Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hypercoagulable and hyperinflammatory responses can lead to a variety of diseases including but not limited to disseminated intravascular coagulation in sepsis, consumptive coagulopathy in trauma, thrombosis in the postsurgical setting, acute respiratory distress syndrome in lung, and other diseases or conditions. Polyphosphate is accumulated by many infectious microorganisms and may be released by damaged infectious microorganisms. In addition, polyphosphate is found in many organs and is released from activated platelets and mast cells. Polyphosphates activate the intrinsic pathway of coagulation that also induces inflammation. Hypercoagulable and hyperinflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death, which occur in many pathological conditions.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: The present invention provides monoclonal antibodies that selectively bind to and inhibit activated protein C without binding to or inhibiting unactivated protein C. Other antibodies inhibit both activated protein C and activation of unactivated protein C. Methods of treatment employing these antibodies are described herein as are methods of screening for and detecting these antibodies.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

Abstract: A Ca2+ dependent recombinant antibody that specifically binds to a specific twelve peptide sequence (E D Q V D P R L I D G K) in the activation region of the Protein C has been constructed. The antibody does not bind to Activated Protein C and can be used to inhibit activation of Protein C by thrombin-thrombomodulin, in purification of Protein C, and in treatment of tumors.

Abstract: Human protein C and activated protein C were shown to bind to endothelium specifically, selectively and saturably (Kd=30 nM, 7000 sites per cell) in a Ca2+ dependent fashion. Expression cloning revealed a 1.3 kb cDNA that coded for a novel type I transmembrane glycoprotein capable of binding protein C. This protein appears to be a member of the CD1/MHC superfamily. Like thrombomodulin, the receptor involved in protein C activation, the endothelial cell protein C receptor (EPCR) function and message are both down regulated by exposure of endothelium to TNF. Identification of EPCR as a member of the CD1/MHC superfamily provides insights into the role of protein C in regulating the inflammatory response, and determination of methods for pharmaceutical use in manipulating the inflammatory response.

Abstract: A highly specific monoclonal antibody, produced by a hybridoma cell has been found. A new assay, highly specific for activated protein C (APC) has been developed which will permit rapid determination of APC levels in clinical situations.

Abstract: Endothelial protein C receptor (EPCR) is found primarily on endothelial cells of large vessels. EPCR translocates from the plasma membrane surface to the nucleus. Molecules which bind to EPCR can be carried from the plasma membrane surface to the nucleus. These molecules include antibodies to EPCR and activated protein C. Protein C, which also binds to EPCR, can be internalized by endothelial cells, but does not enter the nucleus. Thus, EPCR translocation from the plasma membrane to the nucleus provides a means of delivering nucleic acid such as DNA, proteins such as transcription factors, diagnostic agents or other types of drugs to the nucleus of endothelial cells, particularly those on large blood vessels. Conjugates of the materials to be delivered to the nucleus can be formed by ionic or covalent coupling. For example, proteins, including fusion proteins, can be directly conjugated to an anti-EPCR monoclonal antibody.

Abstract: A highly specific monoclonal antibody, produced by a hybridoma cell has been found. A new assay, highly specific for activated protein C (APC) has been developed which will permit rapid determination of APC levels in clinical situations.

Abstract: Compositions, and methods of use thereof, for the inhibition of tumor growth and killing of solid tumors wherein the active agent is a compound blocking the Protein C system, preferably anti-Protein C antibody, anti-Protein S antibody, and C4b binding protein. In the most preferred embodiment, the Protein C blocking compound is provided in combination with a cytokine such as tumor necrosis factor (TNF), gamma interferon, interleukin-1, interleukin-2,p or granulocyte-macrophage colony stimulating factor, or a compound eliciting cytokine production such as endotoxin. Examples are provided demonstrating the administration of the Protein C blocking compound, alone or in combination with TNF or endotoxin, to animals having canine veneral tumors, a fibrosarcoma, and an adenocarcinoma, followed by significant tumor reduction.

Abstract: Human protein C and activated protein C were shown to bind to endothelium specifically, selectively and saturably (Kd=30 nM, 7000 sites per cell) in a Ca2+ dependent fashion. Expression cloning revealed a 1.3 kb CDNA that coded for a novel type I transmembrane glycoprotein capable of binding protein C. This protein appears to be a member of the CD1/MHC superfamily. Like thrombomodulin, the receptor involved in protein C activation, the endothelial cell protein C receptor (EPCR) function and message are both down regulated by exposure of endothelium to TNF. Identification of EPCR as a member of the CD1/MHC superfamily provides insights into the role of protein C in regulating the inflammatory response, and determination of methods for pharmaceutical use in manipulating the inflammatory response.

Abstract: Small, buffer soluble polypeptides having amino acid structures corresponding to residues 234-486, 310-486, and 407-486, of thrombomodulin and functionally equivalent analogs thereof inhibiting the clotting activity of thrombin and increasing protein C activation. The polypeptides can be coated onto the surface of articles adapted for contacting mammalian blood to render the surface non-thrombogenic. In pharmaceutical compositions, the polypeptides act as a natural anticoagulant.

Abstract: The promoter of the EPCR gene has been isolated from both murine (SEQ. ID No. 1) and human (SEQ. ID No. 2) genomic libraries. The promoter includes a region (nucleotides 3130 to 3350 of SEQ. ID No. 1 which affects selective gene expression in endothelial cells), and a region (nucleotides 2270 to 2840 of SEQ. ID No. 1) which affects selective gene expression in large vessel endothelial cells, as compared to expression in all endothelial cells. The EPCR promoter contains a thrombin responsive element, CCCACCCC (SEQ. ID No. 3), (murine, nucleotides 3007 to 3014 SEQ. ID No. 1 and human, nucleotides 2722 to 2729 SEQ. ID No. 2). The EPCR also contains a serum response element (nucleotides 2990 to 3061 of SEQ. ID No. 1). The regulatory sequences present in the EPCR promoter can be used for thrombin or serum controlled recombinant gene expression specific to either all endothelial cells or primarily endothelial cells of large vessels.