Christian Hagel - Academia.edu (original) (raw)

Papers by Christian Hagel

Journal of Investigative Dermatology, May 1, 2000

Oncotarget, 2016

Hyperactive Ras signaling has strong oncogenic effects causing several different forms of cancer.... more Hyperactive Ras signaling has strong oncogenic effects causing several different forms of cancer. Hyperactivity is frequently induced by mutations within Ras itself, which account for up to 30% of all human cancers. In addition, hyperactive Ras signaling can also be triggered independent of Ras by either mutation or by misexpression of various upstream regulators and immediate downstream effectors. We have previously reported that C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) can drive Ras activity and promote tumorigenic transformation by inhibition of the tumor suppressor Merlin. We now describe an additional element of this oncogenic mechanism in the form of the ezrin-radixin-moesin (ERM) protein family, which exhibits opposing roles in Ras activity control. Thus, CPI-17 drives Ras activity and tumorigenesis in a twofold way; inactivation of the tumor suppressor merlin and activation of the growth promoting ERM family. The in vivo significance of this oncogenic switch is highlighted by demonstrating CPI-17's involvement in human melanoma pathogenesis.

Cell, Jan 25, 2016

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive,... more Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS…

Acta neurologica Scandinavica, Jan 15, 2015

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwanno... more Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas METHODS: We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. Eight patients with NF2 and symptomatic ependymoma were treated wi...

Neuro-Oncology, 2002

Neuro-Oncology Cytoplasmic accumulation of wild-type p53 in tumor cells indicates that the tumor ... more Neuro-Oncology Cytoplasmic accumulation of wild-type p53 in tumor cells indicates that the tumor suppressor is inactive with regard to growth suppressive functions. Whether this occurs randomly during tumor development or characterizes a certain tumor cell subset is not known. Here we assayed primary glioblastomas for expression and subcellular localization of p53 and determined a correlation with expression of intermediate lament proteins characterizing glial cell development. Sixty-nine percent of the tumors were p53 positive in immunohistochemistry. A signi cant number of tumors (23%) accumulated wild-type p53 in the cytoplasm, which correlated with the presence of vimentin and glial brillary acidic protein, except for 1 case. Tumors with exclusive nuclear p53 contained none or only one of these intermediate lament proteins. In an alternative approach, tumors positive for glial brillary acidic protein were screened for expression of p53 and vimentin. Thirty-eight percent of these tumors showed cytoplasmic p53, and all of those also expressed vimentin. Tumors with only nuclear p53 were vimentin negative,

Annals of Clinical and Translational Neurology, 2014

Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction o... more Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13‐year‐old girl with mitochondrial membrane protein‐associated neurodegeneration treated with an iron‐chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.

Notfälle mit Bewusstseinsstörungen und Koma

The Journal of Clinical Endocrinology & Metabolism

Human genetics, Jan 13, 2018

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of m... more Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical...

Acta neuropathologica, Jan 5, 2018

Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma ou... more Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN groupe...

Experimental Neurology

The term &amp;#39;Neurofibromatosis&amp;#39; (NF) comprises a group of rare disea... more The term &amp;#39;Neurofibromatosis&amp;#39; (NF) comprises a group of rare diseases with related clinical presentations but distinct genetic conditions. All currently known types - NF1, NF2 and Schwannomatosis - predispose afflicted individuals to the development of glial cell-derived (gliogenic) tumors. Furthermore, the occurrence of neuropathic symptoms, which add to the overall neurologic disability of patients, has been described in all disease entities. We show that neuropathic symptoms are a common and clinically important, yet infrequently studied feature in the NF spectrum. However, the clinical relevance and respective underlying pathogenesis, varies greatly among the different NF types. In this review, we summarize and interpret the latest basic research findings, as well as clinical observations, in respect of Neurofibromatosis-associated neuropathies.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2016

Mucolipidosis II (MLII) is a severe systemic genetic disorder caused by defects in mannose 6-phos... more Mucolipidosis II (MLII) is a severe systemic genetic disorder caused by defects in mannose 6-phosphate-dependent targeting of multiple lysosomal hydrolases and subsequent lysosomal accumulation of non-degraded material. MLII patients exhibit marked facial coarseness and gingival overgrowth soon after birth, accompanied with delayed tooth eruption and dental infections. To examine the pathomechanisms of early craniofacial and dental abnormalities, we analyzed mice with an MLII patient mutation that mimic the clinical and biochemical symptoms of MLII patients. The mouse data were compared with clinical and histological data of gingiva and teeth from MLII patients. Here, we report that progressive thickening and porosity of calvarial and mandibular bones, accompanied by elevated bone loss due to 2-fold higher number of osteoclasts cause the characteristic craniofacial phenotype in MLII. The analysis of postnatal tooth development by microcomputed tomography imaging and histology revealed normal dentin and enamel formation, and increased cementum thickness accompanied with accumulation of storage material in cementoblasts of MLII mice. Massive accumulation of storage material in subepithelial cells as well as disorganization of collagen fibrils led to gingival hypertrophy. Electron and immunofluorescence microscopy, together with (35)S-sulfate incorporation experiments revealed the accumulation of non-degraded material, non-esterified cholesterol and glycosaminoglycans in gingival fibroblasts, which was accompanied by missorting of various lysosomal proteins (α-fucosidase 1, cathepsin L and Z, Npc2, α-l-iduronidase). Our study shows that MLII mice closely mimic the craniofacial and dental phenotype of MLII patients and reveals the critical role of mannose 6-phosphate-dependent targeting of lysosomal proteins for alveolar bone, cementum and gingiva homeostasis.

Parkinsonism & related disorders, Jan 27, 2016

Acta Neurochirurgica, Jul 1, 2003

We present the unusual occurrence of multiple systemic and two central nervous system tuberculoma... more We present the unusual occurrence of multiple systemic and two central nervous system tuberculomas in an immunecompetent young patient. A large left frontal epidural tuberculoma with transcalvarian extension was removed surgically and chemotherapy was initiated. The patient remained on a chemotherapy with INH, RMP, and EMB and was followed clinically and with MRI scans for 24 months. Findings. The clinical presentation and neuroimaging studies initially suggested malignant disease. Surgical resection of the left frontal lesion was required to relive the mass effect. The histological evaluation showed a granulomatous inflammation with epitheloid and Langhans giant cells, but no acid-fast bacilli. Cultures of the specimens yielded a mixed infection with Corynebacterium species and Staphylococcus epidermidis. Based on the histological findings, chemotherapy for tuberculosis was initiated. Subsequently, Mycobacterium tuberculosis was cultured from the surgical specimen and sputum. Interpretation. Parenchymal CNS tuberculosis with or without extracerebral manifestations may present as a space-occupying lesion. Because a tuberculoma is rarely suspected especially if there is atypical morphology, biopsy is required to establish the diagnosis and expedite specific treatment.

Ann Neurol, 2003

We present a juvenile case of Alexander&amp;amp;amp;amp;amp;amp;amp;#39;s disease with at... more We present a juvenile case of Alexander&amp;amp;amp;amp;amp;amp;amp;#39;s disease with atypical focal magnetic resonance imaging-detected lesions and elevated levels of lactate in cerebrospinal fluid. The diagnosis was based on the neuropathological finding of a diffuse accumulation of Rosenthal fibers within the brain and the spinal cord. The diagnosis was confirmed by detection of a mutation in exon 1 at nucleotide position 249 of glial fibrillary acidic protein cDNA, a finding previously reported in cases of infantile Alexander&amp;amp;amp;amp;amp;amp;amp;#39;s disease.

GMS Interdisciplinary plastic and reconstructive surgery DGPW, 2014

Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease... more Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by the triad epilepsy, hamartomas (angiofibroma) and reduced intellectual capacity. Phenotype can vary considerably. Almost all patients with TSC have at least one characteristic dermatologic feature. Facial angiofibroma can cause severe disfigurement. It may involve the cheeks, perioral region and nose, resulting in thick layers of nodular and pustular skin. Aesthetic surgery of the face comprises an individually adapted ablation of the affected skin regions in order to improve physical appearance. Reports on the subject of surgery for nasal angiofibroma confirm the homogenous transformation of the connective tissues by this hamartoma. Hitherto there is only one report in the literature describing the typical epithelial alterations of the nasal skin compatible with a rhinophyma and adjacent angiofibroma. Here we report the successful electrosurgical treatment of a patient...

The Open Neurology Journal, 2015

One of the oldest and probably well-known examples of cerebral palsy is the mummy of the Pharaoh ... more One of the oldest and probably well-known examples of cerebral palsy is the mummy of the Pharaoh Siptah about 1196–1190 B.C., and a letter from Hippocrates (460–390 B.C.). Cerebral palsy (CP) is one of the most common congenital or acquired neurological impairments in paediatric patients, and refers to a group of children with motor disability and related functional defects. The visible core of CP is characterized by abnormal coordination of movements and/or muscle tone which manifest very early in the development. Resulting from pre- or perinatal brain damage CP is not a progressive condition per se. However, without systematic medical and physiotherapeutic support the dystonia leads to muscle contractions and to deterioration of the handicap. Here we review the three general spastic manifestations of CP hemiplegia, diplegia and tetraplegia, describe the diagnostic procedures and delineate a time schedule for an early intervention.

Anticancer research, 2015

Peripheral nerve sheath (PNS) tumors constitute a heterogeneous group of solid tumors. Neurofibro... more Peripheral nerve sheath (PNS) tumors constitute a heterogeneous group of solid tumors. Neurofibroma and schwannoma are the most frequently diagnosed entities. Both tumor types occur sporadically and are associated with syndromes. Current strategies to fight PNS progression by means of pharmaceuticals aim to specifically interfere with vascular growth factors identified in PNS. Furthermore, malignant transformation of PNS tumors is known to be associated with a change in vascularization. The aim of the study was to investigate vascularization of different PNS tumors with respect to sporadic or syndromal state of the entities. One hundred and thirty-two formalin-fixed and paraffin-embedded PNS tissue samples were retrieved from the archives of the Institute of Neuropathology, Eppendorf University Hospital. Lymphatic and blood vessels were immunohistochemically identified and morphometrically analyzed in PNS and controls. Blood vessel density in malignant tumors was significantly highe...

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2003

Several genetic liver diseases can be treated by liver transplantation (LT). However, some geneti... more Several genetic liver diseases can be treated by liver transplantation (LT). However, some genetic defects also may be acquired by this procedure. We describe a patient who developed recurrent deep-vein thromboses after LT for hepatitis C virus-associated hepatocellular carcinoma on the basis of a homozygous Leiden mutation of the factor V gene in the donor liver. Liver donors with a history of venous thrombosis should be screened for the presence of activated protein C (APC) resistance. In addition, we recommend looking for APC resistance in liver recipients who develop venous thromboembolic disease in the post-LT course. Molecular analysis of donor tissue may be necessary to make a definite diagnosis of factor V Leiden mutation in these patients. As a consequence, intensified postoperative thromboprophylaxis or lifelong anticoagulant therapy may be necessary if this thrombophilic gene defect is detected.