Showing papers by "Ulrich Bogdahn published in 2017"

Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation

Abstract: // Verena Leidgens 1 , Judith Proske 1, * , Lisa Rauer 1, * , Sylvia Moeckel 1 , Kathrin Renner 2 , Ulrich Bogdahn 1 , Markus J. Riemenschneider 3 , Martin Proescholdt 4 , Arabel Vollmann-Zwerenz 1 , Peter Hau 1 , Corinna Seliger 1 1 Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany 2 Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany 3 Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany 4 Department of Neurosurgery, University Hospital Regensburg, Regensburg, Germany * These authors have contributed equally to this work Correspondence to: Corinna Seliger, email: corinna.seliger@klinik.uni-regensburg.de Keywords: glioma, BTIC, STAT3, Stattic, metformin Received: August 20, 2016 Accepted: November 21, 2016 Published: December 24, 2016 ABSTRACT Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs). We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs. Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs. In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma.

The TGF-β System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis.

Abstract: Amyotrophic Lateral Sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1 / 400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-s system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-s system is involved in different essential developmental and physiological processes, and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-s system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-s system within the periphery/in life disease stage (serum samples) and a late stage of disease (CNS tissue samples), and a potential influence upon neuronal stem cell activity, immune activation, and fibrosis. An upregulated TGF-s system was suggested with significantly increased TGF-s1 protein serum levels, enhanced TGF-s2 mRNA and protein levels, and a strong trend towards an increased TGF-s1 protein expression within the spinal cord. Stem cell activity appeared diminished, reflected by reduced mRNA expression of neuronal stem cell markers Musashi-1 and Nestin within spinal cord - paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective towards a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of pro-inflammatory chemokines/cytokines were enhanced in ALS sera and spinal cord post mortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-s system in specific tissues in ALS that might lead to a “neurotoxic” immune response, promoting disease progression and neurodegeneration. The TGF-s system therefore may represent a promising target in treatment of ALS patients.

Underutilization of deep brain stimulation for Parkinson's disease? A survey on possible clinical reasons.

Abstract: Only 10% of the up to 15% of patients with advanced Parkinson’s disease (PD) eligible for deep brain stimulation (DBS) are referred to specialized centers. This survey evaluated the reasons for the reluctance of patients and referring physicians regarding DBS. Two different questionnaires containing multiple choice and open verbalized questions were developed, one for neurologists and one for patients with PD. The first questionnaire was sent to 87 neurologists in private practice in the catchment area of the authors’ medical center, the second to patient support groups in the same region with the help of the German Parkinson Association. Of the addressed neurologists, 56.3% completed the questionnaire; 61.2% of them estimated the risk of intracerebral hemorrhage as the most severe complication at 4.3% on average; 30.6% were concerned about patients developing mood changes or depression after DBS. Only 16.3% felt unable to care for patients after DBS; 61.2% already had personal experience with patients after DBS and reported good clinical outcome in 90.0% of patients. Although 87.8% claimed to know the specific criteria for DBS, only 40.8% could actively describe them. Only 14.0% could state each of the three main criteria. Of the 46 patients, 88.1% completing the questionnaire had obtained information on DBS from regional patient organizations and 54.8% also from a physician; 44.7% assumed the risk of severe complications to be ≥5.0%. Not being satisfied with their medical treatment was reported by 22.2%, of whom more than 70% considered DBS a further treatment option. The latter numbers indicate that treating neurologists tend to overestimate the reluctance of their patients to undergo DBS. Therefore, education of patients and neurologists should be improved and give more realistic figures on the actual outcomes and frequencies of possible complications.

Longitudinal Diffusion Tensor Imaging-Based Assessment of Tract Alterations: An Application to Amyotrophic Lateral Sclerosis

Abstract: Objective: The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral microstructural alterations in neurodegenerative diseases is under investigation. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping was applied to the assessment of predefined white matter tracts in amyotrophic lateral sclerosis (ALS), as an example for a rapid progressive neurodegenerative disease. Methods: DTI was performed every 3 months in six patients with ALS (mean (M) = 7.7; range 3 to 15 scans) and in six controls (M = 3; range 2-5 scans) with the identical scanning protocol, resulting in a total of 65 longitudinal DTI datasets. Fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD), and the ratio AD/RD were studied to analyze alterations within the corticospinal tract (CST) which is a prominently affected tract structure in ALS and the tract correlating with Braak's neuropathological stage 1. A correlation analysis was performed between progression rates based on DTI metrics and the revised ALS functional rating scale (ALS-FRS-R). Results: Patients with ALS showed an FA and AD/RD decline along the CST, while DTI metrics of controls did not change in longitudinal DTI scans. The FA and AD/RD decrease progression correlated significantly with ALS-FRS-R decrease progression. Conclusion: On the basis of the longitudinal assessment, DTI-based metrics can be considered as a possible noninvasive follow-up marker for disease progression in neurodegeneration. This finding was demonstrated here for ALS as a fast progressing neurodegenerative disease.

Diabetes, use of metformin, and the risk of meningioma.

Abstract: Background Metformin is a commonly used oral antidiabetic agent that has been associated with decreased cancer risk. However, data regarding the association between metformin use and the risk of meningioma are unavailable. Methods We conducted a matched case-control analysis using data from the U.K.-based Clinical Practice Research Datalink (CPRD) to analyse diabetes status, duration of diabetes, glycemic control, and use of metformin, sulfonylureas, and insulin in relation to the risk of meningioma. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) and adjusted for body mass index, smoking, history of arterial hypertension, myocardial infarction, and use of estrogens (among women). Results We identified 2,027 meningioma cases and 20,269 controls. For diabetes there was the suggestion of an inverse association with meningioma (OR = 0.89; 95%CI = 0.74–1.07), which was driven by an inverse relation among women (OR = 0.78; 95%CI = 0.62–0.98), in whom we also noted a suggestive inverse association with duration of diabetes (p-value for trend = 0.071). For metformin there was a suggestive positive relation, particularly after matching on duration of diabetes and HbA1c level (OR = 1.64; 95%CI = 0.89–3.04). Sulfonylureas showed no clear association (OR = 0.91; 95%CI = 0.46–1.80). For insulin there was the suggestion of an inverse relation, in particular when comparing a high vs. low number of prescriptions (OR = 0.58; 95%CI = 0.18–1.83). Conclusion Further studies are needed to solidify a possible inverse association between diabetes and meningioma risk and to clarify the role of antidiabetics in this context.

Metabolic syndrome in relation to risk of meningioma

Abstract: // Corinna Seliger 1 , Christoph R. Meier 2, 3, 4 , Claudia Becker 2 , Susan S. Jick 3 , Martin Proescholdt 5 , Ulrich Bogdahn 1 , Peter Hau 1 , Michael F. Leitzmann 6 1 Department of Neurology and Wilhelm Sander-NeuroOncology Unit, Regensburg University Hospital, Regensburg, Germany 2 Basel Pharmacoepidemiology Unit, Division of CIinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland 3 Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Boston University, MA, USA 4 Hospital Pharmacy, University Hospital Basel, Basel, Switzerland 5 Department of Neurosurgery, Regensburg University Hospital, Regensburg, Germany 6 Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany Correspondence to: Corinna Seliger, email: corinna.seliger@klinik.uni-regensburg.de Keywords: meningioma, epidemiology, case-control study, metabolic syndrome Received: August 27, 2016 Accepted: November 21, 2016 Published: November 26, 2016 ABSTRACT Background: Meningioma is a frequent primary intracranial tumor, the etiology of which is potentially related to adiposity. Metabolic syndrome (MetS) is an increasingly common disease characterized by having at least three of the following conditions: central adiposity, arterial hypertension, dyslipidemia, and insulin resistance. Only one prior study investigated MetS in relation to meningioma risk and found a positive association between the two. Results: Among 2,027 cases and 20,269 controls, body mass index was positively associated with meningioma ( p-value for trend < 0.0001). Arterial hypertension was also associated with an increased risk of meningioma (OR = 1.34; 95% CI = 1.20– 1.49). By comparison, high-density lipoprotein, triglycerides, fasting serum glucose, and use of ACE-inhibitors, AT-II inhibitors, beta-blockers, diuretics, calcium antagonists, nitrates, or statins were not associated with risk of meningioma. Materials and Methods: We conducted a matched case-control analysis using data from the U.K.-based Clinical Practice Research Datalink (CPRD) to analyse medical conditions and treatments related to MetS in cases with meningioma and meningioma-free controls. We identified all cases with an incident diagnosis of meningioma between 1995 and 2015 and matched each to ten controls on age, sex, calendar time, general practice, and number of years of active history in the CPRD prior to the index date. Exposures were assessed using computerised records. We conducted conditional logistic regression analysis to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for confounding factors. Conclusions: Obesity and arterial hypertension are positively associated with risk of meningioma. Further studies are needed to better understand potential underlying biologic mechanisms.

Intraoperative clinical testing overestimates the therapeutic window of the permanent DBS electrode in the subthalamic nucleus

Abstract: Intraoperative test stimulation is established to optimize target localization in STN DBS, but requires a time-consuming awake surgery in off-medication state. The aim of this study was to compare the thresholds of stimulation-induced effects of test stimulation and the permanent electrode. Fifty-nine PD patients receiving bilateral STN DBS were clinically examined with stepwise increasing monopolar stimulation during surgery and DBS programming at matched stimulation depths. Thresholds of therapeutic and side effects were obtained from standardized examination protocols. Postoperative stimulation via the permanent electrode caused side effects at a significantly lower threshold than predicted during intraoperative test stimulation (P < 0.001); whereas sufficient therapeutic effects were achieved at significantly higher thresholds (P < 0.001). Intraoperative testing may lead to an overestimation of the therapeutic window. The two different electrodes lead to distinct spreading of the electric field in the STN and surrounding tissues that causes different volume of tissue activated (VTA). Clinicians involved in DBS surgery and programming should be aware of the differences in both stimulation settings, concerning electrodes geometry, stimulation modes as well as the impact of time. Therapeutic and side effects of permanent stimulation are not predictable by intraoperative test stimulation. Test stimulation may be an orientating test for very low thresholds of side effects instead.

Fulminant Acute Ascending Hemorrhagic Myelitis Treated with Eculizumab

Abstract: We describe an 18-year-old patient who developed back pain, rapidly ascending sensomotory deficits, bladder dysfunction, Lhermitte's sign, absent abdominal reflexes of all three levels, brisk tendon reflexes, and positive Babinski's sign. Magnetic resonance imaging of the spinal cord showed a long segment of cervical and thoracic intramedullary signal hyperintensity suggesting a longitudinally extensive transverse myelitis possibly within the course of a fast progressing ascending immune-mediated hemorrhagic myelopathy. Throughout his illness, the patient deteriorated with tetraplegia, cardiac arrest, and respiratory failure although he received, after exclusion of infective causes, therapy with steroids, immunoglobulins, plasmapheresis, and cyclophosphamide. Interestingly, treatment with the C5-inhibitor eculizumab to prevent complement-mediated spinal cord injury achieved an arrest of clinical deterioration. We propose eculizumab as treatment in fast progressive and potentially fatal immune-mediated spinal cord injury. Furthermore, this case raises awareness for the process of clinical decision-making in severe myelopathies.

Reply to Greenland: A serious misinterpretation of a consistent inverse association of statin use with glioma across 3 case-control studies.

Abstract: We thank Dr. Greenland for raising an important issue concerning the interpretation of our data and we briefly respond to his points [1], as also presented in other recent articles [2, 3]. Before doing so, we would like to clarify that the title of his response is overstated because it leads the reader into believing that we interpreted the association between statin use and glioma as not being inverse across three studies. In contrast to the misleading wording of Dr. Greenland’s title, we interpreted the data of only one study (namely our own) as there being no association between statins and glioma [4], but consistently referred to previous studies [5, 6] as supporting an inverse relation between the two. Apart from Dr. Greenland’s title profoundly misrepresenting our paper, we agree with some but not all of his comments. One point we agree with is that our abstract did not state that our point estimate showed an inverse relation of statins to glioma. Thus, the wording should have been something like: ‘‘As compared with non-use of statins, use of statins showed a statistically non-significant inverse association with risk of glioma’’. Also, we should have made clear that our findings do support previous sparse evidence of a possible inverse association between statin use and glioma risk. Unfortunately, we were not able to present the full range of data within the context of the abstract, but as shown in our Results section, the point estimates for increasing levels of statin use versus non-use were largely null or slightly above unity for all but the top category (ORs for 2–9, 10–29, 30–59, 60–89, and C90 prescriptions = 1.01, 1.00, 1.11, 1.10, and 0.75). Despite the complete lack of a dose–response relation (p value for test for trend = 0.979), we cannot rule out a threshold effect beginning at 90 prescriptions. An additional point we agree with is that potential biases may be responsible for the magnitude of the inverse association observed between statins and glioma. For example, we were concerned about incomplete control for diabetes and congestive heart failure, variables that were consistently positively associated with statin use and strongly inversely associated with glioma in our dataset. We differ with Dr. Greenland on several of his comments. First, we do not agree with his conclusion that we seriously misinterpreted our data because we specifically discussed the possibility that statins protect against risk of glioma. We feel Dr. Greenland’s response would have been more balanced had he acknowledged our statement that long-term use of statins (approximately 10–20 years of use) was suggestively associated with protection from risk of glioma (please see second sentence of our Discussion section). Second, we do not agree with Dr. Greenland’s view that previous studies consistently show an inverse association between statins and glioma. For example, one previous study [5] actually comprised two datasets, one from & Corinna Seliger corinna.seliger@klinik.uni-regensburg.de