Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ).

Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the tumor suppressor gene. encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of in Schwann cells, leading to constitutively activated p21RAS.

Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation.

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs).

In vitro effect of chlorambucil on human glioma cell lines (SF767 and U87-MG), and human microvascular endothelial cell (HMVEC) and endothelial progenitor cells (ECFCs), in the context of plasma chlorambucil concentrations in tumor-bearing dogs.

The objective of this study was to investigate a possible mechanism of action of metronomic chlorambucil on glioma by studying the in vitro cytotoxicity and anti-angiogenic effects on glioma and endothelial cells, respectively. The in vitro LD50 and IC50 of chlorambucil were determined using human SF767 and U87-MG glioma cell lines, human microvascular endothelial cells (HMVECs) and human endothelial colony forming cells (ECFCs). Results were analyzed in the context of chlorambucil concentrations measured in the plasma of tumor-bearing dogs receiving 4 mg m-2 metronomic chlorambucil.

Weight loss achieved using an energy restriction diet with normal or higher dietary protein decreased the number of CD14CD16 proinflammatory monocytes and plasma lipids and lipoproteins in middle-aged, overweight, and obese adults.

Monocytes are involved in immune responses, and specific monocyte subpopulations (MS) that express intermediate to high levels of CD16 are associated with obesity and cardiovascular events. Consuming high protein (HP) when dieting improves body composition and cardiometabolic health outcomes, but whether HP affects MS during weight loss remains unknown. We assessed the effect of HP on energy restriction (ER)-induced changes in MS in overweight and obese adults.

Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells.

Electroacupuncture (EA) performed in rats and humans using limb acupuncture sites, LI-4 and LI-11, and GV-14 and GV-20 (humans) and Bai-hui (rats) increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSCs) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue, whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation.

Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans.

Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease. Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21(Ras) activity and phosphorylation of multiple downstream kinases, including Erk and Akt. Nf1 heterozygous (Nf1(+/-)) mice develop a robust neointima that mimics human disease.

Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells.

Rationale: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs.

Objective: The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs.

Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation.

Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients.

Differences in Circulating Endothelial Progenitor Cells among Childhood Cancer Survivors Treated with and without Radiation.

Radiation during childhood cancer treatment increases the propensity to atherosclerotic cardiovascular disease among adult survivors of childhood cancer. This is thought to be mediated through the damage to the underlying vascular endothelium. Endothelial progenitor cells (EPCs) involved in vascular endothelial repair after its damage may be affected by radiation therapy but have never been investigated in adult survivors of childhood cancer.

Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox.

The present study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors associated with oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities including diabetes and hyperlipidemia were used as a preclinical model. Arterial occlusion was induced by distal femoral artery ligation in lean and DIO mice.

A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas.

Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony-forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls.

Brief report: Endothelial colony-forming cells and inflammatory monocytes in HIV.

The relationships between HIV infection, monocyte activation, and endothelial colony-forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14 CD16), and nonclassical monocytes (CD14 CD16) levels in HIV-infected participants virologically suppressed on antiretroviral therapy, HIV-infected treatment-naive participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected virologically suppressed group compared with the uninfected controls.

Lung parenchymal development in premature infants without bronchopulmonary dysplasia.

Rationale: While infants who are born extremely premature and develop bronchopulmonary dysplasia (BPD) have impaired alveolar development and decreased pulmonary diffusion (DLCO), it remains unclear whether infants born less premature and do not develop BPD, healthy premature (HP), have impaired parenchymal development. In addition, there is increasing evidence that pro-angiogenic cells are important for vascular development; however, there is little information on the relationship of pro-angiogenic cells to lung growth and development in infants.

Objective: and Methods Determine among healthy premature (HP) and fullterm (FT) infants, whether DLCO and alveolar volume (VA) are related to gestational age at birth (GA), respiratory support during the neonatal period (mechanical ventilation [MV], supplemental oxygen [O2], continuous positive airway pressure [CPAP]), and pro-angiogenic circulating hematopoietic stem/progenitor cells (CHSPCs).

Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth.

Preventing pathological ocular angiogenesis is key to treating retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. At present there is no small molecule drug on the market to target this process and hence there is a pressing need for developing novel small molecules that can replace or complement the present surgical and biologic therapies for these neovascular eye diseases. Previously, an antiangiogenic homoisoflavanone was isolated from the bulb of a medicinal orchid, Cremastra appendiculata.

Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in the development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death.

Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells.

Background: Children born to mothers with gestational diabetes mellitus (GDM) experience increased risk of developing hypertension, type 2 diabetes mellitus, and obesity. Disrupted function of endothelial colony-forming cells (ECFCs) may contribute to this enhanced risk. The goal of this study was to determine whether cord blood ECFCs from GDM pregnancies exhibit altered functionality.

Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation.

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1(+/-)) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury.

Human proangiogenic circulating hematopoietic stem and progenitor cells promote tumor growth in an orthotopic melanoma xenograft model.

We previously identified a distinct population of human circulating hematopoietic stem and progenitor cells (CHSPCs; CD14(-)glyA(-)CD34(+)AC133(+/-)CD45(dim)CD31(+) cells) in the peripheral blood (PB) and bone marrow, and their frequency in the PB can correlate with disease state. The proangiogenic subset (pCHSPC) play a role in regulating tumor progression, for we previously demonstrated a statistically significant increase in C32 melanoma growth in NOD.Cg-Prkdc (scid) (NOD/SCID) injected with human pCHSPCs (p < 0.

Membrane and capillary components of lung diffusion and pro-angiogenic cells in infants.

Angiogenesis is a critical determinant of alveolarisation, which increases alveolar surface area and pulmonary capillary blood volume in infants; however, our understanding of this process is very limited. The purpose of our study was to measure the pulmonary membrane diffusion capacity (DM) and pulmonary capillary blood volume (VC) components of the diffusing capacity of the lung for carbon monoxide (DLCO) in healthy infants and toddlers, and evaluate whether these components were associated with pro-angiogenic circulating haematopoietic stem/progenitor cells (pCHSPCs) early in life. 21 healthy subjects (11 males), 3-25 months of age, were evaluated.

Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway.

Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality.

Peripheral blood biomarkers of solid tumor angiogenesis in dogs: a polychromatic flow cytometry pilot study.

A subset of peripheral blood hematopoietic stem and progenitor cells of bone marrow origin is elevated in humans with solid cancers before treatment and declines with therapy. This biomarker of angiogenesis is not specific to tumor type and has great potential in the objective assessment of treatment response in clinical trials. This pilot study was designed to develop a biomarker of neoangiogenesis in dogs for the diagnosis of cancer, the measurement of treatment response, and the provision of objective data in clinical trials.

Flow cytometric identification and functional characterization of immature and mature circulating endothelial cells.

Objective: We sought to identify and characterize 2 distinct populations of bona fide circulating endothelial cells, including the endothelial colony-forming cell (ECFC), by polychromatic flow cytometry (PFC), colony assays, immunomagnetic selection, and electron microscopy.

Methods And Results: Mononuclear cells from human umbilical cord blood and peripheral blood were analyzed using our recently published PFC protocol. A population of cells containing both ECFCs and mature circulating endothelial cells was determined by varying expressions of CD34, CD31, and CD146 but not AC133 and CD45.

Polychromatic flow cytometry identifies novel subsets of circulating cells with angiogenic potential in pediatric solid tumors.

Background: Pediatric solid tumors depend upon angiogenesis for their growth and metastases. A new polychromatic flow cytometry (PFC) protocol has revealed circulating cells of hematopoietic and endothelial lineages from the peripheral blood (PB) of healthy individuals, and has defined the different cell types involved in the growth of tumor vasculature that are critical in angiogenesis.

Methods: PB was collected from both healthy children and children with different malignant solid tumors and the mononuclear cells (MNCs) were subsequently isolated.