Effect of MUC16 Blockade using the Humanized AR9.6 Antibody in Patient Derived Organoid Models of PDAC

Pancreatic Ductal Adenocarcinoma (PDAC) represents nearly 90% of all pancreatic cancer cases. 49,830 of the 62,210 patients diagnosed in 2022 are estimated to succumb to the malignancy. Early diagnosis of the disease is uncommon as most patients present with symptoms when the cancer is late-stage and metastatic. This decreases the likelihood of successful surgical resection and increases the dependency on standard of care chemotherapy leads to which is met with therapeutic resistance, demonstrated by the 5-year post-diagnosis survival rate of a mere 11.5%. Mucin-16, a heavy glycosylated transmembrane protein is overexpressed in more than 65% PDAC cases. AR9.6 is an anti-MUC16 antibody that has been recently humanized after evidence of its therapeutic potential was found in an orthotopic study utilizing the murine version of the antibody. The HuAR9.6 antibody efficiently binds MUC16 expressed on tumor cells, and can both inhibit downstream oncogenic signaling and elicit tumor killing by signaling the immune system to the tumor. In this project, we used RNA sequencing to evaluate the MUC16 mediated transcriptomic changes by using the humanized AR9.6 antibody in patient-derived organoid models of PDAC. To begin this study, organoids were developed using tumor cells from a primary PDAC tumor with a high MUC16 profile obtained from rapid autopsy patient #142 from the Rapid Autopsy Program at UNMC. The organoids were then treated in triplicates using a monoclonal antibody HuIgG as an isotype control due to its lack of specificity, and the test arm of study, HuAR9.6. These samples were treated with 40 ug/mL of the antibodies for a 24-hour period, post which RNA isolation was performed. RNA sequencing and subsequent Gene Ontology and KEGG enrichment analysis revealed a downregulation of genes involved in the Hippo signaling pathway, fat digestion and absorption and TGF-β signaling. Based on this gene expression profiling, we hypothesize that HuAR9.6 can slow tumor progression by downregulating the Hippo and TGF-β signaling pathways. In the future, we aim to robustly validate these results at the level of the proteome and assess if these results can be reproduced in multiple patient samples with the hope to translate this antibody to the clinic to be used in PDAC patients who have a high MUC16 expression.https://digitalcommons.unmc.edu/surp2022/1038/thumbnail.jp

Characterization of the Jorgensen set in generalized linear models

Natural exponential families, General exponential families, Wishart distributions, Symmetric cones, Inverse gaussian distributions,

Pathogen and Nutrient Transfer Through and Across Agricultural Soils

Human activity can place heavy stress on agricultural soils across the world. Soil systems are continually manipulated in order to support the increase in crop yields and accommodate more intensive livestock production and thus provide the planet’s ever-growing population with a diverse array of ecosystem services, among which food production features highly. The recycling of livestock manures to land provides a sustainable solution to support the ecosystem services that soils provide and a host of benefits both in terms of improving soil structure and also soil fertility. However, livestock manures and feces may contain a high number of fecal microorganisms that pose a threat to human well-being and potentially large concentrations of nutrients harmful to the ecology of freshwater systems that the soils often buffer

Pet roundworms and hookworms: a continuing need for global worming

Abstract Ascarids and ancylostomatids are the most important parasites affecting dogs and cats worldwide, in terms of diffusion and risk for animal and human health. Different misconceptions have led the general public and pet owners to minimize the importance of these intestinal worms. A low grade of interest is also registered among veterinary professions, although there is a significant merit in keeping our guard up against these parasites. This article reviews current knowledge of ascarids and ancylostomatids, with a special focus on pathogenicity, epidemiology and control methods in veterinary and human medicine.</p