Evaluation of the non-linear properties of two computational models of the peripheral auditory system

The output responses of two computational models of the peripheral auditory system were investigated. The models used were the Carney model, described in Zilany et al. (2009) and the Seneff model, as described in Seneff 1988. Of particular interest is the exhibition of the ‘synchrony capture’ phenomenon. This occurs when the auditory nerve fibre preferentially fires in time sync with a single spectral component within a complex sound. The studies of Sinex et al. (2003) and Deng et al. (1987) were used for visual comparison to the modelled responses with regards to synchrony capture. Sinex et al. (2003) showed synchrony capture in the responses of auditory nerve fibres to components within a harmonic tone against increasing intensity. Deng et al. (1987) showed synchrony capture to a component over increasing relative intensity of that component within a harmonic tone. The results revealed that the Seneff model showed strong agreement to the recorded response sets presented in Sinex et al. (2003 and Deng et al. (1987). The Carney model showed strong agreement to the synchrony capture presented in Deng et al. (1987) but responses did not have strong agreement to synchrony capture presented in Sinex et al. (2003)

Tumor beta2-microglobulin and HLA-A expression is increased by immunotherapy and can predict response to CIT in association with other biomarkers

BackgroundDownregulation of MHC class I expression and/or defects in the antigen presentation pathways are commonly reported in human cancers. Numerous studies previously have explored extensively the molecular mechanisms that underlie HLA-class I and Beta2-Microglobulin (B2M) downregulation. However, the techniques presently available to detect expression of MHC class I proteins lack the robustness, specificity and sensitivity needed for systematic integration and analysis in clinical trials. Furthermore, the dynamics of HLA-class I and B2M expression have not been comprehensively studied as a potential biomarker for immunotherapy.MethodsUsing novel, validated, immunohistochemistry (IHC)-based methods for quantifying B2M and HLA-A in tumor samples from diverse cancer types, we have determined loss of B2M and HLA-A proteins in 336 archived, primary specimens and 329 biopsies from metastatic patients collected during Roche-sponsored Phase 1 clinical trials investigating novel immunotherapy candidates as monotherapy or in combination with CPI.ResultsUp to 56% of cases with B2M or HLA-A loss were noted in the investigated tumor types. The frequency of loss was dependent on indication and stage of disease and revealed heterogeneous expression patterns across patients. B2M and HLA-A loss was increased in metastatic lesions compared to primary tumors, indicating selection of MHC class I low clones in metastatic and refractory tumor cells. High on-treatment B2M expression correlated with successful clinical outcome (RECIST), while high baseline B2M did not. A treatment-induced increase of B2M expression was noted in most of the patients with low B2M levels at baseline. The triple biomarker combination of B2M, CD8 and PDL1 strongly improved response prediction to cancer immunotherapy.ConclusionOur results indicate that B2M and HLA-A loss occurs frequently in tumors and is reversed in most instances following immunotherapy which supports the conclusion that MHC class I loss is not the dominant resistance mechanism to CPI treatment. This investigation reveals a highly dynamic expression of HLA-A and B2M in tumors affected by indication, metastatic status, immunophenotype and immunotherapy treatment. Baseline expression levels of B2M on tumors may be of utility as a constituent of a biomarker panel used for selecting patients for immunotherapy clinical trials

A critical assessment for the value of markers to gate-out undesired events in HLA-peptide multimer staining protocols

Background: The introduction of antibody markers to identify undesired cell populations in flow-cytometry based assays, so called DUMP channel markers, has become a practice in an increasing number of labs performing HLA-peptide multimer assays. However, the impact of the introduction of a DUMP channel in multimer assays has so far not been systematically investigated across a broad variety of protocols. Methods: The Cancer Research Institute%27s Cancer Immunotherapy Consortium (CRI-CIC) conducted a multimer proficiency panel with a specific focus on the impact of DUMP channel use. The panel design allowed individual laboratories to use their own protocol for thawing, staining, gating, and data analysis. Each experiment was performed twice and in parallel, with and without the application of a dump channel strategy. Results: The introduction of a DUMP channel is an effective measure to reduce the amount of non-specific MULTIMER binding to T cells. Beneficial effects for the use of a DUMP channel were observed across a wide range of individual laboratories and for all tested donor-antigen combinations. In 48% of experiments we observed a reduction of the background MULTIMER-binding. In this subgroup of experiments the median background reduction observed after introduction of a DUMP channel was 0.053%. Conclusions: We conclude that appropriate use of a DUMP channel can significantly reduce background staining across a large fraction of protocols and improve the ability to accurately detect and quantify the frequency of antigen-specific T cells by multimer reagents. Thus, use of a DUMP channel may become crucial for detecting low frequency antigen-specific immune responses. Further recommendations on assay performance and data presentation guidelines for publication of MULTIMER experimental data are provided

Observation of Fine Time Structures in the Cosmic Proton and Helium Fluxes with the Alpha Magnetic Spectrometer on the International Space Station

International audienceWe present the precision measurement from May 2011 to May 2017 (79 Bartels rotations) of the proton fluxes at rigidities from 1 to 60 GV and the helium fluxes from 1.9 to 60 GV based on a total of $1 \times 10^9$ events collected with the Alpha Magnetic Spectrometer aboard the International Space Station. This measurement is in solar cycle 24, which has the solar maximum in April 2014. We observed that, below 40 GV, the proton flux and the helium flux show nearly identical fine structures in both time and relative amplitude. The amplitudes of the flux structures decrease with increasing rigidity and vanish above 40 GV. The amplitudes of the structures are reduced during the time period, which started one year after solar maximum, when the proton and helium fluxes steadily increase. Above $\sim 3$  GV the p/He flux ratio is time independent. We observed that below $\sim 3$  GV the ratio has a long-term decrease coinciding with the period during which the fluxes start to rise

Tumor-Associated T lymphocytes: Phenotypic and functional idiosyncrasies in healthy donors and in tumor patients

T-Zell basierte Ansätze der Immuntherapie von Krebspatienten setzten neben der Identifikation geeigneter Tumor-assoziierter Antigene ein fundiertes Wissen über die zellulären Vorgänge des Immunsystems im Bereich des Tumors voraus. Zur Entwicklung innovativer Therapieansätze ist die phänotypische und funktionelle Charakterisierung Tumorantigen-spezifischer T-Zellen von zentraler Bedeutung. Die Untersuchung von Zytokeratin 18-spezifischen CD8+ T-Zellen in gesunden Individuen zeigte, dass diese seneszenten und hochdifferenzierten Lymphozyten keine detektierbare regulatorische Funktion auf andere Zellen des peripheren Blutes ausüben. Lymphozyten, welche spezifisch Ker1-Tetramere binden zeigten keine Aktivierung nach der Stimulation mit dem synthetisch hergestellten Ker1-Peptid. Es konnte jedoch erstmals die Induktion einer schwachen Proliferation dieser Zellen durch Stimulation mit einer leicht modifizierten Peptidsequenz in einem gesunden Spender gezeigt werden. In Patienten mit Colorektalem- (CRC) und Nierenzellkarzinom (RCC) war es möglich funktionelle CD4+ T-Zellen gegen HLA Klasse II-restringierte Peptide Tumor-assoziierter Antigene zu identifizieren. Hierbei konnten in RCC-Patienten zwei beschriebene Klasse II-Liganden von cMet und Zytokeratin 18 als T-Zellepitope identifiziert werden. Interessanterweise zeigten zytotoxische CD8+ T-Zellen in den untersuchten Krebspatienten keine Zytokinproduktion nach Stimulation mit verschiedenen Tumor-assoziierten HLA Klasse I-Peptiden. Der Vergleich periphärer und Tumor-infiltrierender T-Lymphozyten von RCC-Patienten zeigte in Letzteren einen erhöhten Anteil von Effektorzellen, welche sowohl zytotoxische, aber auch inhibitorische Oberfächenmarker aufwiesen. Die Tumor-infiltrierenden T-Zellen zeigten zudem eine reduzierte Expression früher Aktivierungsmarker im Vergleich zu denen der Peripherie, welche sich im Falle der CD8+ Lymphozyten nach Antigen-unabhängiger Stimulation in einer verminderten Produktion von TNF-Alpha, IFN-Gamma und IL-2 widerspiegelte. Weiter konnte ein erhöhter Anteil multifunktioneller T-Zellen in der Gruppe der Tumor-infiltrierenden CD4+ Lymphozyten im Vergleich zu T-Zellen aus der Peripherie beobachtet werden. Neben den Effektorzellen wurden in RCCs vermehrt tumor-infiltrierenden T-Zellen mit Markern regulatorischer Lymphozyten detektiert. Hierbei handelte es sich sowohl um regulatorische CD4+ Zellen, als auch um IL-10 produzierende CD8+ T-Lymphozyten. Sollte es in der Zukunft gelingen die Inhibition von Effektorzellen aufzuheben und regulatorische T-Zellen zu kontrollieren, könnte eine effektive Bekämpfung von Tumoren durch das eigene Immunsystem des Patienten möglich werden.T cell based approaches for the Immunotherapy of cancer patients require not only a profound knowledge of the immune system’s cellular processes in areas of tumor growth, but also identification of adequate tumor associated antigens. It is essential to characterize tumor-specific T cells both phenotypically as well as functionally for the development of new and innovative therapeutical strategies. Investigating Cytokeratin 18-specific CD8+ T cells of healthy donors revealed that these senescent and highly differentiated lymphocytes have no detectable regulatory effects on peripheral blood cells. T lymphocytes specifically bound to Ker1-tetramers do not show activation after stimulation with synthetic Ker1-peptide. However, the cells of one healthy individual exhibited moderate proliferation as result of stimulation with a modified peptide sequence. Functional CD4+ T cells specific for HLA class II-restricted tumor-associated antigens could be identified in patients with colorectal (CRC) and renal cell carcinoma (RCC). It was possible to verify two published HLA class II ligands of cMet and Cytokeratin 18 as T cell epitopes. Interestingly, no cytokine production of cytotoxic CD8+ T lymphocytes could be detected upon stimulation with tumor-associated HLA class I peptides. Comparison of peripheral blood and tumor-infiltrating lymphocytes (TILs) of RCC patients showed that the latter exhibit a higher amount of T cells expressing markers associated with cytotoxic effector functions. However, a reduction of early activation markers upon unspecific stimulations such as a decreased production of TNF-alpha, IFN-gamma and IL-2 could be observed in CD8+ TILs in comparison to peripheral T cells. By comparing peripheral and tumor-infiltrating lymphcytes, an increased number of multifunctional CD4+ T cells could be detected in the last group. The increase of effector cells in TILs was accompanied by a higher number of regulatory T cells. Thus, an increase of regulatory CD4+ T lymphocytes and IL-10 producing CD8+ cells were observed in TILs compared to peripheral cells. By undermining the inhibition of effector cells and effectively controlling regulatory T cells, it may be possible to induce immune responses against tumors in cancer patients in the future

Technikaffinität als Ressource für die Arbeit in Industrie 4.0

Die zunehmende Digitalisierung der Arbeitswelt bietet nicht nur vielversprechende Innovationen zur arbeiterzentrierten, adaptiven Aufgabengestaltung, sondern stellt den Einzelnen auch vor die Herausforderung, in höherem Maße mit digitaler Technik zu interagieren. Für die erfolgreiche Interaktion mit Technik sind zwei Faktoren ausschlaggebend: Wissen über bzw. Erfahrung mit technischen Systemen sowie Persönlichkeitsaspekte, die sich als Interaktionsstil im Umgang mit Technik manifestieren. Wir präsentieren das Konzept der interaktionsbezogenen Technikaffinität (affinity for technology interaction, ATI) als zentrale Ressource zum erfolgreichen Umgang mit Technik, und mit der ATI-Skala eine ökonomische und reliable Skala zur Quantifizierung der ATI eines Nutzers. Neben bestehenden Evaluationsergebnissen (N > 1500) stellen wir erste Ergebnisse einer Nutzerstudie vor, die im Rahmen des Projektes Factory2Fit durchgeführt wurde. Die Probanden interagierten mit 3D-Druckern und erlebten unterschiedliche Automatisierungsgrade des Prozesses. Zusätzlich zum Automatisierungsgrad wurde die Erfahrung der Probanden durch unterschiedliche Trainingsintensitäten variiert. Die Ergebnisse liefern erste Hinweise auf die Relevanz von ATI für die Vorhersage des Interaktionserfolgs mit Technologie und damit für Usability-Evaluationen in Industrie 4.0-Umgebungen