High accuracy differentiating autoimmune pancreatitis from pancreatic ductal adenocarcinoma by immunoglobulin G glycosylation.

Clin Proteomics. 2019;16:1

Authors: Shih HC, Chang MC, Chen CH, Tsai IL, Wang SY, Kuo YP, Chen CH, Chang YT

Abstract
Background: Misdiagnosis of autoimmune pancreatitis (AIP) as pancreatic cancer (PDAC) or vice versa can cause dismal patents' outcomes. Changes in IgG glycosylation are associated with cancers and autoimmune diseases. This study investigated the IgG glycosylation profiles as diagnostic and prognostic biomarkers in PDAC and AIP.
Methods: Serum IgG-glycosylation profiles from 86 AIP patients, 115 PDAC patients, and 57 controls were analyzed using liquid chromatography-electrospray ionization mass spectrometry. Classification and regression tree (CART) analysis was applied to build a decision tree for discriminating PDAC from AIP. The result was validated in an independent cohort.
Results: Compared with AIP patients and controls, PDAC patients had significantly higher agalactosylation, lower fucosylation, and sialylation of IgG1, a higher agalactosylation ratio of IgG1 and a higher agalactosylation ratio of IgG2. AIP patients had significantly higher fucosylation of IgG1 and a higher sialylation ratio of IgG subclasses 1, 2 and 4. Using the CART analysis of agalactosylation and sialylation ratios in the IgG to discriminate AIP from PDAC, the diagnostic accuracy of the glycan markers was 93.8% with 94.6% sensitivity and 92.9% specificity. There were no statistically significant difference of IgG-glycosylation profiles between diffuse type and focal type AIP.
Conclusions: AIP and PDAC patients have distinct IgG-glycosylation profilings. IgG-glycosylation could different PDAC from AIP with high accuracy.

PMID: 30622446 [PubMed]

An ensemble model with cluster assumption for warfarin dose prediction in Chinese patients.

IEEE J Biomed Health Inform. 2019 Jan 07;:

Authors: Tao Y, Chen YJ, Xue L, Xie C, Jiang B, Zhang Y

Abstract
The prediction of daily stable warfarin dosage for a specific patient is difficult. To improve the predictive accuracy and build a highly accurate predictive model, we developed an ensemble learning method, called evolutionary fuzzy c-mean (EFCM) clustering algorithm with support vector regression (SVR). A dataset of 517 Han Chinese patients was collected from the data of The First Affiliated Hospital of Soochow University and dataset of International Warfarin Pharmacogenetics Consortium for training and testing. In EFCM+SVR, we adopted SVR to build a generalized base model (SVR model). To achieve an accurate prediction on patients with large dosage, we proposed an EFCM clustering algorithm that can be used to cluster the training set and designed a clustering model on clusters and centroids. The SVR and clustering models were integrated into an ensemble model by stepwise functions. In the experiment, three artificial neural networks, SVR, two ensemble models and three regression models were used as comparators to the EFCM+SVR model, which obtained the smallest mean absolute error (0.67 mg/day) in warfarin dose prediction and the largest R-squared (43.9%). The model achieved satisfactory prediction in terms of the percentage of patients whose predicted dose of warfarin was within 15% and 20% of the actual stable therapeutic dose (15%-p of 36% and 20%-p of 46.6%).

PMID: 30624235 [PubMed - as supplied by publisher]

Pharmacogenetics of tardive dyskinesia in schizophrenia: The role of CHRM1 and CHRM2 muscarinic receptors.

World J Biol Psychiatry. 2019 Jan 09;:1-6

Authors: Boiko AS, Ivanova SA, Pozhidaev IV, Freidin MB, Osmanova DZ, Fedorenko OY, Semke AV, Bokhan NA, Wilffert B, Loonen AJM

Abstract
OBJECTIVES: Acetylcholine M (muscarinic) receptors are possibly involved in tardive dyskinesia (TD). The authors tried to verify this hypothesis by testing for possible associations between two muscarinic receptor genes (CHRM1 and CHRM2) polymorphisms and TD in patients with schizophrenia.
METHODS: A total of 472 patients with schizophrenia were recruited. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale. Fourteen allelic variants of CHRM1 and CHRM2 were genotyped using Applied Biosystems amplifiers (USA) and the MassARRAY System by Agena Bioscience.
RESULTS: The prevalence of the rs1824024*GG genotype of the CHRM2 gene was lower in TD patients compared to the group without it (χ2 = 6.035, p = 0.049). This suggested that this genotype has a protective effect for the development of TD (OR = 0.4, 95% CI: 0.19-0.88). When age, gender, duration of schizophrenia and dosage of antipsychotic treatment were added as covariates in regression analysis, the results did not reach statistical significance.
CONCLUSIONS: This study did identify associations between CHRM2 variations and TD; the results of logistic regression analysis with covariates suggest that the association is, however, likely to be secondary to other concomitant factors.

PMID: 30623717 [PubMed - as supplied by publisher]

Genetic analysis of the relation of telomere length-related gene (RTEL1) and coronary heart disease risk.

Mol Genet Genomic Med. 2019 Jan 08;:e550

Authors: Lu S, Zhong J, Wu M, Huang K, Zhou Y, Zhong Z, Li Q, Zhou H

Abstract
BACKGROUND: Regulator of telomere elongation helicase 1 (RTEL1), a telomere length-related gene, is closely linked to cancer and age-related diseases. The aim of this study was to investigate the association between genetic polymorphisms in the RTEL1 gene and coronary heart disease (CHD) risk.
METHODS: In this case-control study, which includes samples from 596 CHD patients and 603 healthy controls, five SNPs in RTEL1 were selected. The genotypes were studied using the Agena MassARRAY platform, and the statistical analyses were performed using the chi-square and Fisher's exact tests, genetic model analysis, and haplotype analysis.
RESULTS: In the allele model, using the chi-square test, we found that the patients with the "G" allele of rs6010620 and the "C" allele of rs4809324 in the RTEL1 gene showed a decreased risk of CHD once the results were adjusted for age and gender. In the genetic model, logistic regression analyses revealed that the rs6010620 polymorphism conferred a decreased risk of CHD in the codominant model (OR = 0.52, 95% CI: 0.31-0.88, p = 0.007 for the "G/G" genotype) and the recessive model (OR = 0.49, 95% CI: 0.30-0.80, p = 0.004 for the "G/G" genotype). In addition, the haplotype "Grs6010620 Trs6010621 Trs4809324 " of RTEL1 was associated with a 0.03-fold decreased risk of CHD once the results were adjusted for age and gender (OR = 0.03, 95% CI: 0.01-0.12, p < 0.001).
CONCLUSION: Our findings have demonstrated that the genetic variants of RTEL1 may have a protective role against CHD risk.

PMID: 30623606 [PubMed - as supplied by publisher]

No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia.

Hum Psychopharmacol. 2019 Jan 08;:e2685

Authors: Levchenko A, Vyalova N, Pozhidaev IV, Boiko AS, Osmanova DZ, Fedorenko OY, Semke AV, Bokhan NA, Wilffert B, Loonen AJM, Ivanova SA

Abstract
OBJECTIVE: AKT1 and GSK3B take part in one of the intracellular cascades activated by the D2 dopamine receptor (DRD2). This receptor is antagonized by antipsychotics and plays a role in the pathogenesis of antipsychotic-induced tardive dyskinesia (TD). The present study investigated association of several polymorphisms in the two candidate genes, AKT1 and GSK3B, with TD in antipsychotic-treated patients with schizophrenia.
METHODS: DNA samples from 449 patients from several Siberian regions (Russia) were genotyped, and the results were analyzed using chi-squared tests and analyses of variance.
RESULTS: Antipsychotic-induced TD was not associated with either of the tested functional polymorphisms (rs334558, rs1130214, and rs3730358).
CONCLUSIONS: Despite regulation of AKT1 and GSK3B by DRD2, we found no evidence that these two kinases play a major role in the pathogenesis of antipsychotic-induced TD. These results agree with previously published data and necessitate further exploration of other pathogenic mechanisms, such as neurotoxicity due to excessive dopamine metabolism.

PMID: 30623492 [PubMed - as supplied by publisher]

HIV Integrase Inhibitor Pharmacogenetics: An Exploratory Study.

Clin Drug Investig. 2019 Jan 08;:

Authors: Murrell DE, Cluck DB, Moorman JP, Brown SD, Wang KS, Duffourc MM, Harirforoosh S

Abstract
BACKGROUND AND OBJECTIVES: Integrase strand transfer inhibitors (INSTIs), dolutegravir, elvitegravir, and raltegravir, have become integral in the treatment of HIV, with close monitoring of continued efficacy and tolerability. As side effect occurrence varies among subjects receiving these drugs, we sought to perform an exploratory analysis examining the role of several single-nucleotide polymorphisms (SNPs) on drug concentration changes, selected clinical outcomes, and the occurrence of subject-reported adverse events.
METHODS: Adults (aged ≥ 18 years) receiving INSTI-based regimens for treatment of HIV were recruited and genotyped with an iPLEX ADME PGx Pro v1.0 Panel. Multiple linear or logistic regression with covariates [age, sex, BMI, regimen (in the across-regimen group), regimen duration, and baseline variables (for continuous parameters)] was used to detect significant (p < 0.05) association of selected clinical data with genetic variants within the study population.
RESULTS: In a sample (n = 88) with a median age of 52.5 years (IQR 45.7-57.2) being predominately Caucasian (88.6%) and male (86.4%), this exploratory study discovered several associations between variables and SNPs, when using INSTIs. Abnormal dream occurrence was statistically different (p = 0.028) between regimens. Additionally, several SNPs were found to be associated with adverse event profiles primarily when all regimens were grouped together.
CONCLUSION: The associations found in this study point to a need for further assessment, within the population living with HIV, of factors contributing to unfavorable subject outcomes. These exploratory findings require confirmation in larger studies, which then may investigate pharmacogenetic mechanisms.

PMID: 30623371 [PubMed - as supplied by publisher]

Intensive Glucose Control Reduces the Risk Effect of TRIB3, SMARCD3, and ATF6 Genetic Variation on Diabetic Vascular Complications.

Front Pharmacol. 2018;9:1422

Authors: He F, Shu Y, Wang X, Liu X, Liu G, Chen Z, Wang Z, Li L, Liu R, Zhou H, Xu H, Zhang W, Zhou G

Abstract
Type 2 diabetes mellitus is a complex disease. Our previous study revealed that TRIB3 genetic variations were strongly associated with diabetic vascular complications, although TRIB3 regulation pathways remain poorly understood. We used two extreme treatment groups from a 2 × 2 factorial randomized controlled trial to identify a positive association, which was further validated in patients receiving cross treatment to test the effect of genetic polymorphisms among the different treatment groups. A gene-centric score (GS)-weighted model including the three associated genetic variations TRIB3 rs2295490, ATF6 rs12086247, and SMARCD3 rs58125572 was used. The results of the GS model indicated a 46% reduction in the risk of primary vascular complications in patients bearing more than two risk alleles [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.38-0.76, p < 0.001], following intensive glucose control treatment when compared with patients who received standard glucose control treatment. Furthermore, these patients benefited from active blood pressure-lowering treatment (HR 0.39, 95% CI 0.24-0.64, p < 0.001). However, no significant difference was observed between the two interventions in patients with fewer than two risk alleles (HR 1.09, 95% CI 0.86-1.39, p = 0.47). These results indicate that genetic variants in these three genes may be useful biomarkers for individualized drug therapy in diabetic patients.

PMID: 30618737 [PubMed]

The importance of buprenorphine research in the opioid crisis.

Mol Psychiatry. 2019 Jan 07;:

Authors: Pendergrass SA, Crist RC, Jones LK, Hoch JR, Berrettini WH

Abstract
With the urgency to treat patients more effectively for opioid use disorder in the midst of the opioid epidemic, a key area for precision medicine is to improve individualized medication-assisted treatment for opioid use disorder. The expansion of medication-assisted treatment is a key to reducing illicit opioid use, preventing opioid overdose deaths, and reducing the comorbidities and societal impacts of opioid use disorder. The most common medication for opioid use disorder will soon be buprenorphine. Research to date shows the successful impact of buprenorphine treatment, including the pharmacogenomics of buprenorphine response and treatment efficacy. Buprenorphine is also a promising treatment for depression and anxiety, and neonatal opioid withdrawal syndrome (NOWS). However, the rates of success with medication-assisted treatment for opioid use disorder, particularly at the beginning of treatment, still show many individuals relapsing to illicit opioid use. With the scope of the opioid crisis, there is an urgent need for expansion of buprenorphine treatment research to provide critical information for improving outcomes of opioid use disorder. Implementing the best strategies for opioid use disorder treatment is of dire urgency and will save lives.

PMID: 30617273 [PubMed - as supplied by publisher]

UDP-glucuronosyltransferase genetic variation in North African populations: a comparison with African and European data.

Ann Hum Biol. 2019 Jan 07;:1-24

Authors: Novillo A, Gaibar M, Romero-Lorca A, Chaabani H, Nadir A, Moral P, Esteban ME, Fernández-Santander A

Abstract
BACKGROUND: Genetic variation in glucuronosyltransferases (UGT) is crucial in drug metabolism and risk of some diseases Aim: To examine genetic variation in glucuronosyltransferases (UGT)in North African populations.
SUBJECTS & METHODS: Allele frequencies of SNPs UGT1A424Thr, UGT1A448Val, UGT2B1585Tyr, UGT2B15523Thr and UGT2B17 CNV deletion from Morocco, Algeria, Tunisia and Libya were compared to European and Sub-Saharan populations.
RESULTS: North Africans are the group with the highest genetic heterogeneity given by internal differences in the occurrence of UGT2B17 deletion, UGT1A448Val and UGT1A4 haplotypes. UGT2B15 SNPs differentiate Sub-Saharans from the rest of populations.
CONCLUSION: North African populations show high frequency of carriers of UGT2B15523Thr, a variant linked to an increased risk of prostate cancer. High Atlas Moroccans and Algerians show low frequency of UGT2B17del, a variant associated with high concentrations of testosterone and oestradiol.

PMID: 30616396 [PubMed - as supplied by publisher]

Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study.

Diabetologia. 2018 06;61(6):1344-1353

Authors: Siddiqui MK, Kennedy G, Carr F, Doney ASF, Pearson ER, Morris AD, Johnson T, McLaughlin MM, Williams RE, Palmer CNA

Abstract
AIMS/HYPOTHESIS: The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade.
METHODS: This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades.
RESULTS: The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively.
CONCLUSIONS/INTERPRETATION: Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.

PMID: 29623345 [PubMed - indexed for MEDLINE]

Rapamycin - mTOR + BRAF =? Using Relational Similarity to Find Therapeutically Relevant Drug-Gene Relationships in Unstructured Text.

J Biomed Inform. 2019 Jan 04;:103094

Authors: Fathiamini S, Johnson AM, Zeng J, Holla V, Sanchez NS, Meric-Bernstam F, Bernstam EV, Cohen T

PMID: 30615938 [PubMed - as supplied by publisher]

Pharmacokinetic analysis reveals limitations and opportunities for nanomedicine targeting of endothelial and extravascular compartments of tumors.

J Drug Target. 2019 Jan 07;:1-25

Authors: Benchimol MJ, Bourne D, Moghimi SM, Simberg D

Abstract
Targeting of nanoparticles to tumors can potentially improve specificity of imaging and treatments. We have developed a multicompartmental pharmacokinetic model in order to analyze some of the factors that control efficiency of targeting to intravascular (endothelium) and extravascular (tumor cells and stroma) compartments. We make the assumption that transport across tumor endothelium is an important step for subsequent nanoparticle accumulation in the tumor (area-under-the-curve, AUC) regardless of entry route (interendothelial and transendothelial routes) and study this through a multicompartmental simulation. . Our model reveals that increasing endothelial targeting efficiency has a much stronger effect on the AUC than increasing extravascular targeting efficiency. Furthermore, our analysis reveals that both extravasation and intratumoral diffusion rates need to be increased in order to significantly increase the AUC of extravascular-targeted nanoparticles. Increasing the nanoparticle circulation half-life increases the AUC independently of extravasation and intratumoral diffusion. Targeting the extravascular compartment leads to a buildup in the first layer surrounding blood vessels at the expense of deeper layers (binding site barrier). This model explains some of the limitations of tumor targeting, and provides important guidelines for the design of targeted nanomedicines.

PMID: 30614276 [PubMed - as supplied by publisher]

New-onset obesity after liver transplantation-outcomes and risk factors: the Swiss Transplant Cohort Study.

Transpl Int. 2018 11;31(11):1254-1267

Authors: Beckmann S, Denhaerynck K, Stampf S, Saigi-Morgui N, Binet I, Koller M, Boely E, De Geest S, Psychosocial Interest Group, Swiss Transplant Cohort Study

Abstract
Weight gain after liver transplantation (LTx) facilitates development of new-onset obesity; however, its risk factors and outcomes are poorly understood. We identified the impact of new-onset obesity on cardiovascular events (CVEs) and patient survival, and risk factors for new-onset obesity. Multiple Cox regression models examined risk factors for CVEs, patient survival, and new-onset obesity in 253 adults (mean age 52.2 ± 11.6 years, male gender 63.6%, mean follow up 5.7 ± 2.1 years). Cumulative incidence of post-LTx CVE was 28.1%; that of new-onset obesity was 21.3%. Regardless of CVE at LTx, post-LTx CVEs were predicted by new-onset obesity [Hazard Ratio (HR), 2.95; P = 0.002] and higher age at LTx (HR, 1.05; P < 0.001). In patients without known pre-LTx CVEs (n = 214), risk factors for post-LTx CVEs were new-onset obesity (HR, 2.59; P = 0.014) and higher age (HR, 1.04; P = 0.001). Survival was not associated with new-onset obesity (P = 0.696). Alcoholic liver disease predicted new-onset obesity (HR, 3.37; P = 0.025), female gender was protective (HR, 0.39; P = 0.034). In 114 patients with available genetic data, alcoholic liver disease (HR, 12.82; P = 0.014) and hepatocellular carcinoma (HR, 10.02; P = 0.048) predicted new-onset obesity, and genetics remained borderline significant (HR, 1.07; P = 0.071). Early introduction of post-LTx weight management programs may suggest a potential pathway to reduce CVE risk.

PMID: 29984844 [PubMed - indexed for MEDLINE]

Development to enable precision medicine in Africa.

Per Med. 2017 11;14(6):467-470

Authors: Mulder N

PMID: 29749855 [PubMed - indexed for MEDLINE]

Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate.

Pharmacol Res. 2019 Jan 03;:

Authors: Farinato A, Altamura C, Imbrici P, Maggi L, Bernasconi P, Mantegazza R, Pasquali L, Siciliano G, Monaco ML, Vial C, Sternberg D, Carratù MR, Conte D, Desaphy JF

Abstract
Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158 L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158 L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297 K, p.F1298C, p.G1306E, p.I1310 N, and p.T1313 M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293 T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313 M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life.

PMID: 30611854 [PubMed - as supplied by publisher]

Pharmacogenetics and personalized medicine. Are expectations being met?

Med Clin (Barc). 2019 Jan 02;:

Authors: Gervasini G

PMID: 30611536 [PubMed - as supplied by publisher]

The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.

J Neural Transm (Vienna). 2019 Jan 04;:

Authors: Amare AT, Schubert KO, Tekola-Ayele F, Hsu YH, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Kato M, Liu YL, Praphanphoj V, Stingl JC, Bobo WV, Tsai SJ, Kubo M, Klein TE, Weinshilboum RM, Biernacka JM, Baune BT

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

PMID: 30610379 [PubMed - as supplied by publisher]

Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice.

Brain Sci. 2019 Jan 01;9(1):

Authors: Crabbe JC, Metten P, Savarese AM, Ozburn AR, Schlumbohm JP, Spence SE, Hack WR

Abstract
Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.

PMID: 30609665 [PubMed]

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Am J Hum Genet. 2019 Jan 03;104(1):76-93

Authors: Ceyhan-Birsoy O, Murry JB, Machini K, Lebo MS, Yu TW, Fayer S, Genetti CA, Schwartz TS, Agrawal PB, Parad RB, Holm IA, McGuire AL, Green RC, Rehm HL, Beggs AH, BabySeq Project Team

Abstract
Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

PMID: 30609409 [PubMed - in process]

LC-MS application for therapeutic drug monitoring in alternative matrices.

J Pharm Biomed Anal. 2018 Dec 29;166:40-51

Authors: Avataneo V, D'Avolio A, Cusato J, Cantù M, De Nicolò A

Abstract
Nowadays the practice of therapeutic drug monitoring, consisting in the measurement of drugs concentrations in biological matrices in order to guide possible posological adjustments, is becoming more and more important for the management and optimization of several treatments, especially when drugs with narrow therapeutic indexes are administered. Although TDM on plasma samples is currently considered the gold standard, this practice shows some limitations: it requires venous blood sampling, centrifugation and, if necessary, shipment with refrigeration; moreover, drug concentrations in plasma or blood do not necessarily reflect the ones in the target tissues or cells. Therefore, in the recent years great attention has been given to alternative matrices for TDM purpose, in order to reduce invasiveness, costs or to obtain better information about drug concentrations at the active sites. This evolution is strongly sustained by the spreading use of liquid chromatography coupled with mass spectrometry (LC-MS) techniques for the analysis of small molecules, which is constantly increasing sensitivity and specificity of TDM assays. In this review, we present and summarize recently published LC-MS applications providing alternatives to plasma testing, in order to avoid blood withdrawal, plasma separation, refrigerated shipment or, if possible, to obtain better information about drug exposure in target cells. By analyzing the last 5 years of literature, reported in PubMed website, LC-MS/MS applications have been reported, with particular focus on the ones with higher probability to enter in the near future in clinical practice. Microsampling strategies and alternative biological matrices, from urine to tissue samples, have been included.

PMID: 30609393 [PubMed - as supplied by publisher]