Showing papers by "Ulrich Bogdahn published in 2007"

CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.

Abstract: Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.

Striatal grey matter increase in patients suffering from fibromyalgia – A voxel-based morphometry study

Abstract: Fibromyalgia (FM), among other chronic pain syndromes, such as chronic tension type headache and atypical face pain, is classified as a so-called dysfunctional pain syndrome. Patients with fibromyalgia suffer from widespread, "deep" muscle pain and often report concomitant depressive episodes, fatigue and cognitive deficits. Clear evidence for structural abnormalities within the muscles or soft tissue of fibromyalgia patients is lacking. There is growing evidence that clinical pain in fibromyalgia has to be understood in terms of pathological activity of central structures involved in nociception. We applied MR-imaging and voxel-based morphometry, to determine whether fibromyalgia is associated with altered local brain morphology. We investigated 20 patients with the diagnosis of primary fibromyalgia and 22 healthy controls. VBM revealed a conspicuous pattern of altered brain morphology in the right superior temporal gyrus (decrease in grey matter), the left posterior thalamus (decrease in grey matter), in the left orbitofrontal cortex (increase in grey matter), left cerebellum (increase in grey matter) and in the striatum bilaterally (increase in grey matter). Our data suggest that fibromyalgia is associated with structural changes in the CNS of patients suffering from this chronic pain disorder. They might reflect either a consequence of chronic nociceptive input or they might be causative to the pathogenesis of fibromyalgia. The affected areas are known to be both, part of the somatosensory system and part of the motor system.

Long-term outcome after thrombolysis in telemedical stroke care

Abstract: Background: IV thrombolysis represents the most effective acute stroke therapy. However, it is almost exclusively performed in stroke centers and is not available in most community areas. The Telemedical Pilot Project for Integrative Stroke Care (TEMPiS) was started in February 2003. Twelve community hospitals with no or very limited stroke thrombolysis experience and two stroke centers were connected via a network providing online neurologic examination and transfer of neuroradiologic scans. Following recently published preliminary results on acute phase safety of telethrombolysis, the present study reports on its long-term functional outcome. Methods: Modified Rankin Scale (mRS), Barthel Index (BI), and mortality rate were prospectively collected 3 and 6 months after IV thrombolysis in patients of community network hospitals (telemedical group) and the stroke centers. Values of 95/100 for the BI and 0/1 for the mRS were defined as a favorable outcome. Results: Over the first 22 months, 170 patients were treated with tPA in the telemedical hospitals and 132 in the stroke center hospitals. Mortality rates were 11.2% vs 11.5% at 3 months ( p = 0.55) and 14.2% vs 13% at 6 months ( p = 0.45). A good functional outcome after 6 months was found in 39.5% of the telemedical hospitals vs 30.9% of the stroke centers ( p = 0.10) for the mRS and 47.1% vs 44.8% ( p = 0.44) regarding the BI. Conclusions: Mortality rates and functional outcomes for telemedicine-linked community hospitals and stroke centers were similar and comparable to the results from randomized trials.

Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

Abstract: Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.

Long‐term course and mutational spectrum of spatacsin‐linked spastic paraplegia

Abstract: Objective: Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC. Methods: Neurological examination, cerebral magnetic resonance imaging (MRI), 18 fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented. Results: Spastic paraplegia in patients with spatacsin mutations (n 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, 30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18 fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intraaxonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11. Interpretation: We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons. Ann Neurol 2007;62:656 – 665

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2

Abstract: Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-beta2 (TGF-beta2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-beta2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-beta2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-beta2 and inhibited by TGF-beta2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-beta domain of versican was able to reverse the effect of TGF-beta2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-beta2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma

Abstract: We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-gamma agonists in recurrent high-grade gliomas - a phase II study.

Abstract: Objectives: Combined treatment approaches targeting tumor as well as other cells contributing to tumor progression may control chemorefractory malignancies. Methods:

Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease.

Abstract: Muscle–eye–brain disease (MEB, OMIM 253280) is an autosomal recessive disorder characterized by a distinct triad of congenital muscular dystrophy, structural eye abnormalities, and cobblestone lissencephaly. Clinically, MEB patients present with early onset muscular hypotonia, severely compromised motor development, and mental retardation. Magnetic resonance imaging reveals a lissencephaly type II with hypoplasia of the brainstem and cerebellum. MEB is associated with mutations in the gene for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1, OMIM 606822). In this paper, we report the clinical findings of nine MEB patients from eight families. Eight of the nine patients presented typical features of MEB. However, a broad phenotypic variability was observed, ranging from two patients with severe autistic features to another patient with an unusually mild phenotype, initially diagnosed as congenital muscular dystrophy. Furthermore, severe hydrocephalus was reported in two families during a previous pregnancy, emphasizing the phenotypic overlap with Walker–Warburg syndrome. In addition to three previously reported mutations, we identified six novel POMGnT1 mutations (one missense, five truncating) in the present patient cohort. Our data suggest mutational hotspots within the minimal catalytic domain at arginine residue 442 (exon 16) and in intron 17. It is interesting to note that all mutations analyzed so far result in a complete loss of enzyme activity. Therefore, we conclude that the type and position of the POMGnT1 mutations are not of predictive value for the clinical severity. This supports the notion that additional environmental and/or genetic factors may contribute to the observed broad spectrum of POMGnT1-associated phenotypes.

Delayed humoral immunity in a patient with severe tick-borne encephalitis after complete active vaccination.

Abstract: Tick-borne encephalitis virus (TBEV) is a common cause of viral encephalitis in parts of Central and Eastern Europe. Active immunization results in a high rate of seroconversion and is the most effective measure of decreasing the incidence of tick-borne encephalitis (TBE). Currently, booster vaccinations are recommended every 3 years after completion of primary immunization. However, titers of neutralizing antibodies decline with time after vaccination and with age and thus may be insufficient to protect from disease in the elderly. We report on a 54-year-old patient who had received his last booster vaccination 3 years before developing a severe TBE with delayed induction and longterm persistence of anti-TBEV-IgM-antibodies.

Location and type of mutation in the LIS1 gene do not predict phenotypic severity

Abstract: Background: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. Methods: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. Results: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. Conclusion: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.

Toll-like receptor triggered dendritic cell maturation and IL-12 secretion are necessary to overcome T-cell inhibition by glioma-associated TGF-beta2.

Abstract: Malignant gliomas are able to secrete large amounts of immunosuppressive cytokines like transforming growth factor beta 2 (TGF-beta2) and regularly escape from immune surveillance. Many strategies have been developed to induce potent anti-glioma responses, among those the use of dendritic cells (DC) as therapeutic vaccines. Here, we report that both mature DC and IL-12 secretion are necessary to overcome T-cell inhibition by TGF-beta2. Flow cytometric analyses showed that TGF-beta2 does not suppress the upregulation of MHC (major histocompatibility complex) class II molecules and the T cell stimulatory capacity of human DC that were stimulated with a strong cytokine cocktail containing tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-6 and prostaglandin E2 (PGE2). Moreover, TGF-beta2 signaling studies revealed that these cytokine-matured DC become unresponsive to TGF-beta2. Although both mature and immature DC expressed comparable amounts of the TGF-beta receptor type II, Smad2 phosphorylation and subsequent upregulation of Smad7 was inhibited in mature DC, but not immature DC. However, further analysis revealed that mature DC alone are not sufficient to mediate full T cell activation in the presence of TGF-beta2, unless IL-12 is added to the DC/T-cell coculture. Finally, we demonstrate that MHC class II expression and IL-12 secretion by DC are not disturbed by TGF-beta2 after DC stimulation with a modified maturation cocktail containing the Toll-like receptor (TLR)-ligands Poly I:C or R848, TNF-alpha, IL-1beta and INF-gamma. These data imply that mature DC retaining their capacity to produce IL-12 are of favorable use in glioma immunotherapy and suggest that TLR triggering of DC plays an important role to elicit a strong immune response in the immunosuppressive environment of malignant gliomas.

An imbalance between Smad and MAPK pathways is responsible for TGF-beta tumor promoting effects in high-grade gliomas.

Abstract: The transforming growth factor-beta (TGF-beta) plays a pivotal role in the pathobiology of human gliomas: during carcinogenesis, it turns from a tumor suppressor to a tumor promoter. The traditional Smad pathway and the more recently discovered MAPK pathway are the most important pathways for TGF-beta related intracellular signal transduction mediating differential pathobiological effects. In this study, we investigated the effects of TGF-beta2 and the TGF-beta2 antisense phosphorothioate oligodeoxynucleotide (PTO) AS-11 on the functionality of both the Smad and MAPK pathways in high-grade gliomas. We aimed to correlate the imbalance between the pathways with differences in the behaviour of high-grade glioma cells. Gene and protein expression studies were used to detect levels of members of the Smad and MAPK pathways under regulation of TGF-beta2 and AS-11. Proliferation and migration assays were functional readouts for effects caused by these regulating tools. Gene arrays were used to detect yet unknown regulators of these functional effects. The Smad pathway was functional in the tested cell lines. Exogenous TGF-beta2 inhibited proliferation but enhanced migration. Smad 2 mRNA expression and activation were significantly reduced by incubation with AS-11. K-ras was reduced both in gene arrays and quPCR under treatment with AS-11, but there was no influence of K-ras down-regulation on the activity of ERK. Ubiquitination-related genes also were specifically down-regulated with AS-11. Our results indicate the involvement of K-ras in TGF-beta signaling in high-grade gliomas. ERK, which is a member of the MAPK pathway, was not influenced and seems to be activated through RAS independent cascades in glioma. These results suggest that combined antagonization of the TGF-beta and MAPK pathways might be a promising approach for glioma therapy. An imbalance between these two pathways might be responsible for TGF-beta switching to a tumor promoter protein in high-grade gliomas.

Pegylated liposomal doxorubicin in recurrent malignant glioma: analysis of a case series

Abstract: Background: Recurrent malignant glioma has a dismal prognosis, and therapeutic options are scarce. After previous potentially encouraging reports on liposomal pegylated doxorubicin

Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)

Abstract: 2034 Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion ...

Differences in cortical activation during smooth pursuit and saccadic eye movements following cerebellar lesions

Abstract: Current evidence supports the proposal that the cerebellum mediates the activity of other brain areas involved in the control of eye movements. Most of the evidence so far has concentrated on the vermis and flocculi as the cerebellar agents of oculomotor control. But there is also evidence for an involvement of the cerebellar hemispheres in eye movement control. Straube et al. (Ann Neurol 42:891–898, 1997) showed that lateral hemispheric lesions affect initiation of smooth pursuit (SPEM) and saccadic eye movements. Ron and Robinson (J Neurophysiol 36:1004–1022, 1973) evoked smooth pursuit and saccadic eye movements by electrical stimulation of crus I and II, as well as in the dentate nuclei of the monkey. Functional MRI studies also provide evidence that the cerebellar hemispheres play a significant role in SPEM and saccadic eye movements. To clarify the role of the cerebral hemispheres in eye movement control we compared the eye movement related blood oxygen level dependent (BOLD) responses of 12 patients with cerebellar lesions due to stroke with those of an aged-matched healthy control group. Six patients showed oculomotor abnormalities such as dysmetric saccades or saccadic SPEM during the experiment. The paradigm consisted of alternating blocks of fixation, visually guided saccades and visually guided SPEM. A nonparametric random-effects group analysis showed a degraded pattern of activation in the patient group during the performance of SPEM and saccadic eye movements in posterior parietal areas putatively containing the parietal eye fields.

Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009

Abstract: 12521 Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment opt...

Schutz oder Neuaufbau: Neuroprotektive Effekte des Transforming Growth Faktorsβ1 auf Kosten einer reduzierten Neurogenese?

Abstract: Zusammenfassung Mit zunehmender Komplexität des Nervensystems schwindet in der Phylogenie die Fähigkeit zur regenerativen Erneuerung. Dieses Defizit wird teilweise durch neuroprotektive Strategien kompensiert, die allerdings in der Regel unzureichend sind und chronisch fortschreitende neurodegenerative Erkrankungen nicht aufhalten können. Mild verlaufende entzündliche Veränderungen werden praktisch bei allen chronisch neurodegenerativen Erkrankungen beobachtet und spielen wohl für deren Progression eine entscheidende Rolle. Die Regulation dieser Immunantworten rückt immer mehr ins Rampenlicht: Sie dürfen im Gehirn nur moderat ablaufen, um verbleibende Strukturen nicht allzu sehr zu schädigen. Transforming Growth Faktor (TGF)-β1 ist ein bei der Regulation von Entzündungsreaktionen im Gehirn maßgeblich beteiligtes Molekül; es greift - meist als Suppressor - in die Modulation der Zellproliferation von Mikroglia und Astrozyten ein. Neuere Daten weisen darauf hin, dass TGF-β1 auch die Proliferation neuraler Stamm- und Vorläuferzellen im adulten ZNS beeinflusst: Unter Einwirkung von TGF-β1 werden weniger neue Nervenzellen gebildet. Dieser Effekt ist das Ergebnis einer reduzierten Proliferation adulter Stammund Vorläuferzellen. Auch im Verlauf vieler neurodegenerativer Erkrankungen, wie bei Morbus Parkinson oder Morbus Alzheimer, bzw. mit zunehmendem Alter proliferieren weniger Stammzellen im Gehirn. Gleichzeitig ist auch bekannt, dass das Gehirn unter solch pathologischen Bedingungen (und ebenso im Alter) die Expression von TGF-β1 steigert. Vor diesem Zusammenhang verstärken sich die Hinweise, wonach TGF-β1 eine zentrale Rolle bei der Entstehung neurodegenerativer Erkrankungen zukommen könnte. Das Ziel, die Expression des Faktors TGF-β1 zu beeinflussen, stellt bei der Suche nach Wegen zum Eindämmen neurodegenerativer Erkrankungen einen viel versprechenden Ansatz dar. Vor einer therapeutischen Modulation des TGF-β-Spiegels sind jedoch die vielfältigen, oft gegensätzlichen Wirkweisen zu berücksichtigen, welche dieser Faktor je nach zellulärem Kontext ausübt. Demnach kann TGF-β1 einerseits neuroprotektiv wirken, andererseits aber auch die Entstehung neuer Nervenzellen und damit den Neuaufbau verhindern.

A phase IIb actively controlled study with the TGF-beta-2 inhibitor AP 12009 for recurrent or refractory anaplastic astrocytoma

Abstract: 2025 Background: The TGF-β2 antisense phosphorothioate oligonucleotide inhibitor AP 12009 is a targeted anti-tumor therapy for TGF-β2 overexpressing tumors. In three Phase I/II dose escalation stud...