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Condition: Ataxia

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Total 67 results found since Jan 2013.

Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells.
Abstract Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels de...
Source: Cerebellum - April 29, 2017 Category: Neuroscience Authors: Kemp K, Dey R, Cook A, Scolding N, Wilkins A Tags: Cerebellum Source Type: research

Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research

Neurotoxic mechanisms by which the USP14 inhibitor IU1 depletes ubiquitinated proteins and Tau in rat cerebral cortical neurons: relevance to Alzheimer's disease
In conclusion, pharmacologically inhibiting (with low or high IU1 concentrations) or genetically down-regulating USP14 fail to enhance proteasomal degradation of Ub-proteins or Tau in neurons. Graphical abstract
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - April 1, 2017 Category: Molecular Biology Source Type: research

Neurotoxic mechanisms by which the USP14 inhibitor IU1 depletes ubiquitinated proteins and Tau in rat cerebral cortical neurons: relevance to Alzheimer's disease.
In conclusion, pharmacologically inhibiting (with low or high IU1 concentrations) or genetically down-regulating USP14 fail to enhance proteasomal degradation of Ub-proteins or Tau in neurons. PMID: 28372990 [PubMed - as supplied by publisher]
Source: Biochimica et Biophysica Acta - March 31, 2017 Category: Biochemistry Authors: Kiprowska MJ, Stepanova A, Todaro DR, Galkin A, Haas A, Wilson SM, Figueiredo-Pereira ME Tags: Biochim Biophys Acta Source Type: research

E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia
Publication date: 21 February 2017 Source:Cell Reports, Volume 18, Issue 8 Author(s): Monica Benini, Silvia Fortuni, Ivano Condò, Giulia Alfedi, Florence Malisan, Nicola Toschi, Dario Serio, Damiano Sergio Massaro, Gaetano Arcuri, Roberto Testi, Alessandra Rufini Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically rele...
Source: Cell Reports - February 21, 2017 Category: Cytology Source Type: research

Abstract B42: Silencing of DNA repair proteins with ECO/siRNA nanoparticles for the enhancement of radiation response in glioblastoma
In this study we investigate the use of these nanoparticles to deliver siRNA to inhibit ATM and DNApk activity and enhance radiation response in both glioma and glioma stem cell lines.Established glioma (U251) and glioma stem cell (NSC11) lines were used to evaluate the effectiveness of ECO nanoparticle delivery of siRNA in vitro . Cellular uptake of ECO nanoparticles loaded with fluorescent siRNA was assessed using flow cytometry and fluorescent microscopy, demonstrating the rapid uptake of ECO/siRNA nanoparticles in comparison to commercially available transfection agents. Protein and mRNA analyses revealed the kinetics ...
Source: Cancer Research - January 15, 2017 Category: Cancer & Oncology Authors: Jennifer A. Lee, Nadia Ayat, Anita Tandle, Zheng-Rong Lu, Kevin Camphausen Tags: Drug Delivery and Nanomedicine Source Type: research

Low-dose irradiation promotes proliferation of the human breast cancer MDA-MB-231 cells through accumulation of mutant P53.
Abstract Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells. Through cell cycle analyses, we found that LDIR accelerated cell cycle into S phase i...
Source: International Journal of Oncology - December 5, 2016 Category: Cancer & Oncology Authors: Li SJ, Liang XY, Li HJ, Li W, Zhou L, Chen HQ, Ye SG, Yu DH, Cui JW Tags: Int J Oncol Source Type: research

Genomic Characterization of Metformin Hepatic Response
by Marcelo R. Luizon, Walter L. Eckalbar, Yao Wang, Stacy L. Jones, Robin P. Smith, Megan Laurance, Lawrence Lin, Paul J. Gallins, Amy S. Etheridge, Fred Wright, Yihui Zhou, Cliona Molony, Federico Innocenti, Sook Wah Yee, Kathleen M. Giacomini, Nadav Ahituv Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin trea tment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on prima...
Source: PLoS Genetics - November 29, 2016 Category: Genetics & Stem Cells Authors: Marcelo R. Luizon Source Type: research

IGF-1R inhibition sensitizes breast cancer cells to ATM-Related Kinase (ATR) inhibitor and cisplatin.
Authors: O'Flanagan CH, O'Shea S, Lyons A, Fogarty FM, McCabe N, Kennedy RD, O'Connor R Abstract The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-r...
Source: Oncotarget - July 30, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Silencing of ataxia-telangiectasia mutated by siRNA enhances the in vitro and in vivo radiosensitivity of glioma.
In conclusion, silencing of ATM via the siRNA technique could improve the in vitro and in vivo radiosensitivity of glioma cells. PMID: 27108486 [PubMed - as supplied by publisher]
Source: Oncology Reports - April 27, 2016 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

The Role of Staufen1 in Aberrant RNA Metabolism in SCA2 (P6.396)
Conclusions: Our results unravel a novel function for Staufen1 in aberrant RNA processing events and indicate its role in SCA2 pathogenesis. Our results further support a role for aberrant RNA metabolism in neurodegeneration thereby revealing its potential as a therapeutic target. Study Supported by: This work was supported by Grants RO1NS33123 and RC4NS073009 from the National Institutes of Neurological Disorders and Stroke to SMP.Disclosure: Dr. Paul has nothing to disclose. Dr. Dansithong has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Scoles has nothing to disclose. Dr. Pulst has received personal co...
Source: Neurology - April 3, 2016 Category: Neurology Authors: Paul, S., Dansithong, W., Figueroa, K., Scoles, D., Pulst, S. Tags: Movement Disorders: Spinocerebellar Ataxias Source Type: research

The ATM inhibitor KU55933 sensitizes radioresistant bladder cancer cells with DAB2IP gene defect.
CONCLUSIONS: Loss of DAB2IP expression in BCa cells signifies their radioresistance. KU55933, which suppresses ATM phosphorylation upon irradiation, could be applied in the radiotherapy of BCa patients with a DAB2IP gene defect. PMID: 25585815 [PubMed - indexed for MEDLINE]
Source: International Journal of Radiation Biology - February 18, 2016 Category: Radiology Tags: Int J Radiat Biol Source Type: research

Abstract B29: LRP16 is an essential mediator for DNA double-strand breaks induced NF-kappaB activation
In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKgamma. This interaction is essential for efficient interactions among PARP1, IKKgamma, and PIASy, the modifications of IKKgamma, and the activation of NF-kappaB following DSB induction. The regulation of LRP16 in NF-kappaB activation is dependent on its poly (ADP-ribose) binding capability through the unique macro domain. The depletion of the DSB-specific sensor Ku80 resulted in a significant reduction in the physical interactions among LRP16, PARP1 and IKKgamma. Additionally, the knockdown of either endogenous Ku80 or Ku70 by siRNA markedl...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Wu, Z., Wang, C., Bai, M., Li, X., Mei, Q., Li, X., Wang, Y., Fu, X., Luo, G., Han, W. Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research

Androgen Receptor in Telomeres DNA and Chromosomes
Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector...
Source: Journal of Biological Chemistry - October 16, 2015 Category: Chemistry Authors: Reddy, V., Wu, M., Ciavattone, N., McKenty, N., Menon, M., Barrack, E. R., Reddy, G. P.-V., Kim, S.-H. Tags: Cell Biology Source Type: research

Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix and regulates the iron–sulfur cluster (ISC) assembly complex. ISCs are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain. Decreased expression of frataxin is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute t...
Source: Journal of Biomolecular Screening - September 18, 2015 Category: Molecular Biology Authors: Cotticelli, M. G., Acquaviva, F., Xia, S., Kaur, A., Wang, Y., Wilson, R. B. Tags: Original Research Source Type: research