Showing papers by "Ulrich Bogdahn published in 2009"
TL;DR: It is demonstrated that TGF-beta2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin alpha(v)beta(3) receptors, which might constitute a crucial mechanism for glioma migration.
Abstract: Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-beta2 (TGF-beta2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-beta2-mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-beta2 expression, suggesting that lactate metabolism is strongly associated with TGF-beta2 in glioma cells. Here we demonstrate that TGF-beta2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin alpha(v)beta(3) receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin alpha(v)beta(3) abrogated glioma cell migration stimulated by TGF-beta2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A-induced and TGF-beta2-coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alpha(v)beta(3). This novel interaction between lactate metabolism and TGF-beta2 might constitute a crucial mechanism for glioma migration.
210 citations
TL;DR: The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual, and this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by Neurogenesis modulation.
Abstract: Depression constitutes a widespread condition observed in elderly patients. Recently, it was found that several drugs employed in therapies against depression stimulate hippocampal neurogenesis in young rodents and nonhuman primates. As the rate of neurogenesis is dramatically reduced during ageing, we examined the influences of ageing on neurogenic actions of antidepressants. We tested the impact of fluoxetine, a broadly used antidepressant, on hippocampal neurogenesis in mice of three different age groups (100, 200 and over 400 days of age). Proliferation and survival rate of newly generated cells, as well as the percentage of cells that acquired a neuronal phenotype were analyzed in the hippocampus of mice that received fluoxetine daily in a chronic manner. Surprisingly, the action of fluoxetine on neurogenesis was decreasing as a function of age and was only significant in young animals. Hence, fluoxetine increased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age). The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual. Although the function of neurogenesis in the clinical manifestation of depression is currently a matter of speculation, this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by neurogenesis modulation.
136 citations
TL;DR: The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation.
Abstract: Serial magnetic resonance imaging (MRI) was performed to investigate the temporal and spatial relationship between the biphasic nature of blood-brain barrier (BBB) opening and, in parallel, edema formation after ischemia-reperfusion (I/R) injury in rats. T(2)-weighted imaging combined with T(2)-relaxometry, mainly for edema assessment, was performed at 1 h after ischemia, after reperfusion, and at 4, 24 and 48 h after reperfusion. T(1)-weighted imaging was performed before and after gadolinium contrast at the last three time points to assess BBB integrity. The biphasic course of BBB opening with a significant reduction in BBB permeability at 24 h after reperfusion, associated with a progressive expansion of leaky BBB volume, was accompanied by a peak ipsilateral edema formation. In addition, at 4 h after reperfusion, edema formation could also be detected at the contralateral striatum as determined by the elevated T(2)-values that persisted to varying degrees, indicative of widespread effects of I/R injury. The observations of this study may indicate a dynamic temporal shift in the mechanisms responsible for biphasic BBB permeability changes, with complex relations to edema formation. Stroke therapy aimed at vasogenic edema and drug delivery for neuroprotection may also be guided according to the functional status of the BBB, and these findings have to be confirmed in human stroke.
135 citations
TL;DR: Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval.
Abstract: Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.
97 citations
TL;DR: Together, the investigated combination is tolerable and feasible and neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.
Abstract: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx™, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data clinicaltrials.gov NCT00944801.
86 citations
TL;DR: The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS- ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-β2 and is administered intratumorally using convection-enhanced delivery.
Abstract: Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.
64 citations
TL;DR: Although the 1.28‐ppm signal cannot be considered as a specific biomarker for NPCs, it might still serve as a sensor for processes that are tightly associated with neurogenesis and NPCs in vivo, such as apoptosis or stem cell quiescence, however, this requires further experimental evidence.
Abstract: In vivo visualization of endogenous neural progenitor cells (NPCs) is crucial to advance stem cell research and will be essential to ensure the safety and efficacy of neurogenesis-based therapies. Magnetic resonance spectroscopic imaging (i.e., spatially resolved spectroscopy in vivo) is a highly promising technique by which to investigate endogenous neurogenesis noninvasively. A distinct feature in nuclear magnetic resonance spectra (i.e., a lipid signal at 1.28 ppm) was recently attributed specifically to NPCs in vitro and to neurogenic regions in vivo. Here, we demonstrate that although this 1.28-ppm biomarker is present in NPC cultures, it is not specific for the latter. The 1.28-ppm marker was also evident in mesenchymal stem cells and in non-stem cell lines. Moreover, it was absent in freshly isolated NPCs but appeared under conditions favoring growth arrest or apoptosis; it is initiated by induction of apoptosis and correlates with the appearance of mobile lipid droplets. Thus, although the 1.28-ppm signal cannot be considered as a specific biomarker for NPCs, it might still serve as a sensor for processes that are tightly associated with neurogenesis and NPCs in vivo, such as apoptosis or stem cell quiescence. However, this requires further experimental evidence. The present work clearly urges the identification of additional biomarkers for NPCs and for neurogenesis.
43 citations
TL;DR: In the otherwise astrogenic milieu, MSCs established an oligodendrogenic niche for transplanted NPCs, and thus, co-transplantation of M SCs with NPCs might provide an attractive approach to re-myelinate the various regions of the diseased CNS.
Abstract: We have previously shown that soluble factors derived from mesenchymal stem cells (MSCs) induce oligodendrogenic fate and differentiation in adult rat neural progenitors (NPCs) in vitro. Here, we investigated if this pro-oligodendrogenic effect is maintained after cells have been transplanted onto rat hippocampal slice cultures, a CNS-organotypic environment. We first tested whether NPCs, that were pre-differentiated in vitro by MSC-derived conditioned medium, would generate oligodendrocytes after transplantation. This approach resulted in the loss of grafted NPCs, suggesting that oligodendroglial pre-differentiated cells could not integrate in the tissue and therefore did not survive grafting. However, when NPCs together with MSCs were transplanted in situ into hippocampal slice cultures, the grafted NPCs survived and the majority of them differentiated into oligodendrocytes. In contrast to the prevalent oligodendroglial differentiation in case of the NPC/MSC co-transplantation, naive NPCs transplanted in the absence of MSCs differentiated predominantly into astrocytes. In summary, the pro-oligodendrogenic activity of MSCs was maintained only after co-transplantation into hippocampal slice cultures. Therefore, in the otherwise astrogenic milieu, MSCs established an oligodendrogenic niche for transplanted NPCs, and thus, co-transplantation of MSCs with NPCs might provide an attractive approach to re-myelinate the various regions of the diseased CNS.
31 citations
TL;DR: A 45-year-old man was admitted with clinical symptoms of Wallenberg syndrome, including right sided hemiparesis secondary to dissection of the right vertebral artery, and experienced several spells of self limiting cardiac arrests, which made the implantation of a pacemaker necessary.
Abstract: Cardiac arrest is a rare complication in Wallenberg syndrome, despite the fact that the brainstem, especially the lower medulla, modulates sympathetic and parasympathetic activity. In the case reported here, a 45-year-old man was admitted with clinical symptoms of Wallenberg syndrome, including right sided hemiparesis secondary to dissection of the right vertebral artery. During the following days he experienced several spells of self limiting cardiac arrests, which made the implantation of a pacemaker necessary. Magnetic resonance imaging scan showed an infarction on the lower right and dorsolateral medulla. This might have affected the central sympathetic neurons which normally inhibit the nucleus of the solitary tract. The disinhibition of the nucleus tractus solitarii may have led to an increase of parasympathetic outflow resulting in bradycardia/asystolia. This case report describes a rare indication for transient or permanent therapy with a cardiac pacemaker in Wallenberg syndrome.
17 citations
TL;DR: To investigate the feasibility of obtaining high‐resolution MR images for the detection of pathological changes occurring in the injured rat spinal cord with a routine clinical 3.0T imaging system.
Abstract: Results from the present study demonstrate that a routine clinical MR imaging system can be employed for noninvasive analysis of pathological changes occurring in the injured rat spinal cord and thus might represent a more broadly available, powerful tool to monitor the effects of experimental therapeutic interventions in vivo.
17 citations
TL;DR: It is concluded that early surgical exploration in posttraumatic or oto‐/rhinogenic purulent meningitis may improve clinical outcome, minimize intracranial complications, and identify latent CSF‐fistulas.
Abstract: It is still controversial, whether early surgical removal of infectious material and heparin-anticoagulation to reduce vascular complications will improve outcome in acute meningitis. In the present pilot-study 40 patients with acute or delayed post-traumatic or oto-/rhinogenic purulent bacterial meningitis were analysed for neurological outcome by using the Glasgow outcome score (GOS)and the Tuthill functional score; patients were treated either by early surgical revision of the septic focus (Group 1, within 6 days, n = 15), late surgery (Group 2, later than 6 days, n = 19), or no surgery at all (Group 3, n = 6). All patients, independant of surgical approach, received therapeutic heparin-anticoagulation. Patient groups were otherwise comparable for antibiotic treatment, osmotherapy, microbiology, CSF-findings, CT-scans and prognostic factors. Outcome according to GOS was superior in Group 1 compared with Groups 2/3 (non-significant). Although there was no significant difference on admission in the Tuthill functional score, Group 1 achieved a superior final outcome of 96 points compared with Groups 2 and 3, who gained 72 points (p<0.01). In addition, Group 1 patients had significantly less intracranial complications (8/15 patients versus 21/25 patients in Groups 2/3, p<0.01) and were dependant upon respirator treatment for fewer days (10.2 days) than Groups 2/3 (12.5 days, non-significant). In 31 patients CSF-leakage was identified: among these, 17 patients had CSF-leakage, which had not been anticipated by clinical/neuroradiological examinations and revealed only by surgery. The overall mortality in this study population was very low (2.5%), therefore, therapeutic heparin seems to represent an additional favorable treatment measure. We conclude that early surgical exploration in posttraumatic or oto-/rhinogenic purulent meningitis may improve clinical outcome, minimize intracranial complications, and identify latent CSF-fistulas. A prospective, controlled study would be desirable.
TL;DR: The superior long-term survival of trabedersen-treated AA and GBM patients was the basis for extending the follow-up period of this Phase IIb study, and the pivotal Phase III study SAPPHIRE in recurrent or refractory AA patients has started.
Abstract: 2037 Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen (AP 12009), a TGF-beta 2-specific inhibitor, was successfully tested in 3 Phase I/II studies in recurrent or r...
TL;DR: Two cases of subclavian steel syndrome are presented to give an impression of the wide spectrum of possible symptoms and of the commonly used imaging modalities in subClavian steal syndrome.
Abstract: We present two cases of subclavian steel syndrome to give an impression of the wide spectrum of possible symptoms and of the commonly used imaging modalities in subclavian steal syndrome.
Case one is a 49-year-old female with periodic numbness in her left arm, followed by dizziness and nausea, occurring only while hanging laundry. MRI with angiography (fig 1A) and conventional angiography revealed a moderate proximal left subclavian artery stenosis (fig 2A–C), while Duplex ultrasound demonstrated the functional haemodynamic consequences (fig 1B–D) and the stenosis was eventually treated with a stenting procedure (fig 2D).
Figure 1
(A) Contrast-enhanced MRI/angiography of the supra-aortal arteries showing moderate left subclavian artery stenosis and unremarkable finding on time-of-flight MR-angiography of the intracranial vessels. (B) Doppler and duplex Doppler sonography showing …
TL;DR: This review focuses on intracranial arterial vessel occlusions and stenosis important for cerebral ischemia work-up and the general technical requirements of the ultrasound system and the defined transcranial image planes important for stroke diagnostics.
Abstract: Cerebrovascular diagnostics are increasingly important in stroke therapy, especially in cases when the time window for IV rtPA has exceeded, in follow-up and secondary prevention of ischemic stroke Transcranial color-coded duplex sonography (TCCS), a noninvasive and flexible method for vascular and parenchymal imaging of the adult brain, and is considered complementary to CT- and MR-Angio as the investigator depicts intracranial hemodynamics including occlusions, stenosis and the sufficiency of collateral flow After an introduction to the general technical requirements of the ultrasound system and the defined transcranial image planes important for stroke diagnostics we focus on intracranial arterial vessel occlusions and stenosis important for cerebral ischemia work-up UCA have had a tremendous impact on TCCS application and are used in cases of unfavorable acoustic bone windows resulting in superior signal-to-noise and yield high and fast diagnostic confidence In addition, new developments in ultrasound signal processing and transducer technology, such as harmonic B-mode and contrast burst imaging amongst others, take advantage of microbubble specific properties which allow for increased signal retrieval as well as separation of linear and non-linear acoustic responses Bed- side ultrasound perfusion sonography has gained special attention and first encouraging results have visualized and quan- tified perfusion defects in acute stroke patients This review is aimed to guide the unexperienced sonographer to valid and important findings in intracranial cerebrovascular disease
TL;DR: A 23-year-old mountaineer who was hit by a lightning strike to the occiput causing a large central visual field defect and bilateral tympanic membrane ruptures and developed a psychological reaction consisting of nightmares, with reappearance of the complex visual hallucinations and a depressive syndrome.
Abstract: The case of a 23-year-old mountaineer who was hit by a lightning strike to the occiput causing a large central visual field defect and bilateral tympanic membrane ruptures is described. Owing to extreme agitation, the patient was sent into a drug-induced coma for 3 days. After extubation, she experienced simple and complex visual hallucinations for several days, but otherwise largely recovered. Neuropsychological tests revealed deficits in fast visual detection tasks and non-verbal learning and indicated a right temporal lobe dysfunction, consistent with a right temporal focus on electroencephalography. At 4 months after the accident, she developed a psychological reaction consisting of nightmares, with reappearance of the complex visual hallucinations and a depressive syndrome. Using the European Cooperation for Lightning Detection network, a meteorological system for lightning surveillance, the exact geographical location and nature of the lightning strike were retrospectively retraced
01 Jan 2009
TL;DR: Antisense ODNs can be designed specifically against their target mRNA, are sufficiently stable in vivo and show first antitumor efficacy in human clinical trials with an excellent toxicity profile, making them superior to other DNA targeting strategies in humans.
Abstract: Antisense oligonucleotides (ODNs) are single-stranded, chemically-modified DNA-like molecules for the inhibition of gene translation by sequence-specific knockdown of mRNA through Watson–Crick hybridization. In general, their size ranges from 12 to 25 nucleotides in length, with the majority of ODNs being around 18–21 nucleotides. The natural phosphodiester backbone ODNs are rapidly degraded in biological fluids by ubiquitous nucleases. Therefore, a variety of heterocyclic modifications have been developed to strengthen base-pairing and thus stabilize the duplex formation between antisense ODN and their target mRNA. Antisense ODNs have been widely used for determining gene function, validation of drug targets and, finally, as novel therapeutics for human diseases. In this chapter, we will describe the development of antisense ODNs including their modifications, pharmacokinetics, and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced ODN in the therapy of high-grade gliomas is a phosphorothioate modified ODN (S-ODN), AP 12009 (trabedersen), which targets the mRNA encoding transforming growth factor beta2 (TGF-beta2). AP12009 is administered intratumorally using convection-enhanced delivery (CED). A randomized, controlled international Phase III study in recurrent or refractory anaplastic astrocytoma (SAPPHIRE) is planned to start in early 2009. Further antisense molecules targeting malignant glioma in clinical development are Affinitak, a PKC-alpha-S-ODN, and an ODN against IGF type I receptor for ex vivo use. In our opinion, antisense ODNs have potential for clinical applications in cancer patients even in a long-term perspective. They can be designed specifically against their target mRNA, are sufficiently stable in vivo and show first antitumor efficacy in human clinical trials with an excellent toxicity profile. Additionally, novel delivery techniques, like CED, may further improve their pharmacological profile making them superior to other DNA targeting strategies in humans.