20 research outputs found
Non-Extensive Bose-Einstein Condensation Model
The imperfect Boson gas supplemented with a gentle repulsive interaction is
completely solved. In particular it is proved that it has non-extensive
Bose-Einstein condensation, i.e., there is condensation without macroscopic
occupation of the ground state (k=0) level
Conducting Participatory Arts Projects: A Practical Toolkit
This toolkit is intended to help artists and arts
researchers to plan, organise, document and
evaluate participatory arts projects in different contexts. Its publication evolved in the
context of a Europe-wide research project
funded by the EU Research and Innovation programme Horizon 2020. This research project â
Acting on the Margins: Arts as Social Sculpture
(AMASS) â is an arts-based three-year project
(2020-2023) that aims to bring people based
in different European contexts together with
artists to work collaboratively on creative and
experimental research. Through participatory
approaches conducted in new artistic productions and research projects, AMASS explores
and analyses the role of the arts in engaging
with societal challenges and evaluating the
societal impact of the arts. It also addresses the marginalisation of certain groups in
society by analysing power imbalances and
exploring artistic, pedagogical and other ways of promoting inclusive strategies and sharing
the benefits of innovation and service solutions. The many strategies adopted by different AMASS partners call for the involvement
of various stakeholders like NGOs, artists, regional arts advocates, community members
and others in decision-making tactics and
forum group discussions revolving around
social needs and constraints. Strongly embedded in the value of alternative knowledge
systems and the belief that the arts can initiate significant transformations in policy and
perceptions, AMASS is intended as a catalyst
for change in various contexts, and multi-disciplinary results emerging from an evaluation
of its testbed will contribute towards policy
recommendations at local, regional and international levels. This toolkit shares many of
the challenges and enthusiasm for the arts
that characterise AMASS and its activities.peer-reviewe
Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes
Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors(1â3) than in lymphoid malignancies(4, 5). Although active tumor-mediated immunosuppression may play a role in limiting efficacy(6), functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cellsâ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors
T Cells Expressing Constitutively Active Akt Resist Multiple Tumor-associated Inhibitory Mechanisms
Adoptive transfer of antigen-specific cytotoxic T lymphocytes has shown promise for the therapy of cancer. However, tumor-specific T cells are susceptible to diverse inhibitory signals from the tumor microenvironment. The Akt/protein kinase B plays a central role in T-cell proliferation, function, and survival and we hypothesized that expression of constitutively active Akt (caAkt) in T cells could provide resistance to many of these tumor-associated inhibitory mechanisms. caAkt expression in activated human T cells increased proliferation and cytokine production, a likely result of their sustained expression of nuclear factor-ÎşB (NF-ÎşB) and provided resistance to apoptosis by upregulating antiapoptotic molecules. caAkt expressing T cells (caAkt-T-cells) were also relatively resistant to suppression by and conversion into regulatory T cells (Tregs). These characteristics provided a survival advantage to T cells cocultured with tumor cells in vitro; CD3/28-stimulated T cells expressing a chimeric antigen receptor (CAR) specific for disialoganglioside (GD2) that redirected their activity to the immunosuppressive, GD2-expressing neuroblastoma cell line, LAN-1, resisted tumor-induced apoptosis when co-expressing transgenic caAkt. In conclusion, caAkt-transduced T cells showed resistance to several evasion strategies employed by tumors and may therefore enhance the antitumor activity of adoptively transferred T lymphocytes
Immunotherapy for Osteosarcoma: Genetic Modification of T cells Overcomes Low Levels of Tumor Antigen Expression
Human epidermal growth factor receptor 2 (HER2) is expressed by the majority of human osteosarcomas and is a risk factor for poor outcome. Unlike breast cancer, osteosarcoma cells express HER2 at too low, a level for patients to benefit from HER2 monoclonal antibodies. We reasoned that this limitation might be overcome by genetically modifying T cells with HER2-specific chimeric antigen receptors (CARs), because even a low frequency of receptor engagement could be sufficient to induce effector cell killing of the tumor. HER2-specific T cells were generated by retroviral transduction with a HER2-specific CAR containing a CD28.Îś signaling domain. HER2-specific T cells recognized HER2-positive osteosarcoma cells as judged by their ability to proliferate, produce immunostimulatory T helper 1 cytokines, and kill HER2-positive osteosarcoma cell lines in vitro. The adoptive transfer of HER2-specific T cells caused regression of established osteosarcoma xenografts in locoregional as well as metastatic mouse models. In contrast, delivery of nontransduced (NT) T cells did not change the tumor growth pattern. Genetic modification of T cells with CARs specific for target antigens, expressed at too low a level to be effectively recognized by monoclonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy
Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, panâT cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity
Epstein Barr virusâspecific cytotoxic T lymphocytes expressing the anti-CD30Îś artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease
Adoptive transfer of Epstein Barr virus (EBV)âspecific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (Âą 11%) and 22% (Âą 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR+ CTLs killed both autologous EBV+ cells through their native receptor and EBVâ/CD30+ targets through their major histocompatibility complex (MHC)âunrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR+ CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR+ EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBVâ/CD30+ tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD