Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma

Neuroblastoma is an embryonal malignancy of the sympathetic nervous system. Spontaneous regression and differentiation of neuroblastoma is observed in a subset of patients, and has been suggested to represent delayed activation of physiologic molecular programs of fetal neuroblasts. Homeobox genes constitute an important family of transcription factors, which play a fundamental role in morphogenesis and cell differentiation during embryogenesis. In this study, we demonstrate that expression of the majority of the human HOX class I homeobox genes is significantly associated with clinical covariates in neuroblastoma using microarray expression data of 649 primary tumors. Moreover, a HOX gene expression-based classifier predicted neuroblastoma patient outcome independently of age, stage and MYCN amplification status. Among all HOX genes, HOXC9 expression was most prominently associated with favorable prognostic markers. Most notably, elevated HOXC9 expression was significantly associated with spontaneous regression in infant neuroblastoma. Re-expression of HOXC9 in three neuroblastoma cell lines led to a significant reduction in cell viability, and abrogated tumor growth almost completely in neuroblastoma xenografts. Neuroblastoma growth arrest was related to the induction of programmed cell death, as indicated by an increase in the sub-G1 fraction and translocation of phosphatidylserine to the outer membrane. Programmed cell death was associated with the release of cytochrome c from the mitochondria into the cytosol and activation of the intrinsic cascade of caspases, indicating that HOXC9 re-expression triggers the intrinsic apoptotic pathway. Collectively, our results show a strong prognostic impact of HOX gene expression in neuroblastoma, and may point towards a role of Hox-C9 in neuroblastoma spontaneous regression

Migration rules: tumours are conglomerates of self-metastases

Tumours are heterogeneous populations composed of different cells types: stem cells with the capacity for self-renewal and more differentiated cells lacking such ability. The overall growth behaviour of a developing neoplasm is determined largely by the combined kinetic interactions of these cells. By tracking the fate of individual cancer cells using agent-based methods in silico, we apply basic rules for cell proliferation, migration and cell death to show how these kinetic parameters interact to control, and perhaps dictate defining spatial and temporal tumour growth dynamics in tumour development. When the migration rate is small, a single cancer stem cell can only generate a small, self-limited clone because of the finite life span of progeny and spatial constraints. By contrast, a high migration rate can break this equilibrium, seeding new clones at sites outside the expanse of older clones. In this manner, the tumour continually ‘self-metastasises'. Counterintuitively, when the proliferation capacity is low and the rate of cell death is high, tumour growth is accelerated because of the freeing up of space for self-metastatic expansion. Changes to proliferation and cell death that increase the rate at which cells migrate benefit tumour growth as a whole. The dominating influence of migration on tumour growth leads to unexpected dependencies of tumour growth on proliferation capacity and cell death. These dependencies stand to inform standard therapeutic approaches, which anticipate a positive response to cell killing and mitotic arrest

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas

BACKGROUND: High-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation. Recently, soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; however, the role of aberrant DNA methylation in these tumors is not well understood and, consequently, the usefulness of methylation-based classification is unclear. RESULTS: We used the Infinium HumanMethylation27 platform to profile DNA methylation in 80 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 14 representative sarcoma cell lines. The primary samples were partitioned into seven stable clusters. A classification algorithm identified 216 CpG sites, mapping to 246 genes, showing different degrees of DNA methylation between these seven groups. The differences between the clusters were best represented by a set of eight CpG sites located in the genes SPEG, NNAT, FBLN2, PYROXD2, ZNF217, COL14A1, DMRT2 and CDKN2A. By integrating DNA methylation and mRNA expression data, we identified 27 genes showing negative and three genes showing positive correlation. Compared with non-neoplastic fat, NNAT showed DNA hypomethylation and inverse gene expression in myxoid liposarcomas, and DNA hypermethylation and inverse gene expression in dedifferentiated and pleomorphic liposarcomas. Recovery of NNAT in a hypermethylated myxoid liposarcoma cell line decreased cell migration and viability. CONCLUSIONS: Our analysis represents the first comprehensive integration of DNA methylation and transcriptional data in primary high-grade soft tissue sarcomas. We propose novel biomarkers and genes relevant for pathogenesis, including NNAT as a potential tumor suppressor in myxoid liposarcomas

THE CONSERVATION OF RESIDENTIAL WATER: SCARCITY PRICING OF WATER IN NORTHERN NEW CASTLE COUNTY

Demand and Price Analysis, Resource /Energy Economics and Policy,

A SPATIAL ANALYSIS OF THE DISTRIBUTIONAL EFFECTS OF WATER QUANTITY MANAGEMENT

Resource /Energy Economics and Policy,

A Spatial Analysis of the Distributional Effects of Water Quantity Management

Water supply managers in growing areas must address increasing demand for an essentially fixed, though highly variable, resource. This worldwide problem inevitably arises as demand increases with population and standards of living (Loucks 1999, Mayor 1997). Currently, 505 million people live in water-scarce or water-stressed conditions, and this number could rise to 3.2 billion people by the year 2025 (Dunphy 2000). Water-stressed locations are not necessarily arid regions of the world. Nonporous materials in urban and suburban areas prevent rainwater from percolating through the soil. Excess water becomes runoff, which erodes riverbeds, prevents groundwater recharge, and exacerbates water supply issues. Spatially, suburban growth distributes the demand for water over a greater area. Water delivery requires increasingly more infrastructure, including holding tanks, reservoirs, treatment plants, and pumping stations. At the very least, suburban growth adds miles of new piping to the system and requires a tremendous amount of water to keep the lines full. This paper investigates the relationship between the spatial distribution of the residential population and residential water demand. Specifically, three water quantity management strategies are compared in times of deficit. Conservation is the root of demand-side management. However, conservation has many interpretations. Chesnutt and Beecher (1998) describe ecological, hydrological, traditional-economic, and resource-economic perspectives on conservation. The ecological perspective emphasizes ethical constraints to avoid the consequences of over consuming in a common property setting. The hydrological perspective focuses on the water cycle and engineering solutions to maintain water supply. Water allocation efficiency through pricing guides the traditional-economic perspective, while the resource-economic perspective merges a sustainability criterion with the traditional perspective. Any attempt to implement water management policy will undoubtedly satisfy those with one perspective and offend others. For instance, objections to the use of price arise from those who see it as insufficiently addressing ethical or supply concerns. This paper attempts to address such concerns by examining the distributional and supply impacts on residents when water scarcity pricing is implemented