NRAS mutation drives elevated angiopoietin-2 expression in human endothelial cells and a genetic mouse model.

Background: Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRAS mutation has been found in the lesions of KLA patients.

Procedure: Our study tested the hypothesis that the NRAS mutation drives elevated Ang-2 expression in endothelial cells.

NRAS mutation in human endothelial cells causes vascular malformations.

Somatic mutations in NRAS drive the pathogenesis of melanoma and other cancers but their role in vascular anomalies and specifically human endothelial cells is unclear. The goals of this study were to determine whether the somatic-activating NRAS mutation in human endothelial cells induces abnormal angiogenesis and to develop in vitro and in vivo models to identify disease-causing pathways and test inhibitors. Here, we used mutant NRAS and wild-type NRAS (NRAS) expressing human endothelial cells in in vitro and in vivo angiogenesis models.

Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation.

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies characterized by aberrant and enlarged lymphatic and blood vessels. CLVM appear during fetal development and enlarge after birth, causing life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and disfigurement. Treatment includes surgical debulking, amputation, and recurrent sclerotherapy.

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis.

Background: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies.

Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.

Objective- Venous malformations (VMs) arise from developmental defects of the vasculature and are characterized by massively enlarged and tortuous venous channels. VMs grow commensurately leading to deformity, obstruction of vital structures, bleeding, and pain. Most VMs are associated with the activating mutation L914F in the endothelial cell (EC) tyrosine kinase receptor TIE2.

Hypoxia-induced Pulmonary Hypertension in Different Mouse Strains: Relation to Transcriptome.

Patients with pulmonary arterial hypertension (PAH) can harbor mutations in several genes, most commonly in BMPR2. However, disease penetrance in patients with BMPR2 mutations is low. In addition, most patients do not carry known PAH gene mutations, suggesting that other factors determine susceptibility to PAH.

CHILDREN WITH MULTIPLE CONGENITAL DEFECTS: WHAT ARE THE LIMITS BETWEEN THERAPEUTIC OBSTINACY AND THE TREATMENT OF UNCERTAIN BENEFIT?

Objective: Therapeutic approach of children with multiple malformations poses many dilemmas, making it difficult to build a line between the treatment of uncertain benefit and therapeutic obstinacy. The aim of this paper was to highlight possible sources of uncertainty in the decision-making process, for this group of children.

Case Description: An 11-month-old boy, born with multiple birth defects and abandoned by his parents, has never been discharged home.

Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease.

Airway hyperreactivity (AHR) and remodeling are cardinal features of asthma and chronic obstructive pulmonary disease. New therapeutic targets are needed as some patients are refractory to current therapies and develop progressive airway remodeling and worsening AHR. The mammalian target of rapamycin (mTOR) is a key regulator of cellular proliferation and survival.

Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma.

Increases in the epidermal growth factor receptor (EGFR) have been associated with the severity of airway thickening in chronic asthmatic subjects, and EGFR signaling is induced by asthma-related cytokines and inflammation. The goal of this study was to determine the role of EGFR signaling in a chronic allergic model of asthma and specifically in epithelial cells, which are increasingly recognized as playing an important role in asthma. EGFR activation was assessed in mice treated with intranasal house dust mite (HDM) for 3 wk.

Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice.

Transforming growth factor (TGF)-alpha and its receptor, the epidermal growth factor receptor, are induced after lung injury and are associated with remodeling in chronic pulmonary diseases, such as pulmonary fibrosis and asthma. Expression of TGF-alpha in the lungs of adult mice causes fibrosis, pleural thickening, and pulmonary hypertension, in addition to increased expression of a transcription factor, early growth response-1 (Egr-1). Egr-1 was increased in airway smooth muscle (ASM) and the vascular adventitia in the lungs of mice conditionally expressing TGF-alpha in airway epithelium (Clara cell secretory protein-rtTA(+/-)/[tetO](7)-TGF-alpha(+/-)).

Predictive model for the length of hospital stay of children with hematologic malignancies, neutropenia, and presumed infection.

Few studies have assessed the predictive factors for the length of hospital stay for children with malignancies admitted with a diagnosis of presumed infection. We performed an observational prospective study of children 13 years old or younger with hematologic malignancies and neutropenia admitted for presumed infection to set up a predictive model for the length of stay using variables available at admission. Episodes in which children were on induction chemotherapy were excluded from the study.

Vascular growth and remodeling in compensatory lung growth following right lobectomy.

Studies in animal models have shown that, following lobectomy (LBX), there is compensatory growth in the remaining lung. The vascular growth response following right LBX (R-LBX) is poorly understood. To test the hypothesis that arterial growth and remodeling occur in response to LBX, in proportion to the amount of right lung tissue removed, two (24% of lung mass; R-LBX2 group) or three right lobes (52% of lung mass; R-LBX3 group) were removed via thoracotomy from adult rats.