Divergent modulation of activated protein C pleiotropic functions by antibodies that differ by a single amino acid.

Activated protein C (APC) is a pleiotropic plasma protease with diverse functions derived from its anticoagulant, anti-inflammatory, and cytoprotective activities. The selective uncoupling and/or modulation of these APC activities by antibodies may have therapeutic benefit in diseases such as traumatic bleeding, hemophilia, sepsis, and ischemia. TPP-26870 is an antibody that targets a nonactive site of APC for the selective modulation of APC activities.

Selective modulation of activated protein C activities by a nonactive site-targeting nanobody library.

Activated protein C (APC) is a pleiotropic coagulation protease with anticoagulant, anti-inflammatory, and cytoprotective activities. Selective modulation of these APC activities contributes to our understanding of the regulation of these physiological mechanisms and permits the development of therapeutics for the pathologies associated with these pathways. An antibody library targeting the nonactive site of APC was generated using llama antibodies (nanobodies).

Novel exomic rare variants associated with venous thrombosis.

Exomic rare variant polymorphisms (c. 300 000) were analysed in the Scripps Venous Thrombosis (VTE) registry (subjects aged <55 years). Besides coagulation factor V (F5) single nucleotide polymorphisms (SNPs), family with sequence similarity 134, member B (FAM134B; rs78314670, Arg127Cys) and myosin heavy chain 8 (MYH8; rs111567318, Glu1838Ala) SNPs were associated with recurrent VTE (n = 34 cases) (false discovery rate-adjusted P < 0·05).

Cardiac Myosin Promotes Thrombin Generation and Coagulation In Vitro and In Vivo.

Objective: Cardiac myosin (CM) is structurally similar to skeletal muscle myosin, which has procoagulant activity. Here, we evaluated CM's ex vivo, in vivo, and in vitro activities related to hemostasis and thrombosis. Approach and Results: Perfusion of fresh human blood over CM-coated surfaces caused thrombus formation and fibrin deposition.

Limited role of kininogen in the host response during gram-negative pneumonia-derived sepsis.

High-molecular-weight kininogen (HK), together with factor XI, factor XII and prekallikrein, is part of the contact system that has proinflammatory, prothrombotic, and vasoactive properties. We hypothesized that HK plays a role in the host response during pneumonia-derived sepsis. To this end mice were depleted of kininogen (KNG) to plasma HK levels of 28% of normal by repeated treatment with a specific antisense oligonucleotide (KNG ASO) for 3 wk before infection with the common human sepsis pathogen Klebsiella pneumoniae via the airways.

Novel role for p56/Lck in regulation of endothelial cell survival and angiogenesis.

Previous studies have demonstrated that cleaved high-molecular-weight kininogen (HKa) induces endothelial apoptosis and inhibits angiogenesis and have suggested that this occurs through inhibition of Src family kinases. This study assessed the role of tyrosine-protein kinase Lck (p56/Lck) in this pathway. We analyzed early events leading to apoptosis of human endothelial cells exposed to HKa.

Light-Regulated Thyroid Hormone Signaling Is Required for Rod Photoreceptor Development in the Mouse Retina.

Purpose: Ambient light is both a stimulus for visual function and a regulator of photoreceptor physiology. However, it is not known if light can regulate any aspect of photoreceptor development. The purpose of this study was to investigate whether ambient light is required for the development of mouse rod photoreceptors.

Endoscopic management of Barrett's esophagus: advances in endoscopic techniques.

Barrett's esophagus (BE) is a well-known premalignant condition that can be associated with the development of dysplasia and adenocarcinoma. In the past, esophagectomy was the standard treatment for patients with BE with high grade dysplasia (HGD) and early cancer (EC). However, esophagectomy is not necessarily the only treatment response to HGD and EC anymore.

Symptomatic pancreatic sarcoidosis. Case report and review of literature.

Context: Symptomatic pancreatic involvement in sarcoidosis is extremely rare. There are 25 reported cases of detected pancreatic sarcoidosis before death.

Case Report: We report the case of a male patient with a history of pulmonary sarcoidosis, who presented with clinical picture and CT scan findings suggestive of pancreatic cancer.