Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1–deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.

Background Chronic diseases require chronic disease self-management (CDSM). Existing CDSM interventions, while improving outcomes, often do not lead to long-lasting effects. To render existing and new CDSM interventions more effective, an exploration of the concept of CDSM from both the literature and patient perspectives is needed. Purpose To describe the current conceptualization of CDSM in the literature, identify potential inadequacies in this conceptualization based on a comparison of literature- and patient-based CDSM descriptions, and to offer a more comprehensive definition of CDSM. Method A hybrid concept analysis was completed. Discussion In the literature, CDSM is defined as behaviors influenced by individual characteristics. Patients in the fieldwork phase discussed aspects of CDSM not well-represented in the literature. Conclusions CDSM is a complex process involving behaviors at multiple levels of a person's environment. Pilot work to develop and test CDSM interventions based on both individual and external characteristics is needed.

and 5 BloodCenter of Wisconsin, Milwaukee, WI Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombinmediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TM Pro mice expressing a mutant form of TM with reduced thrombin affinity and TM LeD mice lacking the N-terminal lectin-like domain. Studies of TM Pro mice revealed that TM is a powerful determinant of hematogenous metastasis. TM Pro mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TM Pro mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cellassociated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination. (Blood. 2011; 118(10):2889-2895) IntroductionDetailed studies of the role of hemostatic factors in cancer biology have established that metastasis is strongly dependent on a cooperative interplay between tumor cell-associated procoagulant function and circulating hemostatic system components. 1,2 However, the significance of endothelial cell-associated regulators of coagulation to cancer progression remains largely unexplored. Thrombomodulin (TM) is a predominantly endothelial cellassociated transmembrane glycoprotein that serves as a high affinity receptor for thrombin as well as other ligands through distinct extracellular domains. [3][4][5][6] TM engagement of thrombin results in a profound restriction in thrombin-mediated cleavage of prothrombotic substrates, including fibrinogen, factor V, factor VIII, factor XI, factor XIII, and platelet-associated protease activated receptors (PARs), while enhancing the proteolytic activation of the anticoagulant/anti-inflammatory protease zymogen, protein C, and the carboxypeptidase zymogen, thrombin-activatable fibrinolysis inhibitor (TAFI). 5,6 TM also controls multiple biologic processes through thrombin-independent mechanisms that are, at least in part, mediated by the N-terminal lectin-like domain, including complement activation, sequestration of inflammatory mediators, apoptosis, inflammatory cell migration, cytokine production and cell signaling events. 3,[7][8][9][10][11] The broad biologic significance of TM is underscored by studies establishing the early developmental failure of TM-deficient embryos and pr...

The purpose of this descriptive study was to, from the perspective of adult people with epilepsy (PWE) and caregivers of PWE, explore the effects of the current pandemic and resulting societal changes on epilepsy selfmanagement. Ninety-four respondents completed a mixed-methods quantitative and qualitative survey focused on their epilepsy self-management experiences during the coronavirus disease-19 (COVID-19) pandemic. Respondents noted significant disruption in epilepsy self-management. Lack of ability to obtain medications or see epilepsy providers, as well as increased stress, social isolation, and changes in routine were all reported as troublesome, and more than one-third of the sample reported an increase in seizure frequency since the onset of the pandemic. Suggestions are given regarding how to support PWE during future COVID-19 outbreaks and to better prepare PWE and their caregivers for any life-altering events, such as a pandemic, with robust self-management skills that will allow them to maintain the highest level of function possible.

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