http://hdl.handle.net/2440/296 Thu, 20 Jun 2013 01:25:42 GMT 2013-06-20T01:25:42Z http://hdl.handle.net/2440/78419 Title: Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer Author: Ravindranathan, Preethi; Lee, Tae-Kyung; Yang, Lin; Centenera, Margaret Mary; Butler, Lisa Maree; Tilley, Wayne Desmond; Hsieh, Jer-Tsong; Ahn, Jung-Mo; Raj, Ganesh V. Abstract: The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein–protein interactions involving LXXLL motifs in androgen receptor–coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor–coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor–coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer. Description: Extent: 11 p. Mon, 31 Dec 2012 13:30:00 GMT http://hdl.handle.net/2440/78419 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78405 Title: Association between monosodium glutamate intake and sleep-disordered breathing among Chinese adults with normal body weight Author: Shi, Zumin; Wittert, Gary Allen; Yuan, Baojun; Dai, Yue; Gill, Tiffany Kaye; Hu, Gang; Adams, Robert John; Zuo, Hui; Taylor, Anne Winifred Mon, 31 Dec 2012 13:30:00 GMT http://hdl.handle.net/2440/78405 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78393 Title: Ten-year survival and clinical outcome of the AcroFlex lumbar disc replacement for the treatment of symptomatic disc degeneration Author: Meir, Adam R.; Freeman, Brian James Christopher; Fraser, Robert D.; Fowler, Shaun Abstract: BACKGROUND CONTEXT We have previously reported on the osseointegration, stability, and preserved motion of the AcroFlex lumbar disc replacement (LDR) in a nonhuman primate model. Detailed biomechanical testing of the device predicted implant survival for at least 10 years of in vivo use. Significant improvements in the clinical outcome were reported at 2 years. However, mechanical failure of the polyolefin rubber was detected by fine-cut computed tomography (CT) in a number of subjects within 2 years. As a result, no further devices were implanted. PURPOSE To report on the 10-year survival and clinical outcome of the AcroFlex elastomeric LDR when used for the treatment of one- or two-level symptomatic disc degeneration between L4 and S1. STUDY DESIGN Prospective nonrandomized clinical trial with a mean 10-year follow-up. PATIENT SAMPLE Twenty-eight patients with symptomatic disc degeneration who underwent AcroFlex LDR at one or two levels. OUTCOME MEASURES Clinical: Visual Analog Score for back pain, Oswestry Disability Index (ODI), Low Back Outcome Score (LBOS), and Short Form-36 (SF-36). Survival: Kaplan-Meier analysis over 10 years with first revision surgery as the end point. Radiographic: Dynamic flexion/extension radiographs at 2 years. Magnetic resonance imaging (MRI) and CT scans at 10 years. METHODS Twenty-eight subjects (14 male, mean age 41 years) with symptomatic disc degeneration unresponsive to nonsurgical treatment were enrolled into a prospective nonrandomized trial of the AcroFlex LDR. Visual analog score for back pain, ODI, LBOS, and SF-36 questionnaires were administered preoperatively at 6 months, 1, 2, and 10 years after the index procedure. All subjects were invited to undergo an MRI and for those with the device remaining in situ, a lumbar CT scan. Kaplan-Meier survival analysis was performed with first revision surgery as the end point. RESULTS At a mean of 9 years, 8 months (range, 8 years, 8 months–11 years, 3 months) after surgery, 17 of 28 patients did not require a revision surgery, representing a cumulative survival of 60.7%. In contrast, 11 of 28 patients (39.3%) underwent a total of 14 revision procedures; 9 of 11 patients underwent a conversion to anterior lumbar interbody fusion supplemented with pedicle screw fixation. Indications for a revision included device failure in seven and disabling pain in four patients. Mean time to revision was 3 years, 10 months (range, 23 months–8 years, 4 months). Mean ODI at 10 years for nonrevision cases was 27.5 (±17.6) compared with 41.8 (±26) for revision cases. Mean improvement over 10 years in the ODI for nonrevision cases was 17.9 (±16.9) compared with 12 (±16.1) for revision cases. Similar trends were observed in LBOS and SF-36 scores. Radiographic findings in the revision group included midsubstance tears in the rubber, osteolysis, and implant displacement. CT findings in 11 of 17 survivors included heterotopic bone formation (85%), osteolysis (50%), and subsidence (14%). Magnetic resonance imaging in 14 of 23 subjects at the final follow-up demonstrated an adjacent-level disc degeneration in 68% of those with the AcroFlex LDR in situ and in 40% of those who had been converted to fusion. Skip-level disc degeneration was present in 44% of those with AcroFlex device in situ and in 20% of those who had been converted to fusion. CONCLUSIONS The cumulative survival was 60.7% at 10 years when the first revision surgery was taken as the end point. The etiology of the implant failure prompting the revision included failure of osseointegration, midsubstance elastomeric tears, and osteolysis. Further use of this implant is not justified. The incidence of adjacent-level disc degeneration for the AcroFlex was comparable with that observed adjacent to the spinal fusion. Salvage procedures involving conversion to spinal fusion are technically demanding, but appear to improve outcomes modestly. Mon, 31 Dec 2012 13:30:00 GMT http://hdl.handle.net/2440/78393 2012-12-31T13:30:00Z http://hdl.handle.net/2440/78379 Title: Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: Evidence for site-specific skeletal effects Author: Vandyke, Kate; Fitter, Stephen; Drew, Jenny J.; Fukumoto, Seiji; Schultz, Christopher G.; Sims, Natalie A.; Yeung, David Tak On; Hughes, Timothy Peter; Zannettino, Andrew Christopher William Abstract: CONTEXT: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit+ gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume. OBJECTIVE: In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. DESIGN, PATIENTS, AND INTERVENTION: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis. RESULTS: Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck. CONCLUSIONS: These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck. Mon, 31 Dec 2012 13:30:00 GMT http://hdl.handle.net/2440/78379 2012-12-31T13:30:00Z