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2010-9-3 20:30
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siRNA transfection rnai
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Activation of PI 3-kinase/Rac1 and ERK1/2 regulates FGF-2-mediated cell proliferation through phosphorylation of p27 at Ser10 by KIS and at Thr187 by Cdc25A/Cdk2.
Activation of PI 3-kinase/Rac1 and ERK1/2 regulates FGF-2-mediated cell proliferation through phosphorylation of p27 at Ser10 by KIS and at Thr187 by Cdc25A/Cdk2.
Invest Ophthalmol Vis Sci. 2010 Sep 1;
Authors: Lee JG, Kay EP
PURPOSE. To determine the mechanism of p27 phosphorylation through common and differential pathways triggered by FGF-2 in corneal endothelial cells (CECs). METHODS. GTP pull-down assay was performed to identify Rac1-GTP. Expression and activation of protein were analyzed by immunoblotting. Cell proliferation was measured by MTT assay. Transfection of CECs with kinase-interacting stathmin (KIS) siRNA was performed using Lipofectamin RNAiMAX. RESULTS. FGF-2 activated Rac1 through Akt, and Rac1 inhibitor greatly inhibited the FGF-2-stimulated cell proliferation. Rac1 inhibitor reduced p27 phosphorylation at both serine 10 (Ser10) and threonine 187 (Thr187). ERK1/2 was also involved in FGF-2-stimulated CEC proliferation and phosphorylation of p27 at Ser10 and Thr187 in parallel to PI 3-kinase. In both PI 3-kinase/Rac1 and ERK1/2 pathways, Ser10 of p27 is phosphorylated by KIS, confirmed by siRNA to KIS, which subsequently hampered the FGF-2-stimulated cell proliferation, while Thr187 of p27 was phosphorylated through Cdk2 activated by Cdc25A. Cdc25A inhibitor blocked activation of Cdk2, phosphorylation of p27 at Thr187, and cell proliferation. FGF-2 induced both KIS and Cdc25A during G1 phase; the maximum KIS expression was observed 4 h after FGF-2 stimulation, while the maximum Cdc25A expression was observed at 12 h. Blockade of ERK1/2 and Rac1 greatly reduced KIS and Cdc25A expression. CONCLUSIONS. Our results suggest that FGF-2 uses both PI 3-kinase/Rac1 and ERK pathways for cell proliferation; two signals employ common pathways for phosphorylating p27 according to the sites (KIS for Ser10 and Cdc25A/Cdk2 for Thr187) with their characteristic kinetics (early G1 for Ser10 and late G1 for Thr187).
PMID: 20811053 [PubMed - as supplied by publisher]
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2010-9-3 20:30
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siRNA transfection rnai
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beta-catenin siRNA regulation of apoptosis- and angiogenesis-related gene expression in hepatocellular carcinoma cells: potential uses for gene therapy.
beta-catenin siRNA regulation of apoptosis- and angiogenesis-related gene expression in hepatocellular carcinoma cells: potential uses for gene therapy.
Oncol Rep. 2010 Oct;24(4):1093-9
Authors: Wang XH, Sun X, Meng XW, Lv ZW, Du YJ, Zhu Y, Chen J, Kong DX, Jin SZ
The molecular mechanism responsible for hepatocellular carcinoma (HCC) development remains to be defined although a number of gene pathways have been shown to play an active role, such as Wnt/beta-catenin signaling. In this study, beta-catenin small interfering RNA (siRNA) was designed, synthesized, and transfected into HCC HepG2 cells. RT-PCR and western blot assays were performed to detect expression of altered genes and proteins, and the MTT assay was used to detect cell viability. Our data showed that beta-catenin mRNA and protein expression levels were effectively knocked down by beta-catenin siRNA and subsequently, tumor cell proliferation was significantly suppressed. Flow cytometry assay showed that tumor cells were arrested at the G0/G1 phase of the cell cycles. Molecularly, expression of Smad3, p-caspase-3, and Grp78 protein were upregulated after 72 h of beta-catenin siRNA transfection, whereas expression of TERT, caspase-3, XIAP, MMP-2, MMP-9, VEGF-A, VEGF-c, and bFGF protein were reduced. However, there was no change between the expression of STAT3 and the HSP27 protein following transfection. The results from the current study demonstrated the importance of the Wnt/beta-catenin signaling pathway in regulation of gene expression in HCC. Further studies are required to investigate the role of this pathway in HCC development and targeting of this pathway to control HCC.
PMID: 20811694 [PubMed - in process]
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2010-9-3 20:30
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siRNA transfection rnai
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Cyclin B1/Cdk1 Phosphorylation of Mitochondrial p53 Induces Anti-Apoptotic Response.
Cyclin B1/Cdk1 Phosphorylation of Mitochondrial p53 Induces Anti-Apoptotic Response.
PLoS One. 2010;5(8):
Authors: Nantajit D, Fan M, Duru N, Wen Y, Reed JC, Li JJ
The pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% human cancers with intact p53 function. Herein, we reveal an anti-apoptotic role of mitochondrial p53 regulated by the cell cycle complex cyclin B1/Cdk1 in irradiated human colon cancer HCT116 cells with p53(+/+) status. Steady-state levels of p53 and cyclin B1/Cdk1 were identified in the mitochondria of many human and mouse cells, and their mitochondrial influx was significantly enhanced by radiation. The mitochondrial kinase activity of cyclin B1/Cdk1 was found to specifically phosphorylate p53 at Ser-315 residue, leading to enhanced mitochondrial ATP production and reduced mitochondrial apoptosis. The improved mitochondrial function can be blocked by transfection of mutant p53 Ser-315-Ala, or by siRNA knockdown of cyclin B1 and Cdk1 genes. Enforced translocation of cyclin B1 and Cdk1 into mitochondria with a mitochondrial-targeting-peptide increased levels of Ser-315 phosphorylation on mitochondrial p53, improved ATP production and decreased apoptosis by sequestering p53 from binding to Bcl-2 and Bcl-xL. Furthermore, reconstitution of wild-type p53 in p53-deficient HCT116 p53(-/-) cells resulted in an increased mitochondrial ATP production and suppression of apoptosis. Such phenomena were absent in the p53-deficient HCT116 p53(-/-) cells reconstituted with the mutant p53. These results demonstrate a unique anti-apoptotic function of mitochondrial p53 regulated by cyclin B1/Cdk1-mediated Ser-315 phosphorylation in p53-wild-type tumor cells, which may provide insights for improving the efficacy of anti-cancer therapy, especially for tumors that retain p53.
PMID: 20808790 [PubMed - in process]
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2010-9-3 20:30
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siRNA transfection rnai
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Phosphorylation of p27Kip1 at Thr187 by Cyclin-dependent Kinase 5 Modulates Neural Stem Cell Differentiation.
Phosphorylation of p27Kip1 at Thr187 by Cyclin-dependent Kinase 5 Modulates Neural Stem Cell Differentiation.
Mol Biol Cell. 2010 Sep 1;
Authors: Zheng YL, Li BS, Rudrabhatla P, Shukla V, Amin ND, Maric D, Kesavapany S, Kanungo J, Pareek TK, Takahashi S, Grant P, Kulkarni AB, Pant HC
Monitoring Editor: Paul Forscher Cyclin-dependent kinase 5 (Cdk5) plays a key role in the development of the mammalian nervous system; it phosphorylates a number of targeted proteins involved in neuronal migration during development to synaptic activity in the mature nervous system. Its role in the initial stages of neuronal commitment and differentiation of neural stem cells (NSCs), however, is poorly understood. In this study, we show that Cdk5 phosphorylation of p27(Kip1) at Thr187 is crucial to neural differentiation because (A) neurogenesis is specifically suppressed by transfection of p27(Kip1) siRNA into Cdk5(+/+) NSCs; (B) reduced neuronal differentiation in Cdk5(-/-) compared with Cdk5(+/+) NSCs; (C) Cdk5(+/+) NSCs, whose differentiation is inhibited by a nonphosphorylatable mutant, p27/Thr187A, are rescued by cotransfection of a phosphorylation-mimicking mutant, p27/Thr187D; (D) transfection of mutant p27(Kip1) (p27/187A) into Cdk5(+/+) NSCs inhibits differentiation. These data suggest that Cdk5 regulates the neural differentiation of NSCs by phosphorylation of p27(Kip1) at theThr187 site. Additional experiments exploring the role of Ser10 phosphorylation by Cdk5 suggest that together with Thr187 phosphorylation, Ser10 phosphorylation by Cdk5 promotes neurite outgrowth as neurons differentiate. Cdk5 phosphorylation of p27(Kip1), a modular molecule, may regulate the progress of neuronal differentiation from cell cycle arrest through differentiation, neurite outgrowth and migration.
PMID: 20810788 [PubMed - as supplied by publisher]
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2010-9-3 20:30
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siRNA transfection rnai
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Death-associated protein kinase is essential for the survival of various types of uterine cancer cells.
Death-associated protein kinase is essential for the survival of various types of uterine cancer cells.
Int J Oncol. 2010 Oct;37(4):1017-22
Authors: Tanaka T, Bai T, Yukawa K
We recently showed that targeted knockdown of death-associated protein kinase (DAPK) expression induces apoptosis in the human endometrial adenocarcinoma cell line HHUA. To investigate the possibility that DAPK may represent a molecular target for anticancer therapies for advanced uterine cancers, we examined the effects of DAPK siRNA transfections on the viability of five different human uterine cancer cell lines. The five uterine cell lines comprised three differentiated endometrial adenocarcinomas, one leiomyosarcoma and one carcinosarcoma. Cell death assays showed that the DAPK siRNA transfection significantly increased the cell death in all five uterine cancer cells examined. Ribonuclease protection assays did not show any remarkable changes in the bcl-2 family gene expressions after the DAPK siRNA transfection in HHUA cells. Since DAPK-mutant mice were reported to be fertile and do not show lethality, DAPK may play a central role in the immortalization and carcinogenesis of uterine cancer cells, possibly without bcl-2 family-related apoptotic regulation. These results indicate that DAPK can be a convincing candidate for molecularly targeted anticancer therapies for patients with various types of advanced uterine cancers, including carcinosarcoma and leiomyosarcoma.
PMID: 20811724 [PubMed - in process]
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2010-9-3 18:00
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vector pDNA transfection
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The change of immunoactivity of dendritic cells induced by mouse 4-1BBL recombinant adenovirus.
Related Articles
The change of immunoactivity of dendritic cells induced by mouse 4-1BBL recombinant adenovirus.
Yonsei Med J. 2010 Jul;51(4):594-8
Authors: Youlin K, Xiaodong W, Xiuheng L, Zhiyuan C, Hengcheng Z, Hui C, Botao J
PURPOSE: The purpose of this study is to construct a recombinant adenovirus vector carrying mouse 4-1BBL and observe its effects in dendritic cells. MATERIALS AND METHODS: Mouse 4-1BBL cDNA was taken from the plasmid pcDNA3-m4- 1BBL and subcloned into adenovirus shuttle plasmid pAdTrack-CMV, and then transformed into competent BJ5183 with plasmid pAdEasy-1. After recombination in E.coli, Ad-4-1BBL was packaged and amplified in HEK 293 cells. The expression of 4-1BBL in Ad-4-1BBL-transfected mouse prostate cancer cell line RM-1 was detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. After the co-culture of dendritic cells (DCs) with Ad-4-1BBL-transfected RM-1 cells, interleukin (IL)-6 and IL-12 production were assessed by enzyme-linked immunosorbent assay (ELISA) and co-stimulatary molecules (CD80 and CD86) on DCs were analyzed by flow cytometry. RESULTS: The levels of IL-6 (3,960 pg/mL) and IL-12 (249 pg/mL) production in Ad-m4-1BBL-pulsed DCs were more than those in none-pulsed DCs. The differences were statistically significant (p < 0.05). The expression of co-stimulatary molecules (CD80 and CD86) was up-regulated in Ad-m4-1BBL-pulsed DCs. CONCLUSION: The results indicated the recombinant mouse 4-1BBL can effectively activate DCs.
PMID: 20499429 [PubMed - indexed for MEDLINE]
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2010-9-3 18:00
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vector pDNA transfection
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Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies.
Related Articles
Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies.
Clin Cancer Res. 2010 Jul 1;16(13):3431-41
Authors: de Vries NA, Bruggeman SW, Hulsman D, de Vries HI, Zevenhoven J, Buckle T, Hamans BC, Leenders WP, Beijnen JH, van Lohuizen M, Berns AJ, van Tellingen O
PURPOSE: To develop a transgenic mouse model of glioma that can be conveniently used for testing therapy intervention strategies. High-grade glioma is a devastating and uniformly fatal disease for which better therapy is urgently needed. Typical for high-grade glioma is that glioma cells infiltrate extensively into surrounding pivotal brain structures, thereby rendering current treatments largely ineffective. Evaluation of novel therapies requires the availability of appropriate glioma mouse models. EXPERIMENTAL DESIGN: High-grade gliomas were induced by stereotactic intracranial injection of lentiviral GFAP-Cre or CMV-Cre vectors into compound LoxP-conditional mice, resulting in K-Ras(v12) expression and loss of p16(Ink4a)/p19(Arf) with or without concomitant loss of p53 or Pten. RESULTS: Tumors reproduced many of the features that are characteristic for human high-grade gliomas, including invasiveness and blood-brain barrier functionality. Especially, CMV-Cre injection into p53;Ink4a/Arf;K-Ras(v12) mice resulted in high-grade glioma with a short tumor latency (2-3 weeks) and full penetrance. Early detection and follow-up was accomplished by noninvasive bioluminescence imaging, and the practical utility for therapy intervention was shown in a study with temozolomide. CONCLUSION: We have developed a realistic high-grade glioma model that can be used with almost the same convenience as traditional xenograft models, thus allowing its implementation at the forefront of preclinical evaluation of new treatments.
PMID: 20472681 [PubMed - indexed for MEDLINE]
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2010-9-3 18:00
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vector pDNA transfection
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Critical design criteria for minimal antibiotic-free plasmid vectors necessary to combine robust RNA Pol II and Pol III-mediated eukaryotic expression with high bacterial production yields.
Related Articles
Critical design criteria for minimal antibiotic-free plasmid vectors necessary to combine robust RNA Pol II and Pol III-mediated eukaryotic expression with high bacterial production yields.
J Gene Med. 2010 Aug 30;
Authors: Carnes AE, Luke JM, Vincent JM, Anderson S, Schukar A, Hodgson CP, Williams JA
BACKGROUND: For safety considerations, regulatory agencies recommend the elimination of antibiotic resistance markers and non-essential sequences from plasmid DNA-based gene medicines. In the present study, we analyzed antibiotic-free (AF) vector design criteria impacting upon bacterial production and mammalian transgene expression. METHODS: Both CMV-HTLV-I R RNA Pol II promoter (protein transgene) and murine U6 RNA Pol III promoter (RNA transgene) vector designs were studied. Plasmid production yield was assessed through inducible fed-batch fermentation. RNA Pol II-directed enhanced green fluorescent protein and RNA Pol III-directed RNA expression were quantified by fluorometry and quantitative real-time polymerase chain reaction, respectively, after transfection of human HEK293 cells. RESULTS: Sucrose-selectable minimalized protein and therapeutic RNA expression vector designs that combined an RNA-based AF selection with highly productive fermentation manufacturing (>1000 mg/l plasmid DNA) and high-level in vivo expression of encoded products were identified. The AF selectable marker was also successfully applied to convert existing kanamycin-resistant DNA vaccine plasmids gWIZ and pVAX1 into AF vectors, demonstrating a general utility for retrofitting existing vectors. A minimum vector size for high yield plasmid fermentation was identified. A strategy for stable fermentation of plasmid dimers with improved vector potency and fermentation yields up to 1740 mg/l was developed. CONCLUSIONS: We report the development of potent high yield AF gene medicine expression vectors for protein or RNA (e.g. short hairpin RNA or microRNA) products. These AF expression vectors were optimized to exceed a newly-identified size threshold for high copy plasmid replication and direct higher transgene expression levels than alternative vectors. Copyright (c) 2010 John Wiley & Sons, Ltd.
PMID: 20806425 [PubMed - as supplied by publisher]
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2010-9-3 18:00
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vector pDNA transfection
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Persistence of Different Forms of Transient RNAi during Apoptosis in Mammalian Cells.
Related Articles
Persistence of Different Forms of Transient RNAi during Apoptosis in Mammalian Cells.
PLoS One. 2010;5(8):
Authors: Kandan-Kulangara F, Shah RG, Affar el B, Shah GM
Gene silencing by transient or stable RNA-interference (RNAi) is used for the study of apoptosis with an assumption that apoptotic events will not influence RNAi. However, we recently reported that stable RNAi, i.e., a permanent gene-knockdown mediated by shRNA-generating DNA vectors that are integrated in the genome, fails rapidly after induction of apoptosis due to caspase-3-mediated cleavage and inactivation of the endoribonuclease Dicer-1 that is required for conversion of shRNA to siRNA. Since apoptosis studies also increasingly employ transient RNAi models in which apoptosis is induced immediately after a gene is temporarily knocked down within a few days of transfection with RNAi-inducing agents, we examined the impact of apoptosis on various models of transient RNAi. We report here that unlike the stable RNAi, all forms of transient RNAi, whether Dicer-1-independent (by 21mer dsRNA) or Dicer-1-dependent (by 27mer dsRNA or shRNA-generating DNA vector), whether for an exogenous gene GFP or an endogenous gene poly(ADP-ribose) polymerase-1, do not fail for 2-3 days after onset of apoptosis. Our results reflect the differences in dynamics of achieving and maintaining RNAi during the early phase after transfection in the transient RNAi model and the late steady-state phase of gene-knockdown in stable RNAi model. Our results also sound a cautionary note that RNAi status should be frequently validated in the studies involving apoptosis and that while stable RNAi can be safely used for the study of early apoptotic events, transient RNAi is more suitable for the study of both early and late apoptotic events.
PMID: 20805889 [PubMed - in process]
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2010-9-3 18:00
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vector pDNA transfection
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Generation of retroviral particles for the spleen necrosis virus (SNV)-based vector system and their use in transduction of various cell types.
Related Articles
Generation of retroviral particles for the spleen necrosis virus (SNV)-based vector system and their use in transduction of various cell types.
Cold Spring Harb Protoc. 2010 Jun 1;2010(6):pdb.prot5435
Authors: Parveen Z, Mukhtar M, Pomerantz RJ
Genetically engineered retroviruses are widely used for gene delivery into human cells. A number of investigators have studied spleen necrosis virus (SNV) as a vehicle for gene delivery. Vectors developed from SNV and its closely associated avian reticuloendotheliosis virus strain A (REV-A) can be used for gene transfer into a variety of cells, including primary hematopoietic cells and human brain and post-mitotic neuronal cells that are difficult to transduce with other vector systems. SNV-based vector systems have the advantage of being quite safe, because wild-type SNV is unable to infect human cells and has less preference for integration into transcriptionally active sites or genes. However, the generation of retroviral vectors requires cotransfection of more than one plasmid into a packaging cell line, which is a tedious process. The development of stable packaging cell lines expressing envelope (Env) proteins and the structural proteins Gag-Pol will enhance mass production of retroviral vectors for future gene therapy experiments both in vitro and in vivo. This protocol describes the generation of retroviral particles for the SNV-based vector system. These particles can then be used for transduction of various cell types; as an example, a technique for transduction of post-mitotic neurons is also presented.
PMID: 20516173 [PubMed - indexed for MEDLINE]
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2010-9-2 19:40
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Pharmacogenomics
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Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants.
Related Articles
Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants.
Braz J Med Biol Res. 2009 Dec;42(12):1179-84
Authors: Perini JA, Vargens DD, Santana IS, Moriguchi EH, Ribeiro-Dos-Santos AK, Tsutsumi M, Suarez-Kurtz G
Brazil hosts the largest Japanese community outside Japan, estimated at 1.5 million individuals, one third of whom are first-generation, Brazilian-born with native Japanese parents. This large community provides a unique opportunity for comparative studies of the distribution of pharmacogenetic polymorphisms in native Japanese versus their Brazilian-born descendants. Functional polymorphisms in genes that modulate drug disposition (CYP2C9, CYP2C19 and GSTM3) or response (VKORC1) and that differ significantly in frequency in native Japanese versus Brazilians with no Japanese ancestry were selected for the present study. Healthy subjects (200 native Japanese and 126 first-generation Japanese descendants) living in agricultural colonies were enrolled. Individual DNA was genotyped using RFLP (GSTM3 A/B) or TaqMan Detection System assays (CYP2C9 2 and 3; CYP2C19 2 and 3; VKORC1 3673G>A, 5808T>G, 6853G>C, and 9041G>A). No difference was detected in the frequency of these pharmacogenetic polymorphisms between native Japanese and first-generation Japanese descendants. In contrast, significant differences in the frequency of each polymorphism were observed between native or first-generation Japanese and Brazilians with no Japanese ancestry. The VKORC1 3673G>A, 6853G>C and 9041G>A single nucleotide polymorphisms were in linkage disequilibrium in both native and first-generation Japanese living in Brazil. The striking similarity in the frequency of clinically relevant pharmacogenetic polymorphisms between Brazilian-born Japanese descendants and native Japanese suggests that the former may be recruited for clinical trials designed to generate bridging data for the Japanese population in the context of the International Conference on Harmonization.
PMID: 19882083 [PubMed - indexed for MEDLINE]
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2010-9-2 19:40
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Pharmacogenomics
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Opportunities and challenges in nutrigenetics/nutrigenomics: building industry-academia partnerships.
Related Articles
Opportunities and challenges in nutrigenetics/nutrigenomics: building industry-academia partnerships.
World Rev Nutr Diet. 2010;101:160-8
Authors: Gillies PJ, Kris-Etherton PM
PMID: 20436262 [PubMed - indexed for MEDLINE]
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2010-9-2 19:40
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Pharmacogenomics
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Toxicogenomics and studies of genomic effects of dietary components.
Related Articles
Toxicogenomics and studies of genomic effects of dietary components.
World Rev Nutr Diet. 2010;101:115-22
Authors: Thompson K
PMID: 20436258 [PubMed - indexed for MEDLINE]
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2010-9-2 19:40
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Pharmacogenomics
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Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.
Related Articles
Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.
Depress Anxiety. 2010 May;27(5):417-25
Authors: Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, Wu X, Gentile KA, Huang SP, Emison E, Delmonte T, D'Souza BB, Zimbroff DL, Grebb JA, Goddard AW, Stock EG
BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.
PMID: 20455246 [PubMed - indexed for MEDLINE]
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2010-9-2 19:40
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Pharmacogenomics
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[Genodermatoses for practitioners - principles and concepts.]
[Genodermatoses for practitioners - principles and concepts.]
Ther Umsch. 2010 Sep;67(9):483-5
Authors: Itin PH, Burger B
Every disease is a mirror of interactions between genes and the environment. In monogenic disorders only one mutation can lead to a specific phenotype. However the spectrum and the degree of manifestations depend on numerous factors from the environment. Ichthyosis vulgaris is caused by a mutation in the filaggrin gene. However the phenotype is much more pronounced in the winter months. In polygenic disorders such as atopic dermatitis numerous modifying genes influence the phenotype including a mutation in filaggrin. The skin is the organ of the human body which is most commonly involved in monogenic diseases. More than one third of all genetic diseases affect the integument. At the very moment more than 350 genodermatoses are identified with functional insights. The Human Genome Project was finished in 2001 with the aim that all genes can be identified for diagnostics, pharmacogenomics potential gene therapy and to understand the principle basis of diseases. The next project called ENCODE for Enzyclopedia of DNA Elements targets to identify all functional elements in the human genome sequence. MicroRNAs seem to have great importance for the regulation of genefunctions in the skin. At the moment epigenetics is at the epicentre of modern medicine. Epigenetics is the study of non-DNA sequence-related heredity. Epigenetics is an important tool to study the relationship between the genome and the environment. In the second part cases will be presented and the way of diagnosis making will be shown. It will be shown that it is very important to find clinical key features which may allow an allocation to a genetic pathway.
PMID: 20806176 [PubMed - in process]
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