Search results for "Raf"

EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.

2016

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible facto…

OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digi…

2016

Item does not contain fulltext Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentrio…

Angiotensin II and leukocyte trafficking: New insights for an old vascular mediator. Role of redox-signaling pathways.

2019

Abstract Inflammation and activation of the immune system are key molecular and cellular events in the pathogenesis of cardiovascular diseases, including atherosclerosis, hypertension-induced target-organ damage, and abdominal aortic aneurysm. Angiotensin II (Ang-II) is the main effector peptide hormone of the renin-angiotensin system. Beyond its role as a potent vasoconstrictor and regulator of blood pressure and fluid homeostasis, Ang-II is intimately involved in the development of vascular lesions in cardiovascular diseases through the activation of different immune cells. The migration of leukocytes from circulation to the arterial subendothelial space is a crucial immune response in le…

A new approach for the treatment of CLL using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles

2015

Current approaches for the treatment of chronic lymphocytic leukemia (CLL) have greatly improved the prognosis for survival, but some patients remain refractive to these therapeutic regimens. Hence, in addition to reducing the long-term sideeffects of therapeutics for all leukemia patients, there is an urgent need for novel therapeutic strategies for difficult-to-treat leukemia cases. Due to the cytotoxicity of drugs, the major challenge currently is to deliver the therapeutic agents to neoplastic cells while preserving the viability of non-malignant cells. In this study, we propose a therapeutic approach in which high doses of hydroxychloroquine and chlorambucil were loaded into biodegrada…

Stabilization and detection of hydrophylloquinone as di-O-methyl derivative

2016

Phylloquinone is a redox active naphthoquinone involved in electron transport in plants. The function of this reduced form remains unclear due to its instability, which has precluded detection. Herein, a simple method that permits the stabilization of the reduced form of phylloquinone by di-O-methylation and HPLC detection is described. Fil: Sussmann, Rodrigo A. C.. Universidade de Sao Paulo; Brasil Fil: de Moraes, Marcilio M.. Universidade de Sao Paulo; Brasil Fil: Cebrián Torrejón, Gerardo. Universidad de Valencia; España. Universidade de Sao Paulo; Brasil Fil: Porta, Exequiel Oscar Jesús. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - …

Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer

2018

Solid malignancies have been speculated to depend on cancer stem cells (CSCs) for expansion and relapse after therapy. Here we report on quantitative analyses of lineage tracing data from primary colon cancer xenograft tissue to assess CSC functionality in a human solid malignancy. The temporally obtained clone size distribution data support a model in which stem cell function in established cancers is not intrinsically, but is entirely spatiotemporally orchestrated. Functional stem cells that drive tumour expansion predominantly reside at the tumour edge, close to cancer-associated fibroblasts. Hence, stem cell properties change in time depending on the cell location. Furthermore, although…

Electroporation by concentric-type needle electrodes and arrays.

2017

Abstract The efficacy of genomic medicine depends on gene transfer efficiency. In this area, electroporation has been found to be a highly promising method for physical gene transfer. However, electroporation raises issues related to electrical safety, tissue damage, and the number of required wounds. Concentric-type needle electrodes seek to address these issues by using a lower bias (10 V), a single wound, fewer processing steps, and a smaller working area (≈ 10 mm 3 ), thus offering greater accuracy and precision. Moreover, the needle can be arrayed to simultaneously treat several target regions. This paper proposes a novel method using concentric-type needle electrodes to improve the ef…

Airborne disease: a case of a Takotsubo cardiomyopathie as a consequence of nighttime aircraft noise exposure.

2016

Chronic noise exposure (in particular nighttime noise) leads to disturbances of activities, sleep, and communication. As a consequence, emotional responses or annoyance will lead to stress reactions characterized by an activation of the sympathetic nervous system and/or increased levels of circulating stress hormones. We report here a case of a patient, who was exposed to heavy …

Transcutaneous immunization with CD40 ligation boosts cytotoxic T lymphocyte mediated antitumor immunity independent of CD4 helper cells in mice.

2018

Transcutaneous immunization (TCI) is a novel vaccination strategy that utilizes skin-associated lymphatic tissue to induce immune responses. Employing T-cell epitopes and the TLR7 agonist imiquimod onto intact skin mounts strong primary, but limited memory CTL responses. To overcome this limitation, we developed a novel imiquimod-containing vaccination platform (IMI-Sol) rendering superior primary CD8+ and CD4+ T-cell responses. However, it has been unclear whether IMI-Sol per se is restricted in terms of memory formation and tumor protection. In our present work, we demonstrate that the combined administration of IMI-Sol and CD40 ligation unleashes fullblown specific T-cell responses in th…

2017

Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n = 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 i…