Relationship between Lake Stages and Local Ground-water Levels at Horseshoe Lake, Alexander County, Illinois

published or submitted for publicationis peer reviewedOpe

Sedimentation Rates in Horseshoe Lake, Alexander County, Illinois

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Executive Summary: Sediment Management for Horseshoe Lake and Its Watershed, Alexander County, Illinois

published or submitted for publicationis peer reviewedOpe

A connectome and analysis of the adult Drosophila central brain.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain

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

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy

INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TAM receptors and VEGFR2, can shift the tumor microenvironment towards an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPI) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2/4 weeks) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who progressed on/after prior CPI (CPI-experienced) or chemotherapy (CPI-naïve). CPI-experienced patients had prior clinical benefit (PCB; complete/partial response or stable disease for ≥12 weeks then disease progression) or no PCB (NPCB) from CPI. Primary endpoint was objective response rate (ORR); secondary objectives included safety and secondary efficacy endpoints. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naïve patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naïve. Median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naïve, respectively; median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naïve patients; median follow-up 20.4 months). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naïve patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction/interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination demonstrated antitumor activity and encouraging survival in CPI-experienced patients with non-squamous NSCLC