Clinical Utility of Pharmacogenetic Testing and a Clinical Decision Support Tool to Enhance the Identification of Drug Therapy Problems Through Medication Therapy Management in Polypharmacy Patients.

J Manag Care Spec Pharm. 2018 Dec;24(12):1250-1259

Authors: Kim K, Magness JW, Nelson R, Baron V, Brixner DI

Abstract
BACKGROUND: In polypharmacy patients, medication therapy management (MTM) services provide a comprehensive review of current medications and future treatment goals. Pharmacogenetics (PGx) may further optimize the identification of potential drug therapy problems (DTPs); however, the clinical utility of PGx information with a clinical decision support tool (CDST) in an MTM setting in identifying DTPs has not been systematically assessed.
OBJECTIVE: To assess the clinical utility of an MTM service enhanced by pharmacogenetic test results and a clinical decision support tool.
METHODS: This study was a post hoc analysis of the data obtained from an open-label, randomized, observational trial. Polypharmacy patients eligible for MTM service were randomly assigned to 3 intervention arms: standard MTM (SMTM), MTM incorporating CDST (CMTM), and CMTM further enhanced by PGx test results of CYP450 and VKORC1 enzymes (PGxMTM). Allocation for this post hoc analysis was based on patient adherence to the research protocol and completion of a PGx test. The number of DTPs per patient was compared across the 3 arms using analysis of variance. In addition, the frequency of serious DTPs as a categorical variable (grade 3 or above vs. lower grade) was compared across the 3 arms between PGx driven and non-PGx driven DTP recommendations. Statistical significance was tested using the chi-square test. The level of agreement between the DTP seriousness and the acceptance made by prescribers was presented as Cohen's kappa coefficient.
RESULTS: Numbers of patients after cohort reallocation based on completion of PGx testing were 104, 180, and 58 for the SMTM, CMTM, and PGxMTM arms, respectively. On average, 3.08 DTPs were identified for each patient, which was nearly identical across all 3 arms. Blinded clinical pharmacists considered seriousness (grade 3 or 4) in 31% of the PGx-related DTPs in comparison with 4.9% of the non-PGx DTPs (P < 0.001). The more serious (i.e., grade 3 or above) DTP recommendations were more likely to be accepted by prescribers with the odds ratios of 1.95 (P = 0.05) and 2.39 (P = 0.15), when the analysis was performed for all DTPs and DTPs from the PGxMTM arm only, respectively.
CONCLUSIONS: MTM enhanced by PGx testing and the clinical decision support tool did not increase the number of DTPs identified. However, PGx testing and the decision support software helps pharmacists determine more serious DTPs, and resulting subsequent recommendations were more readily accepted by a prescriber. Future study of the patient safety outcomes and overall health care costs associated with the utility of the decision support is warranted.
DISCLOSURES: No funding was received for conducting the post hoc analysis presented in this study. Magness is employed by Magellan Health, which received funding from Genelex for costs to administrate the medication management program. The open-label randomized trial was sponsored by Genelex (Clinicaltrials.gov ID number NCT02428660). PGx tests were provided and laboratory analysis was performed by Genelex. Valerie Baron is an employee of YouScript, which created the clinical decision support tool used in this study and formerly was part of Genelex. The other authors have nothing to disclose.

PMID: 30479202 [PubMed - in process]

Involvement of miRNA polymorphism in mucositis development in childhood acute lymphoblastic leukemia treatment.

Pharmacogenomics. 2018 Dec;19(18):1403-1412

Authors: Gutierrez-Camino Á, Umerez M, Lopez-Lopez E, Santos-Zorrozua B, Martin-Guerrero I, de Andoin NG, Ana S, Navajas A, Astigarraga I, Garcia-Orad A

Abstract
AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk.
PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols.
RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively.
CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.

PMID: 30479191 [PubMed - in process]

Autonomic dysfunction and HPV immunization: an overview.

Immunol Res. 2018 Nov 27;:

Authors: Blitshetyn S, Brinth L, Hendrickson JE, Martinez-Lavin M

Abstract
This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

PMID: 30478703 [PubMed - as supplied by publisher]

Being Overweight or Obese and the Development of Asthma.

Pediatrics. 2018 Nov 26;:

Authors: Lang JE, Bunnell HT, Hossain MJ, Wysocki T, Lima JJ, Finkel TH, Bacharier L, Dempsey A, Sarzynski L, Test M, Forrest CB

Abstract
OBJECTIVES: Adult obesity is linked to asthma cases and is estimated to lead to 250 000 new cases yearly. Similar incidence and attributable risk (AR) estimates have not been developed for children. We sought to describe the relationship between overweight and obesity and incident asthma in childhood and quantify AR statistics in the United States for overweight and obesity on pediatric asthma.
METHODS: The PEDSnet clinical data research network was used to conduct a retrospective cohort study (January 2009-December 2015) to compare asthma incidence among overweight and/or obese versus healthy weight 2- to 17-year-old children. Asthma incidence was defined as ≥2 encounters with a diagnosis of asthma and ≥1 asthma controller prescription. Stricter diagnostic criteria involved confirmation by spirometry. We used multivariable Poisson regression analyses to estimate incident asthma rates and risk ratios and accepted formulas for ARs.
RESULTS: Data from 507 496 children and 19 581 972 encounters were included. The mean participant observation period was 4 years. The adjusted risk for incident asthma was increased among children who were overweight (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.10-1.25) and obese (RR: 1.26; 95% CI: 1.18-1.34). The adjusted risk for spirometry-confirmed asthma was increased among children with obesity (RR: 1.29; 95% CI: 1.16-1.42). An estimated 23% to 27% of new asthma cases in children with obesity is directly attributable to obesity. In the absence of overweight and obesity, 10% of all cases of asthma would be avoided.
CONCLUSIONS: Obesity is a major preventable risk factor for pediatric asthma.

PMID: 30478238 [PubMed - as supplied by publisher]

Distinct expression profiles and functions of Kindlins in breast cancer.

J Exp Clin Cancer Res. 2018 Nov 26;37(1):281

Authors: Azorin P, Bonin F, Moukachar A, Ponceau A, Vacher S, Bièche I, Marangoni E, Fuhrmann L, Vincent-Salomon A, Lidereau R, Driouch K

Abstract
BACKGROUND: Kindlin-1, - 2, and - 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described.
METHODS: To better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n = 58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n = 438) and protein (n = 129) levels and we evaluated their correlation with the clinical outcome.
RESULTS: We determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients' outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients.
CONCLUSION: This study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors. These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression.

PMID: 30477537 [PubMed - in process]

Interaction of the phosphorylated DNA-binding domain in nuclear receptor CAR with its ligand-binding domain regulates CAR activation.

J Biol Chem. 2018 01 05;293(1):333-344

Authors: Shizu R, Min J, Sobhany M, Pedersen LC, Mutoh S, Negishi M

Abstract
The nuclear protein constitutive active/androstane receptor (CAR or NR1I3) regulates several liver functions such as drug and energy metabolism and cell growth or death, which are often involved in the development of diseases such as diabetes and hepatocellular carcinoma. CAR undergoes a conversion from inactive homodimers to active heterodimers with retinoid X receptor α (RXRα), and phosphorylation of the DNA-binding domain (DBD) at Thr-38 in CAR regulates this conversion. Here, we uncovered the molecular mechanism by which this phosphorylation regulates the intramolecular interaction between CAR's DBD and ligand-binding domain (LBD), enabling the homodimer-heterodimer conversion. Phosphomimetic substitution of Thr-38 with Asp increased co-immunoprecipitation of the CAR DBD with CAR LBD in Huh-7 cells. Isothermal titration calorimetry assays also revealed that recombinant CAR DBD-T38D, but not nonphosphorylated CAR DBD, bound the CAR LBD peptide. This DBD-LBD interaction masked CAR's dimer interface, preventing CAR homodimer formation. Of note, EGF signaling weakened the interaction of CAR DBD T38D with CAR LBD, converting CAR to the homodimer form. The DBD-T38D-LBD interaction also prevented CAR from forming a heterodimer with RXRα. However, this interaction opened up a CAR surface, allowing interaction with protein phosphatase 2A. Thr-38 dephosphorylation then dissociated the DBD-LBD interaction, allowing CAR heterodimer formation with RXRα. We conclude that the intramolecular interaction of phosphorylated DBD with the LBD enables CAR to adapt a transient monomer configuration that can be converted to either the inactive homodimer or the active heterodimer.

PMID: 29133527 [PubMed - indexed for MEDLINE]

Humanity in a Dish: Population Genetics with iPSCs.

Trends Cell Biol. 2018 01;28(1):46-57

Authors: Warren CR, Cowan CA

Abstract
Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype. Recent publications have described iPSC cohort studies of common genetic variants and their effects on gene expression and cellular phenotypes. These in vitro quantitative trait locus (QTL) studies are the first experiments in a new paradigm with great potential: iPSC-based functional population genetic studies. iPSC collections from large cohorts are currently under development to facilitate the next wave of these studies, which have the potential to discover the effects of common genetic variants on cellular phenotypes and to uncover the molecular basis of common genetic diseases. Here, we describe the recent advances in this developing field, and provide a road map for future in vitro functional population genetic studies and trial-in-a-dish experiments.

PMID: 29054332 [PubMed - indexed for MEDLINE]

Cancer and mTOR inhibitors in kidney transplantation recipients.

PeerJ. 2018;6:e5864

Authors: Kao CC, Liu JS, Chang YK, Lin MH, Lin YC, Chen HH, Chang WC, Hsu CC, Wu MS

Abstract
Background: Previous studies show that mTOR inhibitors decrease the risk of cancer development after kidney transplantation. However, the effect of cumulative doses of mTOR inhibitors on cancer after kidney transplantation is not well known.
Methods: In the current study, patients were registered into a national database in Taiwan. Between year 2000 and 2013, 4,563 patients received kidney transplantation. They were divided into two groups, according to mTOR inhibitors usage. The cumulative dose of mTOR inhibitors was recorded. Patients were followed-up until de novo cancer development, death, or the end of 2014.
Results: Patients were divided into two groups: mTOR inhibitors users (study group, n = 828) and mTOR inhibitors non-users (control group, n = 3,735). The median follow-up duration was 7.8 years. The risk of de novo cancer (hazards ratio (HR) 0.80, 95% CI [0.60-1.09], p = 0.16) and risk of death (HR 1.14, 95% CI [0.82-1.60], p = 0.43) was not different between mTOR inhibitor user and non-user groups. Neither high- nor low-dose exposure to mTOR inhibitors was associated with increased risk of cancer or mortality. Analysis of cancer subtypes showed no influence by mTOR inhibitors. In addition, the cause of mortality was not significantly different between the two groups.
Discussion: We could not find the association of mTOR inhibitors use and risk of de novo cancer development or mortality in patients with kidney transplantation in Chinese patients. Cumulative exposure to mTOR inhibitors did not change the results.

PMID: 30473931 [PubMed]

Association Between Plasma Caffeine and Other Methylxanthines and Metabolic Parameters in a Psychiatric Population Treated With Psychotropic Drugs Inducing Metabolic Disturbances.

Front Psychiatry. 2018;9:573

Authors: Delacrétaz A, Vandenberghe F, Glatard A, Levier A, Dubath C, Ansermot N, Crettol S, Gholam-Rezaee M, Guessous I, Bochud M, von Gunten A, Conus P, Eap CB

Abstract
Importance: Multiple studies conducted in the general population identified an association between self-reported coffee consumption and plasma lipid levels. To date, no study assessed whether and which plasma methylxanthines (caffeine and/or its metabolites, i.e., paraxanthine, theophylline, and theobromine) are associated with plasma lipids. In psychiatric patients, an important coffee consumption is often reported and many psychotropic drugs can induce a rapid and substantial increase of plasma lipid levels. Objective: To determine whether plasma methylxanthines are associated with metabolic parameters in psychiatric patients receiving treatments known to induce metabolic disturbances. Design, Setting, and Participants: Data were obtained from a prospective study including 630 patients with metabolic parameters [i.e., body mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and fasting triglycerides (TG)] monitored routinely during psychotropic treatment. Exposures: Plasma methylxanthines levels. Main Outcomes and Measures: Metabolic variables including BMI and plasma lipid levels. Results: Multivariate analyses indicated that BMI, TC, HDL-C, and non-HDL-C increased significantly with increasing total methylxanthines (p corrected ≤ 0.05). In addition, compared to patients with plasma caffeine concentration in the lowest quartile, those with caffeine concentration in the highest quartile were twice more prone to suffer from non-HDL hypercholesterolemia (p corrected = 0.05), five times more likely to suffer from hypertriglyceridemia (p corrected = 0.01) and four times more susceptible to be overweight (p corrected = 0.01). Conclusions and Relevance: This study showed that plasma caffeine and other methylxanthines are associated with worsening of metabolic parameters in patients receiving psychotropic treatments known to induce metabolic disturbances. It emphasizes that important caffeine consumption could be considered as an additional environmental risk factor for metabolic worsening in patients receiving such treatments.

PMID: 30473668 [PubMed]

Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial.

JAMA Oncol. 2018 Nov 21;:

Authors: Cremolini C, Rossini D, Dell'Aquila E, Lonardi S, Conca E, Del Re M, Busico A, Pietrantonio F, Danesi R, Aprile G, Tamburini E, Barone C, Masi G, Pantano F, Pucci F, Corsi DC, Pella N, Bergamo F, Rofi E, Barbara C, Falcone A, Santini D

Abstract
Importance: Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA).
Objective: To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy.
Design, Setting, and Participants: Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment.
Interventions: Biweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2.
Main Outcomes and Measures: Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA.
Results: Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03).
Conclusions and Relevance: This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients.
Trial Registration: ClinicalTrials.gov Identifier: NCT02296203.

PMID: 30476968 [PubMed - as supplied by publisher]

Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome.

Hum Reprod. 2018 Nov 24;:

Authors: Maione L, Fèvre A, Nettore IC, Manilall A, Francou B, Trabado S, Bouligand J, Guiochon-Mantel A, Delemer B, Flanagan CA, Macchia PE, Millar RP, Young J

Abstract
STUDY QUESTION: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS.
WHAT IS KNOWN ALREADY: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS.
STUDY DESIGN, SIZE, DURATION: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families.
MAIN RESULTS AND THE ROLE OF CHANCE: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart.
LIMITATIONS, REASONS FOR CAUTION: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here.
WIDER IMPLICATIONS OF THE FINDINGS: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest.

PMID: 30476149 [PubMed - as supplied by publisher]

AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection.

PLoS One. 2018;13(5):e0198221

Authors: Papp AC, Azad AK, Pietrzak M, Williams A, Handelman SK, Igo RP, Stein CM, Hartmann K, Schlesinger LS, Sadee W

Abstract
Human alveolar macrophages (HAM) are primary bacterial niche and immune response cells during Mycobacterium tuberculosis (M.tb) infection, and human blood monocyte-derived macrophages (MDM) are a model for investigating M.tb-macrophage interactions. Here, we use a targeted RNA-Seq method to measure transcriptome-wide changes in RNA expression patterns of freshly obtained HAM (used within 6 h) and 6 day cultured MDM upon M.tb infection over time (2, 24 and 72 h), in both uninfected and infected cells from three donors each. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit (AmpliSeq) uses primers targeting 18,574 mRNAs and 2,228 non-coding RNAs (ncRNAs) for a total of 20,802 transcripts. AmpliSeqTM yields highly precise and reproducible gene expression profiles (R2 >0.99). Taking advantage of AmpliSeq's reproducibility, we establish well-defined quantitative RNA expression patterns of HAM versus MDM, including significant M.tb-inducible genes, in networks and pathways that differ in part between MDM and HAM. A similar number of expressed genes are detected at all time-points between uninfected MDM and HAM, in common pathways including inflammatory and immune functions, but canonical pathway differences also exist. In particular, at 2 h, multiple genes relevant to the immune response are preferentially expressed in either uninfected HAM or MDM, while the HAM RNA profiles approximate MDM profiles over time in culture, highlighting the unique RNA expression profile of freshly obtained HAM. MDM demonstrate a greater transcriptional response than HAM upon M.tb infection, with 2 to >10 times more genes up- or down-regulated. The results identify key genes involved in cellular responses to M.tb in two different human macrophage types. Follow-up bioinformatics analysis indicates that approximately 30% of response genes have expression quantitative trait loci (eQTLs in GTEx), common DNA variants that can influence host gene expression susceptibility or resistance to M.tb, illustrated with the TREM1 gene cluster and IL-10.

PMID: 29847580 [PubMed - indexed for MEDLINE]

Activation of Constitutive Androstane Receptor Ameliorates Renal Ischemia-Reperfusion-Induced Kidney and Liver Injury.

Mol Pharmacol. 2018 03;93(3):239-250

Authors: Choi YJ, Zhou D, Barbosa ACS, Niu Y, Guan X, Xu M, Ren S, Nolin TD, Liu Y, Xie W

Abstract
Acute kidney injury (AKI) is associate with high mortality. Despite evidence of AKI-induced distant organ injury, a relationship between AKI and liver injury has not been clearly established. The goal of this study is to investigate whether renal ischemia-reperfusion (IR) can affect liver pathophysiology. We showed that renal IR in mice induced fatty liver and compromised liver function through the downregulation of constitutive androstane receptor (CAR; -90.4%) and inhibition of hepatic very-low-density lipoprotein triglyceride (VLDL-TG) secretion (-28.4%). Treatment of mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) prevented the development of AKI-induced fatty liver and liver injury, which was associated with the attenuation of AKI-induced inhibition of VLDL-TG secretion. The hepatoprotective effect of TCPOBOP was abolished in CAR-/- mice. Interestingly, alleviation of fatty liver by TCPOBOP also improved the kidney function, whereas CAR ablation sensitized mice to AKI-induced kidney injury and lethality. The serum concentrations of interleukin-6 (IL-6) were elevated by 27-fold after renal IR, but were normalized in TCPOBOP-treated AKI mice, suggesting that the increased release of IL-6 from the kidney may have mediated the AKI responsive liver injury. Taken together, our results revealed an interesting kidney-liver organ cross-talk in response to AKI. Given the importance of CAR in the pathogenesis of renal IR-induced fatty liver and impaired kidney function, fatty liver can be considered as an important risk factor for kidney injury, and a timely management of hepatic steatosis by CAR activation may help to restore kidney function in patients with AKI or kidney transplant.

PMID: 29351922 [PubMed - indexed for MEDLINE]

Identification and validation of potential target genes in papillary thyroid cancer.

Eur J Pharmacol. 2018 Nov 22;:

Authors: Zhang K, Liu J, Li C, Peng X, Li H, Li Z

Abstract
Thyroid cancer (TC) is one of the most common endocrine malignancies, and the incidence of TC has almost tripled over the past three decades. This increase may partially own to overdiagnosis and approximately 15% to 30% of cytological indeterminate thyroid nodules cannot be evaluated by means of fine-needle aspiration. The present study aimed to identify potential crucial genes of PTC and provide new sights into improving the diagnosis of thyroid lesions for future study. We adopted an integrated analysis of Gene expression profiles of PTC patients and adjacent normal controls and data from The Cancer Genome Atlas databases (TCGA). The differentially expressed genes (DEGs) were screened using the Limma package in R software. Connectivity Map (CMap) was used to predict potential drugs for PTC. STRING and Cytoscape software were employed to perform GO, KEGG pathway enrichment analysis and module analysis for DEGs. RT-qPCR was used to validate hub genes screened using module analysis. A total of 218 DEGs were screened, including 55 down-regulated and 163 up-regulated DEGs. GO analysis showed that these DEGs were primary enriched in cell adhesion, extracellular region and glycosaminoglycan binding. KEGG pathway analysis revealed that DEGs primarily participated in ECM-receptor interaction. PPI network and module analysis identified seven-hub genes, including FN1, SERPINA1, ECM1, MMRN1, PROS1, CFD, TIMP1. RT-qPCR results validated that the expression levels of seven-hub genes were consistent with the bioinformatics analysis. These findings have identified seven-hub genes which may helpful for the development of gene panel for thyroid nodules diagnosis.

PMID: 30472204 [PubMed - as supplied by publisher]

Glutathione S-transferase M1 and T1 null allele frequencies among Indonesian ethnics toward improved disease risk assessment.

Environ Toxicol Pharmacol. 2018 Nov 02;65:14-17

Authors: Prayuni K, Razari I, Yuliwulandari R

Abstract
Genetic variations in the glutathione S-transferase genes GSTT1 and GSTM1 have been widely studied, and homozygous deletions or null genotypes have been reported in different populations. Previous studies suggest that individuals who are homozygous-null at the GSTM1 or GSTT1 locus may have an increased risk of environmentally related cancers and drug-induced hepatotoxicity. The aim of the present study was to determine the GSTM1 and GSTT1 polymorphisms in 154 healthy, unrelated individuals from the Javanese-Sundanese and Malay ethnic populations of Indonesia to provide a resource for improving the prognosis of possible susceptibilities in specific populations. The subjects were genotyped for the presence of GSTM1 and GSTT1 using the multiplex polymerase chain reaction technique. The GSTM1-null genotype was more frequent among Javanese-Sundanese ethnics (99%) than among the Indonesian Malay (67.2%). Similarly, Javanese-Sundanese ethnics showed a higher frequency of the GSTT1-null genotype (66.7%) than the Indonesian Malay (36.2%). Analysis of the combined distribution of the GSTM1 and GSTT1 genes revealed that 66.7% of the individuals from the Javanese-Sundanese population lack both the genes, whereas only 21.1% of the Indonesian Malay is GSTM1-null and GSTT1-null. This study contributes significant information on the variability of GSTT1 and GSTM1 gene polymorphisms worldwide, which can provide new knowledge about the relationship between ethnicity and the prevalence of certain diseases.

PMID: 30471640 [PubMed - as supplied by publisher]

Pharmacogenetics of artemether-lumefantrine influence on nevirapine disposition: clinically significant drug-drug interaction?

Br J Clin Pharmacol. 2018 Nov 24;:

Authors: Abdullahi ST, Olagunju A, Soyinka JO, Bolarinwa RA, Olarewaju OJ, Bakare-Odunola MT, Owen A, Khoo S

Abstract
AIMS: In this study the influence of first-line antimalarial drug artemether-lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients.
METHODS: This was a two-period, single sequence crossover study conducted in two stages. In stage 1, 150 HIV-infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for 7 SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorised as poor, intermediate and extensive metabolisers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine and intensive pharmacokinetic sampling was conducted on day 3.
RESULTS: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3,400 ng ml-1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolisers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolisers).
CONCLUSIONS: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolisers when nevirapine is co-administered with artemether-lumefantrine.

PMID: 30471138 [PubMed - as supplied by publisher]

The pivotal oncogenic role of Jab1/CSN5 and its therapeutic implications in human cancer.

Gene. 2018 Nov 20;:

Authors: Guo Z, Wang Y, Zhao Y, Shu Y, Liu Z, Zhou H, Wang H, Zhang W

Abstract
Jab1/CSN5 is a conserved multifunctional protein involved in ubiquitin-mediated protein degradation. Deregulation of Jab1/CSN5 can exert dramatic effects on diverse cellular functions, including DNA repair, cell cycle control, apoptosis, angiogenesis, and signal transduction, all of which are critical for tumor development. Although increasing evidence has demonstrated that Jab1/CSN5 was overexpressed in a variety of human cancers and usually correlated with poor prognosis, little was known about the underlying regulatory principles that coordinated its function. In this review, we highlight recent advances of the oncogenic role of Jab1/CSN5 and its potential as a therapeutic target for anticancer intervention.

PMID: 30468907 [PubMed - as supplied by publisher]

The Case for Pharmacogenetics-Guided Prescribing of Codeine in Children.

Clin Pharmacol Ther. 2018 Nov 22;:

Authors: Gammal RS, Caudle KE, Quinn CT, Wang WC, Gaedigk A, Prows CA, Haidar CE, Taylor AK, Klein TE, Sangkuhl K, Hankins JS, Crews KR

PMID: 30467830 [PubMed - as supplied by publisher]

Exogenous Factors May Differentially Influence the Selective Costs of mtDNA Mutations.

Adv Anat Embryol Cell Biol. 2018 Nov 23;:

Authors: Aw WC, Garvin MR, Ballard JWO

Abstract
In this review, we provide evidence to suggest that the cost of specific mtDNA mutations can be influenced by exogenous factors. We focus on macronutrient-mitochondrial DNA interactions as factors that may differentially influence the consequences of a change as mitochondria must be flexible in its utilization of dietary proteins, carbohydrates, and fats. To understand this fundamental dynamic, we briefly discuss the energy processing pathways in mitochondria. Next, we explore the mitochondrial functions that are initiated during energy deficiency or when cells encounter cellular stress. We consider the anterograde response (nuclear control of mitochondrial function) and the retrograde response (nuclear changes in response to mitochondrial signaling) and how this mito-nuclear crosstalk may be influenced by exogenous factors such as temperature and diet. Finally, we employ Complex I of the mitochondrial electron transport system as a case study and discuss the potential role of the dietary macronutrient ratio as a strong selective force that may shape the frequencies of mitotypes in populations and species. We conclude that this underexplored field likely has implications in the fundamental disciplines of evolutionary biology and quantitative genetics and the more biomedical fields of nutrigenomics and pharmacogenomics.

PMID: 30467693 [PubMed - as supplied by publisher]

Qualitative study of system-level factors related to genomic implementation.

Genet Med. 2018 Nov 23;:

Authors: Zebrowski AM, Ellis DE, Barg FK, Sperber NR, Bernhardt BA, Denny JC, Dexter PR, Ginsburg GS, Horowitz CR, Johnson JA, Levy MA, Orlando LA, Pollin TI, Skaar TC, Kimmel SE

Abstract
PURPOSE: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects.
METHODS: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs.
RESULTS: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement.
CONCLUSION: Implementation of genomic medicine is hindered by several system-level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice.

PMID: 30467402 [PubMed - as supplied by publisher]