167 research outputs found
Market structure and hospital efficiency: Evaluating potential effects of deregulation in a national health service
No full textIn this article we examine the potential effect of market structure on hospital technical efficiency as a measure of performance controlled by ownership and regulation. This study is relevant to provide an evaluation of the potential effects of recommended and initiated deregulation policies in order to promote market reforms in the context of a European National Health Service. Our goal was reached through three main empirical stages. Firstly, using patient origin data from hospitals in the region of Catalonia in 1990, we estimated geographic hospital markets through the Elzinga--Hogarty approach, based on patient flows. Then we measured the market level of concentration using the Herfindahl--Hirschman index. Secondly, technical and scale efficiency scores for each hospital was obtained specifying a Data Envelopment Analysis. According to the data nearly two--thirds of the hospitals operate under the production frontier with an average efficiency score of 0.841. Finally, the determinants of the efficiency scores were investigated using a censored regression model. Special attention was paid to test the hypothesis that there is an efficiency improvement in more competitive markets. The results suggest that the number of competitors in the market contributes positively to technical efficiency and there is some evidence that the differences in efficiency scores are attributed to several environmental factors such as ownership, market structure and regulation effects.Geographic markets, market concentration, technical efficiency, data envelopment analysis, censored regression model
Bibliographie
No full textAckerman, N. W., The psychodynamics of family life, New York, Basic Books, 1958. Aguilera, D. C., Intervention en situation de crise, Paris, InterÉditions, 1995. American Psychiatric Association, Manuel diagnostique et statistique des troubles mentaux (4e édition), Paris, Masson, 1996. Anderson, C. M., G. E. Hogarty et D. J. Reiss, « Family treatment of adult schizophrénic patients: A psycho-educational approach », Schizophrenia Bulletin, vol. 6, 1980, p. 490-505. Andersen, T., « The reflecti..
A Structural Approach to Market Definition With an Application to the Hospital Industry
No full textMarket definition is essential to merger analysis. Because no standard approach to market definition exists, opposing parties in antitrust cases often disagree about the extent of the market. These differences have been particularly relevant in the hospital industry, where the courts have denied seven of eight merger challenges since 1994, due largely to disagreements over geographic market definition. We compare geographic markets produced using common ad hoc methodologies to a method that directly applies the “SSNIP test” to hospitals in California using a structural model. Our results suggest that previously employed methods overstate hospital demand elasticities by a factor of 2.4 to 3.4 and define larger markets than would be implied by the merger guidelines’s hypothetical monopolist test. The use of these methods in differentiated product industries may lead to mistaken geographic market delineation, and was likely a contributing factor to the permissive legal environment for hospital mergers.
Abstract 1630: Modulation of the neuroblastoma microenvironment via polyamine blockade
No full textAbstract
Despite improvements in therapy over the last few decades, neuroblastoma (NB) still accounts for a considerable portion of childhood cancer-related mortalities and 5-year survival rates in patients with high-risk disease remains poor (40-50%). Amplification of MYCN and dysregulation in downstream Myc-related pathways result in NBs with high-risk features. Notably, MYCN-amplified NBs have elevated polyamine (PA) levels, and the gate-keeper enzyme in the PA synthesis pathway, ornithine decarboxylase (ODC1), is a direct target of Myc. Yet, ODC1 activity can be irreversibly inhibited by the FDA-approved drug difluoromethylornithine (DFMO), and exposure of NB cell lines in vitro to DFMO reduces cellular growth. In a mouse model of MYCN-driven NB (TH-MYCN+/+ transgenic mice), inhibition of PA synthesis with DFMO led to reductions in NB burden and extension of survival that appeared more profound than that predicted by the in vitro activity of the drug, suggesting that in addition to tumor-intrinsic effects, DFMO may have significant effects on the NB tumor microenvironment (TME). We therefore sought to characterize the tumor microenvironment of NB in TH-MYCN+/+ mice in the presence or absence of DFMO-mediated PA blockade. Tumors from DFMO treated and untreated mice were dissected, mechanically and enzymatically dissociated, and the number and frequencies of various TIL subsets were assessed using an optimized flow cytometry-based protocol. Our results indicate that DFMO reduces tumor growth and results in distinct and reproducible alterations in the cellular composition of the NB TME, the most profound of which was a significant increase in the frequency of NK cells. Moreover, we found an increase in the percentage of tumor cells expressing NK cell ligands. Concordantly, we also witnessed a shift in the NK cell expression of activating and inhibitory receptors. These findings are consistent with the hypothesis that PA blockade induces distinct TME changes that predispose to more efficient immune control of NB growth. To probe the contribution of NK cells to this process, we are now testing whether antibody-mediated depletion of NK cells in DFMO-treated TH-MYCN+/+ mice results in loss of the extension in survival afforded by PA blockade. In parallel, we are also performing transcriptomic analysis on tumor and NK cells sorted from DFMO-treated and untreated tumors, to ascertain whether specific signaling pathways may be being altered by exposure to DFMO. It is our hope that these studies will complement the data being accrued from phase I/II clinical studies using DFMO in various therapeutic strategies for NB, and will allow for an increased understanding of how to more effectively combine PA blockade with other immunotherapies for this disease.
Citation Format: Adriana D. Benavides, Annette Vu, Gabrielle M. Ferry, Michael D. Hogarty, Hamid Bassiri. Modulation of the neuroblastoma microenvironment via polyamine blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1630. doi:10.1158/1538-7445.AM2017-1630</jats:p
Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas
No full textThis article is available open access through the publisher’s website. Copyright @ 2009 The Authors.Background - Clusterin expression in various types of human cancers may be higher or lower than in normal tissue, and clusterin may promote or inhibit apoptosis, cell motility, and inflammation. We investigated the role of clusterin in tumor development in mouse models of neuroblastoma. Methods - We assessed expression of microRNAs in the miR-17-92 cluster by real-time reverse transcription–polymerase chain reaction in MYCN-transfected SH-SY5Y and SH-EP cells and inhibited expression by transfection with microRNA antisense oligonucleotides. Tumor development was studied in mice (n = 66) that were heterozygous or homozygous for the MYCN transgene and/or for the clusterin gene; these mice were from a cross between MYCN-transgenic mice, which develop neuroblastoma, and clusterin-knockout mice. Tumor growth and metastasis were studied in immunodeficient mice that were injected with human neuroblastoma cells that had enhanced (by clusterin transfection, four mice per group) or reduced (by clusterin short hairpin RNA [shRNA] transfection, eight mice per group) clusterin expression. All statistical tests were two-sided. Results - Clusterin expression increased when expression of MYCN-induced miR-17-92 microRNA cluster in SH-SY5Y neuroblastoma cells was inhibited by transfection with antisense oligonucleotides compared with scrambled oligonucleotides. Statistically significantly more neuroblastoma-bearing MYCN-transgenic mice were found in groups with zero or one clusterin allele than in those with two clusterin alleles (eg, 12 tumor-bearing mice in the zero-allele group vs three in the two-allele group, n = 22 mice per group; relative risk for neuroblastoma development = 4.85, 95% confidence interval [CI] = 1.69 to 14.00; P = .005). Five weeks after injection, fewer clusterin-overexpressing LA-N-5 human neuroblastoma cells than control cells were found in mouse liver or bone marrow, but statistically significantly more clusterin shRNA-transfected HTLA230 cells (3.27%, with decreased clusterin expression) than control-transfected cells (1.53%) were found in the bone marrow (difference = 1.74%, 95% CI = 0.24% to 3.24%, P = .026). Conclusions - We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.Sport Aiding Medical Research for Kids (SPARKS), Great Ormond Street
Hospital/National Health Service, the National
Cancer Institute and University of Parma
Why Mergers Fail
No full textA number of empirical studies have shown that negative abnormal returns often result shortly after a once promising merger is consummated. There are few consistent explanations, however, as to why so many mergers result in such poor performance. This paper sheds light on this issue by examining the effect that structural factors (including market concentration and R&D intensity) have on post-merger abnormal returns. The paper also attempts to assess how differences in valuation among bidders, along with the presence of multiple bidders, influencethe performance of the merged firm. Our findings show that firm value is positively impacted in the first one to three years post merger by acquiring related assets, but that participating in a merger wave in these years has a negative influence. Over longer periods of time these effects are not evident and instead post-merger performance is impacted foremost by intangible asset intensity.Mergers, Challenges, Abnormal Returns, Research and Development (R&D), Market Concentration
Using cognitive enhancement therapy to prevent further impairment due to the impact of the symptoms of schizophrenia and the implications for counseling at assertive community treatment programs
No full textAbstract 1201: Disrupted endoplasmic reticulum-mitochondria contacts promote multidrug resistance
No full textAbstract
Background: Most high-risk neuroblastoma patients succumb to lethal therapy resistant disease acquired during the course of intensive multimodality treatment. This acquired therapy resistance is largely attributed to insensitivity to drug-induced apoptosis, however the exact mechanisms remain unknown. Apart from integrating death signals, mitochondria (mito) interact with the endoplasmic reticulum (ER) at close contact sites known as mitochondria associated membranes (MAM) of the ER to regulate calcium and lipid transfer and apoptotic sensitivity, a process often derailed in therapy resistant cancers. ER-mito contact sites are juxtaposed by various tethering protein complexes that include MFN2 and PACS2. Pathologic deregulation of these contact sites has been implicated in the genesis of neurodegenerative and metabolic disorders. Here, we show that disruption of bona fide ER-mito tethering proteins in therapy sensitive neuroblastomas induces apoptotic insensitivity and a drastic shift towards a resistance-like phenotype.
Methods and Results: Previously we showed that isolated mitochondria from tumors at relapse resist induction of mitochondrial apoptosis when primed with the terminal death effectors that are downstream of therapeutic stress (tBid and Bim-BH3 peptide). We isolated mitochondria from seven matched isogenic tumor pairs obtained at diagnosis (DX) and relapse (REL) and quantified their apoptotic response to tBid and Bim by measuring cytochrome C release by ELISA. Electron microscopy (EM) image analyses of ER-mito contact sites revealed that REL tumors contain up to 70% fewer ER-mito interactions than their matched DX tumors, as confirmed by IB for organelle-specific proteins. Here, we recapitulate the post-therapy resistance phenotype in DX therapy sensitive cells by shRNA silencing of MFN2 or PACS2 and confirm their apoptotic resistance by BH3 profiling and drug response in vitro. A 60% decrease in MFN2 protein in DX cells partially phenocopied the resistance profile of isogenic REL cells. The degree of apoptotic resistance correlated with the extent of protein knockdown for MFN2. Treatment of shMFN2 and shPACS2 DX cells with ABT-737, a BH3 mimetic, or carboplatin, increased their IC50s multiple-fold compared to control cells, paralleling their blunted mitochondrial apoptotic response.
Conclusions: Our data implicate ER-mito contact sites as positive regulators of apoptosis, whose disruption may be necessary for apoptotic attenuation in therapy resistant cancer cells to enable apoptosis evasion and survival. We present a potential mechanism for broad therapy resistance arising under therapeutic stress that selects for reduced communication of ER with mitochondria.
Citation Format: Jorida Coku, Madison C. Pedrotty, David M. Booth, Sharon Kim, Annette Vu, C. Patrick Reynolds, György Hajnóczky, Michael D. Hogarty. Disrupted endoplasmic reticulum-mitochondria contacts promote multidrug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1201. doi:10.1158/1538-7445.AM2017-1201</jats:p
Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells
No full textBACKGROUND: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. RESULTS: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. CONCLUSION: A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target
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