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  • 1
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(5), p.e0127123
    Description: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0-230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: Annals of Neurology, May 2012, Vol.71(5), pp.624-633
    Description: Objective: Anticoagulation with dabigatran etexilate (DE) has a favorable risk-to-benefit profile for the prevention of ischemic events in patients with atrial fibrillation compared to warfarin. Whereas warfarin constitutes a strong contraindication for thrombolysis, it is unclear whether patients anticoagulated with DE can be thrombolysed. We compared the risk of thrombolysis-associated hemorrhagic transformation (HT) after pretreatment with DE or warfarin in a mouse model of ischemic stroke. Methods: Thirty-nine C57BL/6 mice were pretreated orally with 75mg/kg DE, 112.5mg/kg DE, 2mg/kg warfarin, or saline. We performed right middle cerebral artery occlusion for 3 hours, administered recombinant tissue plasminogen activator (rt-PA) directly before reperfusion, and assessed neurological deficit and HT blood volume after 24 hours. Results: Warfarin anticoagulation increased HT secondary to rt-PA treatment as compared to nonanticoagulated controls (6.9 plus or minus 5.5 mu l vs 0.8 plus or minus 0.6 mu l, p 〈 0.05). In contrast, the rate of HT after pretreatment with 75mg/kg DE, which led to plasma levels comparable to the highest plasma levels observed in participants of the RE-LY trial, did not differ significantly from controls (1.6 plus or minus 0.8; p 〉 0.05 vs control). However, a high-dose group receiving 112.5mg/kg DE showed a considerable extent of HT (9.2 plus or minus 5.6 mu l, p 〈 0.01). Interpretation: Our experimental data suggest that the risk of thrombolysis-associated HT may not be increased under DE pretreatment with standard doses leading to plasma levels of up to 400ng/ml, a concentration that was not exceeded in the majority of DE trial patients. At higher DE plasma levels, however, the risk of severe HT rises considerably, emphasizing the need for a readily available assay of DE anticoagulant activity. ANN NEUROL 2012
    Keywords: Transformation ; Thrombolysis ; Anticoagulants ; Data Processing ; Stroke ; Animal Models ; Warfarin ; Ischemia ; Hemorrhage ; Clinical Trials ; T-Plasminogen Activator ; Reperfusion ; Blood ; Plasma Levels ; Fibrillation ; Cerebral Blood Flow ; Neurology & Neuropathology;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(8), p.e22312
    Description: PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.
    Keywords: Research Article ; Biology ; Medicine ; Molecular Biology ; Oncology
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Medical Microbiology and Immunology, 2011, Vol.200(1), pp.1-5
    Description: The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence.
    Keywords: Cytomegalovirus ; Cancer ; Oncomodulation ; Tumour virus ; Glioblastoma ; Neuroblastoma
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 5
    Language: English
    In: Epilepsy & Behavior, November 2018, Vol.88, pp.146-151
    Description: Meningiomas belong to the most common intracranial neoplasms in adults. One of the most common symptoms patients with meningioma experience is seizures. However, it remains unclear whether prophylactic preoperative anticonvulsant treatment is worthwhile. Furthermore, it is not clear which patients are likely to experience seizures in the course of the disease. In recent years, many studies and meta-analyses addressed this question with particular contradictory results. Therefore, we aimed to identify the most important risk factors for seizures in patients with meningiomas. For the search terms “meningioma and seizure”, “meningioma and epilepsy”, and “Simpson and seizure” Medline query identified 865 articles. After applying inclusion and exclusion criteria, 20 papers were chosen for further study. The papers were analyzed for all risk factors for pre- and postoperative risk factors for seizures. Preoperative seizures were mostly associated with extensive brain edema, localization, and bigger tumor size. Even though data were sometimes very contradictory, higher postoperative seizure rate in patients with meningioma was associated with distinct localizations, preoperative seizures, tumor size, brain edema, extent of resection, tumor recurrence, and new neurological deficits. There were no randomized trials showing a prophylactic effect of anticonvulsant drugs. There are relevant risk factors for seizures in patients with meningioma. There is the need for a double blind randomized trial for the prophylactic use of antiepileptic drugs (AEDs).
    Keywords: Meningioma ; Seizure ; Antiepileptic Drugs ; Prophylactic Anticonvulsant Treatment ; Epilepsy ; Medicine
    ISSN: 1525-5050
    E-ISSN: 1525-5069
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e64873
    Description: Yeast cells can be killed upon expression of pro-apoptotic mammalian proteins. We have established a functional yeast survival screen that was used to isolate novel human anti-apoptotic genes overexpressed in treatment-resistant tumors. The screening of three different cDNA libraries prepared from metastatic melanoma, glioblastomas and leukemic blasts allowed for the identification of many yeast cell death-repressing cDNAs, including 28% of genes that are already known to inhibit apoptosis, 35% of genes upregulated in at least one tumor entity and 16% of genes described as both anti-apoptotic in function and upregulated in tumors. These results confirm the great potential of this screening tool to identify novel anti-apoptotic and tumor-relevant molecules. Three of the isolated candidate genes were further analyzed regarding their anti-apoptotic function in cell culture and their potential as a therapeutic target for molecular therapy. PAICS, an enzyme required for de novo purine biosynthesis, the long non-coding RNA MALAT1 and the MAST2 kinase are overexpressed in certain tumor entities and capable of suppressing apoptosis in human cells. Using a subcutaneous xenograft mouse model, we also demonstrated that glioblastoma tumor growth requires MAST2 expression. An additional advantage of the yeast survival screen is its universal applicability. By using various inducible pro-apoptotic killer proteins and screening the appropriate cDNA library prepared from normal or pathologic tissue of interest, the survival screen can be used to identify apoptosis inhibitors in many different systems.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: European Spine Journal, 2016, Vol.25(3), pp.732-739
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00586-015-3864-7 Byline: Jehuda Soleman (1), Peter Baumgarten (1), Wolfgang Nicolas Perrig (1), Javier Fandino (1), Ali-Reza Fathi (1) Keywords: Aspirin; Extradural spine surgery; Low-dose acetylsalicylic acid; Non-instrumented spinal surgery Abstract: Purpose Coronary artery disease (CAD) affects over one-third of adults and is the leading cause of overall mortality and morbidity. Acetylsalicylic acid (ASA) is widely used in the prevention of CAD. As the population continues to mature, the number of patients presenting for spinal surgery that are under ASA treatment is rising. Studies investigating the outcome of lumbar spine surgeries without discontinuation of ASA therapy are lacking. The purpose of this study is to evaluate the peri- and postoperative bleeding and cardiovascular complication rates of patients undergoing non-instrumented, extradural, lumbar spine surgery with or without discontinuation of low-dose ASA. Methods We retrospectively compared the intra- and postoperative blood loss, morbidity, mortality, blood transfusion requirements and hematologic findings in the ASA group (40 patients) and the control group (62 patients). The diagnosis in all patients was either lumbar disc herniation or spinal canal stenosis. Results Intraoperative blood loss was 221 ml in the ASA group and 140.16 ml in the control group, showing no statistical difference (p = 0.08). Postoperative blood loss was 146.58 and 167.97 ml in the ASA and control groups, respectively, also without statistical difference (p = 0.76). In the ASA group one patient developed a postoperative epidural hematoma needing revision surgery, while in the control group no postoperative epidural hematomas were seen (p = 0.40). In addition, blood transfusion requirements, hematologic findings, morbidity and mortality showed no significant difference. Conclusion The continuation of ASA treatment in patients undergoing non-instrumented extradural lumbar spinal surgery seems to be safe and its perioperative continuation might therefore be recommended. Further studies confirming these results are needed. Author Affiliation: (1) Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse, 5001, Aarau, Switzerland Article History: Registration Date: 05/03/2015 Received Date: 13/11/2014 Accepted Date: 04/03/2015 Online Date: 11/03/2015
    Keywords: Aspirin ; Extradural spine surgery ; Low-dose acetylsalicylic acid ; Non-instrumented spinal surgery
    ISSN: 0940-6719
    E-ISSN: 1432-0932
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  • 8
    Language: English
    In: Surgical neurology international, 2016, Vol.7(Suppl 29), pp.S775-S778
    Description: Intracerebral foreign body granuloma is rarely reported. We present the case of a male patient with a cerebral foreign body granuloma. Initial admission of a 67-year-old male patient was after an aphasia followed by secondary generalized seizures. Cranial computed tomography (CCT) showed a metal-dense, wedge-shaped foreign body in the range of the frontal sinus on the left side, breaking through the frontal sinus, and creating a connection to the frontal cerebral lobe. The patient did not report previous trauma or accident. A concomitant inflammatory response could not be excluded in CCT imaging. In clinical examination, the patient showed no sensorimotor deficit. Operative resection and dural reconstruction was performed. Several tiny, metal-like foreign-body fragments and one stone-like body could be detected and removed. Histopathological examination showed an intracerebral granuloma with areas of acute granulocytic inflammatory reaction. Cerebral foreign body granuloma is a rare entity without initially provoking clinical symptoms, and causing clinical symptoms even years after the initial event. In most reported cases, wooden or metallic bodies are reported. In addition, hemostatic materials and non-resorbable cotton sheets can cause intracerebral granuloma. There is a high risk of infection with a high mortality rate in case of an existent intracranial abscess. In case of first presentation of seizures, a foreign body should be kept in mind if a traumatic injury cannot be reported. Therefore, possible foreign bodies provoking clinical symptoms such as seizures should always be radiologically excluded, and if present and operatively accessible, removal should be done as soon as possible.
    Keywords: Cerebral Granuloma ; Foreign Body ; Seizures
    ISSN: 2229-5097
    E-ISSN: 21527806
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  • 9
    Language: English
    In: World Neurosurgery, April 2018, Vol.112, pp.e442-e453
    Description: Evidence for cerebral reorganization after resection of low-grade glioma has mainly been obtained by serial intraoperative cerebral mapping. Noninvasively collected data on cortical plasticity in tumor patients over a surgery-free period are still scarce. The present study therefore aimed at evaluating motor cortex reorganization by navigated transcranial magnetic stimulation (nTMS) in patients after perirolandic glioma surgery. nTMS was performed preoperatively and postoperatively in 20 patients, separated by 26.1 ± 24.8 months. Further nTMS mapping was conducted in 14 patients, resulting in a total follow-up period of 46.3 ± 25.4 months. Centers of gravity (CoGs) were calculated for every muscle representation area, and Euclidian distances between CoGs over time were defined. Results were compared with data from 12 healthy individuals, who underwent motor cortex mapping by nTMS in 2 sessions. Preoperatively and postoperatively pooled CoGs from the area of the dominant abductor pollicis brevis muscle and of the nondominant leg area differed significantly compared with healthy individuals ( 〈 0.05). Most remarkably, during the ensuing follow-up period, a reorganization of all representation areas was observed in 3 patients, and a significant shift of hand representation areas was identified in further 3 patients. Complete functional recovery of postoperative motor deficits was exclusively associated with cortical reorganization. Despite the low potential of remodeling within the somatosensory region, long-term reorganization of cortical motor function can be observed. nTMS is best suited for a noninvasive evaluation of this reorganization.
    Keywords: Glioma ; Motor Cortex ; Ntms ; Plasticity ; Reorganization ; Surgery
    ISSN: 1878-8750
    E-ISSN: 1878-8769
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  • 10
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2014, Vol.1135, pp.187-203
    Description: The formation of new blood vessels is a major hallmark in the process of malignant transformation in human glioblastomas. In diffusely infiltrating gliomas, enhanced angiogenesis is associated with decreased patient survival rates and therefore serves as a central diagnostic criterion according to the WHO (World Health Organization) classification of tumors of the central nervous system (CNS). However, the assessment of what a newly built blood vessel really is and how the extent of glioma-associated angiogenesis can be estimated in vivo is often a highly subjective procedure with imprecise criteria depending on the experience of the neuropathologist. The increased interest in translational medicine and anti-angiogenic treatment strategies implies that basic researchers in glioma angiogenesis are frequently asked to validate their findings in patient material to provide evidence for potential clinical relevance of their results. Therefore, more precise methods and measurement techniques are needed to objectively measure the extent of angiogenesis in human glioblastoma samples. The present synopsis provides an overview about morphological methods to assess the formation of new blood vessels by quantitative imaging using histological and immunohistochemical marker profiles.
    Keywords: Brain Neoplasms -- Blood Supply ; Glioblastoma -- Blood Supply
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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