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

A General Formulation of Neutron Noise for Fast Reactor Systems

286 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1982.A general space- and energy-dependent formalism is developed in order to analyze zero-power neutron noise experiments in fast reactor systems. A generalized dispersion equation is combined with theoretical expressions for the experimentally measured power spectral density and variance-to-mean ratio which makes it possible to express these quantities in terms of a double moment of the Laplace and Fourier transformed Green's function of a slowing-down operator rather than those of the full Boltzmann operator.Several spatial approximations are analyzed in the context of the general formalism. In each case, the power spectral density and variance-to-mean ratio are written in terms of an appropriate fast reactor dispersion law for the medium which can be calculated from the solution to a simple slowing-down equation. The resultant expressions for the power spectral density are analyzed for various combinations of neutron migration descriptions, slowing-down kernels, fission spectrum and cross section models, and detector geometries. The combinations are chosen so to determine the effects of the diffusion theory approximation, detector geometry, reactor geometry, and energy-dependent neutron migration descriptions on the power spectral density, and to evaluate the significance of various space and energy effects in the determination of subcritical reactivity from power spectral density measurements. The results of these analyses demonstrate that energy-dependent descriptions of neutron migration are extremely important in the determination of reliable and accurate subcritical reactivities from power spectral density measurements in fast reactor systems. In addition, they provide a firm foundation for the understanding and proper interpretation of zero-power neutron noise measurements in all types of reactor systems.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Epigenetic treatment of neuropsychiatric disorders: autism and schizophrenia

Please note: this work is permanently embargoed in OpenBU. No public access is forecasted for this item. To request private access, please click on the locked Download file link and fill out the appropriate web form.Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.We thank the MitoCure Foundation for generous support of the underlying experimentation, PhenoMatriX for provision of small molecules, and both the US National Science Foundation and Auburn University for support of original research studies. We acknowledge efforts of Drs. Matthew V. Cannon, Kodeeswaran Parameshwaran, Vishnu Suppiramaniam, David N. Harpp, Edward G. Spack and Robert J. Zamboni, and the latter for his assistance with the chemical synthesis of PMX-500FI; and Drs. Susan P. Perrine, Michael S. Boosalis, and Jose Sangerman of the Boston University Cancer Research Center for their invaluable advice and helpful discussions in preparation of this manuscript. Conflict of interest: KS owns shares in PhenoMatriX. WM and KS have collaborated in the past on cancer projects as part of a formal agreement between SRI International and PhenoMatriX. The remaining authors declare no conflict of interest. (MitoCure Foundation; US National Science Foundation; Auburn University)Accepted manuscript2031-01-0