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The receptor tyrosine kinase ErbB2 (HER2) is overexpressed in multiple human tumors of epithelial origin. High ErbB2 expression is functionally involved in tumorigenesis and correlates with poor clinical prognosis. For immunotherapy of ErbB2 expressing tumors, we developed a strategy to supply the tumor cells with costimulatory activity. A bispecific fusion protein was constructed (BIg5), containing the IgV-like domain of huCD86, the CH2/CH3 domain of huIgG1 and the ErbB2-specific single chain antibody fragment scFv(FRP5). A similar fusion protein lacking the CD86 domain (Ig5) was used as a control. Upon binding of BIg5 to ErbB2 on tumor cells, these cells display CD86 on their surface and thus can deliver costimulatory signals for T-cell activation. In addition, NK cells could be activated by CD86 binding to CD28. BIg5 is secreted by eukaryotic cells as a homodimer with increased stability compared to monomers and possibly enhanced costimulatory activity due to crosslinking of CD28 on effector cells. By FACS analysis, specific binding of the scFv(FRP5) domain to ErbB2 as well as CD86 IgV binding to CTLA-4 could be demonstrated. Together with anti-CD3 antibody, BIg5 stimulates proliferation of human CD2-purified lymphocytes in vitro. After binding to ErbB2 on murine Renca-lacZ/ErbB2 tumor cells, about 50% of initially bound BIg5 is still present on the cell surface after 4 hours. For delivery of chimeric fusion proteins in vivo, we used syngeneic, stably transfected HC11 mammary epithelial cells continuously secreting the proteins. Inoculation of these bystander cells close to subcutaneously growing Renca-lacZ/ErbB2 tumors should provide a long-lasting source to achieve high local concentrations of BIg5 at the tumor site. In vivo HC11-BIg5 cells proved to be non-tumorigenic and secreted BIg5 for several weeks, causing a strong anti-BIg5 antibody response. Treatment of established Renca-lacZ/ErbB2 or ErbB2-negative Renca-lacZ tumors by peritumoral inoculation of either HC11-BIg5 or HC11-Ig5 cells led to rejection of all Renca-lacZ/ErbB2, but none of the Renca-lacZ tumors. HC11neo control cells had no effect on tumor growth. Rejection of ErbB2+ tumors led to long-term protection also against subsequent challenge with intravenously injected ErbB2- tumor cells. Intraperitoneal injection of bystander cells secreting the fusion proteins did not lead to tumor regression suggesting that high local concentrations at the tumor site are necessary to target ErbB2 on tumor cells and to overcome elimination of BIg5 or Ig5 by neutralizing antibodies. The CD86 IgV domain of BIg5 did not play a major role in the observed antitumoral immune response suggesting NK-cell mediated ADCC as the initial effector mechanism followed by activation of tumor specific T cells. Targeting of ErbB2 on tumor cells with antibody fusion proteins that interact specifically with the host immune system could be an efficient and specific approach for therapy of solid ErbB2+ tumors.
Tumor-specific T lymphocytes can be regarded as a highly effective mechanism for tumor rejection. A substantial number of T-cell defined tumor antigens including mutated oncoproteins and differentiation antigens have been identified. However, while most spontaneous tumors appear to be antigenic, few are immunogenic. Activation of tumor-specific cytotoxic T cells (CTL) requires presentation of tumor antigens by professional antigen presenting cells (APCs) via MHC I molecules. Due to their crucial role in T-cell activation, APCs are being exploited for active cancer immunotherapy. Present experimental strategies include the incubation of dendritic cells with synthetic, tumor specific peptides to achieve uptake of tumor antigens and presentation in the context of MHC molecules. Alternatively, gene therapeutic approaches are aimed at the endogenous expression of tumor antigens in APCs upon transfer of suitable vector constructs. Our strategy for the presentation of tumor antigens by APCs is based on the intracellular delivery of tumor antigens as part of a fusion protein specifically targeted to APC cell surface receptors. We have constructed prototype molecules that contain a soluble fragment of CTLA-4 for cell binding via interaction with B7 molecules, genetically fused to a protein fragment derived from the tumor-associated antigen ErbB2. To improve uptake and direct the antigenic determinant preferentially to the MHC class I pathway, in one of these protein vaccines also the translocation domain of the bacterial Pseudomonas exotoxin A has been included. In the parental toxin this protein domain facilitates escape from the endosomal compartment to the cytosol upon receptor mediated endocytosis. Here we have investigated the in vitro cell binding activity of such reagents and their antitumoral activity in immunocompetent murine model systems. Specific binding to B7 molecules and uptake of bacterially expressed protein vaccines could be demonstrated. Ex vivo restimulation with an ErbB2-derived peptide of splenocytes from Balb/c mice injected with the fusion proteins resulted in enhanced IFN-gamma production by T cells. Protective and therapeutic effects of ErbB2 protein vaccines were also investigated. Vaccinated animals were protected against subsequent challenge with syngeneic ErbB2 expressing tumor cells. Likewise, s.c. injection of ErbB2 protein vaccines in the vicinity of established tumors resulted in tumor rejection and long lasting protection indicating that immunological memory was induced. Our results suggest that chimeric proteins combining a tumor antigen and specific recognition of APCs in a single molecule are suitable for targeted delivery of antigens to professional APCs and might become valuable tools for cancer immunotherapy.
We study the phase diagram of dense, locally neutral three-flavor quark matter as a function of the strange quark mass, the quark chemical potential, and the temperature, employing a general nine-parameter ansatz for the gap matrix. At zero temperature and small values of the strange quark mass, the ground state of matter corresponds to the color-flavor-locked (CFL) phase. At some critical value of the strange quark mass, this is replaced by the recently proposed gapless CFL (gCFL) phase. We also find several other phases, for instance, a metallic CFL (mCFL) phase, a so-called uSC phase where all colors of up quarks are paired, as well as the standard two-flavor color-superconducting (2SC) phase and the gapless 2SC (g2SC) phase.
We discuss gapless colour superconductivity for neutral quark matter in β equilibrium at zero as well as at nonzero temperature. Basic properties of gapless superconductors are reviewed. The current progress and the remaining problems in the understanding of the phase diagram of strange quark matter are discussed.
During the past decade, processes associated with what is popularly though perhaps misleadingly known as globalization have come within the purview of anthropology. Migration and mobility ‐ and the footloose or even rootless social groups that they produce ‐ as well as the worldwide diffusion of commodities, media images, political ideas and practices, technologies and scientific knowledge today are on anthropology's research agenda. As a consequence, received notions about the ways in which culture relates to territory have been abandoned. The term transnationalisation captures cultural processes that stream across the borders of nation states. Anthropologists have been forced to revise the notion that transnationalisation would inevitably bring about a culturally homogenized world. Instead, we are witnessing a surge of greatly increasing cultural diversity. New cultural forms grow out of historically situated articulations of the local and the global. Rather than left-over relics from traditional orders, these are decidedly modern, yet far from uniform. The essay engages the idea of the pluralization of modernities, explores its potential for interdisciplinary research agendas, and also inquires into problematic assumptions underlying this new theoretical concept.
As of today, estimating interest rate reaction functions for the Euro Area is hampered by the short time span since the conduct of a single monetary policy. In this paper we circumvent the common use of aggregated data before 1999 by estimating interest rate reaction functions based on a panel including actual EMU Member States. We find that exploiting the cross-section dimen- sion of a multi-country panel and accounting for cross-country heterogeneity in advance of the single monetary policy pays off with regard to the estimated reaction functions' ability to describe actual interest rate dynamics. We retrieve a panel reaction function which is demonstrated to be a valuable tool for evaluating episodes of monetary policy since 1999. JEL - Klassifikation: E43 , E58 , C33
This paper employs individual bidding data to analyze the empirical performance of the longer term refinancing operations (LTROs) of the European Central Bank (ECB). We investigate how banks’ bidding behavior is related to a series of exogenous variables such as collateral costs, interest rate expectations, market volatility and to individual bank characteristics like country of origin, size, and experience. Panel regressions reveal that a bank’s bidding depends on bank characteristics. Yet, different bidding behavior generally does not translate into differences concerning bidder success. In contrast to the ECB’s main refinancing operations, we find evidence for the winner’s curse effect in LTROs. Our results indicate that LTROs do neither lead to market distortions nor to unfair auction outcomes. JEL classification: E52, D44
Even though tourism has been recognised as an important field for transnational research today, there are few attempts to place tourism in the context of transnational theories or to think about transnationalism from the perspective of tourists. I argue that in researching tourist practices one can add important aspects to transnational approaches. The prerequisites of mobility and interaction for example are the features chosen by backpackers to describe what their Round-The-World-Trip is about. A form of tourism is adopted, or created, that itself confronts many aspects of globalisation: First of all there is the immense dynamic that is involved. Backpackers try to cover as many places and experiences as possible, travelling at high speed. They adopt all kinds of touristic experiences ranging from beach to adventure to culture tourism. They don't focus on a specific area or country but travel the world. They cross national borders perpetually. Additionally they form a transnational network in which they interact with strangers of similar backgrounds (other backpackers, tourist professionals). This network helps them interacting with people from different backgrounds (the socalled hosts or locals). Considering my research Backpackers forge a certain identity from these transnational practices which I want to name globedentity. Globedentity expresses a type of identity construction that not only refers to the individual (I) but reflects the world (globe) in this identity. This globedentity is not fixed but is perpetually re-created and re-defined. It also embraces the increasing popular awareness of globalisation which backpackers, coming from highly educated middle class backgrounds, in particular have identified with. Due to the constant awareness of the latest global social, cultural and economic developments in these educated milieus they know exactly which tools to use to become successful parts of their societies.
I analysed the importance of shell size, shell shape, habitat preferences and availability, experienced climate, active dispersal and influence of Pleistocene glaciations for the range sizes of 37 Western Palaearctic Helicidae s.l. species for which a phylogeny was available. In both cross-species and phylogenetically controlled analyses, the range sizes were positively correlated to climatic tolerance, shell size, active dispersal and influence of Pleistocene glaciations. In addition, range sizes increased significantly with latitude. Multiple regression suggested that, predominantly, the influence of Pleistocene glaciations, tolerance to large annual temperature ranges and shell size influenced the distributional range sizes. Habitat preference, range and availability, active dispersal and shell shape explained no additional variance. The results suggest that the processes influencing species range size of the Helicidae s.l. are mainly related to the climatic shifts after the Pleistocene.
FGF-2, a potent multifunctional and neurotrophic growth factor, is widely expressed in the brain and upregulated in cerebral ischemia. Previous studies have shown that intraventricularly or systemically administered FGF-2 reduces the size of cerebral infarcts. Whether endogenous FGF-2 is beneficial for the outcome of cerebral ischemia has not been investigated. We have used mice with a null mutation of the fgf2 gene to explore the relevance of endogenous FGF-2 in brain ischemia. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCAO). We found a 75% increase in infarct volume in fgf2 knock-out mice versus wild type littermates (P < 0.05). This difference in the extent of ischemic damage was observed after 24 h, and correlated with decreased viability in fgf2 mutant mice following MCA occlusion. Increased infarct volume in fgf2 null mice was associated with a loss of induction in hippocampal BDNF and trkB mRNA expression. These findings indicate that signaling through trkB may contribute to ameliorating brain damage following ischemia and that bdnf and trkB may be target genes of FGF-2. Together, our data provide the first evidence that endogenous FGF-2 is important in coping with ischemic brain damage suggesting fgf2 as one crucial target gene for new therapeutic strategies in brain ischemia.