ABSTRACT
Cost sharing and cost shifting mechanisms are of vital importance in a prospective payment system. This paper employed the difference-in-differences method to estimate the impacts of a per diem system with inverted-U-shape rates on medical costs and the length of stay based on data from a health insurance institution. The supply side cost sharing mechanism worked so that the new payment system significantly reduced medical costs by 17.59 percent while the average length of stay varied little. After further analyzing the mechanism, we found that heterogeneous effects emerged mainly due to the special rates design. The reform decreased the cases that incurred relatively high medical costs and lengths of stay. However, cost shifting existed so that physicians could be motivated to provide unnecessary services to the patients who should have been discharged before the average length of stay. Therefore, payment rates in the per diem system require a sophisticated design to constrain its distortion to medical service provision even though medical expenditures were successfully contained.
Subject(s)
Cost Sharing , Insurance, Health , Humans , Length of Stay , Cost Allocation , Health Expenditures , ChinaABSTRACT
Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of ErbB2. Knockdown of laminin-binding integrins (alpha6beta4, alpha3beta1) or associated tetraspanin protein CD151 reversed laminin-5 resistance and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and focal adhesion kinase (FAK). Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers.
Subject(s)
Antigens, CD/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Adhesion Molecules/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Cell Line, Tumor , Drug Synergism , Enzyme Activation , Humans , Integrin alpha3beta1/metabolism , Integrin alpha6beta4/metabolism , Lapatinib , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Signal Transduction , Tetraspanin 24 , Trastuzumab , KalininABSTRACT
The primary cilium plays a key role in the development of mammals and in the maintenance of health. Primary cilia are assembled and maintained by the process of intraflagellar transport (IFT). In this work, we characterize mouse IFT complex B by identifying all of the mammalian orthologues of complex B and B-associated proteins previously identified in Chlamydomonas and Caenorhabditis and also identify a new component (IFT25/Hspb11) of complex B by database analysis. We tagged each of these proteins with the FLAG epitope and show that all except IFT172 and IFT20 localize to cilia and the peri-basal body or centrosomal region at the base of cilia. All of the proteins except IFT172 immunoprecipitate IFT88 indicating that they are co-assembled into a complex. IFT20 is the only complex B protein that localizes to the Golgi apparatus. However, overexpression of IFT54/Traf3ip1, the mouse orthologue of Dyf-11/Elipsa, displaces IFT20 from the Golgi apparatus. IFT54 does not localize to the Golgi complex nor does it interact with GMAP210, which is the protein that anchors IFT20 to the Golgi apparatus. This suggests that IFT54s effect on IFT20 is a dominant negative phenotype caused by its overexpression. Cell Motil. Cytoskeleton 2009. (c) 2009 Wiley-Liss, Inc.
Subject(s)
Carrier Proteins/metabolism , Adaptor Proteins, Signal Transducing , Animals , Blotting, Western , Cell Line , Cilia/metabolism , Cytoskeletal Proteins , Flagella/metabolism , Golgi Apparatus/metabolism , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Nuclear Proteins/metabolism , Protein Binding , Tumor Suppressor Proteins/metabolismABSTRACT
Eukaryotic cells often use proteins localized to the ciliary membrane to monitor the extracellular environment. The mechanism by which proteins are sorted, specifically to this subdomain of the plasma membrane, is almost completely unknown. Previously, we showed that the IFT20 subunit of the intraflagellar transport particle is localized to the Golgi complex, in addition to the cilium and centrosome, and hypothesized that the Golgi pool of IFT20 plays a role in sorting proteins to the ciliary membrane. Here, we show that IFT20 is anchored to the Golgi complex by the golgin protein GMAP210/Trip11. Mice lacking GMAP210 die at birth with a pleiotropic phenotype that includes growth restriction, ventricular septal defects of the heart, omphalocele, and lung hypoplasia. Cells lacking GMAP210 have normal Golgi structure, but IFT20 is no longer localized to this organelle. GMAP210 is not absolutely required for ciliary assembly, but cilia on GMAP210 mutant cells are shorter than normal and have reduced amounts of the membrane protein polycystin-2 localized to them. This work suggests that GMAP210 and IFT20 function together at the Golgi in the sorting or transport of proteins destined for the ciliary membrane.
