TY  - JOUR
A1  - Said, Harun M.
A1  - Polat, Buelent
A1  - Stein, Susanne
A1  - Guckenberger, Mathias
A1  - Hagemann, Carsten
A1  - Staab, Adrian
A1  - Katzer, Astrid
A1  - Anacker, Jelena
A1  - Flentje, Michael
A1  - Vordermark, Dirk
T1  - Inhibition of N-Myc down regulated gene 1 in in vitro cultured human glioblastoma cells
JF  - World Journal of Clinical Oncology
N2  - AIM: To study short dsRNA oligonucleotides (siRNA) as a potent tool for artificially modulating gene expression of N-Myc down regulated gene 1 (NDRG1) gene induced under different physiological conditions (Normoxia and hypoxia) modulating NDRG1 transcription, mRNA stability and translation.

METHODS: A cell line established from a patient with glioblastoma multiforme. Plasmid DNA for transfections was prepared with the Endofree Plasmid Maxi kit. From plates containing 5 x 10(7) cells, nuclear extracts were prepared according to previous protocols. The pSUPER-NDRG1 vectors were designed, two sequences were selected from the human NDRG1 cDNA (5'-GCATTATTGGCATGGGAAC-3' and 5'-ATGCAGAGTAACGTGGAAG-3'. reverse transcription polymerase chain reaction was performed using primers designed using published information on -actin and hypoxia-inducible factor (HIF)-1 mRNA sequences in GenBank. NDRG1 mRNA and protein level expression results under different conditions of hypoxia or reoxygenation were compared to aerobic control conditions using the Mann-Whitney U test. Reoxygenation values were also compared to the NDRG1 levels after 24 h of hypoxia (P < 0.05 was considered significant).

RESULTS: siRNA- and iodoacetate (IAA)-mediated downregulation of NDRG1 mRNA and protein expression in vitro in human glioblastoma cell lines showed a nearly complete inhibition of NDRG1 expression when compared to the results obtained due to the inhibitory role of glycolysis inhibitor IAA. Hypoxia responsive elements bound by nuclear HIF-1 in human glioblastoma cells in vitro under different oxygenation conditions and the clearly enhanced binding of nuclear extracts from glioblastoma cell samples exposed to extreme hypoxic conditions confirmed the HIF-1 Western blotting results.

CONCLUSION: NDRG1 represents an additional diagnostic marker for brain tumor detection, due to the role of hypoxia in regulating this gene, and it can represent a potential target for tumor treatment in human glioblastoma. The siRNA method can represent an elegant alternative to modulate the expression of the hypoxia induced NDRG1 gene and can help to monitor the development of the cancer disease treatment outcome through monitoring the expression of this gene in the patients undergoing the different therapeutic treatment alternatives available nowadays.
KW  - Strahlentherapie
KW  - brain cancer
KW  - radiotherapy
KW  - human cancer diseases
KW  - Short dsRNA oligonucleotides
KW  - N-Myc down regulated gene 1
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123385
VL  - 3
IS  - 7
ER  - 
TY  - JOUR
A1  - Davis, Lea K.
A1  - Yu, Dongmei
A1  - Keenan, Clare L.
A1  - Gamazon, Eric R.
A1  - Konkashbaev, Anuar I.
A1  - Derks, Eske M.
A1  - Neale, Benjamin M.
A1  - Yang, Jian
A1  - Lee, S. Hong
A1  - Evans, Patrick
A1  - Barr, Cathy L.
A1  - Bellodi, Laura
A1  - Benarroch, Fortu
A1  - Berrio, Gabriel Bedoya
A1  - Bienvenu, Oscar J.
A1  - Bloch, Michael H.
A1  - Blom, Rianne M.
A1  - Bruun, Ruth D.
A1  - Budman, Cathy L.
A1  - Camarena, Beatriz
A1  - Campbell, Desmond
A1  - Cappi, Carolina
A1  - Cardona Silgado, Julio C.
A1  - Cath, Danielle C.
A1  - Cavallini, Maria C.
A1  - Chavira, Denise A.
A1  - Chouinard, Sylvian
A1  - Conti, David V.
A1  - Cook, Edwin H.
A1  - Coric, Vladimir
A1  - Cullen, Bernadette A.
A1  - Deforce, Dieter
A1  - Delorme, Richard
A1  - Dion, Yves
A1  - Edlund, Christopher K.
A1  - Egberts, Karin
A1  - Falkai, Peter
A1  - Fernandez, Thomas V.
A1  - Gallagher, Patience J.
A1  - Garrido, Helena
A1  - Geller, Daniel
A1  - Girard, Simon L.
A1  - Grabe, Hans J.
A1  - Grados, Marco A.
A1  - Greenberg, Benjamin D.
A1  - Gross-Tsur, Varda
A1  - Haddad, Stephen
A1  - Heiman, Gary A.
A1  - Hemmings, Sian M. J.
A1  - Hounie, Ana G.
A1  - Illmann, Cornelia
A1  - Jankovic, Joseph
A1  - Jenike, Micheal A.
A1  - Kennedy, James L.
A1  - King, Robert A.
A1  - Kremeyer, Barbara
A1  - Kurlan, Roger
A1  - Lanzagorta, Nuria
A1  - Leboyer, Marion
A1  - Leckman, James F.
A1  - Lennertz, Leonhard
A1  - Liu, Chunyu
A1  - Lochner, Christine
A1  - Lowe, Thomas L.
A1  - Macciardi, Fabio
A1  - McCracken, James T.
A1  - McGrath, Lauren M.
A1  - Restrepo, Sandra C. Mesa
A1  - Moessner, Rainald
A1  - Morgan, Jubel
A1  - Muller, Heike
A1  - Murphy, Dennis L.
A1  - Naarden, Allan L.
A1  - Ochoa, William Cornejo
A1  - Ophoff, Roel A.
A1  - Osiecki, Lisa
A1  - Pakstis, Andrew J.
A1  - Pato, Michele T.
A1  - Pato, Carlos N.
A1  - Piacentini, John
A1  - Pittenger, Christopher
A1  - Pollak, Yehunda
A1  - Rauch, Scott L.
A1  - Renner, Tobias J.
A1  - Reus, Victor I.
A1  - Richter, Margaret A.
A1  - Riddle, Mark A.
A1  - Robertson, Mary M.
A1  - Romero, Roxana
A1  - Rosàrio, Maria C.
A1  - Rosenberg, David
A1  - Rouleau, Guy A.
A1  - Ruhrmann, Stephan
A1  - Ruiz-Linares, Andreas
A1  - Sampaio, Aline S.
A1  - Samuels, Jack
A1  - Sandor, Paul
A1  - Sheppard, Broke
A1  - Singer, Harvey S.
A1  - Smit, Jan H.
A1  - Stein, Dan J.
A1  - Strengman, E.
A1  - Tischfield, Jay A.
A1  - Valencia Duarte, Ana V.
A1  - Vallada, Homero
A1  - Van Nieuwerburgh, Flip
A1  - Veenstra-VanderWeele, Jeremy
A1  - Walitza, Susanne
A1  - Wang, Ying
A1  - Wendland, Jens R.
A1  - Westenberg, Herman G. M.
A1  - Shugart, Yin Yao
A1  - Miguel, Euripedes C.
A1  - McMahon, William
A1  - Wagner, Michael
A1  - Nicolini, Humberto
A1  - Posthuma, Danielle
A1  - Hanna, Gregory L.
A1  - Heutink, Peter
A1  - Denys, Damiaan
A1  - Arnold, Paul D.
A1  - Oostra, Ben A.
A1  - Nestadt, Gerald
A1  - Freimer, Nelson B.
A1  - Pauls, David L.
A1  - Wray, Naomi R.
A1  - Stewart, S. Evelyn
A1  - Mathews, Carol A.
A1  - Knowles, James A.
A1  - Cox, Nancy J.
A1  - Scharf, Jeremiah M.
T1  - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture
JF  - PLoS Genetics
N2  - The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
KW  - TIC disorders
KW  - missing heritability
KW  - complex diseases
KW  - neuropsychiatric disorders
KW  - common SNPS
KW  - gilles
KW  - family
KW  - brain
KW  - expression
KW  - autism
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127377
SN  - 1553-7390
VL  - 9
IS  - 10
ER  -