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Purpose: Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. While surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need. Experimental Design: We adopted an ex-vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cut using a vibratome to make 150 mm slices cultured in media. Results: Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calciumimaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early phase clinical trials. In 5 of 6 donor samples, TAK981 treated slices cultures had reduced viability, and regulatory T cells (TREGs). These data were consistent with TAK981 activity in purified TREGs using an in-vitro murine model. Conclusions: This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low five-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAMs) that promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting pro-tumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, “re-educated” pro-tumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the anti-tumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC.

Dysregulation of reactive oxygen species (ROS) production and ROS-regulated pathways in cancer cells leads to abnormal accumulation of reactive oxygen species, displaying a double-edged role in cancer progression, either supporting transformation/proliferation and stimulating tumorigenesis or inducing cell death. Cancer cells can accommodate reactive oxygen species by regulating them at levels that allow the activation of pro-cancer signaling pathways without inducing cell death via modulation of the antioxidant defense system. Therefore, targeting reactive oxygen species is a promising approach for cancer treatment. Ginsenosides, their derivatives, and related drug carriers are well-positioned to modulate multiple signaling pathways by regulating oxidative stress-mediated cellular and molecular targets to induce apoptosis; regulate cell cycle arrest and autophagy, invasion, and metastasis; and enhance the sensitivity of drug-resistant cells to chemotherapeutic agents of different cancers depending on the type, level, and source of reactive oxygen species, and the type and stage of the cancer. Our review focuses on the pro- and anticancer effects of reactive oxygen species, and summarizes the mechanisms and recent advances in different ginsenosides that bring about anticancer effects by targeting reactive oxygen species, providing new ideas for designing further anticancer studies or conducting more preclinical and clinical studies.

Investment decisions in the financial markets require careful analysis of information available from multiple data sources. In this paper, we present Atlas, a novel entity-based information analysis and content aggregation platform that uses heterogeneous data sources to construct and maintain the "ecosystem" around tangible and logical entities such as organizations, products, industries, geographies, commodities and macroeconomic indicators. Entities are represented as vertices in a directed graph, and edges are generated using entity co-occurrences in unstructured documents and supervised information from structured data sources. Significance scores for the edges are computed using a method that combines supervised, unsupervised and temporal factors into a single score.Important entity attributes from the structured content and the entity neighborhood in the graph are automatically summarized as the entity "fingerprint". A highly interactive user interface provides exploratory access to the graph and supports common business use cases.We present results of experiments performed on five years of news and broker research data, and show that Atlas is able to accurately identify important and interesting connections in real-world entities. We also demonstrate that Atlas entity fingerprints are particularly useful in entity similarity queries, with a quality that rivals existing humanmaintained databases.