Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers.

Front Genet. 2018;9:721

Authors: Zhang S, Li Z, Yan X, Bao L, Deng Y, Zeng F, Wang P, Zhu J, Yin D, Liao F, Zhou X, Zhang D, Xia X, Wang H, Yang X, Zhang W, Gao H, Zhang W, Yang L, Hou Q, Xu H, Zhang Y, Shu Y, Wang Y

Abstract
Germline variants of PIP4K2A impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of PIP4K2A in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of PIP4K2A and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with PIP4K2A expression in ALL patients, with known cancer-related genes rankings the top (e.g., RAC2, RBL2, and TFDP1). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. PIP4K2A is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, PIP4K2A and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival (p < 0.05). Our findings reveal the transcriptional regulatory network of PIP4K2A in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.

PMID: 30697230 [PubMed]

The Role of the Pediatric Pharmacist in Precision Medicine and Clinical Pharmacogenomics for Children.

J Pediatr Pharmacol Ther. 2018 Nov-Dec;23(6):499-501

Authors: Brown JT, Gregornik D, Kennedy MJ, Advocacy and Research Committees

Abstract
With the initiatives by the National Institutes of Health and the US Food and Drug Administration, pharmacogenomics is transitioning from the laboratory to patient care. Nearly 200 drug products now contain pharmacogenomic information as part of their labeling; many of these products are commonly used in the pediatric population. Because pharmacogenomic testing can provide patient-specific predictors for drug response, pharmacists are positioned to assume a leadership role in pharmacogenomic testing, clinical interpretation of results, and recommendations for individualization of drug therapy. Opportunities for pharmacists exist in both inpatient and outpatient settings, such as pharmacist-managed clinical pharmacogenomics consultation services and educating patients and families about pharmacogenomic testing. Given the potential for genetic and age-dependent factors to influence drug selection and dosing, pediatric pharmacists should be involved in the development of dosing recommendations and interprofessional practice guidelines regarding pharmacogenomic testing in pediatric patients. Opportunities to become knowledgeable and competent in pharmacogenomics extend from coursework as part of the pharmacy curriculum to postgraduate education (e.g., residencies, fellowship, continuing education). The Pediatric Pharmacy Advocacy Group acknowledges a need for increased education of both students and practicing pharmacists with consideration for infants and children.

PMID: 30697138 [PubMed]

Safety and Pharmacokinetics of Standardized Extract of Centella asiatica (ECa 233) Capsules in Healthy Thai Volunteers: A Phase 1 Clinical Study.

Planta Med. 2019 Jan 30;:

Authors: Songvut P, Chariyavilaskul P, Tantisira MH, Khemawoot P

Abstract
The aim of this study was to investigate the safety and pharmacokinetic profiles of a newly developed, standardized extract of Centella asiatica (ECa 233) capsule in healthy Thai volunteers. This study was designed as an open-labeled, 2-sequence dosage, single- and repeated-dose study investigated under fasting conditions. Plasma concentrations of the parent compounds and their relative acid metabolites were measured and pharmacokinetic parameters were calculated using noncompartmental analysis. Tolerability was assessed based on physical examinations, monitoring of vital signs, clinical laboratory tests, and any observed adverse events. A key finding of this study was that the pharmacokinetics of ECa 233 in healthy volunteers did not correspond with its pharmacokinetics in animal studies. As indicated in human pharmacokinetic parameters, maximum plasma concentration and area under the curve of the parent compounds (madecassoside and asiaticoside) were very low, while their respective metabolites (madecassic acid and asiatic acid) demonstrated higher values. Based on the pharmacokinetic results observed in the dose comparison, accumulation of active metabolites after repeated dose is highly suggestive. In addition, the asiatic acid profile showed 2-fold increase in Cmax and AUC(0-t) after increasing dose from 250 to 500 mg of ECa 233. Lastly, the safety and tolerability evaluation illustrated that single and multiple doses in both 250 and 500 mg oral administration of ECa 233 were well tolerated, and none of the volunteers discontinued their participation due to adverse effects during the study.

PMID: 30699457 [PubMed - as supplied by publisher]

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.

Clin Exp Allergy. 2019 Jan 29;:

Authors: Hernandez-Pacheco N, Farzan N, Francis B, Karimi L, Repnik K, Vijverberg SJ, Soares P, Schieck M, Gorenjak M, Forno E, Eng C, S Oh S, Pérez-Méndez L, Berce V, Tavendale R, Samedy LA, Hunstman S, Hu D, Meade K, Farber HJ, Avila PC, Serebrisky D, Thyne SM, Brigino-Buenaventura E, Rodriguez-Cintron W, Sen S, Kumar R, Lenoir M, Rodriguez-Santana JR, Celedón JC, Mukhopadhyay S, Potočnik U, Pirmohamed M, Verhamme KM, Kabesch M, Palmer CNA, Hawcutt DB, Flores C, van der Zee AHM, Burchard EG, Pino-Yanes M

Abstract
BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.
OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS, and to validate previous GWAS findings.
METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1,347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analyzing 8.7 million genetic variants. Those with p≤5x10-6 were followed up for replication in 1,697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.
RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (p≤5x10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, p = 7.52x10-3 ) and was also associated with change in lung function after treatment with ICS (p = 4.91x10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.
CONCLUSIONS & CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment. This article is protected by copyright. All rights reserved.

PMID: 30697902 [PubMed - as supplied by publisher]

Adenylate kinase 4 modulates oxidative stress and stabilizes HIF-1α to drive lung adenocarcinoma metastasis.

J Hematol Oncol. 2019 Jan 29;12(1):12

Authors: Jan YH, Lai TC, Yang CJ, Lin YF, Huang MS, Hsiao M

Abstract
BACKGROUND: Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear.
METHODS: Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer.
RESULTS: We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer.
CONCLUSIONS: Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.

PMID: 30696468 [PubMed - in process]

Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy.

IUBMB Life. 2018 03;70(3):183-191

Authors: Li YQ, Yin JY, Liu ZQ, Li XP

Abstract
Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression. We also discuss the possible mechanisms of platinum drug resistance mediated by ATP7A/7B and provide novel strategies for overcoming resistance. This review may be helpful for understanding the roles of ATP7A and ATP7B in platinum drug resistance. © 2018 IUBMB Life, 70(3):183-191, 2018.

PMID: 29394468 [PubMed - indexed for MEDLINE]

Severe reduction in tacrolimus concentrations with concomitant metamizole (dipyrone) therapy in transplant patients.

Eur J Clin Pharmacol. 2019 Jan 29;:

Authors: Sigaroudi A, Jetter A, Mueller TF, Kullak-Ublick G, Weiler S

Abstract

PMID: 30694339 [PubMed - as supplied by publisher]

Incidental Pharmacogenetics Findings in an HLA-related Research: Considerations for Primary Prevention.

Clin Exp Allergy. 2019 Jan 28;:

Authors: Bakhtiar F, Too CL, Tang MM, Sulaiman S, Tan LK, Ahmad-Fauzi NA, Kwok FY, Murad S, Rayyapa GC

Abstract
Hypersensitivity drug reactions (HDRs) are an immense public health problem where significant proportions may lead to mortality. HDRs can manifest in various phenotypes, mainly cutaneous reactions that range from the mild; i.e. exanthem, urticaria, and angioedema to the critical; i.e. severe cutaneous adverse reactions (SCARs). SCARs are life-threatening reactions that include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and less commonly, acute generalized exanthematous pustulosis (AGEP). Previously, these reactions were unavoidable as they are linked to the intrinsic properties of drugs and an individual's genetic predisposition. Nevertheless, with the advent of pharmacogenomics and the vast pharmacogenetic studies performed in the last two decades, this is set to change in future. This article is protected by copyright. All rights reserved.

PMID: 30693574 [PubMed - as supplied by publisher]

An LC-MS/MS method for quantification of abiraterone, its active metabolites D(4)-abiraterone (D4A) and 5α-abiraterone, and their inactive glucuronide derivatives.

J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Jan 01;1104:249-255

Authors: Caron P, Turcotte V, Lévesque E, Guillemette C

Abstract
Abiraterone acetate (AA) is a prodrug of abiraterone, a selective and potent steroidal cytochrome P450 17alpha- hydroxylase-17,20-lyase (CYP17A1) blocking androgen synthesis in the treatment of advanced prostate cancer. Abiraterone (Abi) is metabolized to D(4)-abiraterone (D4A) directly blocking CYP17A1 and other steroidogenic enzymes and antagonizing the androgen receptor (AR). D4A is converted by 5α-reductase to 3-keto-5α-abiraterone (5α-Abi), an AR agonist. Our recent work suggests phase II biotransformation of Abi, D4A and 5α-Abi conjugated to glucuronic acid in vitro leading to four glucuronides (G). We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a 6500 Qtrap mass analyzer coupled with a Shimadzu Nexera system for quantification of Abi, its active metabolites and their G derivatives in human plasma samples with deuterated internal standards. Validation was carried out according to FDA guidelines for bioanalytical method and results were within the acceptance limits. Analytes were extracted from 50 μL of plasma using a solid phase extraction procedure. Multiple reaction monitoring was used with electrospray ionization in a positive mode. Linearity, precision, and accuracy were validated over a large range of concentrations for each compound (range of 0.5-100 ng/mL for Abi and for metabolites and 0.05-10.00 ng/mL for glucuronides). The method could measure all seven analytes with sensitivity, accuracy (87-106%), and reproducibility (CV < 10.7%). Its clinical application was further examined with plasma samples obtained from prostate cancer patients under AA treatment. This reliable and validated LC-MS/MS method could be a useful tool for human biomonitoring studies.

PMID: 30537624 [PubMed - indexed for MEDLINE]

The GRK2 Promoter Is Regulated by Early-Growth Response Transcription Factor EGR-1.

Basic Clin Pharmacol Toxicol. 2018 Dec;123(6):660-669

Authors: Klenke S, Engler A, Ecker D, Ochsenfarth C, Danowski N, Peters J, Siffert W, Frey UH

Abstract
The G-protein-coupled receptor kinase 2 (GRK2) plays a major role in cardiovascular diseases, and its expression is increased in heart failure. However, only little is known about factors being involved in up-regulation of GRK2 expression through transcriptional regulation of its promoter. Since the transcription factor early-growth response 1 (EGR-1) is also up-regulated in patients with heart failure, we tested the hypothesis that EGR-1 regulates GRK2 transcription. Stimulation of immortalized rat cardiomyocytes (H9c2) with phorbol 12-myristate 13-acetate (PMA) resulted in up-regulation of Egr-1 and subsequently of Grk2 mRNA expression, with maximum Grk2 expression (p = 0.008) 5 hr after PMA stimulation and being abolished by actinomycin D, indicating a transcriptional mechanism. To identify naturally occurring variants affecting promoter transcriptional activity, we identified a novel G(-43)A polymorphism (rs182084609), which surrounded a putative EGR-1-binding site. While the minor A allele frequency was rare (0.02), this variant was used to explore regulation by EGR-1 and promoter construct with altered alleles at nt-43 were subjected of reporter assays in human embryonic kidney cells (Hek293). Here, EGR-1 over-expression resulted in a more than twofold increase in GRK2 promoter activity but only in the presence of the G-allele (p = 0.04). In electrophoretic mobility shift assays, EGR-1 over-expression resulted in a specific binding of transcription factors only to the G oligonucleotide. Finally, EGR-1 over-expression resulted in increased GRK2 mRNA expression (p = 0.03). We identified EGR-1 as a regulator of GRK2 transcription. Suppression of GRK2 expression by inhibition of EGR-1 binding to GRK2 might be a promising approach to mitigate adrenergic desensitization.

PMID: 29905975 [PubMed - indexed for MEDLINE]

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G-CSF administration favours SDF-1 release and activation of neutrophils and monocytes in recipients of autologous peripheral blood progenitor cells.

Cytokine. 2019 Jan 24;116:38-47

Authors: Gębura K, Butrym A, Chaszczewska-Markowska M, Wróbel T, Kuliczkowski K, Bogunia-Kubik K

Abstract
G-CSF is a growth factor widely used to mobilise CD34+ progenitor cells for clinical applications. The present study aimed to assess expression of G-CSF receptor (CSF3R) on neutrophils and monocytes, as well as SDF-1 and G-CSF serum levels in relation to efficacy of G-CSF-induced mobilisation for autologous transplantation. For this purpose, 105 patients with haematological disorders and 46 healthy controls were investigated. Before mobilisation patients were characterised with significantly higher percentage of CSF3R expressing neutrophils (p < 0.001) and monocytes (p = 0.002), than controls. G-CSF administration resulted in a decrease of CSF3R+ neutrophils (p < 0.001) and monocytes (p < 0.001), while presence of G-CSF receptor on neutrophils tended to negatively affect mobilisation yield (p = 0.075). G-CSF concentration increased during mobilisation (p < 0.001). On the 5th day of mobilisation a positive correlation was observed between G-CSF and SDF-1 serum levels (p < 0.001) and the number of CD34+ cells released from bone marrow seemed to be related to both G-CSF (p = 0.036) and SDF-1 levels (p = 0.084). As compared to Hodgkin's lymphoma patients, those with multiple myeloma had lower basal percentage of CSF3R+ neutrophils (p = 0.014) while Non-Hodgkin's lymphoma cases exhibited higher G-CSF (p = 0.026) and SDF-1 (p = 0.006) concentration on mobilisation day 5. Hodgkin's lymphoma patients were also characterised with worse mobilisation efficacy than multiple myeloma (p = 0.022) and Non-Hodgkin's lymphoma (p = 0.013) patients. These results suggest that both SDF-1 and G-CSF play a role in HSC release into peripheral blood and show that G-CSF administration affects expression of CSF3R on monocytes and neutrophils, implying potential role of these cell subpopulations in mobilisation process.

PMID: 30685602 [PubMed - as supplied by publisher]

Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors.

Cancer Treat Rev. 2019 Jan 19;74:21-28

Authors: Fogli S, Del Re M, Curigliano G, van Schaik RH, Lancellotti P, Danesi R

Abstract
CDK4/6 inhibitors are a new class of anticancer drugs used for the treatment of women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Polypharmacy is a well-known problem in advanced cancer causing potential drug-drug interactions (DDIs), which, in turn, may limit the therapeutic value of CDK4/6 inhibitors. Therefore, understanding the mechanisms underlying potential DDIs in patients taking CDK4/6 inhibitors may be useful in decision-making processes and represent an important step towards treatment personalization. The present review is aimed at describing the potential DDIs that might occur in breast cancer patients receiving CDK4/6 inhibitors based on direct evidence from the literature and mechanistic considerations tailored on specific class of drugs used in combination.

PMID: 30685576 [PubMed - as supplied by publisher]

Prediction of drug response and adverse drug reactions: From twin studies to Next Generation Sequencing.

Eur J Pharm Sci. 2019 Jan 23;:

Authors: Lauschke VM, Ingelman-Sundberg M

Abstract
Understanding and predicting inter-individual differences related to the success of drug therapy is of tremendous importance, both during drug development and for clinical applications. Importantly, while seminal twin studies indicate that the majority of inter-individual differences in drug disposition are driven by hereditary factors, common genetic polymorphisms explain only less than half of this genetically encoded variability. Recent progress in Next Generation Sequencing (NGS) technologies has for the first time allowed to comprehensively map the genetic landscape of human pharmacogenes. Importantly, these projects have unveiled vast numbers of rare genetic variants, which are estimated to contribute substantially to the missing heritability of drug metabolism phenotypes. However, functional interpretation of these rare variants remains challenging and constitutes one of the important frontiers of contemporary pharmacogenomics. Furthermore, NGS technologies face challenges in the interrogation of genes residing in complex genomic regions, such as CYP2D6 and HLA genes. We here provide an update of the implementation of pharmacogenomic variations in the clinical setting and present emerging strategies that facilitate the translation of NGS data into clinically useful information. Importantly, we anticipate that these developments will soon result in a paradigm shift of pre-emptive genotyping away from the interrogation to candidate variants and towards the comprehensive profiling of an individuals genotype, thus allowing for a true individualization of patient drug treatment regimens.

PMID: 30684656 [PubMed - as supplied by publisher]

ADRB2 p.Thr164Ile association with hospitalization depends upon asthma severity.

J Allergy Clin Immunol. 2019 Jan 22;:

Authors: Condreay LD, Chiano MN, Li L, Harris E, Fraser DJ, Meyers DA, Bleecker ER, Crim C, Stempel D, Yancey SW, Ghosh S

Abstract
In LABA-treated patients, the ADRB2 p.Thr164Ile only associate with asthma exacerbation risk in some patients with severe asthma but is not predictive of asthma exacerbation risk in all asthmatics.

PMID: 30682460 [PubMed - as supplied by publisher]

ARL15 overexpression attenuates high glucose-induced impairment of insulin signaling and oxidative stress in human umbilical vein endothelial cells.

Life Sci. 2019 Jan 22;:

Authors: Shen J, Liu M, Xu J, Sun B, Xu H, Zhang W

Abstract
AIMS: Endothelial dysfunction (ED) plays a pivotal role in the development and progression of cardiovascular disease. Recently, genomic studies have found that ARL15, and some of its common genetic variants are associated with type 2 diabetes and coronary atherosclerosis. Since, the function of ARL15 is unclear we aimed at investigating the role of ARL15 in ED induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs).
MAIN METHODS: Quantitative real-time PCR was used to access the mRNA expression of ARL15. After exposure to different glucose media, nitric oxide (NO) production and the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS) were studied. The underlying signaling pathway was also examined by western blot.
KEY FINDINGS: Up-regulation of ARL15 attenuates HG-induced impairment in HUVECs. With insulin-stimulation, NO production and the active phosphorylation of the IR/IRS1/AKT/eNOS pathway were significantly increased. ARL15 overexpression was found to decrease the ROS and MDA production and increase SOD level. It could also reduce ERK1/2-Thr183-Tyr185 phosphorylation, NOX2 and NOX4 expression in HG medium.
SIGNIFICANCE: These results suggest that ARL15 could significantly alleviate the dysfunction of HUVECs induced by HG. Our findings help to identify new potential protective effects of ARL15 in HG-induced endothelial impairment.

PMID: 30682341 [PubMed - as supplied by publisher]

Effects of coagulation factor VII polymorphisms on warfarin sensitivity and responsiveness in Jordanian cardiovascular patients during the initiation and maintenance phases of warfarin therapy.

Pharmgenomics Pers Med. 2019;12:1-8

Authors: Al-Eitan LN, Almasri AY, Al-Habahbeh SO

Abstract
Purpose: This study aims to investigate the relationships between genetic polymorphisms of the coagulation factor VII (FVII) gene and warfarin responsiveness and sensitivity.
Patients and methods: The study population consisted of 417 subjects (207 Jordanian cardiovascular patients and 210 healthy individuals). Cardiovascular patients were classified into two groups: those sensitive to warfarin dosage (sensitive, moderate, and resistant) and those responsive to warfarin based on International Normalized Ratios (INRs; poor, good, and extensive responders). The HVR4 polymorphism of the FVII gene was genotyped.
Results: Our results showed that there are significant differences between patients and controls according to both genotypic and allelic frequencies (P<0.0001) in the genetic susceptibility study. Moreover, the pharmacogenetics study reported that HVR4 had no association with warfarin sensitivity or responsiveness during the initiation and maintenance phases of therapy, the only significant differences were in the INR outcome measured during the maintenance phase of therapy (P=0.012).
Conclusion: Our data suggests lacking of association between the HVR4 polymorphism in the FVII gene and warfarin sensitivity and responsiveness during the initiation and maintenance phases of therapy. It is possible that these patients carry additional mutations in genes involved in the coagulation pathway.

PMID: 30679919 [PubMed]

Fish Oil Supplementation in Overweight/Obese Patients with Uncontrolled Asthma: A Randomized Trial.

Ann Am Thorac Soc. 2019 Jan 25;:

Authors: Lang JE, Mougey EB, Hossain MJ, Livingston F, Balagopal PB, Langdon S, Lima JJ

Abstract
RATIONALE: Omega-3 fatty acid (n3PUFA) supplementation has been proposed as a promising anti-asthma strategy. The rs59439148 ALOX5 polymorphism affects leukotriene production and possibly inflammatory responses to n3PUFA.
OBJECTIVE: Assess the effects of n3PUFA supplementation and ALOX5 genotype on asthma control in patients with obesity and uncontrolled asthma.
METHODS: This multi-center trial among 12-25 year olds with overweight/obesity and uncontrolled asthma randomized subjects in a 3:1 allotment to n3PUFA (4g/day) or soy oil control for 24 weeks. Asthma Control Questionnaire (ACQ) was the primary outcome; secondary outcomes included blood leukocyte n3PUFA levels, urinary leukotriene-E4 (uLTE4), spirometry, and asthma-related events. The number of SP1 tandem repeats in rs59439148 determined ALOX5 genotype status. Simple and multivariable generalized linear models assessed effects on outcomes.
RESULTS: Ninety-eight participants were randomized (77 to PUFA, 21 to control), and > 86% completed all visits. Asthma and demographic characteristics were similar among treatment groups. N3PUFA treatment increased n3-to-n6PUFA ratio in granulocytes (p=0.003) and monocytes (p=0.002), but did not affect mean (95% CI) ACQ change at 6 months (N3PUFA: -0.09 (-.09, .10) vs. control: -0.18 (-.42, .06), p=0.58). Changes in uLTE (p=0.24), FEV1 percent predicted (p=0.88) and exacerbations (RR=0.92, 95% CI 0.30-2.89) at 6 months were similar in both groups. N3PUFA-treatment was associated with reduced asthma-related phone contacts (RR=0.34, 95% CI 0.13-0.86, p=0.02). ALOX5 genotype did not affect n3PUFA treatment responses.
CONCLUSION: We did not find evidence that n3PUFA use improves most asthma-related outcomes and cannot recommend it as a prevention strategy for overweight/obese patients with asthma. Clinical trial registered with ClinicalTrials.gov (NCT01027143).

PMID: 30678465 [PubMed - as supplied by publisher]

Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis.

Int J Cancer. 2018 10 15;143(8):1943-1953

Authors: Huang RL, Chen HJ, Chen LY, Chao TK, Lin WY, Liew PL, Su PH, Weng YC, Wang YC, Liao CC, Hsu YW, Wang HC, Lai HC

Abstract
Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high-methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL-6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3-O-sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.

PMID: 29732534 [PubMed - indexed for MEDLINE]

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study.

J Psychiatr Res. 2019 Jan 04;111:59-67

Authors: Greden JF, Parikh SV, Rothschild AJ, Thase ME, Dunlop BW, DeBattista C, Conway CR, Forester BP, Mondimore FM, Shelton RC, Macaluso M, Li J, Brown K, Gilbert A, Burns L, Jablonski MR, Dechairo B

Abstract
Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial - a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent ('use as directed' or 'use with caution' test categories) or incongruent ('use with increased caution and with more frequent monitoring' test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement [change in 17-item Hamilton Depression Rating Scale (HAM-D17)] at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).

PMID: 30677646 [PubMed - as supplied by publisher]