Medieval Academy of America

CAR T-cell therapy remains an unsolved challenge for pancreatic cancer. The discovery of tumor-intrinsic mechanisms of resistance has been largely limited by current experimental models. Using large-scale genomic screening in an orthotopic, immunocompetent model of pancreatic cancer, we uncover a role for cell-intrinsic metabolic states in regulating CAR T-cell response.

Introduction: Calciphylaxis is a rare, understudied disease of accelerated vascular calcification affecting the skin and soft tissue leading to painful wounds, amputations, and reduced survival. The underlying mechanisms of calciphylaxis remain incompletely understood. Objective: In this study, we aimed to identify altered signaling pathways and novel differentially expressed genes (DEGs) associated with calciphylaxis and to characterize the protein expression of top DEGs in the vasculature. Methods: 6 case and 3 control tissues were obtained from our institution’s calciphylaxis biorepository (NCT03032835). RNA sequencing analysis and pathway analysis were performed using the KEGG database. Immunofluorescent (IF) staining with co-localization analysis was performed on independent case-control samples for the top 9 upregulated DEGs. In vitro functional assessment was performed using human vascular smooth muscle cells (VSMC). Results: 783 DEGs (FDR-adjusted p-value ≤0.05) were identified, 543 of which were upregulated (Fig 1A). 27 altered pathways enriched for calcification, thrombosis, and inflammation were identified. The top 9 upregulated DEGs (adjusted p-values ≤1.2 x10-7) were KYNU, IFI16, KCNJ15, RAB31, FNDC1, HIF1α, DEPP1, NFIL3, and TSP1. On IF, 7 of the top 9 upregulated DEGs exhibited higher protein expression compared to matched controls, some of which are highlighted in Figure 1B. These 7 genes were all upregulated in RNA sequencing analysis of human coronary arteries with atherosclerotic lesions compared to coronaries without lesions. Functional assessment of the top 3 genes in this coronary artery disease analysis (FNDC1, KYNU & KCNJ15) revealed potent effects on calcification, proliferation, and migration of VSMCs. Conclusions: Novel genes identified in this transcriptomic study of calciphylaxis uncovered similarities with coronary artery disease and have identified previously unknown regulators of VSMC calcification.

Introduction: Cardiometabolic HFpEF is characterized by T cell systemic inflammation and can be modeled preclinically with high fat diet (HFD) and L-NAME. Metabolic perturbations can alter T cell function through modulation of the unfolded protein response (UPR). How T cells are activated in HFpEF and whether T cell inflammation can be tuned by removing cardiometabolic stress remains unknown. Hypothesis: HFD and L-NAME induce reversible alterations in T cell UPR signaling that modulate T cell dependent cardiac inflammation and pathology in experimental HFpEF. Methods: Male C57/BL6J mice (wild-type, WT), OT-II antigen restricted mice, and CD4 Cre Xbp1 fl/fl mice were fed a high-fat diet (HFD) and L-NAME (H/L) for 5 weeks. WT mice were switched to standard diet (STD) for two additional weeks. WT mice receiving HFD or L-NAME only, or TAC surgery (a model of HF with reduced EF) were used as controls. Left ventricular (LV) end diastolic pressure volume relationship (EDPVR) was assessed using invasive hemodynamic analyses and LV EF by echocardiography. Cardiac and splenic T cells were characterized by flow cytometry and T cell UPR was evaluated by qPCR and Western blot. Results: 5 weeks of H/L was sufficient to induce cardiac T cell infiltration and splenic T cell activation. OTII mice fed H/L showed increased cardiac CD4 + T cell infiltration compared to STD controls, indicating T cell activation is not cardiac antigen restricted. Furthermore, splenic T cell characterization revealed H/L resulted in decreased phosphorylation of the UPR protein inositol-requiring enzyme 1α (IRE1α) and reduced expression of X box-binding protein 1 ( Xbp1s/u ) compared to T cells from mice exposed to HFD or L-NAME alone, STD, or WT TAC controls. CD4 Cre+ Xbp1 fl/fl mice (T cell Xbp1 -/- ) fed with H/L had increased cardiac T cell infiltration compared to Cre - controls. Lastly, Xbp1s expression in splenic CD4 + T cells was recovered after withdrawal of H/L and resulted in partial reduction of cardiac hypertrophy, decreased EDPVR, as well as less cardiac T cell infiltration compared to mice kept on H/L. Conclusions: Reversible downregulation of the T cell IRE1α-XBP1 axis is a unique T cell signature of HFpEF that contributes to T cell inflammation and adverse cardiac remodeling.

By the time Andreas Vesalius (1514–64) created his energetic depiction of a woman’s dissection to grace the front of his anatomical masterwork On the Fabric of the Human Body (1543), the iconography of the dissection scene—a corpse laid on a table surrounded by a crowd of gesticulating men, one wielding a knife, overseen by a lecturer reading from a text—had become firmly emblematic of the field of anatomy. The image appealed at once to educated, professional medical practitioners as well as to members of the general public, increasingly hungry for accessible medical texts, signifying human dissection’s arrival as a central component in the study of medicine. While this may seem natural to modern viewers, human dissection was not performed at all until the late Middle Ages and it took two centuries to become an acceptable part of medical curricula. By delving into the origins of the iconography of the dissection scene in manuscript and print, this essay will tell the story of human dissection in medieval Europe, from the first demonstration in Bologna in the early fourteenth century, to the slow spread of the practice throughout European universities, and arriving at its eventual establishment as an integral part of the practice of medicine by Vesalius’s time. Dissection scene images, which began as a luxurious addition to manuscripts seen only by a small amount of wealthy and educated viewers, became one of the most popular images ever printed as Vesalius’s book soared to fame, reflecting the growing acceptance of the practice.