Opportunities and Obstacles in Genotypic Prediction of Cytochrome P450 Phenotypes.

Expert Opin Drug Metab Toxicol. 2018 Jun 04;:

Authors: McGraw J, Gerhardt A, Morris TC

PMID: 29863909 [PubMed - as supplied by publisher]

Related Articles

REST, not REST4, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

Drug Des Devel Ther. 2018;12:1363-1371

Authors: Li C, Zou H, Wang Z, Tang X, Fan X, Zhang K, Liu J, Li Z

Abstract
Background/aim: Repressor element silencing transcription factor (REST) is a transcription repressor, expressed in several malignancies. This study aims to evaluate the prognostic values of REST and its splicing variant REST4 in glioma, and investigate the potential correlation between REST and REST4.
Methods: REST and REST4 expression values were evaluated by qRT-PCR in 89 patients with gliomas and 10 with normal brain tissues.
Results: Upregulation of REST was related to higher World Health Organization (WHO) grade, larger tumor size, higher ki67, and higher p53 positive rate. After radiotherapy+temozolomide (RT+TMZ) treatment, low REST expression patients could get better therapeutic efficacy (P=0.031). The positive rate of REST4 expression was only 13.5% in glioma tissues, and REST4 expression was not associated with clinical characteristics and REST expression in this study.
Conclusions: REST was a prognostic factor in glioma, while REST4 was not. REST expression can be a predictor in evaluating the survival outcome of gliomas patients treated with RT+TMZ after surgery.

PMID: 29861627 [PubMed - in process]

Related Articles

Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression.

Cell Death Dis. 2017 Oct 12;8(10):e3122

Authors: Li S, Wu Z, Ma P, Xu Y, Chen Y, Wang H, He P, Kang Z, Yin L, Zhao Y, Zhang X, Xu X, Ma X, Guan M

Abstract
The downregulation of receptor tyrosine kinase EphA7 is frequent in epithelial cancers and linked to tumor progression. However, the detailed mechanism of EphA7-mediated prostate tumor progression remains elusive. To test the role of EphA7 receptor in prostate cancer (PCa) progression directly, we generated EphA7 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its phosphorylation by site-directed mutagenesis. Overexpression of wild-type (WT) EphA7 in PCa cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, ectopic expression of WT EphA7 both can delay PCa cell proliferation and could inhibit PCa cell migration and invasion. This protein can also induce PCa cell apoptosis that correlated with increasing the protein expression levels of Bax, elevating the caspase-3 activities, reducing the protein expression levels of Bcl-2 and facilitating the dephosphorylation of Akt, which is further increased by the stimulation of ephrinA5-Fc. However, expression of these EphA7 mutants in PCa cells has no effect in vivo and in vitro. The expression of EphA7 and ephrinA5 was significantly decreased in PCa specimens compared with BPH tissues or paired normal tissues. Moreover, the phosphorylation of EphA7 was positively related with ephrinA5 expression in human prostate tissues. In sum, receptor phosphorylation of EphA7, at least in part, suppress PCa tumor malignancy through targeting PI3K/Akt signaling pathways.

PMID: 29022918 [PubMed - indexed for MEDLINE]

Related Articles

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.

Sci Rep. 2016 07 20;6:29930

Authors: Winter S, Fisel P, Büttner F, Rausch S, D'Amico D, Hennenlotter J, Kruck S, Nies AT, Stenzl A, Junker K, Scharpf M, Hofmann U, van der Kuip H, Fend F, Ott G, Agaimy A, Hartmann A, Bedke J, Schwab M, Schaeffeler E

Abstract
Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.

PMID: 27435027 [PubMed - indexed for MEDLINE]

Funding Opportunity PA-18-818 from the NIH Guide for Grants and Contracts. The reproducibility and comparability of research on dietary supplements is enhanced by rigorous analytical characterization of key experimental materials and the publication of validated analytical methods that accurately and precisely characterized and quantify constituents in dietary supplement ingredients and products. This FOA builds on existing NIH awards to support the performance and publication of formal single-laboratory validation studies of quantitative analytical methods. The methods proposed for validation must be used to identify and quantify dietary supplement-relevant chemical constituents (i.e., active or marker chemical compounds, adulterants, contaminants) or their metabolites in experimental reagents, raw materials, and/or clinical specimens (for example urine or plasma samples). Methods must have been developed or utilized in fulfillment of the active parent grants specific aims. Candidate constituents for quantitative method validation studies include (but are not limited to): phytochemicals, nutrients, and potentially deleterious substances such as pesticides and mycotoxins. Multi-laboratory validation studies will not be supported through this FOA.

Notice NOT-HL-18-631 from the NIH Guide for Grants and Contracts

Notice NOT-DE-18-019 from the NIH Guide for Grants and Contracts

Notice NOT-EB-18-018 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-185 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-18-817 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) announces the availability of administrative supplements to support research in which the supplemental funding would investigate the role of dietary supplements and/or their ingredients in health maintenance and disease prevention. Parent awards need not be focused on dietary supplements; this FOA may provide support to include dietary supplements within the scope of relevant research projects. Research interests of ODS are not limited to specific health conditions, organ systems or population groups. ODS supports all types of research, including pre-clinical, clinical, behavioral, and epidemiological. Additionally, ODS supports research and training programs that build future research capacity for studying the role of dietary supplements in health and disease prevention. Primary consideration for support will be given to applications that stimulate dietary supplement research where it is lacking or lagging, clarify gaps, opportunities and balance between benefits and risks where data are in conflict, target special population groups where additional science on dietary supplements is needed, and focus on the use of dietary supplements in improving or maintaining health and reducing the risk of chronic disease. This FOA will not support new clinical trials.

Funding Opportunity PA-18-815 from the NIH Guide for Grants and Contracts. Fetal bovine serum (FBS) is the most widely used growth supplement for cell culture because it cost-effectively supports the survival and growth of many cell lines. Although serum is an effective growth promotor, it is highly variable in its composition, activity, and physiological effects on cells. This variability introduces inconsistencies into cell culture research. This Funding Opportunity Announcement (FOA) will support SBIR projects to develop novel, reliable, and cost-effective tools that will make it easier for researchers to standardize or replace serum in cell culture.

Funding Opportunity PA-18-816 from the NIH Guide for Grants and Contracts. Fetal bovine serum (FBS) is the most widely used growth supplement for cell culture because it cost-effectively supports the survival and growth of many cell lines. Although serum is an effective growth promotor, it is highly variable in its composition, activity, and physiological effects on cells. This variability introduces inconsistencies into cell culture research. This Funding Opportunity Announcement (FOA) will support STTR projects to develop novel, reliable, and cost-effective tools that will make it easier for researchers to standardize or replace serum in cell culture.

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

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/05

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.

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

"systems biology"

These pubmed results were generated on 2018/06/05

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.

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

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/06/05

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.

The detection and significance of cystic fibrosis transmembrane conductance regulator gene promoter mutations in Chinese patients with congenital bilateral absence of the vas deferens.

Gene. 2018 Jun 01;:

Authors: Bai S, Du Q, Liu X, Tong Y, Wu B

Abstract
OBJECTIVE: Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene can be involved in the development of congenital bilateral absence of the vas deferens (CBAVD). This study was aimed at investigating mutations in the promoter region of the CFTR gene and its associated effects on CFTR transcription in Chinese patients with CBAVD.
METHODS: To identify CFTR promoter region mutations in Chinese CBAVD patients, fragments 1.4 kb upstream of the ATG start codon of the CFTR gene were sequenced in 66 Chinese patients with CBAVD and compared to the corresponding sequences from 60 healthy subjects and sequence data present in the NCBI database. The relationship between the mutations and gene regulation was explored using Transfac analysis and a phylogenetic footprint method. Plasmids were constructed by incorporating statistically significant variant sequences. The effects of the mutations on CFTR transcription were investigated using a dual luciferase reporter gene assay.
RESULTS: a total of six point mutations, which included c.-150G > T, c.-205 T > C, c.-245C > T, c.-871G > T, c.-966 T > G and c.-1062G > C, and one deletion mutation, namely c.-861delT, were identified in the promoter region of the CFTR gene in Chinese CBAVD patients. Among them, c.-966 T > G had the highest frequency and presented in either a homozygous or heterozygous mutation state. The frequency of G/G genotype in the CBAVD group was 33/66 (50.00%), while the T/G and T/T genotypes had frequencies of 18/66 (27.27%) and 15/66 (22.73%), respectively. A significant difference was found between the CBAVD and control group (P < 0.01). The locus for this variant was found in a conserved sequence. The Transfac tool showed that transcription factors EHF and STAT3, which are closely associated with reproduction, can bind to the sequence containing the variant locus. Two types of plasmid vectors, one carrying the G/G variant and the other the wild type T/T sequences, were constructed and respectively transfected into human cervical cancer cells (HeLa), human renal epithelial cells (HEK-293), and human colon cancer cells (SW480). It was found that the homozygous c.-966 T > G mutation significantly reduced CFTR transcription efficiency by 18.75%-35.50%.
CONCLUSION: Mutations in the promoter region of the CFTR gene in Chinese CBAVD patients are different from those found in comparable Caucasian patients. The homozygous c.-966 T > G mutation state had the highest frequency, which reduced the CFTR transcriptional level and showed significant tissue-specificity.

PMID: 29864494 [PubMed - as supplied by publisher]

Targeting of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with a technetium-99m imaging probe.

ChemMedChem. 2018 Jun 04;:

Authors: Ferreira VFC, Oliveira BL, Santos JD, Correia JDG, Farinha CM, Mendes FF

Abstract
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug-based therapies. Herein, we report the first proof-of-principle study of a non-invasive imaging probe able to detect CFTR at the plasma membrane. We radiolabelled the CFTR inhibitor, CFTRinh-172a, with technetium-99m via a pyrazolyl-diamine chelating unit, yielding a novel 99mTc(CO)3-complex. A non-radioactive surrogate showed that the structural modifications introduced in the inhibitor did not affect its activity. The radioactive complex was able to detect plasma membrane-CFTR, shown by its significantly higher uptake in wild-type versus mutated cells. Furthermore, assessment of F508del-CFTR pharmacological correction in human cells using the radioactive complex, revealed differences in corrector versus control uptake, recapitulating the biochemical correction observed for the protein.

PMID: 29864241 [PubMed - as supplied by publisher]

Related Articles

Exploring knowledge and perceptions of palliative care to inform integration of palliative care education into cystic fibrosis care.

Pediatr Pulmonol. 2018 Jun 03;:

Authors: Dellon EP, Helms SW, Hailey CE, Shay R, Carney SD, Schmidt HJ, Brown DE, Prieur MG

Abstract
BACKGROUND: Individuals with cystic fibrosis (CF) face the challenges of managing a chronic, progressive disease. While palliative care is a standard of care in serious illnesses, there are no guidelines for its incorporation into CF care. Patients with CF, caregivers, and CF care providers may lack knowledge about palliative care and perceive barriers to integrated care.
OBJECTIVES: To: 1) explore knowledge and perceptions of palliative care among patients with CF, caregivers, and CF care providers; 2) solicit opinions about incorporating palliative care into routine CF care; and 3) solicit recommendations for CF-specific palliative care education for patients and caregivers.
METHODS: We conducted semi-structured interviews with adult patients with CF, parents of adolescents with CF, and CF care providers to assess knowledge and perceptions of palliative care. Discussion included suggestions for palliative care education and integration into CF care. The sample was characterized using summary statistics. Key themes were identified using qualitative content analysis.
RESULTS: Ten patients with CF, ten parents, and eight CF care providers participated. Many had minimal knowledge of palliative care and endorsed the association with end of life as a barrier to palliative care, but after learning more about palliative care, thought it could be helpful, and should be introduced earlier.
CONCLUSIONS: In this single center study, many patients with CF, caregivers, and providers lacked knowledge about palliative care. These findings warrant replication in a larger, multisite study to inform palliative care educational interventions as a step toward consistent integration of palliative care into routine CF care.

PMID: 29862668 [PubMed - as supplied by publisher]

Related Articles

Recent advances in the understanding and management of cystic fibrosis pulmonary exacerbations.

F1000Res. 2018;7:

Authors: Skolnik K, Quon BS

Abstract
Pulmonary exacerbations are common events in cystic fibrosis and have a profound impact on quality of life, morbidity, and mortality. Pulmonary exacerbation outcomes remain poor and a significant proportion of patients fail to recover their baseline lung function despite receiving aggressive treatment with intravenous antibiotics. This focused review provides an update on some of the recent advances that have taken place in our understanding of the epidemiology, pathophysiology, diagnosis, and management of pulmonary exacerbations in cystic fibrosis as well as direction for future study.

PMID: 29862015 [PubMed]

Related Articles

The Efficacy of MAG-DHA for Correcting AA/DHA Imbalance of Cystic Fibrosis Patients.

Mar Drugs. 2018 May 26;16(6):

Authors: Morin C, Cantin AM, Vézina FA, Fortin S

Abstract
Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementations are thought to improve essential fatty acid deficiency (EFAD) as well as reduce inflammation in Cystic Fibrosis (CF), but their effectiveness in clinical studies remains unknown. The aim of the study was to determine how the medical food containing docosahexaenoic acid monoglyceride (MAG-DHA) influenced erythrocyte fatty acid profiles and the expression levels of inflammatory circulating mediators. We conducted a randomized, double blind, pilot trial including fifteen outpatients with Cystic Fibrosis, ages 18⁻48. The patients were divided into 2 groups and received MAG-DHA or a placebo (sunflower oil) for 60 days. Patients took 8 × 625 mg MAG-DHA softgels or 8 × 625 mg placebo softgels every day at bedtime for 60 days. Lipid analyses revealed that MAG-DHA increased docosahexaenoic acid (DHA) levels and decrease arachidonic acid (AA) ratio (AA/DHA) in erythrocytes of CF patients following 1 month of daily supplementation. Data also revealed a reduction in plasma human leukocyte elastase (pHLE) complexes and interleukin-6 (IL-6) expression levels in blood samples of MAG-DHA supplemented CF patients. This pilot study indicates that MAG-DHA supplementation corrects erythrocyte AA/DHA imbalance and may exert anti-inflammatory properties through the reduction of pHLE complexes and IL6 in blood samples of CF patients.
TRIAL REGISTRATION: Pro-resolving Effect of MAG-DHA in Cystic Fibrosis (PREMDIC), NCT02518672.

PMID: 29861448 [PubMed - in process]