Mycoplasma hyorhinis reduces sensitivity of human lung carcinoma cells to Nutlin-3 and promotes their malignant phenotype.

J Cancer Res Clin Oncol. 2018 May 08;:

Authors: Boyarskikh UA, Shadrina AS, Smetanina MA, Tsepilov YA, Oscorbin IP, Kozlov VV, Kel AE, Filipenko ML

Abstract
PURPOSE: MDM2 inhibitors are promising anticancer agents that induce cell cycle arrest and tumor cells death via p53 reactivation. We examined the influence of Mycoplasma hyorhinis infection on sensitivity of human lung carcinoma cells NCI-H292 to MDM2 inhibitor Nutlin-3. In order to unveil possible mechanisms underlying the revealed effect, we investigated gene expression changes and signal transduction networks activated in NCI-H292 cells in response to mycoplasma infection.
METHODS: Sensitivity of NCI-Н292 cells to Nutlin-3 was estimated by resazurin-based cell viability assay. Genome-wide transcriptional profiles of NCI-H292 and NCI-Н292Myc.h cell lines were determined using Illumina Human HT-12 v3 Expression BeadChip. Search for key transcription factors and key node molecules was performed using the geneXplain platform. Ability for anchorage-independent growth was tested by soft agar colony formation assay.
RESULTS: NCI-Н292Myc.h cells were shown to be 1.5- and 5.2-fold more resistant to killing by Nutlin-3 at concentrations of 15 and 30 µM than uninfected NCI-Н292 cells (P < 0.05 and P < 0.001, respectively). Transcriptome analysis revealed differential expression of multiple genes involved in cancer progression and metastasis as well as epithelial-mesenchymal transition (EMT). Moreover, we have shown experimentally that NCI-Н292Myc.h cells were more capable of growing and dividing without binding to a substrate. The most likely mechanism explaining the observed changes was found to be TLR4- and IL-1b-mediated activation of NF-κB pathway.
CONCLUSIONS: Our results provide evidence that mycoplasma infection is an important factor modulating the effect of MDM2 inhibitors on cancer cells and is able to induce EMT-related changes.

PMID: 29737431 [PubMed - as supplied by publisher]

Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer.

Surg Oncol. 2017 Sep;26(3):278-285

Authors: Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, Molina MÁ, Robles AI, Villar E, Delgado JR, Faus-Dáder MJ, Calleja-Hernández MÁ

Abstract
BACKGROUND: Surgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients.
METHODS: A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time.
RESULTS: Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes.
CONCLUSIONS: Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients.

PMID: 28807247 [PubMed - indexed for MEDLINE]

16 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 2018/05/08

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.

Development and validation of an HPLC-UV method for quantification of elvitegravir and others new antiretrovirals, dolutegravir and rilpivirine, in the plasma of HIV-positive patients.

Biomed Chromatogr. 2018 May 04;:e4274

Authors: Tempestilli M, Ammassari A, D'Avolio A, Cicalini S, Gallo AL, Fazio S, Antinori A, Pucillo LP

Abstract
Therapeutic drug monitoring may be crucial in selected clinical conditions for the management of HIV infection. In the last years, new antiretrovirals have been introduced and in particular elvitegravir (EVG) is now recommended for first-line and in simplification treatment as well as dolutegravir (DTG) and rilpivirine (RPV). The aim of this study was to develop and validate a High Performance Liquid Chromatography-Ultra Violet (HPLC-UV) method for determining EVG and others newest antiretrovirals DTG and RPV in human plasma. A solid-phase extraction was applied to a 600 μL plasma sample. Chromatographic separation of the three drugs and internal standard were achieved with a gradient of acetonitrile and phosphate buffer on a C-18 reverse-phase analytical column with a 20-minute analytical run time. EVG, DTG were detected at 265nm and RPV at 290nm. Mean intra-day and inter-day precisions were < 10%; the mean accuracy was < 15%. Extraction recovery ranged between 105% and 82% for the drugs analyzed. Calibration curves were optimized according to the expected ranges of drug concentrations in patients; the coefficient of determination was higher than 0.997 for all drugs. This method allows for monitoring EVG, DTG and RPV in the plasma of HIV-positive patients using HPLC-UV.

PMID: 29726595 [PubMed - as supplied by publisher]

Expression levels of the runt-related transcription factor 1 and 3 genes in the development of acute myeloid leukemia.

Oncol Lett. 2018 May;15(5):6733-6738

Authors: Krygier A, Szmajda D, Żebrowska M, Jeleń A, Balcerczak E

Abstract
The aim of the present study was to evaluate the mRNA expression level of the runt-related transcription factor 1 (RUNX1) and runt-related transcription factor 3 (RUNX3) genes in patients with acute myeloid leukemia (AML). The etiology of AML is not yet fully known, but certain genetic factors may contribute to its manifestation. The RUNX1 and RUNX3 genes have been demonstrated to serve a role in the transcription process. The group investigated in the present study included 43 patients diagnosed with AML, and the relative RUNX1 and RUNX3 expression levels were determined using reverse transcription-quantitative polymerase chain reaction. The results indicated that RUNX1 and RUNX3 expression was associated with clinicopathological features, including sex and mortality risk. Expression levels of the RUNX1 gene were higher and more variable among females (P=0.044), and mortality was more frequent among patients with a higher RUNX3 expression level (P=0.036). The data obtained from the present study suggested that RUNX3 expression may have potential value as a prognostic factor; furthermore, sex is potentially a factor that may affect the difference in RUNX1 gene expression level among females and males. Further analyses in this field will aid in the identification and elucidation of the molecular basis of leukemia.

PMID: 29725413 [PubMed]

Pharmacogenomic biomarkers: Interpretation of information included in United States and Japanese drug labels.

J Clin Pharm Ther. 2018 May 02;:

Authors: Shimazawa R, Ikeda M

Abstract
WHAT IS KNOWN AND OBJECTIVES: Many drug labels contain information on pharmacogenomic biomarkers (PGBMs), but the information is not necessarily actionable. Pharmacogenomics Knowledgebase (PharmGKB) aims to clarify the level of action for PGBMs (PGx levels) implied in each label as issued by the US Food and Drug Administration. We wished to evaluate the association between the PGx level for US and Japanese drug labels and the insurance coverage for PGBM testing or approval for in vitro diagnostics (IVDs) in each country.
METHODS: We investigated the information on PGBMs in US and Japanese drug labels with PGx levels, insurance coverage of PGBM tests and IVD approval in the US and Japan. We analysed the relationship of PGx levels with insurance coverage.
RESULTS: A total of 243 labels were listed by PharmGKB, and 215 (88%) had PGx levels for US labels and 52 (21%) for Japanese labels. Of the 215 US labels, 54 were designated as "Testing Required" in PGx levels. PGx levels in US labels were strongly associated with coverage of PGBM testing. Tests in 52 (96%) of the 54 labels with Testing Required had insurance coverage, 2 (50%) of 4 in "Testing Recommended," 38 (38%) of 100 in "Actionable PGx," 11 (19%) of 57 in "Informative PGx" and 3 (11%) of 28 in "No Level." In Japanese labels, only 14 of 52 were listed as Testing Required, and all were covered by the National Health Insurance in Japan.
WHAT IS NEW AND CONCLUSION: The PGx level given in drug labels provides information on availability of PGBM testing. Higher PGx levels, based on better evidence of usefulness of PGBM testing, provide a route to broader test coverage.

PMID: 29722046 [PubMed - as supplied by publisher]

Pharmacogenomic survey of Qatari populations using whole-genome and exome sequences.

Pharmacogenomics J. 2018 May 03;:

Authors: Sivadas A, Scaria V

Abstract
The Arabs represent one of the most genetically heterogeneous populations characterized by a high prevalence of Mendelian disorders due to consanguinity. Population-scale genomic datasets provide a unique opportunity to understand the epidemiology of variants associated with differential therapeutic response. We analyzed publicly available genomic data for 1005 Qatari individuals encompassing five subpopulations. The frequencies of known and novel pharmacogenetic variants were compared with global populations. Impact of genetic substructure on the pharmacogenetic landscape of the population was studied. We report an average of three clinically actionable pharmacogenetic variants with FDA-recommended genetic testing per Qatari individual regardless of their genetic ancestry. We observed extensive differences in the frequencies of clinically actionable pharmacogenetic variants among the Qatari subpopulations. Our analysis revealed 3579 deleterious pharmacogenetic variants potentially altering the function of 1163 genes associated with 1565 drugs. This study has thus compiled the first comprehensive landscape of pharmacogenetic variants for any Arab population.

PMID: 29720721 [PubMed - as supplied by publisher]

Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.

Pharmacogenomics J. 2018 May 03;:

Authors: Jiménez-Jiménez FJ, Esguevillas G, Alonso-Navarro H, Zurdo M, Turpín-Fenoll L, Millán-Pascual J, Adeva-Bartolomé T, Cubo E, Navacerrada F, Amo G, Rojo-Sebastián A, Rubio L, Díez-Fairén M, Pastor P, Calleja M, Plaza-Nieto JF, Pilo-de-la-Fuente B, Arroyo-Solera M, García-Albea E, Agúndez JAG, García-Martín E

Abstract
The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48-46.44] and 1.66[1.16-2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS.

PMID: 29720720 [PubMed - as supplied by publisher]

A LC/MS/MS method for determination of tenofovir in human plasma and its application to toxicity monitoring.

J Chromatogr B Analyt Technol Biomed Life Sci. 2018 May 15;1085:89-95

Authors: Wiriyakosol N, Puangpetch A, Manosuthi W, Tomongkon S, Sukasem C, Pinthong D

Abstract
Tenofovir disoproxil fumarate is a pro-drug of the active metabolite tenofovir widely used against the HIV1, HIV2, and Hepatitis B virus. Several studies have been conducted and found kidney injury associated with tenofovir exposure. High tenofovir plasma concentration correlated with kidney injury in tenofovir-exposed patients. The present study developed and validated a simple and cost-effective LC/MS/MS method to determine tenofovir level in human plasma. A small plasma volume of 80 μl is utilized for the sample preparation. The samples were separated by Luna C18 (100 mm × 2.0 mm, 3 μm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile (90:10, v/v). The detection was achieved through multiple reaction monitoring using positive ionization mode on the triple quadrupole mass spectrometer with a run time of 10 min. The monitoring transitions were set at m/z 288.0 → 176.1 and 136.1 for tenofovir and m/z 226.1 → 152.0 for acyclovir (as the internal standard). This standard curve was linear from 10 to 640 ng/ml, with the lower limit of quantification of 10 ng/ml. The inter- and intra-day precision results were less than 12.3% and their accuracies were within the acceptable range of 84.9-113.1%. The validated method was successfully applied to the study of tenofovir induced kidney injury in HIV-1 infected patients taking 300 mg once daily for more than 4 weeks.

PMID: 29635209 [PubMed - indexed for MEDLINE]

Impact of CYP1A1, GSTP1 and XRCC1 genes polymorphisms on toxicity and response to chemotherapy in childhood acute lymphoblastic leukemia.

J Egypt Natl Canc Inst. 2017 Sep;29(3):127-133

Authors: Abo-Bakr A, Mossallam G, El Azhary N, Hafez H, Badawy R

Abstract
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The interindividual genetic variations in drug metabolizing enzymes and DNA repair genes influence the efficacy and toxicity of numerous chemotherapeutic drugs affecting the treatment outcome.
AIM OF THE WORK: The aim of the study was to investigate the impact of drug metabolizing CYP1, GSTP1 and DNA repair (XRCC1) genes polymorphisms on the toxicity and response to chemotherapy in childhood ALL.
PATIENTS AND METHODOLOGY: Ninety seven ALL pediatric patients were genotyped for CYP1A1, GSTP1 ILe105Val and XRCC1 Arg194Tryp single nucleotide polymorphisms (SNPs) using PCR-RFLP.
RESULTS: No statistically significant differences were observed between the wild and variant (homozygous and heterozygous) genotypes of the polymorphisms studied in CYP1A1, GSTP1 or XRCC1 genes regarding age, total leukocyte count, immunophenotyping, cytogenetic or risk group. The SNPs in CYP1A1, GSTP1 and XRCC1 genes did not show significant association with complete remission (CR) rate, overall survival (OS) or event free survival (EFS). However, XRCC1 Arg194Trp SNP was associated with higher drug toxicity; carriers of variant genotypes (CT and TT) had a significantly higher frequency of myelosuppression compared to those with the wild CC genotype (21/43[48.8%]) compared to (14/54[25.9%]) (p=0.020). The analysis of the combined effect of studied SNPs did not show any significant association with patient outcome.
CONCLUSION: Our study reported a significant association between the DNA repair gene polymorphism and myelosuppression in childhood ALL patients. Adjustment of the dose of chemotherapeutic agents according to XRCC1 Arg194Trp polymorphism may improve outcome in cases with risk of toxicity.

PMID: 28844589 [PubMed - indexed for MEDLINE]

Endonuclease G promotes mitochondrial genome cleavage and replication.

Oncotarget. 2018 Apr 06;9(26):18309-18326

Authors: Wiehe RS, Gole B, Chatre L, Walther P, Calzia E, Ricchetti M, Wiesmüller L

Abstract
Endonuclease G (EndoG) is a nuclear-encoded endonuclease, mostly localised in mitochondria. In the nucleus EndoG participates in site-specific cleavage during replication stress and genome-wide DNA degradation during apoptosis. However, the impact of EndoG on mitochondrial DNA (mtDNA) metabolism is poorly understood. Here, we investigated whether EndoG is involved in the regulation of mtDNA replication and removal of aberrant copies. We applied the single-cell mitochondrial Transcription and Replication Imaging Protocol (mTRIP) and PCR-based strategies on human cells after knockdown/knockout and re-expression of EndoG. Our analysis revealed that EndoG stimulates both mtDNA replication initiation and mtDNA depletion, the two events being interlinked and dependent on EndoG's nuclease activity. Stimulation of mtDNA replication by EndoG was independent of 7S DNA processing at the replication origin. Importantly, both mtDNA-directed activities of EndoG were promoted by oxidative stress. Inhibition of base excision repair (BER) that repairs oxidative stress-induced DNA damage unveiled a pronounced effect of EndoG on mtDNA removal, reminiscent of recently discovered links between EndoG and BER in the nucleus. Altogether with the downstream effects on mitochondrial transcription, protein expression, redox status and morphology, this study demonstrates that removal of damaged mtDNA by EndoG and compensatory replication play a critical role in mitochondria homeostasis.

PMID: 29719607 [PubMed]

Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients.

Pulm Circ. 2018 Apr-Jun;8(2):2045894018773049

Authors: Duarte JD, Kansal M, Desai AA, Riden K, Arwood MJ, Yacob AA, Stamos TD, Cavallari LH, Zamanian RT, Shah SJ, Machado RF

Abstract
The biological mechanisms behind the development of pulmonary hypertension in the setting of left heart failure (HF-PH), including combined pre- and post-capillary pulmonary hypertension (Cpc-PH), remains unclear. This study aimed to use candidate polymorphisms in nitric oxide synthase (NOS) genes to explore the role of NOS in HF-PH. DNA samples from 118 patients with HF-PH were genotyped for the NOS3 rs1799983 and NOS2 rs3730017 polymorphisms. A multiple regression model was used to compare hemodynamic measurements between genotype groups. Patients with the T/T genotype at rs1799983 possessed a nearly 10 mmHg increased transpulmonary gradient (TPG) compared to those with other genotypes ( P = 0.006). This finding was replicated in an independent cohort of 94 HF-PH patients ( P = 0.005). However, when tested in a cohort of 162 pre-capillary pulmonary arterial hypertension patients, no association was observed. In a combined analysis of both HF-PH cohorts, mean pulmonary artery pressure (mPAP), diastolic pulmonary gradient (DPG), and CpcPH status were also associated with rs1799983 genotype ( P = 0.005, P = 0.03, and P = 0.02, respectively). In patients with HF-PH, the NOS3 rs1799983 polymorphism is associated with TPG, and potentially mPAP and DPG as well. These findings suggest that endothelial NOS (encoded by NOS3) may be involved in the pulmonary vascular remodeling observed in Cpc-PH and warrants further study.

PMID: 29718770 [PubMed]

Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway.

Cell Physiol Biochem. 2018 Apr 26;46(5):1971-1984

Authors: Liu YB, Mei Y, Tian ZW, Long J, Luo CH, Zhou HH

Abstract
BACKGROUND/AIMS: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism.
METHODS: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients' responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo.
RESULTS: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis.
CONCLUSIONS: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients' response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.

PMID: 29719287 [PubMed - as supplied by publisher]

Relationship Between Polymorphisms in Methotrexate Pathway Genes and Outcome of Methotrexate Treatment in a Cohort of 119 Patients with Juvenile Idiopathic Arthritis.

J Rheumatol. 2017 Aug;44(8):1216-1223

Authors: Zajc Avramovič M, Dolžan V, Toplak N, Accetto M, Lusa L, Avčin T

Abstract
OBJECTIVE: To identify clinical and pharmacogenetic determinants of efficacy and toxicity of methotrexate (MTX) in juvenile idiopathic arthritis (JIA) over time.
METHODS: A cohort of 119 consecutive patients with JIA treated with MTX was reviewed. The Juvenile Arthritis Disease Activity Score including 71 joints was used to measure disease activity. Nonresponders were patients who did not reach a minimum of 30% improvement after 6 months of treatment or were switched to biologic drugs in the first 6 months because of inefficacy. All adverse events (AE) were noted. Genotyping of single-nucleotide polymorphisms (SNP) in the genes coding for MTX transporters, folate pathway, and adenosine pathway was performed using real-time PCR methods. Univariate and multivariable penalized logistic and Cox regression were used to analyze data.
RESULTS: Thirty patients (25.8%) were defined as nonresponders and 55 (47.2%) were switched to biologics during the followup. Sixty-five patients (54.5%) reported AE in a total of 405 patient-years, and 10 patients (8.4%) discontinued MTX because of AE. AMPD1 rs17602729 and MTHFD1 rs2236225 were associated with gastrointestinal AE while the latter together with MTRR rs1801394 also demonstrated associations with developing hepatoxicity. MTHFR rs1801131, ABCG2 rs2231137, wild-type of MTR rs1805087, and wild-type of ABCC2 rs2273697 were identified as potential markers for discontinuing MTX treatment because of AE. MTHFR rs1801133, MTRR rs1801394, and ABCC2 rs2273697 were associated with switching to biologics.
CONCLUSION: SNP in different MTX metabolic pathways influence treatment with MTX. Genetic variability is a better marker for toxicity than efficacy.

PMID: 28572465 [PubMed - indexed for MEDLINE]

14 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 2018/05/02

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.

13 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 2018/05/02

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.

14 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 2018/05/01

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.

Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver.

J Pharmacokinet Pharmacodyn. 2018 Apr 27;:

Authors: Ayyar VS, Sukumaran S, DuBois DC, Almon RR, Qu J, Jusko WJ

Abstract
A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated. The MPL-induced suppression of circulating lymphocytes was modeled by coupling its effect on cell trafficking with pharmacogenomic effects on cell apoptosis via the hepatic (STAT3-regulated) acute phase response. Transcriptomic and proteomic time-course profiles measured in steroid-treated rat liver were utilized to model the dynamics of mechanistically relevant gene products, which were linked to associated systemic end-points. While time-courses of TAT mRNA, protein, and activity were well described by transcription-mediated changes, additional post-transcriptional processes were included to explain the lack of correlation between PEPCK mRNA and protein. The immune response model quantitatively discerned the relative roles of cell trafficking versus gene-mediated lymphocyte apoptosis by MPL. This systems pharmacodynamic model provides insights into the contributions of selected molecular events occurring in liver and explores mechanistic hypotheses for the multi-factorial control of clinically relevant pharmacodynamic outcomes.

PMID: 29704219 [PubMed - as supplied by publisher]

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.

Diabetes. 2018 Apr 27;:

Authors: van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, Ladenvall C, Ziemek D, Fauman E, Robertson NR, McKeigue PM, Valo E, Forsblom C, Harjutsalo V, FINNDIANE Study centres, Perna A, Rurali E, Marcovecchio ML, Igo RP, Salem RM, Perico N, Lajer M, Käräjämäki A, Imamura M, Kubo M, Takahashi A, Sim X, Liu J, van Dam RM, Jiang G, Tam CHT, Luk AOY, Lee HM, Lim CKP, Szeto CC, So WY, Chan JCN, Hong Kong Diabetes Registry TRS Project Group, Ang SF, Dorajoo R, Wang L, Hua Clara TS, McKnight AJ, Duffy S, Warren 3/UK GoKinD Study Group, Pezzolesi MG, Consortium G, Marre M, Gyorgy B, Hadjadj S, Hiraki LT, DCCT/EDIC group, Ahluwalia TS, Almgren P, Schulz CA, Orho-Melander M, Linneberg A, Christensen C, Witte DR, Grarup N, Brandslund I, Melander O, Paterson AD, Tregouet D, Maxwell AP, Lim SC, Ma RCW, Tai ES, Maeda S, Lyssenko V, Tuomi T, Krolewski AS, Rich SS, Hirschhorn JN, Florez JC, Dunger D, Pedersen O, Hansen T, Rossing P, Remuzzi G, SUMMIT Consortium, Brosnan MJ, Palmer CNA, Groop PH, Colhoun HM, Groop LC, McCarthy MI

Abstract
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases).Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'eGFR'.We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.

PMID: 29703844 [PubMed - as supplied by publisher]

Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population.

Drug Metab Pharmacokinet. 2018 Mar 15;:

Authors: Hiratsuka M, Hirasawa N, Oshima Y, Kodama S, Miyata T, Dan T, Takatoku H, Kuribayashi H, Nakamura R, Saito Y

Abstract
Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients. We anticipate that this paper will be helpful in drug development for the regulatory usage of pharmacogenomic information, most notably pharmacokinetics.

PMID: 29703433 [PubMed - as supplied by publisher]