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Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy., Competing Interests: The authors declare no competing interests., (© 2023.)

The Leader in Medicine (LIM) Program of the Cumming School of Medicine, University of Calgary, hosted its 7th Annual LIM Research Symposium on October 30, 2015 and participation grew once again, with a total of six oral and 99 posters presentations! Over 45 of our Faculty members also participated in the symposium. This year's LIM Symposium theme was "Innovations in Medicine" and the invited guest speaker was our own Dr. Breanne Everett (MD/MBA). She completed her residency in plastic surgery at University of Calgary and holds both a medical degree and an MBA from the University of Calgary. In her inspiring talk, entitled "Marrying Business and Medicine: Toe-ing a Fine Line", she described how she dealt with a clinical problem (diabetic foot ulcers), came up with an innovation that optimized patient care, started her own company and delivered her product to market to enhance the health of the community. She clearly illustrated how to complete the full circle, from identifying a clinical problem to developing and providing a solution that both enhances clinical care and patient health as well as reduces health care costs and hospital admissions. The research symposium was an outstanding success and the abstracts are included in companion article in CIM.

TOn October 30th, 2015, the Leaders in Medicine (LIM) program at the Cumming School of Medicine, University of Calgary hosted its 7th Annual Research Symposium. Dr. Breanne Everett, President and CEO of Orpyx Medical Technologies and holder both of medical and MBA degrees from the University of Calgary, presented a lecture entitled "Marrying Business and Medicine: Toe-ing a Fine Line". The LIM symposium also provides a forum for both LIM and non-LIM medical students to present their research work in oral and poster presentation formats. This year over 100 students submitted their work and six oral presentations and 99 posters were presented. The oral presentations were as follows: Ryan Lewinson, Prediction of wedged insole-induced changes to knee joint moments during walkingLindsey Logan, Robotic measures provide insight on sensorimotor and cognitive impairments following traumatic brain injury Jackie Mann, What medication information do community doctors want to receive in discharge summaries for safer transfers? Ashley Jensen, Increased mortality associated with resident handoff periods at ten veterans administration medical centers Jason Bau, Keratinocyte growth factor protects against C. difficile-induced cell injury and death Michael Keough, A novel drug class promotes regeneration of central nervous system myelin by overcoming inhibitory scar molecules in vitro and in vivo For further details on the University of Calgary Leaders in Medicine Program see "A Prescription that Addresses the Decline of Basic Science Education in Medical School" (Clinical and Investigative Medicine. 2014;37(5):E29). The LIM Symposium has the following objectives: (1) to showcase the variety of projects undertaken by students in the LIM Program as well as University of Calgary medical students; (2) to encourage medical student participation in research and special projects; (3) to inform students and faculty about the diversity of opportunities available for research and special projects during medical school and beyond; and, (4) to enhance student and staff interactions, with the ultimate goal being to enhance translational medicine improve health.

Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students.

The cytoadherence of Plasmodium falciparum-infected erythrocytes (IRBCs) to endothelium is mediated by adhesion molecules within the physical constraints of a viscous fluid containing mostly erythrocytes. The volume fraction of erythrocytes (hematocrit) and their physical properties, such as deformability, are important properties of blood that affect cell recruitment to the vascular wall. In the present study, we examined the effect of hematocrit on IRBC rolling and adhesion on human microvascular endothelial cells in a flow chamber system in vitro. We found hematocrit to be a major determinant of IRBC/endothelial cell interactions. There was a 5-fold and 12-fold increase in IRBC rolling and adhesion, respectively, when hematocrit increased from 10% to 30%, as a result of changes in shear rate. Similar effects were seen in the presence of less deformable erythrocytes, serum proteins, and on endothelium stimulated with tumor necrosis factor-alpha. The results indicate that hemorheologic variations are an important determinant of the degree of cytoadherence.

Plasmodium falciparum-infected erythrocytes (IRBCs) have been shown to interact with a number of endothelial adhesion molecules expressed on transfectants, on cell lines, and as immobilized purified receptor proteins under flow conditions. However, the experiments were designed in such a way that maximal numbers of adhesion molecules were provided as substratum. Whether the interactive events actually occur on microvascular endothelium, where the distribution and expression of adhesion molecules may be less, remains undetermined. In this study, the cytoadherance of IRBCs on human dermal microvascular endothelial cells (HDMECs) as a model of human microvasculature was examined. IRBCs were observed to tether, roll, and adhere on resting HDMECs, which constitutively expressed CD36 and intercellular adhesion molecule-1 (ICAM-1) at an optimal shear stress of 1 dyne/cm(2). Stimulation of HDMECs with tumor necrosis factor-alpha for 5 and 24 hours, which resulted in up-regulation of ICAM-1 and induction of vascular cell adhesion molecule-1 expression, significantly increased the percentage of rolling cells that adhered without affecting the rolling flux. In contrast, P-selectin expression on HDMECs induced by oncostatin M led to an increase in both rolling flux and adhesion. Inhibition studies with receptor-specific monoclonal antibodies revealed that adhesion of IRBCs on HDMECs was largely CD36 dependent, whereas rolling could be mediated by any of the adhesion molecules studied. Collectively, these findings indicate that IRBCs interact synergistically with multiple adhesion molecules on vascular endothelium. The rolling of IRBCs may be the rate-limiting step in cytoadherance, since it can be modulated by cytokines to enhance CD36-mediated IRBC adhesion.