Homeobox b5(Hoxb5) regulates the expression of Forkhead box D3 gene (Foxd3) in neural crest

Patterning of neural crest (NC) for the formation of specific structures along the anterio-posterior (A-P) body axis is governed by a combinatorial action of Hox genes, which are expressed in the neuroepithelium at the time of NC induction. Hoxb5 was expressed in NC at both induction and migratory stages, and our previous data suggested that Hoxb5 played a role in the NC development. However, the underlying mechanisms by which Hoxb5 regulates the early NC development are largely unknown. Current study showed that both the human and mouse Foxd3 promoters were bound and trans-activated by Hoxb5 in NC-derived neuroblastoma cells. The binding of Hoxb5 to Foxd3 promoter in vivo was further confirmed in the brain and neural tube of mouse embryos. Moreover, Wnt1-Cre mediated perturbation of Hoxb5 signaling at the dorsal neural tube in mouse embryos resulted in Foxd3 down-regulation. In ovo, Foxd3 alleviated the apoptosis of neural cells induced by perturbed Hoxb5 signaling, and Hoxb5 induced ectopic Foxd3 expression in the chick neural tube. This study demonstrated that Hoxb5 (an A-P patterning gene) regulated the NC development by directly inducing Foxd3 (a NC specifier and survival gene).postprin

Frameless stereotactic radiosurgery for brain metastases: a review of outcomes and prognostic scores evaluation

Introduction: Stereotactic brain radiosurgery provides good local control in patients with limited brain metastases. A newly developed frameless system allows pain-free treatment. We reviewed the effectiveness of this frameless stereotactic brain radiosurgery and identified prognostic factors that may aid better patient selection. Methods: Medical records of patients with brain metastases treated with linear accelerator–based frameless stereotactic brain radiosurgery between January 2010 and July 2015 in a university affiliated hospital in Hong Kong were reviewed. Outcomes including local and distant brain control rate, progression-free survival, and overall survival were analysed. Prognostic factors were identified by univariable and multivariable analyses. Association of outcomes with four common prognostic scores was performed. Results: In this study, 64 patients with 94 lesions were treated with a median dose of 18 Gy (range, 12-22 Gy) in a single fraction. The median follow-up was 11.5 months. One-year actuarial local and distant brain control rates were 72% and 71%, respectively. The median overall survival was 13.0 months. On multivariable analysis, Karnofsky performance status score (>50 vs ≤50) and number of lesions (1-2 vs ≥3) were found to associate significantly with distinct brain progression-free survival (P=0.022, hazard ratio=0.20, 95% confidence interval 0.05-0.80 and P=0.003, hazard ratio=0.31, 95% confidence interval 0.14-0.68, respectively). Overall survival was associated significantly with Basic Score for Brain Metastases (P=0.031), Score Index for Radiosurgery in Brain Metastases (P=0.007), and Graded Prognostic Assessment (P=0.003). Improvement in overall survival was observed in all groups of different prognostic scores. Conclusion: Frameless stereotactic brain radiosurgery is effective in patients with oligometastases of brain and should be increasingly considered in patients with favourable prognostic scoring.published_or_final_versio

Dose reduction to normal tissues as compared to the gross tumor by using intensity modulated radiotherapy in thoracic malignancies

BACKGROUND AND PURPOSE: Intensity modulated radiotherapy (IMRT) is a powerful tool, which might go a long way in reducing radiation doses to critical structures and thereby reduce long term morbidities. The purpose of this paper is to evaluate the impact of IMRT in reducing the dose to the critical normal tissues while maintaining the desired dose to the volume of interest for thoracic malignancies. MATERIALS AND METHODS: During the period January 2002 to March 2004, 12 patients of various sites of malignancies in the thoracic region were treated using physical intensity modulator based IMRT. Plans of these patients treated with IMRT were analyzed using dose volume histograms. RESULTS: An average dose reduction of the mean values by 73% to the heart, 69% to the right lung and 74% to the left lung, with respect to the GTV could be achieved with IMRT. The 2 year disease free survival was 59% and 2 year overall survival was 59%. The average number of IMRT fields used was 6. CONCLUSION: IMRT with inverse planning enabled us to achieve desired dose distribution, due to its ability to provide sharp dose gradients at the junction of tumor and the adjacent critical organs

Roles of Hoxb5 in the development of vagal and trunk neural crest cells

Neural crest cells (NC) are a group of multipotent stem cells uniquely present in vertebrates. They are destined to form various organs according to their anterior-posterior (A-P) levels of origin in the neural tube (NT). They develop into a wide spectrum of cell lineages under the influence of signaling cascades, neural plate border genes and NC specifier genes. Although this complex gene regulatory network (GRN) specifies the fate of NC and the combinatory action of Hox genes executed at the time of NC induction governs the patterning of NC for the formation of specific structures along the A-P axis, not much information on how GRN and Hox genes directly interact and orchestrate is available. This review summarizes recent findings on the multiple roles of Hoxb5 on the survival and cell lineage differentiation of vagal and trunk NC cells during early development, by direct transcriptional regulation of NC specifier genes (Sox9 and Foxd3) of the GRN. We will also review findings on the transcriptional regulation of Ret by Hoxb5 in the population of the vagal NC that are committed to the enteric neuron and glia lineages. Functional redundancy between Hox proteins (Hoxa5 and Hoxc5) from the same paralogue group as Hoxb5, and the cooperative effects of Hox cofactors, collaborators and transcription factors in the Hoxb5 transcriptional regulation of target genes will also be discussed. © 2015 Japanese Society of Developmental Biologists.link_to_OA_fulltex

Expression of engrailed-Hoxb5 transcriptional repressor by Wnt1-Cre produces neurocristopathies of pigmentation and enteric nervous system defects in mice

Poster: P-33

Peritonitis induces native and EDA+ fibronectin synthesis in human peritoneal mesothelial cells through PI3K and MAPK activation

Thursday Poster Session - Peritoneal Dialysis 2: no. FR-PO819BACKGROUND: Peritonitis is a severe complication of peritoneal dialysis (PD), which could lead to progressive structural and functional deterioration of the peritoneum and PD failure. EDA+ fibronectin (FN) is induced during disease states, but its expression in PD associated peritonitis has not been investigated. We examined peritoneal expression of native and EDA+ FN in an experimental model of peritonitis and their association with mesothelial epithelial-to mesenchymal transition. METHODS: Male C57BL/6 mice were challenged with PBS or lipopolysaccharide (LPS, 500mg) by intraperitoneal injection for 2, 3 and 6 times (n=6), after which time the parietal peritoneum was excised for further studies. Confluent, growth arrested human peritoneal mesothelial cells (HPMC) were stimulated with spent peritonitis PD fluid, LPS, or exogenous TGF-β1 or CTGF (growth factors that are increased during peritonitis) either alone or in combination, for periods up to 72h to investigate their effect on cell morphology, and FN, collagen and SNAIL synthesis. RESULTS: Mice exposed to six, but not fewer, challenges of LPS exhibited mesothelial denudation, influx of infiltrating cells and substantial submesothelial thickening attributed to increased collagen and native and EDA+ FN deposition. Peritonitis PD fluid induced phenotypic changes, and SNAIL, collagen I, and native and EDA+ FN synthesis in HPMC. Exogenous TGF-β1, but not CTGF, significantly increased native and EDA+ FN by 4.3- fold and 6.2-fold respectively (P < 0.05 for both). Cells co-stimulated with TGF-β1 and CTGF showed synergistic increase of native and EDA+ FN. This was mediated in part through PI3K, ERK and p38 MAPK activation. TGF-β1 and CTGF neutralizing antibody significantly decreased native and EDA+ FN synthesis, but had no effect on collagen I or SNAIL expression in HPMC. CONCLUSIONS: Our data demonstrated that peritonitis, especially when recurrent, induced progressive peritoneal deposition of collagen, and native and EDA+ FN. TGF-β1 and CTGF synergistically induced native and EDA+ FN synthesis in HPMC, and play important roles in peritoneal fibrosis induced by bacterial peritonitis. Funding: Government Support - Non-U.S

MicroRNA-200c Inhibits TGF-beta1-induced Epithelial-to-mesenchymal Transition and Fibrogenesis in Peritoneal Mesothelial Cells

Poster Presentation - Session: Peritoneal Dialysis –

Laryngeal carcinoma: Five-year survival and patterns of failure in 202 consecutive patients treated with primary or post-operative radiotherapy in Hong Kong

Objectives: We aimed to conduct a retrospective analysis of patients treated with radiotherapy for laryngeal carcinoma at a single institution. Methods: We analysed data from 202 consecutive patients treated with primary or post-operative radiotherapy for laryngeal carcinoma over a 10-year period. Results: Sixty-nine patients had a T1, 65 a T2, 39 a T3 and 29 a T4 lesion. Forty-one patients were node-positive. The clinical stage was I in 67 patients, II in 53, III in 36 and IV in 46. Primary radiotherapy was given to 152 patients. The median follow up was 60 months. The five-year overall local control rate was 86 per cent, the ultimate local control rate was 93 per cent, the five-year regional control rate was 96 per cent, the five-year relapse-free survival rate was 82 per cent and the five-year overall survival rate was 69 per cent. Conclusions: Patients with laryngeal carcinoma treated with primary or post-operative radiotherapy had a five-year overall survival rate of 69 per cent. © 2006 JLO (1984) Limited.link_to_subscribed_fulltex

Nasopharyngectomy and surgical margin status: A survival analysis

Objective: To explore whether the margin status at surgical salvage nasopharyngectomy for local residual or recurrent nasopharyngeal carcinoma affects patient survival. Design: Retrospective case series review. Setting: Academic tertiary referral center. Patients: Seventy-nine consecutive patients with operable local residual or recurrent nasopharyngeal carcinoma after failure of primary treatment with radiotherapy with or without chemotherapy underwent surgical salvage nasopharyngectomy with curative intent between November 28, 1987, and November 17, 2003. Sixty-one patients were men and 18 were women. Their mean age was 48 years (age range, 26-70 years). Intervention: Surgical salvage nasopharyngectomy. Main Outcome Measures: The status of the closest margin at surgery was assessed as clear, close, or positive. Survival time was measured from the date of surgery to the date of the last follow-up, to the date of an event occurrence, or to the date of death. The Kaplan-Meier method was used to estimate the probability of local progression-free survival and overall survival at 5 years. Differences in survival rates between surgical margin statuses were assessed using the log-rank test. Results: Five-year overall survival for patients with clear margins was 77%, for patients with close margins was 46% (P = .05), and for patients with positive margins was 23% (P < .001). Conclusion: Clear surgical margins at the time of surgical salvage nasopharyngectomy for residual or recurrent nasopharyngeal carcinoma positively affect patient survival. ©2007 American Medical Association. All rights reserved.link_to_subscribed_fulltex

Nasopharyngectomy and surgical margin status: A survival analysis

Objective: To explore whether the margin status at surgical salvage nasopharyngectomy for local residual or recurrent nasopharyngeal carcinoma affects patient survival. Design: Retrospective case series review. Setting: Academic tertiary referral center. Patients: Seventy-nine consecutive patients with operable local residual or recurrent nasopharyngeal carcinoma after failure of primary treatment with radiotherapy with or without chemotherapy underwent surgical salvage nasopharyngectomy with curative intent between November 28, 1987, and November 17, 2003. Sixty-one patients were men and 18 were women. Their mean age was 48 years (age range, 26-70 years). Intervention: Surgical salvage nasopharyngectomy. Main Outcome Measures: The status of the closest margin at surgery was assessed as clear, close, or positive. Survival time was measured from the date of surgery to the date of the last follow-up, to the date of an event occurrence, or to the date of death. The Kaplan-Meier method was used to estimate the probability of local progression-free survival and overall survival at 5 years. Differences in survival rates between surgical margin statuses were assessed using the log-rank test. Results: Five-year overall survival for patients with clear margins was 77%, for patients with close margins was 46% (P = .05), and for patients with positive margins was 23% (P < .001). Conclusion: Clear surgical margins at the time of surgical salvage nasopharyngectomy for residual or recurrent nasopharyngeal carcinoma positively affect patient survival. ©2007 American Medical Association. All rights reserved.link_to_subscribed_fulltex