 2019 Jun 22;:

Authors: Kim DJ, Lee DH, Ahn S, Jung J, Kiem S, Kim SW, Shin JG

Abstract
WHAT IS KNOWN AND OBJECTIVE: Although patients may have received vancomycin therapy with therapeutic drug monitoring (TDM), those treated with high-strength and long-term vancomycin therapy might have unstable and time-varying renal function. The methods used to estimate renal function should not be considered interchangeable with pharmacokinetic (PK) modeling and model-based estimation of vancomycin pharmacokinetics. While Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for renal function estimation has been widely integrated into clinical practice, a population PK model including CKD-EPI has not been established. The study was aimed at developing a new population PK model for optimal vancomycin prediction in patients with time-varying and variable renal function to evaluate the interchangeability of estimation methods. METHODS: The most suitable population PK model was explored and evaluated using non-linear mixed-effect modelling for the best fit of vancomycin concentrations from patients who needed to maintain high trough vancomycin concentrations of >10 mg/L or >15 mg/L. Renal function was estimated using the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations. NONMEM 7.4 was used to develop the population PK model. RESULTS: A total of 328 vancomycin concentrations in 99 patients were used to develop the population PK model. Vancomycin pharmacokinetics was best described by a two-compartment model. The CKD-EPI equation for vancomycin clearance was included in the final model among the estimation methods of renal function. A new covariate model, including extended covariate parameters that explain changes in renal function from the population-predicted value and individual dosing time, provided the best explanation for vancomycin pharmacokinetics among the various models tested. WHAT IS NEW AND CONCLUSION: A new extended covariate model for vancomycin using the CKD-EPI method may afford suitable dose adjustment for high-strength and long-term vancomycin therapy that results in unstable renal function.

PMID: 31228353 [PubMed - as supplied by publisher]

Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose dependent manner: Implications for inotropy.

Cardiovasc Res. 2019 Jun 22;:

Authors: Efentakis P, Varela A, Chavdoula E, Sigala F, Sanoudou D, Tenta R, Gioti K, Kostomitsopoulos N, Papapetropoulos A, Tasouli A, Farmakis D, Davos CH, Klinakis A, Suter T, Cokkinos DV, Iliodromitis EK, Wenzel P, Andreadou I

Abstract
AIMS: Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.
METHODS AND RESULTS: Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative) and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS) and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, PLN-/- mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg) and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer bearing (BC) mice were divided into: Control (N/S 0.9%), DXR (18 mg/kg), LEVO and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with L-NAME, DT-2 and H-89 (eNOS, PKG and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single-bolus administration of levosimendan abrogated doxorubicin-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/-mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating Ca2+-overload.
CONCLUSIONS: Single-dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-phospholamban pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.

PMID: 31228183 [PubMed - as supplied by publisher]

A pilot study of the implementation of pharmacogenomic pharmacist initiated pre-emptive testing in primary care.

Eur J Hum Genet. 2019 Jun 21;:

Authors: Bank PCD, Swen JJ, Schaap RD, Klootwijk DB, Baak-Pablo R, Guchelaar HJ

Abstract
Despite the nationwide availability of pharmacogenomic (PGx) guidelines in electronic medication surveillance systems in The Netherlands, PGx guided prescribing is still uncommon in primary care. We set out to investigate the adoption of pharmacist initiated PGx testing in primary care. Community pharmacists were offered a free PGx test covering 40 variants in 8 genes to test patients receiving an incident prescription (IRx) of a selection of 10 drugs. Results of the PGx test along with predicted phenotypes and a therapeutic recommendation based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines were transferred to the pharmacist and physician. Adoption was defined as the percentage of eligible patients that received genotyping. From November 2014-July 2016, 200 patients were included with an adoption of 18.0%. Of the included patients 57.5% received an IRx for atorvastatin, 14.5% started with simvastatin and 28.0% received an IRx for amitriptyline, (es)citalopram, nortriptyline, or venlafaxine. 90% of the patients carried at least one actionable PGx test result in the selected PGx-panel. In 31.0% of the incident prescriptions a combination between a drug with a known gene-drug interaction and an actionable genotype was present and a therapeutic recommendation was provided. The provided recommendations were accepted by the clinicians in 88.7% of the patients. Pharmacist initiated implementation of PGx in primary care is feasible, and the frequency of actionable gene-drug interactions for the selected drugs is high.

PMID: 31227807 [PubMed - as supplied by publisher]

Pharmacogenetics of Postoperative Nausea and Vomiting.

J Perianesth Nurs. 2019 Jun 18;:

Authors: Aroke EN, Hicks TL

Abstract
Postoperative nausea and vomiting (PONV) remains one of the most common adverse effects of anesthesia, affecting up to 80% of high-risk patients within 24 hours after surgery. Patient-related factors, surgical procedure, and perioperative medications such as opioids determine a patient's risk for PONV. To prevent and manage PONV, ondansetron, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, is frequently administered. Ondansetron is metabolized predominantly by hepatic cytochrome P450 (CYP2D6) enzymes, encoded by the CYP2D6 gene, whereas most of the effects of opioids are exerted at the opioid mu-1 receptor, encoded by the OPRM1 gene. Genetic polymorphisms of the CYP2D6 and OPRM1 genes may have a role in interindividual variation in the occurrence of PONV. Specifically, the occurrence of the G-allele produced by the OPRM1 A118G appears to be protective against PONV, whereas CYP2D6 ultrarapid metabolism increases the risk for PONV. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations for ondansetron. However, further studies are needed to investigate the role of genetic polymorphism in the occurrence of PONV and response to antiemetics.

PMID: 31227296 [PubMed - as supplied by publisher]

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol. 2019 Jun 25;73(24):3118-3131

Authors: Noordam R, Young WJ, Salman R, Kanters JK, van den Berg ME, van Heemst D, Lin HJ, Barreto SM, Biggs ML, Biino G, Catamo E, Concas MP, Ding J, Evans DS, Foco L, Grarup N, Lyytikäinen LP, Mangino M, Mei H, van der Most PJ, Müller-Nurasyid M, Nelson CP, Qian Y, Repetto L, Said MA, Shah N, Schramm K, Vidigal PG, Weiss S, Yao J, Zilhao NR, Brody JA, Braund PS, Brumat M, Campana E, Christofidou P, Caulfield MJ, De Grandi A, Dominiczak AF, Doney ASF, Eiriksdottir G, Ellervik C, Giatti L, Gögele M, Graff C, Guo X, van der Harst P, Joshi PK, Kähönen M, Kestenbaum B, Lima-Costa MF, Linneberg A, Maan AC, Meitinger T, Padmanabhan S, Pattaro C, Peters A, Petersmann A, Sever P, Sinner MF, Shen X, Stanton A, Strauch K, Soliman EZ, Tarasov KV, Taylor KD, Thio CHL, Uitterlinden AG, Vaccargiu S, Waldenberger M, Robino A, Correa A, Cucca F, Cummings SR, Dörr M, Girotto G, Gudnason V, Hansen T, Heckbert SR, Juhl CR, Kääb S, Lehtimäki T, Liu Y, Lotufo PA, Palmer CNA, Pirastu M, Pramstaller PP, Ribeiro ALP, Rotter JI, Samani NJ, Snieder H, Spector TD, Stricker BH, Verweij N, Wilson JF, Wilson JG, Jukema JW, Tinker A, Newton-Cheh CH, Sotoodehnia N, Mook-Kanamori DO, Munroe PB, Warren HR

Abstract
BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.
OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.
METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.
RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.
CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

PMID: 31221261 [PubMed - in process]

Correction to: Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial.

Trials. 2019 Jun 20;20(1):368

Authors: de Leeuw TG, Mangiarini L, Lundin R, Kaguelidou F, van der Zanden T, Della Pasqua O, Tibboel D, Ceci A, de Wildt SN, GAPP consortium

Abstract
Following publication of the original article [1], we have been notified that the tagging of one of the author names was done incorrectly in the XML version of the paper. Original and corrected tagging can be seen below.

PMID: 31221222 [PubMed - in process]

Off-label use of tacrolimus in children with Henoch-Schönlein purpura nephritis: a pilot study.

Arch Dis Child. 2018 08;103(8):772-775

Authors: Zhang DF, Hao GX, Li CZ, Yang YJ, Liu FJ, Liu L, Yuan XY, Li RH, Dong L, Dong Q, Jacqz-Aigrain E, Zhao W

Abstract
BACKGROUND: Tacrolimus is used off-label in the treatment of Henoch-Schönlein purpura nephritis (HSPN) in children, with limited evidence-based data. Based on clinical empirical experience and mechanism of action, tacrolimus might be promoted as treatment for childhood HSPN. The objectives of this pilot study were to assess its effectiveness and safety, and to explore the potential impact of CYP3A5 genotype.
METHODS: Children with HSPN receiving tacrolimus as empirical treatment were included in this prospective, observational study. Effectiveness was classified as complete remission, partial remission or non-response. General safety data analyses during and after study drug exposure included adverse events, reasons for discontinuation, deaths, laboratory data and vital signs. Trough concentration was determined using high-performance liquid chromatography with tandem mass spectrometry. Pharmacogenetic analysis was performed on the CYP3A5 gene.
RESULTS: A total of 20 patients with a mean age of 7.5 (SD 2.1) years participated in the whole process of the study. Twelve patients reached complete remission and eight patients reached partial remission at the end of 6-month treatment. No patients discontinued tacrolimus treatment due to adverse events, and no drug-related adverse events were shown to have a causal association with tacrolimus therapy. Dose-adjusted trough concentration was significantly higher in children with CYP3A5*1 allele as compared with patients with CYP3A5*3/*3 genotype (170.7±100.9 vs 79.8±47.4 (ng/mL)/(mg/kg)).
CONCLUSION: This pilot study showed that tacrolimus might be an effective and well-tolerated drug for the treatment of HSPN in children. CYP3A5 polymorphism had a significant impact on tacrolimus concentration.

PMID: 29535109 [PubMed - indexed for MEDLINE]

Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities.

Annu Rev Pharmacol Toxicol. 2018 01 06;58:161-185

Authors: Lauschke VM, Barragan I, Ingelman-Sundberg M

Abstract
Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.

PMID: 29029592 [PubMed - indexed for MEDLINE]

Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery.

Annu Rev Pharmacol Toxicol. 2018 01 06;58:65-82

Authors: Ewart L, Dehne EM, Fabre K, Gibbs S, Hickman J, Hornberg E, Ingelman-Sundberg M, Jang KJ, Jones DR, Lauschke VM, Marx U, Mettetal JT, Pointon A, Williams D, Zimmermann WH, Newham P

Abstract
Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism. By focusing on MPS models that have been developed for these organs, alongside other relevant in vitro models, we review the current state of the art and the challenges that still need to be overcome to ensure application of this technology in enhancing drug discovery.

PMID: 29029591 [PubMed - indexed for MEDLINE]

Loss of ZNF587B and SULF1 contributed to cisplatin resistance in ovarian cancer cell lines based on Genome-scale CRISPR/Cas9 screening.

Am J Cancer Res. 2019;9(5):988-998

Authors: Ouyang Q, Liu Y, Tan J, Li J, Yang D, Zeng F, Huang W, Kong Y, Liu Z, Zhou H, Liu Y

Abstract
Ovarian cancer is one of the most lethal malignancies of the female reproductive system. Platinum-resistance is the major obstacle in the successful treatment of ovarian cancer. Previous studies largely failed to identify the key genes associated with platinum-resistance by using candidate genes testing, bioinformatic analysis and GWAS method. The aim of the study was to utilize the whole human Genome-scale CRISPR-Cas9 knockout (GeCKO) library to screen for novel genes involved in cisplatin resistance in ovarian cancer cell lines. The GeCKO library targeted 19052 genes with 122417 unique guide sequences. Six candidate genes had been screened out including one previously validated gene SULF1 and five novel genes ZNF587B, TADA1, SEMA4G, POTEC and USP17L20. After validated by CCK-8 and RT-PCR analysis, two genes (ZNF587B and SULF1) were discovered to be involved in cisplatin resistance. ZNF587B may serve as a new biomarker for predicting cisplatin resistance.

PMID: 31218106 [PubMed]

Emerging Concepts in Precision Medicine and Cardiovascular Diseases in Racial and Ethnic Minority Populations.

Circ Res. 2019 Jun 21;125(1):7-13

Authors: Mensah GA, Jaquish C, Srinivas P, Papanicolaou GJ, Wei GS, Redmond N, Roberts MC, Nelson C, Aviles-Santa L, Puggal M, Green Parker MC, Minear MA, Barfield W, Fenton KN, Boyce CA, Engelgau MM, Khoury MJ

Abstract
Cardiovascular diseases remain the leading cause of mortality and a major contributor to preventable deaths worldwide. The dominant modifiable risk factors and the social and environmental determinants that increase cardiovascular risk are known, and collectively, are as important in racial and ethnic minority populations as they are in majority populations. Their prevention and treatment remain the foundation for cardiovascular health promotion and disease prevention. Genetic and epigenetic factors are increasingly recognized as important contributors to cardiovascular risk and provide an opportunity for advancing precision cardiovascular medicine. In this review, we explore emerging concepts at the interface of precision medicine and cardiovascular disease in racial and ethnic minority populations. Important among these are the lack of racial and ethnic diversity in genomics studies and biorepositories; the resulting misclassification of benign variants as pathogenic in minorities; and the importance of ensuring ancestry-matched controls in variant interpretation. We address the relevance of epigenetics, pharmacogenomics, genetic testing and counseling, and their social and cultural implications. We also examine the potential impact of precision medicine on racial and ethnic disparities. The National Institutes of Health's All of Us Research Program and the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Initiative are presented as examples of research programs at the forefront of precision medicine and diversity to explore research implications in minorities. We conclude with an overview of implementation research challenges in precision medicine and the ethical implications in minority populations. Successful implementation of precision medicine in cardiovascular disease in minority populations will benefit from strategies that directly address diversity and inclusion in genomics research and go beyond race and ethnicity to explore ancestry-matched controls, as well as geographic, cultural, social, and environmental determinants of health.

PMID: 31219738 [PubMed - in process]

Machine learning for differentiating metastatic and completely responded sclerotic bone lesion in prostate cancer: A retrospective radiomics study.

Br J Radiol. 2019 Jun 20;:20190286

Authors: Acar E, Leblebici A, Ellidokuz BE, Başbınar Y, Kaya GÇ

Abstract
OBJECTIVE: Using computed tomography (CT) texture analysis and machine learning methods, this study aims to distinguish the lesions imaged via 68Ga-PSMA PET/CT as metastatic and completely responded in patients with known bone metastasis and who were previously treated.
METHODS: We retrospectively reviewed the 68Ga-PSMA PET/CT images of 75 patients after treatment, who were previously diagnosed with prostate cancer and had known bone metastasis. A texture analysis was performed on the metastatic lesions showing PSMA expression and completely responded sclerotic lesions without PSMA expression through CT images. Textural features were compared in two groups. Thus, the distinction of metastasis/completely responded lesions and the most effective parameters in this issue were determined by using various methods [decision tree, discriminant analysis, support vector machine (SVM), k-nearest neighbor (KNN), ensemble classifier] in machine learning.
RESULTS: In 28 of the 35 texture analysis findings, there was a statistically significant difference between the two groups. The Weighted KNN method had the highest accuracy and area under the curve, has been chosen as the best model. The weighted KNN algorithm was succeeded to differentiate sclerotic lesion from metastasis or completely responded lesions with 0.76 AUC. GLZLM_SZHGE and histogram-based kurtosis were found to be the most important parameters in differentiating metastatic and completely responded sclerotic lesions.
CONCLUSIONS: Metastatic lesions and completely responded sclerosis areas in CT images, as determined by 68Ga-PSMA PET, could be distinguished with good accuracy using texture analysis and machine learning (Weighted KNN algorithm) in prostate cancer.
ADVANCES IN KNOWLEDGE: Our findings suggest that, with the use of newly emerging software, CT imaging can contribute to identifying the metastatic lesions in prostate cancer.

PMID: 31219712 [PubMed - as supplied by publisher]