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Potential Therapeutic Intervention (potential + therapeutic_intervention)
Selected AbstractsAn estrogen receptor , suppressor, microRNA-22, is downregulated in estrogen receptor ,-positive human breast cancer cell lines and clinical samplesFEBS JOURNAL, Issue 7 2010Jianhua Xiong Previous studies have suggested that microRNAs (miRNAs) may play important roles in tumorigenesis, but little is known about the functions of most miRNAs in cancer development. In the present study, we set up a cell-based screen using a luciferase reporter plasmid carrying the whole , 4.7 kb 3,-UTR of estrogen receptor , (ER,) mRNA cotransfected with a synthetic miRNA expression library to identify potential ER,-targeting miRNAs. Among all the miRNAs, miR-22 was found to repress robustly the luciferase signal in both HEK-293T and ER,-positive MCF-7 cells. Mutation of the target site was found to abrogate this repression effect of miR-22, whereas antagonism of endogenous miR-22 in MDA-MB-231 cells resulted in elevated reporter signals. We assessed the miR-22 expression patterns in five breast cancer cell lines and 23 clinical biopsies and revealed that there is a significant inverse association between the miR-22 levels and ER, protein expression. To evaluate the potential of miR-22 as a potential therapeutic intervention, we found that reduction of endogenous ER, protein levels and suppression of cancer cell growth could be achieved in MCF-7 cells by miR-22 overexpression in a way that can be recapitulated by the introduction of specific small interfering RNA against ER,. The phenomena can be rescued by the reintroduction of ER,. Taken together, our data indicate that miR-22 was frequently downregulated in ER,-positive human breast cancer cell lines and clinical samples. Direct involvement in the regulation of ER, may be one of the mechanisms through which miR-22 could play a pivotal role in the pathogenesis of breast cancer. [source] Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injuryHIPPOCAMPUS, Issue 6 2006E. Schwarzbach Abstract Traumatic brain injury (TBI) is a significant health issue that often causes enduring cognitive deficits, in particular memory dysfunction. The hippocampus, a structure crucial in learning and memory, is frequently damaged during TBI. Since long-term potentiation (LTP) is the leading cellular model underlying learning and memory, this study was undertaken to examine how injury affects area CA1 LTP in mice using lateral fluid percussion injury (FPI). Brain slices derived from FPI animals demonstrated an inability to induce LTP in area CA1 7 days postinjury. However, area CA1 long-term depression could be induced in neurons 7 days postinjury, demonstrating that some forms of synaptic plasticity can still be elicited. Using a multidisciplined approach, potential mechanisms underlying the inability to induce and maintain area CA1 LTP were investigated. This study demonstrates that injury leads to significantly smaller N -methyl- D -aspartate potentials and glutamate-induced excitatory currents, increased dendritic spine size, and decreased expression of ,-calcium calmodulin kinase II. These findings may underlie the injury-induced lack of LTP and thus, contribute to cognitive impairments often associated with TBI. Furthermore, these results provide attractive sites for potential therapeutic intervention directed toward alleviating the devastating consequences of human TBI. © 2006 Wiley-Liss, Inc. [source] Regional and Developmental Expression of the Npc1 mRNA in the Mouse BrainJOURNAL OF NEUROCHEMISTRY, Issue 3 2000A. Prasad Abstract: Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive disorder of cholesterol metabolism that results in progressive central nervous system deterioration and premature death. Recently, a gene mutated in NP-C disease (NPC1) was identified in both human patients and in the npcnih mouse model. Although the function of the NPC1 gene is at present unknown, determining the pattern of its expression in the brain may facilitate identification of the mechanisms underlying the neuropathology of this disease and in identifying relevant targets for any potential therapeutic intervention. We have used in situ hybridization techniques to characterize the pattern of Npc1 mRNA expression in both the wild-type and the npcnih mutant mouse brain. In adult animals of both genotypes, the Npc1 mRNA was detected in the majority of neurons in nearly all regions, but at significantly higher levels in the cerebellum and in specific pontine nuclei. Analysis of Npc1 mRNA levels during development in the wild-type mouse indicated that this transcript was expressed in neurons as early as embryonic day 15 and that a significant region-specific pattern of expression was established by postnatal day 7. Our data suggest that whereas the NPC1 gene is widely expressed in neurons of the brain, the higher levels of expression in the cerebellum and pontine structures established by early postnatal ages may make these regions more susceptible to neuronal dysfunction in NP-C disease. [source] Vitamin E as a protective antioxidant in progressive renal failureNEPHROLOGY, Issue 1-2 2000Michael J Fryer SUMMARY: Progression to renal failure is significantly worsened by oxidative stress in chronic inflammatory kidney disease (IgA nephropathy, antiglomerular basement membrane nephritis, focal segmental glomerulosclerosis), rhabdomyolysis (myoglobinic acute renal failure), diabetic nephropathy and in poisoning by nephrotoxic compounds such as transition metals, paraquat and drugs such as cyclosporine A and cisplatin. The membrane antioxidant vitamin E (,-tocopherol) is examined as a potential therapeutic intervention that may help to slow the rate of decline of kidney function in such conditions. An impaired plasma antioxidant defence system is characteristic of chronic renal failure and the uremic state. Vitamin E therapy is also considered as a means of correcting plasma antioxidant status and attenuating the cardiovascular disease that accompanies kidney failure. [source] Apoptosis in amyotrophic lateral sclerosis: a review of the evidenceNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2001S. Sathasivam Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition. [source] Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiencyHAEMOPHILIA, Issue 3 2004L. A. Valentino Summary., Haemophilia is a genetic disease as a result of the deficiency of blood coagulation factor VIII or IX. Bleeding is common, especially into joints where an inflammatory, proliferative synovitis develops resulting in a debilitating arthritis, haemophilic arthropathy. The pathogenesis of blood-induced haemophilic synovitis (HS) is poorly understood. The gross, microscopic and ultrastructural changes that occur in the synovial membrane following human and experimental hemarthrosis have been described. Repeated episodes of bleeding induce synoviocyte hypertrophy and hyperplasia, an intense neovascular response and inflammation of the synovial membrane. The component(s) in blood that initiates these changes is(are) not known, although iron is often proposed as one possibility. Here, we describe a novel murine model of human haemophilia A, which facilitates the examination of large number of animals and tissue specimens. The effects of hemarthrosis on the physical, gross and microscopic changes evoked following joint bleeding are described. Controlled, blunt trauma to the knee joint consistently resulted in joint swelling because of a combination of bleeding and inflammation. Hemosiderin was found in the synovial membrane. Similar to hemarthrosis in human haemophilia, joint bleeding resulted in acute morbidity evidenced by inactivity, weight loss and immobility. With time the animals recovered. The model of experimental murine HS described here has utility in the study of the pathogenesis of HS. This is the first of a series of articles, which will discuss the pathophysiology and characterize the model, with comparison of his model to others which have been published previously. It should provide a useful model to test potential therapeutic interventions. [source] Biomarker as a classifier in pharmacogenomics clinical trials: a tribute to 30th anniversary of PSI,,PHARMACEUTICAL STATISTICS: THE JOURNAL OF APPLIED STATISTICS IN THE PHARMACEUTICAL INDUSTRY, Issue 4 2007Sue-Jane Wang Abstract Pharmacogenetics is one of many evolving sciences that have come to the fore since the formation of the Statisticians in the Pharmaceutical Industry (PSI) 30 years ago. Following the completion of the human genome project and the HapMap in the early 21st century, pharmacogenetics has gradually focused on studies of whole-genome single-nucleotide-polymorphisms screening associating disease pathophysiology with potential therapeutic interventions. Around this time, transcription profiling aiming at similar objectives has also been actively pursued, known as pharmacogenomics. It has become increasingly apparent that treatment effects between different genomic patient subsets can be dissimilar, and the value and need for genomic biomarkers to help predict effects, particularly in cancer clinical studies, have become issues of paramount importance. Pharmacogenomics/pharmaogenetics has thus become intensely focused on the search for genomic biomarkers for use as classifiers to select patients in randomized-controlled trials. We highlight that the predictive utility of a genomic classifier has tremendous clinical appeal and that there will be growing examples in which use of a companion diagnostic will need to be considered and may become an integral part in the utilization of drugs in medical practice. The credible mechanism to test the clinical utility of a genomic classifier is to employ the study results from a prospective trial that recruits all patients. Such investigations, if well designed, will allow analysis of all relevant performance factors in the drug and diagnostic combination including the sensitivity, specificity, positive and negative predictive values of the diagnostic test and the efficacy of the drug. Published in 2007 by John Wiley & Sons, Ltd. [source] Regulation of STARS and its downstream targets suggest a novel pathway involved in human skeletal muscle hypertrophy and atrophyTHE JOURNAL OF PHYSIOLOGY, Issue 8 2009Séverine Lamon Skeletal muscle atrophy is a severe consequence of ageing, neurological disorders and chronic disease. Identifying the intracellular signalling pathways controlling changes in skeletal muscle size and function is vital for the future development of potential therapeutic interventions. Striated activator of Rho signalling (STARS), an actin-binding protein, has been implicated in rodent cardiac hypertrophy; however its role in human skeletal muscle has not been determined. This study aimed to establish if STARS, as well as its downstream signalling targets, RhoA, myocardin-related transcription factors A and B (MRTF-A/B) and serum response factor (SRF), were increased and decreased respectively, in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. The mRNA levels of the SRF target genes involved in muscle structure, function and growth, such as ,-actin, myosin heavy chain IIa (MHCIIa) and insulin-like growth factor-1 (IGF-1), were also measured. Following resistance training, STARS, MRTF-A, MRTF-B, SRF, ,-actin, MHCIIa and IGF-1 mRNA, as well as RhoA and nuclear SRF protein levels were all significantly increased by between 1.25- and 3.6-fold. Following the de-training period all measured targets, except for RhoA, which remained elevated, returned to base-line. Our results show that the STARS signalling pathway is responsive to changes in skeletal muscle loading and appears to play a role in both human skeletal muscle hypertrophy and atrophy. [source] | |||||||||||||