http://hdl.handle.net/2027.42/78557 Wed, 22 May 2013 12:07:40 GMT 2013-05-22T12:07:40Z http://deepblue.lib.umich.edu:80/bitstream/id/280501/216680.gif http://hdl.handle.net/2027.42/78557 http://hdl.handle.net/2027.42/78313 Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma Shahi, Mehdi H; Afzal, Mohammad; Sinha, Subrata; Eberhart, Charles G; Rey, Juan A; Fan, Xing; Castresana, Javier S Abstract Background The Sonic hedgehog (Shh) signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. Methods We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR) to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Results Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63%) and primary astrocytoma tumor samples (32%), but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Conclusions Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes. Mon, 08 Nov 2010 00:00:00 GMT http://hdl.handle.net/2027.42/78313 2010-11-08T00:00:00Z http://hdl.handle.net/2027.42/75020 Management of Intrathecal Catheter-Tip Inflammatory Masses: A Consensus Statement Hassenbusch, Samuel; Burchiel, Kim; Coffey, Robert J.; Cousins, Michael J.; Deer, Tim; Hahn, Marc B.; Pen, Stuart Du; Follett, Kenneth A.; Krames, Elliot; Rogers, James N.; Sagher, Oren; Staats, Peter S.; Wallace, Mark; Willis, Kenneth Dean In a companion article, we synthesized current clinical and preclinical data to formulate hypotheses about the etiology of drug administration catheter-tip inflammatory masses. In this article, we communicate our recommendations for the detection, treatment, mitigation, and prevention of such masses. Methods. We reviewed published and unpublished case reports and our own experiences to find methods to diagnose and treat catheter-tip inflammatory masses in a manner that minimized adverse neurological sequelae. We also formulated hypotheses about theoretical ways to mitigate, and possibly, prevent the formation of such masses. Results. Human cases have occurred only in patients with chronic pain who received intrathecal opioid drugs, alone or mixed with other drugs, or in patients who received agents that were not labeled for long-term intrathecal use. Most patients had noncancer pain owing to their large representation among the population with implanted pumps. Such patients also had a longer life expectancy and exposure to intrathecal drugs, and they received higher daily doses than patients with cancer pain. Clues to diagnosis included the loss of analgesic drug effects accompanied by new, gradually progressive neurological symptoms and signs. When a mass was diagnosed before it filled the spinal canal or before it caused severe neurological symptoms, open surgery to remove the mass often was not required. Anecdotal reports and the authors' experiences suggest that cessation of drug administration through the affected catheter was followed by shrinkage or disappearance of the mass over a period of 2-5 months. Conclusions. Attentive follow-up and maintenance of an index of suspicion should permit timely diagnosis, minimally invasive treatment, and avoidance of neurological injury from catheter-tip inflammatory masses. Whenever it is feasible, positioning the catheter in the lumbar thecal sac and/or keeping the daily intrathecal opioid dose as low as possible for as long possible may mitigate the seriousness, and perhaps, reduce the incidence of such inflammatory masses. Sun, 01 Dec 2002 00:00:00 GMT http://hdl.handle.net/2027.42/75020 2002-12-01T00:00:00Z http://hdl.handle.net/2027.42/74405 Letters to the Editors Barkan, Ariel L. Wed, 01 Dec 1999 00:00:00 GMT http://hdl.handle.net/2027.42/74405 1999-12-01T00:00:00Z http://hdl.handle.net/2027.42/73651 CT Angiography is Cost-Effective for Confirmation of Internal Carotid Artery Occlusions Brown, Devin L.; Hoffman, Stuart N.; Jacobs, Teresa L.; Gruis, Kirsten L.; Johnson, Susan L.; Chernew, Michael E. BACKGROUND AND PURPOSE While sensitive to internal carotid artery (ICA) occlusion, carotid ultrasound can produce false-positive results. CT angiography (CTA) has a high specificity for ICA occlusion and is safer and cheaper than catheter angiography, although less accurate. We determined the cost-effectiveness of CTA versus catheter angiography for confirming an ICA occlusion first suggested by carotid ultrasound. METHODS A Markov decision-analytic model was constructed to estimate the cost-effectiveness of CTA compared with catheter angiography in a hypothetical cohort of symptomatic patients with a screening examination consistent with an ICA occlusion. Costs in 2004 dollars were estimated from Medicare reimbursement. Effectiveness was measured in quality-adjusted life years. RESULTS The 2-year cost in the CTA scenario was $9,178, and for catheter angiography, $11,531, consistent with a $2,353 cost-savings per person for CTA. CTA resulted in accrual of 1.83 quality-adjusted life years while catheter angiography resulted in 1.82 quality-adjusted life years. CTA was less costly and marginally more effective than catheter angiography. In sensitivity analyses, when CTA sensitivity and specificity were allowed to vary across a plausible range, CTA remained cost-effective. CONCLUSIONS After screening examination has suggested an ICA occlusion, confirmatory testing with CTA provides similar effectiveness to catheter angiography and is less costly. J Neuroimaging 2008;18:355–359. Wed, 01 Oct 2008 00:00:00 GMT http://hdl.handle.net/2027.42/73651 2008-10-01T00:00:00Z