Enteric Neural Crest Differentiation in Ganglioneuromas Implicates Hedgehog Signaling in Peripheral Neuroblastic Tumor Pathogenesis

Peripheral neuroblastic tumors (PNTs) share a common origin in the sympathetic nervous system, but manifest variable differentiation and growth potential. Malignant neuroblastoma (NB) and benign ganglioneuroma (GN) stand at opposite ends of the clinical spectrum. We hypothesize that a common PNT progenitor is driven to variable differentiation by specific developmental signaling pathways. To elucidate developmental pathways that direct PNTs along the differentiation spectrum, we compared the expression of genes related to neural crest development in GN and NB. In GNs, we found relatively low expression of sympathetic markers including adrenergic biosynthesis enzymes, indicating divergence from sympathetic fate. In contrast, GNs expressed relatively high levels of enteric neuropeptides and key constituents of the Hedgehog (HH) signaling pathway, including Dhh, Gli1 and Gli3. Predicted HH targets were also differentially expressed in GN, consistent with transcriptional response to HH signaling. These findings indicate that HH signaling is specifically active in GN. Together with the known role of HH activity in enteric neural development, these findings further suggested a role for HH activity in directing PNTs away from the sympathetic lineage toward a benign GN phenotype resembling enteric ganglia. We tested the potential for HH signaling to advance differentiation in PNTs by transducing NB cell lines with Gli1 and determining phenotypic and transcriptional response. Gli1 inhibited proliferation of NB cells, and induced a pattern of gene expression that resembled the differential pattern of gene expression of GN, compared to NB (p<0.00001). Moreover, the transcriptional response of SY5Y cells to Gli1 transduction closely resembled the transcriptional response to the differentiation agent retinoic acid (p<0.00001). Notably, Gli1 did not induce N-MYC expression in neuroblastoma cells, but strongly induced RET, a known mediator of RA effect. The decrease in NB cell proliferation induced by Gli1, and the similarity in the patterns of gene expression induced by Gli1 and by RA, corroborated by closely matched gene sets in GN tumors, all support a model in which HH signaling suppresses PNT growth by promoting differentiation along alternative neural crest pathways

Mobility, risk behavior and HIV/STI rates among female sex workers in Kaiyuan City, Yunnan Province, China

<p>Abstract</p> <p>Background</p> <p>The mobility of female sex workers (FSWs) is a factor in the geographic spread of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). This study describes FSW mobility patterns in a high risk area of China to identify factors associated with increased mobility, and to study the incidence and prevalence of HIV/STIs in this group.</p> <p>Methods</p> <p>270 FSWs recruited from a baseline cross-sectional study were invited to participate in a one-year monthly follow-up cohort study in Kaiyuan City, Yunnan Province, China from 2006 to 2007. Laboratory tests were conducted for HIV/STIs at baseline, 6 and 12 months.</p> <p>Results</p> <p>A total of 117 (43.3%) FSWs moved to another city during the year. Risk factors for increased mobility included being from another city within Yunnan (adjusted hazard ratio [AHR] 1.67, 95% confidence interval [CI] 1.09-2.56), being from outside Yunnan (AHR 1.58, 95% CI 1.04-2.54), and working in lower risk entertainment establishments (AHR 1.55, 95% CI 1.03-2.35). HIV-positive subjects, drug users and FSWs in higher risk venue were less likely to change residence, less likely to use condoms with clients, and earned less per client, but had more working locations and more clients each month.</p> <p>Conclusions</p> <p>The least mobile FSWs were from Kaiyuan, worked in higher risk venues, were more likely to use drugs and be HIV-infected. Because FSWs characteristics differ according to the venue at which they work, future prevention work should tailor programs according to venue with a particular focus on FSWs in higher risk venues.</p