7 research outputs found

    Impact of Semaphorin 7A expression on tumorigenicity and immunogenicity of malignant gliomas

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    Die Prognose von Patienten mit malignen Gliomen ist infaust und bisher ist eine kurative Therapie nicht möglich. Maligne Gliome zeichnen sich durch ihr stark migratorisches Verhalten, die sehr frühe und diffuse Infiltration von benachbarten Hirnarealen und die Resistenz gegenüber verschiedenen apoptotischen Stimuli oder Immunabwehrmechanismen zum Schutz vor einer Bekämpfung durch das Immunsystem aus. Das Oberflächenprotein Semaphorin 7A nimmt bei der Entwicklung und Regenerationsprozessen des ZNS eine wichtige Rolle ein, indem es die Ausbildung und Wegfindung von Axonen lenkt, die Migration von Neuronen steuert und nach spinalen Verletzungen des adulten ZNS die Einwanderung von aktivierten Astrozyten und Glianarbenbildung fördert. Auch bei der Interaktion zwischen Nervensystem und Immunsystem scheint Semaphorin 7A eine wichtige, wenn auch widersprüchliche Funktion zu haben. Das Ziel dieser Arbeit war es herauszufinden, ob Gliomzellen Semaphorin 7A exprimieren und welche Bedeutung dieses Oberflächenprotein für die Tumorigenität und Immunogenität von malignen Gliomen besitzt. Es wurde erstmals gezeigt, dass Gliomzellen Semaphorin 7A auf mRNA- und Proteinebene exprimieren. Die mRNA-Expression des Semaphorin 7A Rezeptors Plexin C1 konnte in der konventionellen PCR in fast allen untersuchten Gliomzelllinien nachgewiesen werden. Die Expression des zweiten Semaphorin 7A Rezeptors alpha1beta1-Integrin wurde mittels Durchflusszytometrie untersucht. Auf funktioneller Ebene konnte die Migrations- und Invasionsfähigkeit von U87MG Gliomzellen durch eine Suppression der Semaphorin 7A Proteinexpression mittels siRNAs herabgesetzt werden. Eine vermehrte Semaphorin 7A Expression könnte somit eine Ursache des diffusen und frühen Migrations- und Invasionsverhalten von Gliomzellen in das umliegende gesunde Hirngewebe sein, wodurch eine kurative Behandlung durch Resektion unmöglich ist. In NK-Zelllyseassays hatte die Semaphorin 7A Expression auf Gliomzellen keinen Einfluss auf die Zytotoxizität von NK-Zellen. Daher scheint Semaphorin 7A die Erkennung von Gliomzellen als Targetzellen und die Aktivierung der NK-Zellen als zytotoxische Effektorzellen in diesem Paradigma nicht zu beeinflussen. Aufgrund dieser Arbeit ist anzunehmen, dass sich durch die Antagonisierung von Semaphorin 7A die Migration und Invasion maligner Gliome hemmen lässt, was Gegenstand zukünftiger Studien sein sollte.The prognosis of patients afflicted by malignant gliomas remains poor and a curable therapy does not exist as of yet. Malignant gliomas are characterized by their strong migratory behavior, their early and diffuse infiltration of the surrounding healthy tissue and their resistance to apoptotic stimuli and to immune defense mechanisms which protect the tumor against the combat of the immune system. Semaphorin 7A is a membrane-bound protein which plays an important role in the development and regeneration of the central nervous system (CNS) by regulating the neurit outgrowth, migration and axonal pathfinding. After spinal damage of the adult CNS, Semaphorin 7A promotes the invasion of activated astrocytes and the building of a glial scar. Furthermore, Semaphorin 7A seems to have an important but controversial function in the interaction between the immune and nervous system. The purpose of this thesis was to find out if gliomas express Semaphorin 7A and what a Semaphorin 7A expression means for the tumorigenicity and immunogenicity of malignant gliomas. It was shown that Gliomas express Semaphorin mRNA and protein as well as mRNA of the Semaphorin 7A receptor Plexin C1. Expression of the second Semaphorin 7A receptor alpha1beta1-Integrin was shown by flow cytometry. Silencing of Semaphorin 7A by RNA interference reduces migration and invasion of malignant glioma cells. Thus, an overexpression of Semaphorin 7A could be one reason for the strong migratory behavior and the early and diffuse infiltration of the surrounding healthy tissue of malignant gliomas that make a curative resection impossible. The suppression of Semaphorin 7A expression by RNA did not effect the lysis of glioma cells by natural killer (NK) in vitro. Thus, in this paradigma, Semaphorin 7A seems to have no influence on the identification of glioma cells as target cells and the activation of NK cells into cytotoxic effector cells. Due to this, it is assumable that antagonisation of Semaphorin 7A could constrain migration and invasion of malignant gliomas which should be content of prospective studies

    Clinical reasoning: a 30-year-old woman with recurrent seizures and a cerebral lesion progressing over 2 decades

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    A 30-year-old woman presented with a history of generalized tonic-clonic seizures since childhood, occurring for the first time at age 9. The initial diagnostic workup at age 13 demonstrated a distinctive calcified mass of the left frontal lobe on CT (figure, A). Together with a single facial nevus, the lesion was suspected to represent Sturge-Weber-like phakomatosis; however, the patient's clinical history and physical examination failed to reveal further evidence of a neurocutaneous syndrome. Neither MRI nor biopsy for histologic confirmation of the diagnosis was performed. At age 18 the patient was lost to follow-up at the children's hospital

    Tumor-associated edema in brain cancer patients: pathogenesis and management

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    The long-term treatment of peritumoral edema remains a major challenge in clinical neuro-oncology. Steroids have been and will remain the backbone of any anti-edematous therapy because of their striking activity, convenient oral administration and also because of their cost-effectiveness. Their side effects, however, can compromise quality of life, particularly upon continuous administration. Therapeutic alternatives which may replace or - at least - help to reduce the steroid dose are limited. However, with the development of new agents such as corticorelin acetate, there is a hope that steroid-induced side effects can be delayed and reduced. The administration of anti-angiogenic agents with steroid-sparing effects, for example, bevacizumab, is limited due to their costs. Increased knowledge on boswellic acids and cyclooxygenase-2 inhibitors which are available for clinical application may help to exploit their anti-edema activity more efficiently in the future

    Clinical management and outcome of histologically verified adult brainstem gliomas in Switzerland: a retrospective analysis of 21 patients

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    Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas (BSGs) remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult BSGs. A retrospective chart review of adults (age >18 years) was conducted. BSG was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. Twenty one patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 vs. 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (three in each group), radiochemotherapy (2 vs. 6), chemotherapy alone (0 vs. 2) or no postoperative therapy (3 vs. 1). Median PFS (24.1 vs. 5.8 months; log-rank, p = 0.009) and mOS (30.5 vs. 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. Histologically verification of adult BSGs is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities

    Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

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    IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes
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