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Background: Cancer-associated thrombosis (CAT) is a leading cause of death in patients diagnosed with cancer. However, pharmacologic thromboprophylaxis use in cancer patients must be carefully evaluated due to a 2-fold increased risk of experiencing a major bleeding event within this population. The electronic health record CAT (EHR-CAT) risk assessment model (RAM) was recently developed, and reports improved performance over the widely used Khorana score. Extensive RAM external validation is crucial to determine accuracy across diverse patient populations prior to clinical utilization. Objectives: To externally validate EHR-CAT using data from 2103 patients with cancer at the Boston Medical Center (BMC), New England’s largest safety-net hospital, and to compare this RAM with the Khorana score. Methods: We conducted a retrospective study of BMC cancer patients diagnosed between January 2014 and December 2022 using data from the BMC tumor registry and EHR system. We validated the RAM using measures of discrimination and calibration. Results: The EHR-CAT score exhibited a strong ability to discriminate the risk of CAT (C statistic, 0.67), which was substantially higher than the classic Khorana score (C statistic, 0.58). This increased discrimination power reflects the 20% of patients that were reclassified into high or low risk by the expanded score. Model calibration was also strong in this dataset. Conclusion: In our external validation, the recently published EHR-CAT score showed clear and improved separation of patients at high and low risk for CAT. The utilization of this expanded CAT score could facilitate improved targeting of at-risk cancer patients for prophylactic therapy.

Summary: Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2V617F) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted JAK2V617F expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that JAK2V617Fmutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells. Key Words: clonal hematopoiesis, left ventricular hypertrophy, myocardial infarction

The ability of transcriptional regulators to drive lineage conversion of somatic cells offers great potential for the treatment of human disease. To explore the concept of switching on specific target genes in heterologous cells, we developed a model system to screen candidate factors for their ability to activate the archetypal megakaryocyte-specific chemokine platelet factor 4 (PF4) in fibroblasts. We found that co-expression of the transcriptional regulators GATA1 and FLI1 resulted in a significant increase in levels of PF4, which became magnified over time. This finding demonstrates that such combinations can be used to produce potentially beneficial chemokines in readily available heterologous cell types. Keywords: Platelet factor 4, Reprogramming, Megakaryocyte, Fibroblast

Perlecan is a major heparan sulfate (HS) proteoglycan in the arterial wall. Previous studies have linked it to atherosclerosis. Perlecan contains a core protein and three HS side chains. Its core protein has five domains (DI–DV) with disparate structures and DII is highly homologous to the ligand-binding portion of LDL receptor (LDLR). The functional significance of this domain has been unknown. Here, we show that perlecan DII interacts with LDL. Importantly, the interaction largely relies on O-linked glycans that are only present in the secreted DII. Among the five repeat units of DII, most of the glycosylation sites are from the second unit, which is highly divergent and rich in serine and threonine, but has no cysteine residues. Interestingly, most of the glycans are capped by the negatively charged sialic acids, which are critical for LDL binding. We further demonstrate an additive effect of HS and DII on LDL binding. Unlike LDLR, which directs LDL uptake through endocytosis, this study uncovers a novel feature of the perlecan LDLR-like DII in receptor-mediated lipoprotein retention, which depends on its glycosylation. Thus, perlecan glycosylation may play a role in the early LDL retention during the development of atherosclerosis.