The Political Dimension of Knowledge: From ‘Academic Tribe’ to ‘Thought Collective’

The article suggests that one, probably the most important, source of neolibe- ralism is to be found in the interwar Viennese intellectual life. A group of scientists around the leader (or chief) Ludwig Mises developed in their discussions the new liberal thinking. Outside the academic world for several reasons they acted nevertheless as an ‘academic tribe’. As a substitute for academic careers the Institut für Konjunkturforschung (Institute for business cycle research) was founded. It was directed by Friedrich August von Hayek and later on by Oskar Morgenstern. After World War II the academic tribe expanded to a thought collective.The article suggests that one, probably the most important, source of neolibe- ralism is to be found in the interwar Viennese intellectual life. A group of scientists around the leader (or chief) Ludwig Mises developed in their discussions the new liberal thinking. Outside the academic world for several reasons they acted nevertheless as an ‘academic tribe’. As a substitute for academic careers the Institut für Konjunkturforschung (Institute for business cycle research) was founded. It was directed by Friedrich August von Hayek and later on by Oskar Morgenstern. After World War II the academic tribe expanded to a thought collective

Hypoxic Signaling in Skeletal Muscle Maintenance and Regeneration: A Systematic Review

In skeletal muscle tissue, oxygen (O2) plays a pivotal role in both metabolism and the regulation of several intercellular pathways, which can modify proliferation, differentiation and survival of cells within the myogenic lineage. The concentration of oxygen in muscle tissue is reduced during embryogenesis and pathological conditions. Myogenic progenitor cells, namely satellite cells, are necessary for muscular regeneration in adults and are localized in a hypoxic microenvironment under the basal lamina, suggesting that the O2 level could affect their function. This review presents the effects of reduced oxygen levels (hypoxia) on satellite cell survival, myoblast regeneration and differentiation in vertebrates. Further investigations and understanding of the pathways involved in adult muscle regeneration during hypoxic conditions are maybe clinically relevant to seek for novel drug treatments for patients with severe muscle damage. We especially outlined the effect of hypoxia-inducible factor 1-alpha (HIF1A), the most studied transcriptional regulator of cellular and developmental response to hypoxia, whose investigation has recently been awarded with the Nobel price

Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice

Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized and antitumor efficacy was tested in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM. All the three CARs demonstrated FAP-specific functionality Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality. Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted

Synergies of Targeting Tumor Angiogenesis and Immune Checkpoints in Non-Small Cell Lung Cancer and Renal Cell Cancer: From Basic Concepts to Clinical Reality

In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment

Biomarkers in tumor angiogenesis and anti-angiogenic therapy

Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies