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Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.

Using practice theory and an empirical illustration of reciprocal exchange of knowledge between resource-integrating actors, this paper contributes to Service-Dominant Logic by deepening the unders ...

PurposeThe objective of this paper is to present an empirically founded outline of value creation and the orchestration of this process.Design/methodology/approachA qualitative study of the video game industry was undertaken for which data were collected through use of both primary and secondary sources. The gathered data enabled a categorization of the industry, from both a user and a firm perspective, into different archetypical modes of value creation.FindingsThe study adds to the understanding of value creation by illustrating that a firm can orchestrate the process through which value is created by being: an inspirator; a facilitator, and an attendant. In illustrating the continuity of this process, the paper introduces the orchestrating firm and the value emergence process.Research limitations/implicationsIn describing the modes through which interaction occurs within the video game industry, the paper provides an outline which can be used for further investigations of value creation. This industry holds, however, certain features making the arguments presented in need of further research.Practical implicationsBased on the empirical findings, an outline is provided for the allocation and deployment of internal resources in order to enable continuous value creation.Originality/valueThe paper empirically exemplifies how value creation is orchestrated by developing firms within the video game industry and illustrates value creation as a continuous process; a value emergence process.

Gliomas are highly heterogeneous and therapy resistant tumors with a poor prognosis. Novel experimental therapeutic approaches have shown some promising results, but often target specific molecular mechanisms or antigens, and careful characterization of the molecular subgroup of the tumors will therefore likely be important. Thorough investigations of gene and protein alterations are also important to better understand the tumorigenic mechanisms. We have undertaken a proteomic approach, using 2-D DIGE and LC-MS/MS protein identification, to investigate 38 human gliomas and normal brains. We show that the proteome profile can discriminate between normal brain and tumors, and between tumors of varying grade by a supervised classifier. Furthermore, an analysis of the identified proteins shows an enrichment of proteins associated to pathways known to be central in gliomas, such as MEK/Erk signaling and actin cytoskeleton. It also shows a shift between different glial fibrillary acidic protein (GFAP) representatives in different grades. In a previous study the gene expression profile was characterized in an almost identical set of tumors, which enabled a paired analysis of the gene and protein expression profiles. We show that there is often a weak correlation between the mRNA and protein level. This, together with the ability of proteomics to identify PTMs, emphasizes the benefit of characterization on a protein level.

Gliomas are among the most aggressive malignant tumors and the most refractory to therapy, in part due to the propensity for malignant cells to disseminate diffusely throughout the brain. Here, we have used 27 K cDNA microarrays to investigate global gene expression changes between normal brain and high-grade glioma (glioblastoma multiforme) to try and better understand gliomagenesis and to identify new therapeutic targets. We have also included smaller groups of grade II and grade III tumors of mixed astrocytic and oligodendroglial origin as comparison. We found that the expression of hundreds of genes was significantly correlated to each group, and employed a naïve Bayesian classifier with leave-one-out cross-validation to accurately classify the samples. We developed a novel algorithm to analyze the gene expression data from the perspective of chromosomal position, and identified distinct regions of the genome that displayed coordinated expression patterns that correlated significantly to tumor grade. The regions identified corresponded to previously known genetic copy number changes in glioma (e.g. 10q23, 10q25, 7q, 7p) as well as regions not previously associated significantly with glioma (e.g. 1p13, 6p22). Furthermore, to enrich for more suitable targets for therapy, we took a bioinformatics approach and annotated our signatures with two published datasets that identified membrane/secreted genes from cytosolic genes. The resulting focused list of 31 genes included interesting novel potential targets as well as several proteins already being investigated for immunotherapy (e.g. CD44 and tenascin-C). Software for the chromosome analysis was developed and is freely available at http://base.thep.lu.se.

A major problem regarding glioblastomas is the capacity of glioma cells to inactivate the body’s immune response. The complement system acts as a functional bridge between the innate and adaptive immune response. Previously, it was thought that the complement system was upregulated in glioblastomas. However, only downstream components were studied. Here, we focus on C1, the initiating step of the complement cascade. We here show that the C1 inactivator (C1IA) is upregulated in glioblastomas. The main function of complement 1 inactivator (C1-IA) is to inhibit activation of the complement system through the classical pathway, by irreversibly binding to and inactivating of C1r and C1s proteases in the C1 complex of the classical pathway. The C1IA upregulation is seen both on gene and protein levels, as seen in data from a publicly available database and our own mRNA material from glioblastoma patients. Furthermore, we demonstrated the presence of C1-IA in vitro by using immunohistochemistry on glioma cells from both humans and rats. Finally, we could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with glioma cells pre-coated with C1-IA antibodies as compared to control animals. We tested both human anti-C1IA antibodies, and rat anti-C1IA antibodies, and could demonstrate the same pattern as compared to control animals. We could also see that the protein structure is quite similar in human C1IA and rat C1IA. Taken together, our findings indicate that overexpression of C1-IA is present in glioblastomas and that it is an interesting target to explore further.

This chapter presents a longitudinal study of an open, co-created, innovation—ICA Student. It illustrates some of the challenges inherent in the consideration, adaptation and adoption of user knowledge and competence throughout an open innovation process, demonstrating the involvement of users both during the phases of content generation and commercialisation. Findings from the study illustrate five important issues for managers and practitioners to address when co-creating an innovation with future users: (1) the framing of an open innovation; (2) the identification of suitable participants; (3) the absorption and use of diverse inputs; (4) innovation entails both content generation and commercialisation and (5) the realisation that consideration, adaptation and adoption of knowledge and competence will affect the solution space. We conclude the chapter with a discussion on the relative openness of open innovation.

Purpose: Glioblastoma multiforme (GBM) is a frequent and aggressive type of primary brain tumor with a heterogeneous origin. GBM is highly therapy resistant and carries a dismal prognosis for the patient. The purpose of this discovery study was to define candidate plasma biomarker signatures for improved classification and novel means for selecting patients for refined individualized therapy. Experimental design: Here, we have for the first time investigated the applicability of large-scale recombinant antibody-based microarrays, targeting mainly immunoregulatory analytes, for sensitive and selective plasma protein profiling of GBM patients undergoing immunotherapy with autologous IFN-gamma transfected glioma cells Results: This proof-of-concept study showed that candidate plasma protein signatures associated with GBM were outlined that could be used for GBM classification, monitoring the effects of the immunotherapy as well as for stratifying patients according to the beneficial effect of the adopted immunotherapy Further, central key cytokines that could be utilized for optimization and/or refinement of the immunotherapeutic regime were indicated. Conclusions and clinical relevance: Candidate plasma proteins signatures associated with GBM was outlined, that could be used for GBM classification and for pre-operatively stratifying patients according to the beneficial effect of the adopted immunotherapy. (Less)

Antibodies specifically targeting tumor-associated antigens have proved to be important tools in the treatment of human cancer. A desirable target antigen should be unique to tumor cells, abundantly expressed, and readily available for antibody binding. The Ku70/80 DNA-repair protein is expressed in the nucleus of most cells; it is, however, also present on the cell surface of tumor cell lines, and antibodies binding Ku70/80 at the cell surface were recently shown to internalize into tumor cells. To evaluate the potential of Ku70/80-antigen as a therapeutic target for immunotoxins in glioblastoma multiforme, we investigated binding and localization of Ku70/80-specific antibodies in tissue samples from glioblastomas and normal human brains, and in glioma cell cultures. Furthermore, the internalization and drug-delivery capacity were evaluated by use of immunotoxicity studies. We demonstrate that Ku70/80 is localized on the cell plasma membrane of glioma cell lines, and is specifically present in human glioblastoma tissue. Antibodies bound to the Ku70/80 antigen on the cell surface of glioma cells were found to internalize via endocytosis, and shown to efficiently deliver toxins into glioblastoma cells. The data further imply that different antibodies directed against Ku70/80 possess different abilities to target the antigen, in relation to its presentation on the cell surface or intracellular localization. We conclude that Ku70/80 antigen is uniquely presented on the plasma membrane in glioblastomas, and that antibodies specific against the antigen have the capacity to selectively bind, internalize, and deliver toxins into tumor cells. These results imply that Ku70/80 is a potential target for immunotherapy of glioblastoma multiforme.

Meeting abstracts Expansion of antigen-specific T cells, from peripheral blood specific for tumor-associated antigens (TAAs) is a prerequisite for the advanced cellular therapy. Such antigen-specific T cells should express a Th1-functional phenotype and are able to enter tumor-tissue. We identified

Meeting abstracts The generation of T lymphocytes with specific reactivity against autologous tumor cells is a prerequisite for effective targeted cellular therapies. We established a protocol for tumor infiltrating lymphocytes (TILs) cultures from small biopsies or surgically resected material

Meeting abstracts Tumor-infiltrating T cells (TIL) may represent a viable source of T cells for the biological treatment of patients with tumors of the central nervous system. We established a rapid TIL expansion protocol for patients with glioblastoma, and tested the recognition of short-term

Meeting abstracts Active cellular therapy (ACT) using ex-vivo expanded T cells from patients with cancer, obtained by apheresis, can represent a viable source for anti-cancer directed cellular therapy. TAAs expressed in glioblastoma may represent attractive targets for i) CARS, ii) transgenic T