Cripto-1: potential target for cancer immunotherapy?!

Cancer immunotherapy refers to the stimulation of the immune system to eliminate cancer cells and can be applied by several different means. One form of cancer immunotherapy is therapeutic vaccination with the goal to generate de novo, and boost existing tumor antigen specific T cells. A crucial step in the development of a cancer vaccine is antigen selection. Ideally, an antigen should be uniquely expressed by tumor cells with low or no expression in healthy tissue. Also, the antigen should also be immunogenic and expressed on the cell surface, to be targetable both by cellular and humoral immunity. Cripto-1 (Cr-1) is a membrane bound oncofetal glycoprotein expressed in human cancer. Furthermore, Cr-1 is involved in epithelial-mesenchymal transition and found to be expressed by cancer stem cells (CSC). Thus, Cr-1 could represent a potential candidate for cancer immunotherapy. Circulating Cr-1 has also been found at elevated levels in patients with cancer and has been proposed as a biomarker in patients with non-small cell lung cancer. However, T cell reactivity against Cr-1 has not yet been reported in humans. We studied if vaccination against Cr-1 would result in protective anti-tumor immunity in models of melanoma and breast cancer. Furthermore, we explored the potential of soluble Cr-1 as a prognostic biomarker for patients with advanced melanoma and evaluated peripheral T cell reactivity to Cr-1 in these patients. We found that Cr-1 DNA vaccination elicits a Cr-1 specific cellular and humoral immune response in C57Bl/6 and BALB/c mice respectively. The induced Cr-1 directed immune response was protective in murine melanoma and mammary carcinoma models. Prophylactic vaccination particularly reduced metastatic burden and partially prevented tumor formation from CSC. In patients with advanced melanoma we showed that low serum levels of soluble Cr-1 after surgery correlated with longer survival. Additionally, we detected Cr-1 reactive T cells in peripheral blood of patients with advanced melanoma and the presence of Cr-1 reactive T cells before surgery correlated with improved survival. In summary, vaccination against Cr-1 elicits antigen-specific protective immune responses against melanoma and breast cancer. Furthermore, soluble Cr-1 protein and T cell reactivity against Cr-1 can serve as biomarkers in patients with advanced melanoma. Altogether, our observations demonstrate that Cr-1 is a potential target for cancer immunotherapy

Eine Renaissance: Stadtgeschichte(n) des vorrevolutionären Russlands

1. Vorbemerkung 2. Stadtentwicklung in Russland im Spiegel der älteren Forschungsliteratur 3. Neue Forschungsansätze nach 1991 3.1. St. Petersburg und Moskau – die dominanten Metropolen 3.2. Das russische Unternehmertum: jenseits der Stereotypen 3.3. Civil society im vorrevolutionären Russland? 3.4. Städte an der Peripherie 3.4.1. Die Städte am Rande des europäischen Teils des Russländischen Imperi-ums 3.4.2. Die Städte Zentralasiens 3.4.3. Die sibirischen Städte 4. Forschungsdesiderata 5. Resümee 6. Bibliographi

Parkinson’s disease speech production network as determined by graph-theoretical network analysis

AbstractParkinson’s disease (PD) can affect speech as well as emotion processing. We employ whole-brain graph-theoretical network analysis to determine how the speech-processing network (SPN) changes in PD, and assess its susceptibility to emotional distraction. Functional magnetic resonance images of 14 patients (aged 59.6 ± 10.1 years, 5 female) and 23 healthy controls (aged 64.1 ± 6.5 years, 12 female) were obtained during a picture-naming task. Pictures were supraliminally primed by face pictures showing either a neutral or an emotional expression. PD network metrics were significantly decreased (mean nodal degree, p < 0.0001; mean nodal strength, p < 0.0001; global network efficiency, p < 0.002; mean clustering coefficient, p < 0.0001), indicating an impairment of network integration and segregation. There was an absence of connector hubs in PD. Controls exhibited key network hubs located in the associative cortices, of which most were insusceptible to emotional distraction. The PD SPN had more key network hubs, which were more disorganized and shifted into auditory, sensory, and motor cortices after emotional distraction. The whole-brain SPN in PD undergoes changes that result in (a) decreased network integration and segregation, (b) a modularization of information flow within the network, and (c) the inclusion of primary and secondary cortical areas after emotional distraction

Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes

Multi-Messenger Gravitational Wave Searches with Pulsar Timing Arrays: Application to 3C66B Using the NANOGrav 11-year Data Set

When galaxies merge, the supermassive black holes in their centers may form binaries and, during the process of merger, emit low-frequency gravitational radiation in the process. In this paper we consider the galaxy 3C66B, which was used as the target of the first multi-messenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C66B to less than $(1.65\pm0.02) \times 10^9~{M_\odot}$ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits, and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data to `blind' pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.Comment: 14 pages, 6 figures. Accepted by Ap

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples

Objectives: To WA the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. Materials and Methods: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. Results: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. Conclusions: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients