Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis.

J Pers Med. 2018 Oct 03;8(4):

Authors: Valanti EK, Dalakoura-Karagkouni K, Sanoudou D

Abstract
Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1-/- × Apoe-/- mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis.

PMID: 30282955 [PubMed]

Review of core-multishell nanostructured models for nano-biomedical and nano-biopharmaceutical application.

Biomed Mater Eng. 2018;29(4):451-471

Authors: Šetrajčić-Tomić AJ, Popović JK, Vojnović M, Džambas LD, Šetrajčić JP

Abstract
The main advantage of a theoretical approach is essential knowledge of the mechanisms that allow us to comprehend the experimental conditions that we have to fulfill to be able to get the desired results. Based on our research in ultrathin crystal structures performed so far, superlattices, Q-wires and Q-dots, we will consider the materials that can act as carriers for medicines and tagged substances. For this purpose we established a shell-model of ultrathin crystals and investigated their fundamental characteristics. This could be considered as a form of nano-engineering. In this paper we will analyze application of nanomaterials in biomedicine, that is to say we will present the recent accomplishments in basic and clinical nanomedicine. Achieving full potential of nanomedicine may be years or even decades away, however, potential advances in drug delivery, diagnosis, and development of nanotechnology-related drugs start to change the landscape of medicine. Site-specific targeted drug delivery (made possible by the availability of unique delivery platforms, such as dendrimers, nanoparticles and nanoliposomes) and personalized medicines (result of the advance in pharmacogenetics) are just a few concepts on the horizon of research. In this paper, especially, we have analyzed the changes in basic physical properties of spherical-shaped nanoparticles that can be made in several (nano)layers and have, at the same time, multiple applications in medicine. This paper presents a review of our current achievement in the field of theoretical physics of ultrathin films and possible ways to materialize the same in the field of nanopharmacy.

PMID: 30282343 [PubMed - in process]

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects.

Basic Clin Pharmacol Toxicol. 2018 Oct 03;:

Authors: Saiz-Rodríguez M, Ochoa D, Herrador C, Belmonte C, Román M, Alday E, Koller D, Zubiaur P, Mejía G, Hernández-Martínez M, Abad-Santos F

Abstract
Fentanyl is an agonist of the μ-opioid receptor commonly used in the treatment of moderate-severe pain. In order to study whether pharmacogenetics explain some of the variability in the response to fentanyl, several genes related to fentanyl receptors, transporters and metabolic enzymes have been analysed. Thirty-five healthy volunteers (19 men and 16 women) receiving a single 300 μg oral dose of fentanyl were genotyped for 9 polymorphisms in cytochrome P450 (CYP) enzymes (CYP3A4 and CYP3A5), ATP binding cassette subfamily B member 1 (ABCB1), opioid receptor mu 1 (OPRM1), catechol-O-methyltransferase (COMT) and adrenoceptor beta 2 (ADRB2) by real-time PCR. Fentanyl concentrations were measured by ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-MS/MS). Fentanyl pharmacokinetics is affected by sex. Carriers of the CYP3A4*22 allele, which is known to reduce the mRNA expression, showed higher area under the concentration-time curve (AUC) and lower clearance (Cl) values. Although this finding might be of importance, its validity needs to be confirmed in other similar settings. Furthermore carriers of the ABCB1 C1236T T/T genotype presented a lower AUC and higher Cl, as well as lower half-life (T1/2 ). As subjects were blocked with naltrexone, the effect of fentanyl on pharmacodynamics might be biased; however, we could observe that fentanyl had a hypotensive effect. Moreover, ADRB2 C523A A allele carriers showed a tendency towards reducing systolic blood pressure. Likewise, OPRM1 and COMT minor allele variants were risk factors for development of somnolence. CYP3A5*3, ABCB1 C3435T and ABCB1 G2677T/A were not associated with fentanyl's pharmacokinetics, pharmacodynamics and safety profile. This article is protected by copyright. All rights reserved.

PMID: 30281924 [PubMed - as supplied by publisher]

Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.

J Med Econ. 2018 Oct 03;:1-19

Authors: Kelley EF, Snyder EM, Alkhatib NS, Snyder SC, Sprissler R, Olson TP, Akre MK, Abraham I

Abstract
AIMS: Hypertension is the strongest modifiable risk factor for cardiovascular disease, affecting 80 million individuals in the United States and responsible for approximately 360,000 deaths, at total annual costs of $93.5 billion. Antihypertension therapies guided by single genotypes are clinically more effective and may avert more adverse events than the standard of care of layering anti-hypertensive drug therapies, thus potentially decreasing costs. We aimed to determine the economic benefits of the implementation of multi-gene panel guided therapies for hypertension from the payer perspective within a three-year time horizon.
MATERIALS AND METHODS: A simulation analysis was conducted for a panel of 10 million insured patients categorized clinically as untreated, treated but uncontrolled, and treated and controlled over a three-year treatment period. Inputs included research data; empirical data from a 11-gene panel with known functional, heart, blood vessel, and kidney genotypes; and therapy efficacy and safety estimates from literature. Cost estimates were categorized as related to genetic testing, evaluation and management, medication, or adverse events.
RESULTS: Multi-gene panel guided therapy yielding savings of $6,256,607,500 for evaluation and management, $908,160,000 for medications, and $37,467,508,716 for adverse events, after accounting for incremental testing costs of $2,355,540,000. This represents a total 3-year savings of $276,736,216, or a 47% reduction, and 3-year savings of $4,228 and annual savings of $1,409 per covered patient.
CONCLUSIONS: A precision medicine approach to genetically guided therapy for hypertension patients using a multi-gene panel reduced total 3-year costs by 47%, yielding savings exceeding $42.3 billion in an insured panel of 10 million patients. Importantly, 89% of these savings are generated by averting specific adverse events and thus optimizing choice of therapy in function of both safety and efficacy.

PMID: 30280614 [PubMed - as supplied by publisher]

An opportunity for clinical pharmacology trained physicians to improve patient drug safety: A retrospective analysis of adverse drug reactions in teenagers.

F1000Res. 2018;7:677

Authors: Eugene AR, Eugene B

Abstract
Background: Adverse drug reactions (ADRs) are a major cause of hospital admissions, prolonged hospital stays, morbidity, and drug-related mortality. In this study, we sought to identify the most frequently reported medications and associated side effects in adolescent-aged patients in an effort to prioritize clinical pharmacology consultation efforts for hospitals seeking to improve patient safety.   Methods: Quarterly reported data were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 and ending in the third quarter of 2017. We then used the GeneCards database to map the pharmacogenomic biomarkers associated with the most reported FAERS drugs. Data homogenization and statistics analysis were all conducted in R for statistical programming. Results: We identified risperidone (10.64%) as the compound with the most reported ADRs from all reported cases. Males represented 90.1% of reported risperidone cases with gynecomastia being the most reported ADR. Ibuprofen OR=188 (95% CI, 105.00 - 335.00) and quetiapine fumarate OR=116 (95% CI, 48.40 - 278.00) were associated with the highest odds of completed suicide in teenagers. Ondansetron hydrochloride OR=7.12 (95% CI, 1.59 - 31.9) resulted in the highest odds of pneumothorax. Lastly, olanzapine (8.96%) represented the compound with the most reported drug-drug interactions cases, while valproic acid OR=221 (95% CI, 93.900 - 522.00) was associated with the highest odds of drug-drug interactions. Conclusion: Despite any data limitations, physicians prescribing risperidone in males should be aware of the high rates of adverse drug events and an alternative psychotropic should be considered in male patients. Further, patients with a history of pneumothorax or genetically predisposed to pneumothorax should be considered for an alternative antiemetic to ondansetron hydrochloride, due to increased odds associated with the drug and adverse event.

PMID: 30271581 [PubMed - in process]

TNF-α serum levels are elevated in women with clinically symptomatic uterine fibroids.

Int J Immunopathol Pharmacol. 2018 Jan-Dec;32:2058738418779461

Authors: Ciebiera M, Włodarczyk M, Wrzosek M, Wojtyła C, Błażej M, Nowicka G, Łukaszuk K, Jakiel G

Abstract
Uterine fibroids (UFs) are one of the most common pathologies of the female genital tract. The incidence of UFs has been estimated at 25-80%. Tumor necrosis factor (TNF)-α is a cell-signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. The aim of the study was to evaluate the impact of clinically symptomatic UFs on TNF-α serum levels. A total of 149 Caucasian women were included: 85 patients admitted for surgery due to clinically symptomatic UFs (n = 85; study group) and 64 age-matched UF-free controls (n = 64). TNF-α serum concentrations between the groups were compared. Receiver operating characteristic (ROC) curves were also used as a statistical model to evaluate TNF-α as a marker for UFs. Mean TNF-α serum concentration in the study group was 0.34 ± 0.14 pg/mL; (in half of the subjects, the level did not exceed 0.39 pg/mL. Mean TNF-α serum concentration in the control group was 0.17 ± 0.09 pg/mL; in half of the subjects, the level did not exceed 0.14 pg/mL. The difference was statistically significant. Using the area under the ROC curve, we found that TNF-α serum concentration of 0.34 pg/mL can be used as a predictor for UFs in selected populations. In our study, we confirmed higher TNF-α serum concentrations in women with clinically symptomatic UFs.

PMID: 29809057 [PubMed - indexed for MEDLINE]

Gender-Specific Association Between ABCC2 -24C>T SNP and Reduction in Triglycerides in Chilean Patients Treated With Atorvastatin.

Basic Clin Pharmacol Toxicol. 2018 May;122(5):517-522

Authors: Prado Y, Arencibia A, Zambrano T, Salazar LA

Abstract
Statins are the first-line therapy prescribed to lower plasma cholesterol levels. Although being safe and showing several beneficial cholesterol-independent pleiotropic effects, a significant variability regarding statin's therapeutic goals has been abundantly documented, but less understood. We aimed to investigate the influence of the ABCC2 -24C>T single nucleotide polymorphism on Chilean hypercholesterolaemic individuals treated for 4 weeks with 10 mg/day atorvastatin. A total of 127 individuals medicated with atorvastatin 10 mg/day/4 weeks were included. Lipid profiles were determined before and after drug administration by conventional assays. Genotyping of the ABCC2 rs717620 SNP (-24C>T) was performed with TaqMan® Drug Metabolism Genotyping Assays. As expected, atorvastatin reduced TC, LDL-C and TG concentrations (p < 0.05). Also, HDL-C levels were increased (p < 0.05). Minor allele frequency for the rs717620 was 0.232. Overall, atorvastatin response was not associated with the ABCC2 rs717620 SNP (p > 0.05). Nonetheless, in male individuals carrying the -24T allele, we observed an attenuated reduction in both TG values and the TG/HDL-C ratio after 10 mg/day atorvastatin. This study indicates that TG levels and the TG/HDL-C ratio are affected by the rs717620 SNP in Chilean males but not female individuals after atorvastatin treatment.

PMID: 29178257 [PubMed - indexed for MEDLINE]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon.

Leuk Res. 2018 Sep 15;74:10-13

Authors: de Carvalho DC, Wanderley AV, Dos Santos AMR, Fernandes MR, Cohen Lima de Castro AN, Leitão LPC, de Carvalho JAN, de Souza TP, Khayat AS, Dos Santos SEB, de Assumpção PP, Dos Santos NPC

Abstract
The treatment of Acute Lymphoblastic Leukemia (ALL) in children has a high clinical success rate, although toxicological complications are frequent, and often result in the interruption of the treatment. Various studies have shown that toxicities resulting from the treatment are influenced by pharmacogenetic variants. Most of this research has focused on relatively homogeneous populations, and the influence of these variants in highly admixed populations, such as that of Brazil, is still poorly understood. The present study investigated the association between pharmacogenetic variants and severe toxicities in pediatric B-cell ALL patients from an admixed population of the Brazilian Amazon. The rs2306283 (of SLCO1B1) mutant allele increased the risk of neurotoxicity threefold, and the homozygous mutant rs9895420 (of ABCC3) genotype was associated with a fivefold increase in protection against severe gastrointestinal toxicity. This indicates that the rs2306283 and rs9895420 polymorphisms may be relevant to the prediction of severe toxicity in pediatric ALL patients.

PMID: 30269037 [PubMed - as supplied by publisher]

Endothelial Colony-Forming Cells Do Not Participate to Fibrogenesis in a Bleomycin-Induced Pulmonary Fibrosis Model in Nude Mice.

Stem Cell Rev. 2018 Sep 28;:

Authors: Blandinières A, Gille T, Sadoine J, Bièche I, Slimani L, Dizier B, Gaussem P, Chaussain C, Planes C, Dorfmüller P, Israël-Biet D, Smadja DM

Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by fibroblast proliferation, extracellular matrix deposition, destruction of pulmonary alveolar architecture and vascular remodeling. Apart pirfenidone or nintendanib that only slow down the fibrotic process, there is no curative treatment other than lung transplantation. Because cell therapy approaches have been proposed in IPF, we hypothesized that injection of endothelial colony-forming cells (ECFCs), the vasculogenic subtype of endothelial progenitor cells, could modulate fibrosis in a Nude mouse model of bleomycin induced-pulmonary fibrosis. Mice were injected with ECFCs isolated from cord blood and from peripheral blood of adult IPF patients at two time-points: during the development of the fibrosis or once the fibrosis was constituted. We assessed morbidity, weight variation, collagen deposition, lung imaging by microCT, Fulton score and microvascular density. Neither ECFCs isolated from cord blood nor from IPF patients were able to modulate fibrosis or vascular density during fibrogenesis or when fibrosis was constituted. These findings indicate that human ECFCs do not promote an adaptive regenerative response in the lung upon fibrosis or angiogenic process in the setting of bleomycin-induced pulmonary fibrosis in Nude mice.

PMID: 30267203 [PubMed - as supplied by publisher]

Ustekinumab in psoriatic arthritis and related phenotypes.

Ther Adv Chronic Dis. 2018 Oct;9(10):191-198

Authors: Dobbin-Sears I, Roberts J, O'Rielly DD, Rahman P

Abstract
Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.

PMID: 30263103 [PubMed]

Homozygosity disequilibrium associated with treatment response and its methylation regulation.

BMC Proc. 2018;12(Suppl 9):45

Authors: Yang HC, Chen CW

Abstract
Homozygosity disequilibrium (HD), indicating a nonrandom pattern of sizable runs of homozygosity that deviates from a random allocation of homozygous and heterozygous genotypes in the genome, is an important phenomenon in population genomics and medical genomics. We performed the first genome-wide study investigating the roles of HD in pharmacogenomics and pharmacoepigenomics by analyzing GAW20 data. We inferred whole-genome profiles of homozygosity intensities and performed genome-wide homozygosity association analyses to identify regions of HD associated with triglyceride (TG) response to fenofibrate by using LOHAS (Loss-of-Heterozygosity Analysis Suite) software. The analysis identified a region of HD contained in MACROD2 at 20p12 to be significantly associated with TG response to fenofibrate. We also examined the common genetic component in TG and methylation responses to fenofibrate. The methylation response to fenofibrate was regarded as a methylation quantitative trait, and our methylation quantitative trait locus analysis identified a cis-acting regulation association with marginal significance between the homozygosity intensity of MACROD2 and the methylation response to fenofibrate. These findings may help delineate the genetic basis of pharmacogenomic and pharmacoepigenomic responses to fenofibrate intervention.

PMID: 30263048 [PubMed]

GAW20: methods and strategies for the new frontiers of epigenetics and pharmacogenomics.

BMC Proc. 2018;12(Suppl 9):26

Authors: Tintle NL, Fardo DW, de Andrade M, Aslibekyan S, Bailey JN, Bermejo JL, Cantor RM, Ghosh S, Melton P, Wang X, MacCluer JW, Almasy L

Abstract
GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.

PMID: 30263042 [PubMed]

Genome-wide enrichment of m6A-associated single-nucleotide polymorphisms in the lipid loci.

Pharmacogenomics J. 2018 Sep 27;:

Authors: Mo X, Lei S, Zhang Y, Zhang H

Abstract
N6-methyladenosine (m6A) plays critical roles in many fundamental biological processes and a variety of diseases. The aim of this study was to investigate the effect of m6A-SNPs on lipid levels. We examined the association of m6A-SNPs with lipid levels in a genome-wide association studies (GWAS) of 188,578 individuals. Furthermore, we performed expression quantitative trait loci and differential expression analyses to add additional information for the identified m6A-SNPs. We found 1,655 m6A-SNPs in the GWAS dataset. Among them, 395 (23.9%) were nominally (P < 0.05) associated with lipid levels, and 22 reached the genome-wide significance level (P < 5.0 × 10-8). Using the fgwas method we found that SNPs, which influence high-density lipoprotein cholesterol (log2 enrichment of 3.35, 95% CI: (0.92, 4.48)) and TG (log enrichment of 3.22, 95% CI: (1.18, 4.44)), were enriched in m6A methylation. The high confidence (determined by miCLIP experiment) m6A-SNP rs6859 at the 3'-untranslated region of PVRL2 was associated with high-density lipoprotein cholesterol (P = 1.21 × 10-15), low-density lipoprotein cholesterol (P = 1.77 × 10-106), total cholesterol (P = 4.82 × 10-82), and triglycerides (P = 8.10 × 10-5) levels, coronary artery disease (P = 0.01), as well as PVRL2 mRNA expression in artery tibial (P = 2.38 × 10-6) and whole blood (P = 5.59 × 10-19). Moreover, PVRL2 was differentially expressed in adipose tissue of familial combined hyperlipidemia (P = 9.27 × 10-4). The present study found plenty of lipid-associated m6A-SNPs and demonstrated that m6A-SNPs may play important roles in lipid metabolisms. Further studies were needed to elucidate the mechanisms.

PMID: 30262821 [PubMed - as supplied by publisher]

Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial.

Diabetes Care. 2018 Sep 27;:

Authors: Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, Hastings T, Buranasupkajorn P, Motsinger-Reif AA, Rotroff DM, Sigal RJ, Marcovina SM, Kraft P, Buse JB, Wagner MJ, Gerstein HC, Mychaleckyj JC, Parè G, Doria A

Abstract
OBJECTIVE: We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk.
RESEARCH DESIGN AND METHODS: A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression.
RESULTS: The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, P = 4 × 10-10, and HR per SD 1.35, 95% CI 1.16-1.58, P = 2 × 10-4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10-4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years.
CONCLUSIONS: When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.

PMID: 30262460 [PubMed - as supplied by publisher]

Differential Expression Profile of MicroRNAs During Prolonged Storage of Platelet Concentrates As a Quality Measurement Tool in Blood Banks.

OMICS. 2018 Sep 27;:

Authors: Maués JHDS, Moreira-Nunes CFA, Pontes TB, Vieira PCM, Montenegro RC, Lamarão LM, Lima EM, Burbano RMR

Abstract
Platelet concentrate (PC) is a key blood component, which even in good storage conditions, susceptible to cellular damage over time. Hence, blood banks discard unused PC bags after 5 days of storage. Biomarkers of PC quality are therefore highly sought after in blood bank governance. We used the data (Gene Expression Omnibus: GSE61856) generated with next-generation sequencing to examine the expression profiles of microRNAs (miRNAs) from PCs that were stored for 6 days in a blood bank, that is, 1 day longer than is normally stored PC. We identified the 14 most differentially expressed miRNAs by comparing a control PC on the first day of storage with the PCs on each of the subsequent 5 days of storage from day 1 to 6. In all, we identified nine miRNAs with the downregulated profile (miR-145-5p, miR-150-5p, miR-183-5p, miR-26a-5p, miR-331-3p, miR-338-5p, miR-451a, miR-501-3p, and miR-99b-5p) and five upregulated miRNAs (miR-1304-3p, miR-411-5p, miR-432-5p, miR-668-3p, and miR-939-5p). These miRNAs were validated by real-time quantitative PCR in 100 PC units. As each PC unit is composed of platelets of five individuals, the validation was thus performed in 500 individuals (250 men and 250 women, comprised 18-40 years old adults). The data were analyzed with hierarchical clustering and principal component analysis, which revealed the variation of mean relative expression and the instability of miRNAs half-life on the fourth day of PC storage, which coincides with time of onset of platelet storage lesions. These new observations can usefully inform future decision-making and governance in blood banks concerning PC quality.

PMID: 30260743 [PubMed - as supplied by publisher]

A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).

Clin Pharmacol Ther. 2018 Sep 27;:

Authors: Rashkin SR, Chua KC, Ho C, Mulkey F, Jiang C, Mushiroda T, Kubo M, Friedman PN, Rugo HS, McLeod HL, Ratain MJ, Castillos F, Naughton M, Overmoyer B, Toppmeyer D, Witte JS, Owzar K, Kroetz DL

Abstract
Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods such as elastic net regularization have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival of 468 advanced breast cancer patients in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 SNPs in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an AUC integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting progression-free survival with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs. This article is protected by copyright. All rights reserved.

PMID: 30260474 [PubMed - as supplied by publisher]

Precision medicine in oncology: what is it exactly and where are we?

Per Med. 2018 Sep 27;:

Authors: Le Tourneau C, Kamal M, Bièche I

PMID: 30260312 [PubMed - as supplied by publisher]