Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY79-09743)National Bureau of Standards (Grant NB-8-NAHA-3017)Joint Services Electronics Program (Contract DAAG29-80-C-0104)National Science Foundation (Grant PHY82-10486)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0183)National Science Foundation (Grant CHE79-02967-A04)U.S. Air Force - Office of Scientific Research (Contract AFOSR-81-0067)Joint Services Electronics Program (Contract DAAG29-83-K-0003

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Implications of Gate Design on RF Performance of Sub-100nm Strained-Si/SiGe nMODFETs

Abstract The effects of gate structure design on RF performance of strained-Si/SiGe nMODFETs are studied using device simulation and experiments. It is found that while gate resistance only affects f max , fringing gate capacitance can have a significant impact on both f T and f max , indicating that the physical gate structure has to be optimized for any specific application. The experiments suggest that low-κ material is needed as sidewall spacer (if any) and passivation for reducing fringing gate capacitance. Furthermore, the simulations show that if low gate resistance can be achieved by using a multi-finger geometry, a rectangular-shaped gate should be used in order to reduce fringing gate capacitance. If not, a T-gate should be used to reduce gate resistance for high f max . Introduction Strained Si/SiGe nMODFETs with high electron mobility are potentially promising devices for future RF applications due to expected low power, low noise and high spee

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

Abstract Background Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. Methods Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario. Results PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. Conclusions In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden

Continent-wide analysis of how urbanization affects bird-window collision mortality in North America

Characteristics of buildings and land cover surrounding buildings influence the number of bird-window collisions, yet little is known about whether bird-window collisions are associated with urbanization at large spatial scales. We initiated a continent-wide study in North America to assess how bird-window collision mortality is influenced by building characteristics, landscaping around buildings, and regional urbanization. In autumn 2014, researchers at 40 sites (N = 281 buildings) used standardized protocols to document collision mortality of birds, evaluate building characteristics, and measure local land cover and regional urbanization. Overall, 324 bird carcasses were observed (range = 0–34 per site) representing 71 species. Consistent with previous studies, we found that building size had a strong positive effect on bird-window collision mortality, but the strength of the effect on mortality depended on regional urbanization. The positive relationship between collision mortality and building size was greatest at large buildings in regions of low urbanization, locally extensive lawns, and low-density structures. Collision mortality was consistently low for small buildings, regardless of large-scale urbanization. The mechanisms shaping broad-scale variation in collision mortality during seasonal migration may be related to habitat selection at a hierarchy of scales and behavioral divergence between urban and rural bird populations. These results suggest that collision prevention measures should be prioritized at large buildings in regions of low urbanization throughout North America