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Dive into the research topics where Joseph S. Palumbo is active.

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Featured researches published by Joseph S. Palumbo.


Journal of Clinical Investigation | 2007

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Matthew J. Flick; Christine M. LaJeunesse; Kathryn E. Talmage; David P. Witte; Joseph S. Palumbo; Malinda D. Pinkerton; Sherry Thornton; Jay L. Degen

Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib–) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin αMβ2 binding motif (Fibγ390–396A) or the αIIbβ3 platelet integrin-binding motif (FibγΔ5), were challenged with collagen-induced arthritis (CIA). Fib– mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ390–396A mice, which retain full clotting function. In contrast, arthritis in FibγΔ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib– and Fibγ390–396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that αMβ2-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to αMβ2-mediated inflammatory processes.


Journal of Thrombosis and Haemostasis | 2008

Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function

Joseph S. Palumbo; K. A. Barney; E. A. Blevins; M. A. Shaw; A. Mishra; Matthew J. Flick; Keith W. Kombrinck; K. E. Talmage; Masayoshi Souri; Akitada Ichinose; Jay L. Degen

Summary.  Background: Multiple studies suggest that the hemostatic and innate immune systems functionally cooperate in establishing the fraction of tumor cells that successfully form metastases. In particular, platelets and fibrinogen have been shown to support metastatic potential through a mechanism coupled to natural killer (NK) cell function. As the transglutaminase that ultimately stabilizes platelet/fibrin thrombi through the covalent crosslinking of fibrin, factor (F) XIII is another thrombin substrate that is likely to support hematogenous metastasis. Objective: Directly define the role of FXIII in tumor growth, tumor stroma formation, and metastasis. Methods: Tumor growth and metastatic potential were quantitatively and qualitatively evaluated in wild‐type mice and gene‐targeted mice lacking the catalytic FXIII‐A subunit. Results: Loss of FXIIIa function significantly diminished hematogenous metastatic potential in both experimental and spontaneous metastasis assays in immunocompetent mice. However, FXIII was not required for the growth of established tumors or tumor stroma formation. Rather, detailed analyses of the early fate of circulating tumor cells revealed that FXIII supports the early survival of micrometastases by a mechanism linked to NK cell function. Conclusions: Factor XIII is a significant determinant of metastatic potential and supports metastasis by impeding NK cell‐mediated clearance of tumor cells. Given that these findings parallel previous observations in fibrinogen‐deficient mice, an attractive hypothesis is that FXIII‐mediated stabilization of fibrin/platelet thrombi associated with newly formed micrometastases increases the fraction of tumor cells capable of evading NK cell‐mediated lysis.


Cancer Research | 2010

Colitis-Associated Cancer Is Dependent on the Interplay between the Hemostatic and Inflammatory Systems and Supported by Integrin αMβ2 Engagement of Fibrinogen

Kris A. Steinbrecher; Netanel A. Horowitz; Elizabeth A. Blevins; Kelley A. Barney; Maureen A. Shaw; Eleana Harmel-Laws; Fred D. Finkelman; Matthew J. Flick; Malinda D. Pinkerton; Kathryn E. Talmage; Keith W. Kombrinck; David P. Witte; Joseph S. Palumbo

A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor alpha(M)beta(2) binding motif (Fibgamma(390-396A)), revealed that alpha(M)beta(2)-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibgamma(390-396A) mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibgamma(390-396A) mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-alpha(M)beta(2) interactions may be useful in preventing and/or treating this important subset of malignancies.


Blood | 2011

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain

Netanel Horowitz; Elizabeth A. Blevins; Whitney Miller; A.R. Perry; Kathryn E. Talmage; Eric S. Mullins; Matthew J. Flick; K.C.S. Queiroz; K. Shi; C.A. Spek; Edward M. Conway; Brett P. Monia; Hartmut Weiler; Jay L. Degen; Joseph S. Palumbo

Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated 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 cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.


Blood | 2013

Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia.

Matthew J. Flick; Xinli Du; Joni M. Prasad; Harini Raghu; Joseph S. Palumbo; Emanuel Smeds; Magnus Höök; Jay L. Degen

Fibrinogen can support host antimicrobial containment/clearance mechanisms, yet selected pathogens appear to benefit from host procoagulants to drive bacterial virulence. Here, we explored the hypothesis that host fibrin(ogen), on balance, supports Staphylococcus aureus infection in the context of septicemia. Survival studies following intravenous infection in control and fibrinogen-deficient mice established the overall utility of host fibrin(ogen) to S. aureus virulence. Complementary studies in mice expressing mutant forms of fibrinogen-retaining clotting function, but lacking either the bacterial ClfA (Fibγ(Δ5)) binding motif or the host leukocyte integrin receptor αMβ2 (Fibγ(390-396A)) binding motif, revealed the preeminent importance of the bacterial ClfA-fibrin(ogen) interaction in determining host survival. Studies of mice lacking platelets or the platelet integrin receptor subunit αIIb established that the survival benefits observed in Fibγ(Δ5) mice were largely independent of platelet αIIbβ3-mediated engagement of fibrinogen. Fibγ(Δ5) mice exhibited reduced bacterial burdens in the hearts and kidneys, a blunted host proinflammatory cytokine response, diminished microscopic tissue damage, and significantly diminished plasma markers of cardiac and other organ damage. These findings indicate that host fibrin(ogen) and bacterial ClfA are dual determinants of virulence and that therapeutic interventions at the level of fibrinogen could be advantageous in S. aureus septicemia.


Thrombosis Research | 2012

Hemostatic factors, innate immunity and malignancy

Jay L. Degen; Joseph S. Palumbo

Genetics-based studies have established the critical importance of tumor cell-associated tissue factor, circulating and endothelial cell-associated regulators of thrombin function and multiple thrombin substrates in metastasis. There appear to be multiple pathways by which procoagulants influence tumor biology, but the capacity of hemostatic factors to regulate innate immune function is at least one emerging theme. Several reports have shown that the platelet/fibrin(ogen) axis supports metastasis by limiting natural killer cellmediated lysis of newly-localized micrometastases. Furthermore, there is increasingly compelling evidence that hemostatic and innate immune system interactions also support very early events in cancer development. Analyses of the role of fibrin(ogen) in inflammation-driven colon cancer established a major role for this provisional matrix protein in early tumor development. A seminal property of fibrin(ogen) driving tumor formation in this context is the capacity to support local leukocyte activation events through engagement of the leukocyte integrin α(M)β(2). More recent studies have also suggested that hemostatic factors can, in at least some settings, program the malignant phenotype in tumor cells. Platelet-derived TGF-β1 and other platelet products were reported to trigger a more invasive and prometastatic epithelial-mesenchymal-like transition in embolic tumor cells. These findings support the intriguing concept that tumor cell functional properties can continue to evolve, even beyond the primary tumor site, in response to tumor cell-hemostatic factor interactions in the bloodstream. Taken together, there is strong evidence that the hemostatic system plays a multifaceted role in cancer pathogenesis and that therapies targeting selected hemostatic factors may present a powerful means to impede tumor development and metastasis.


Journal of Thrombosis and Haemostasis | 2004

Role of fibrinogen‐ and platelet‐mediated hemostasis in mouse embryogenesis and reproduction

Joseph S. Palumbo; Mark Zogg; Kathryn E. Talmage; Jay L. Degen; Hartmut Weiler; Berend Isermann

Summary.  Studies of mice with genetic deficits in specific coagulation factors have shown that many, but not all, components of the hemostatic system serve an essential role in mouse embryogenesis and pregnancy. Although the developmental failures observed in these mice are typically associated with severe hemorrhage, it is uncertain whether the role of coagulation factors in embryogenesis and reproduction is specifically tied to their function in thrombus formation and prevention of blood loss (i.e. hemostasis). Here, we show (i) that a complete loss of fibrinogen‐ and platelet‐dependent hemostatic capacity does not reproduce the developmental defects occurring in mice with either deficits in thrombin generation or unfettered thrombin consumption; (ii) that the essential role of fibrinogen in the maintenance of pregnancy does not involve interaction with platelets; and (iii) that the previously described in utero growth retardation of gene‐targeted mice lacking NF‐E2, a transcription factor critical for megakaryopoieis, is not caused by a loss of platelet‐dependent hemostatic function. In addition, we demonstrate (iv) that fibrinogen can confer physiologically relevant hemostatic function in the absence of platelets, but that a complete loss of hemostatic capacity results if a combined absence of these components is genetically imposed. These findings support the notion that the function of coagulation factors for in utero development and pregnancy is mechanistically distinct from their ability to mediate the formation of hemostatic platelet‐fibrin(ogen) aggregates.


Annals of the New York Academy of Sciences | 2006

Genetic manipulation of fibrinogen and fibrinolysis in mice

Jay L. Degen; Angela F. Drew; Joseph S. Palumbo; Keith W. Kombrinck; Jorge A. Bezerra; Mary Jo S. Danton; Kenn Holmbäck; Theodore T. Suh

Abstract: Vascular integrity is maintained by a sophisticated system of circulating and cell associated hemostatic factors that control local platelet deposition, the conversion of soluble fibrinogen to an insoluble fibrin polymer, and the dissolution of fibrin matrices. However, hemostatic factors are likely to be biologically more important than merely maintaining vascular patency and controlling blood loss. Specific hemostatic factors have been associated with a wide spectrum of physiological processes, including development, reproduction, tissue remodeling, wound repair, angiogenesis, and the inflammatory response. Similarly, it has been proposed that hemostatic factors are important determinants of a variety of pathological processes, including vessel wall disease, tumor dissemination, infectious disease, and inflammatory diseases of the joint, lung, and kidney. The development of gene targeted mice either lacking or expressing modified forms of selected hemostatic factors has provided a valuable opportunity to test prevailing hypotheses regarding the biological roles of key coagulation and fibrinolytic system components in vivo. Genetic analyses of fibrin(ogen) and its interacting factors in transgenic mice have proven to be particularly illuminating, often challenging long standing concepts. This review summarizes the key findings made in recent studies of gene targeted mice with single and combined deficits in fibrinogen and fibrinolytic factors. Studies illustrating the role and interplay of these factors in disease progression are highlighted.


Heart | 2015

Strategies for thromboprophylaxis in Fontan circulation: a meta-analysis

Tarek Alsaied; Said Alsidawi; Catherine C Allen; Jenna M. Faircloth; Joseph S. Palumbo; Gruschen R. Veldtman

Background The Fontan circulation is associated with an increased risk of thromboembolic events (TEs). As many as 25% of these thrombotic events result in fatality. More subtle adverse effects on the pulmonary circulation from embolic thrombi may further impair adequate functioning of the circuit. Despite these well-documented phenomena, the most optimal approaches to thromboprophylaxis are still not clearly defined. Objective A meta-analysis of published trials in English on PubMed and Cochrane libraries that evaluated the role of using TE prophylaxis in patients who underwent the Fontan procedure was conducted. Methods 10 studies with a total number of 1200 patients with an average follow-up time of 7.1 years were identified. A random effect model was used. Results The incidence of TE was significantly less in patients who received TE prophylaxis (using either aspirin or warfarin) compared with patients who did not receive TE prophylaxis (OR 0.425, 95% CI 0.194 to 0.929, p<0.01, I2=37%). The incidence of TE was significantly lower in patients who received aspirin compared with no TE prophylaxis (OR 0.363, 95% CI 0.177 to 0.744, p<0.01, I2=0%) and who received warfarin compared with no TE prophylaxis (OR 0.327, 95% CI 0.168 to 0.634, p<0.01, I2=2.5%). There was no significant difference in incidence of TE between warfarin and aspirin (OR 0.936, 95% CI 0.609 to 1.438, p=0.54, I2=0%). Furthermore, there was no significant difference in incidence of early TE (within 6 months of the operation) or late TE (>6 months) between patients receiving warfarin and aspirin (OR 0.784, 95% CI 0.310 to 1.982, p=0.37, I2=8%) and (OR 0.776, 95% CI 0.249 to 2.42, p=0.3, I2=45%), respectively. When only total cavopulmonary connection patients were included, there was again no difference between warfarin and aspirin in the incidence of TE (OR 0.813, 95% CI 0.471 to 1.401, p=0.34, I2=11%). Conclusions This study shows a significantly lower incidence of TE after Fontan procedure if either aspirin or warfarin is used. This meta-analysis suggests no significant difference in incidence of early or late TE in patients receiving aspirin compared with warfarin.


Blood | 2011

The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A

Matthew J. Flick; Anil K. Chauhan; Malinda Frederick; Kathryn E. Talmage; Keith W. Kombrinck; Whitney Miller; Eric S. Mullins; Joseph S. Palumbo; Xunzhen Zheng; Naomi L. Esmon; Charles T. Esmon; Sherry Thornton; Ann De Becker; Leslie A. Pelc; Enrico Di Cera; Denisa D. Wagner; Jay L. Degen

Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII(WE)), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)-dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring antithrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII(WE) mutations within the endogenous prothrombin gene. Unlike fII-null embryos, fII(WE/WE) mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII(WT/WE) mice were viable and fertile despite a shift toward an antithrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl₃ vessel injury. More interestingly, prothrombin(WE) expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin(WE) also suppressed the development of CIA in wild-type mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes.

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Jay L. Degen

Cincinnati Children's Hospital Medical Center

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Matthew J. Flick

Cincinnati Children's Hospital Medical Center

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Kathryn E. Talmage

Cincinnati Children's Hospital Medical Center

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Eric S. Mullins

Cincinnati Children's Hospital Medical Center

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Keith W. Kombrinck

Cincinnati Children's Hospital Medical Center

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Whitney Miller

Cincinnati Children's Hospital Medical Center

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David P. Witte

Cincinnati Children's Hospital Medical Center

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Sherry Thornton

Cincinnati Children's Hospital Medical Center

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Elizabeth A. Blevins

Cincinnati Children's Hospital Medical Center

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