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Book ; Thesis: Characterization of the effect of small-hairpin RNA-mediated gene suppression of mTOR in human malignant glioma cells

2009

Author's details	vorgelegt von Michael Wilfried Ronellenfitsch
Subject code	616.994
Language	English
Size	70 S. : Ill., graph. Darst., 21 cm
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Tübingen, Univ., Diss., 2009
HBZ-ID	HT016758970
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Histologische und molekularpathologische Besonderheiten von Tumoren des peripheren Nervensystems.

Harter, Patrick N / Weber, Katharina J / Ronellenfitsch, Michael W

Pathologie (Heidelberg, Germany)

2023 Volume 44, Issue 3, Page(s) 197–208

Abstract: Tumours of the peripheral nervous system occur sporadically in adults and except for a minority of entities, these tumours are usually benign. The most common are nerve sheath tumours. Because these tumours grow in direct proximity or even invade ... ...

Title translation	Histological and molecular characteristics of tumours of the peripheral nervous system.
Abstract	Tumours of the peripheral nervous system occur sporadically in adults and except for a minority of entities, these tumours are usually benign. The most common are nerve sheath tumours. Because these tumours grow in direct proximity or even invade peripheral nerve bundles, they can lead to severe pain and motion deficits. From the neurosurgical perspective these tumours are technically challenging, and especially for tumours with an invasive growth pattern complete resection may not be possible. Peripheral nervous system tumours that are associated with tumour syndromes such as neurofibromatosis type 1 and 2 or schwannomatosis are a particular clinical challenge. The goal of the current article is to present histological and molecular characteristics of peripheral nervous system tumours. Furthermore, future targeted therapy strategies are presented.
MeSH term(s)	Humans ; Neurilemmoma/genetics ; Nerve Sheath Neoplasms/genetics ; Peripheral Nervous System Neoplasms/genetics ; Neurofibromatoses ; Neurofibromatosis 1/diagnosis
Language	German
Publishing date	2023-04-28
Publishing country	Germany
Document type	English Abstract ; Journal Article
ISSN	2731-7196
ISSN (online)	2731-7196
DOI	10.1007/s00292-023-01198-1
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Article ; Online: Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

Purwien, Leonore / Schubert-Bast, Susanne / Kieslich, Matthias / Ronellenfitsch, Michael W / Merker, Michael / Czabanka, Marcus / Willems, Laurent M / Rosenow, Felix / Strzelczyk, Adam

CNS drugs

2023 Volume 37, Issue 11, Page(s) 993–1008

Abstract: Background and objectives: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug ... ...

Abstract	Background and objectives: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. Methods: The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. Results: This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. Conclusion: Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.
MeSH term(s)	Humans ; Child ; Adult ; Female ; Middle Aged ; Aged ; Aged, 80 and over ; Male ; Anticonvulsants/adverse effects ; Phenytoin/adverse effects ; Midazolam ; Levetiracetam/therapeutic use ; Valproic Acid/therapeutic use ; Propofol ; Lacosamide/therapeutic use ; Hospitals, University ; Status Epilepticus/drug therapy ; Phenobarbital/therapeutic use ; Benzodiazepines/therapeutic use ; Medical Records
Chemical Substances	Anticonvulsants ; Phenytoin (6158TKW0C5) ; Midazolam (R60L0SM5BC) ; Levetiracetam (44YRR34555) ; Valproic Acid (614OI1Z5WI) ; Propofol (YI7VU623SF) ; Lacosamide (563KS2PQY5) ; Phenobarbital (YQE403BP4D) ; Benzodiazepines (12794-10-4)
Language	English
Publishing date	2023-11-18
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	1203800-3
ISSN	1179-1934 ; 1172-7047
ISSN (online)	1179-1934
ISSN	1172-7047
DOI	10.1007/s40263-023-01049-w
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Article ; Online: EGFR and mTOR as therapeutic targets in glioblastoma.

Ronellenfitsch, Michael W / Luger, Anna-Luisa / Steinbach, Joachim P

Oncotarget

2019 Volume 10, Issue 46, Page(s) 4721–4723

Language	English
Publishing date	2019-07-30
Publishing country	United States
Document type	Editorial
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27094
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Article: Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell death.

Sauer, Benedikt / Lorenz, Nadja I / Divé, Iris / Klann, Kevin / Luger, Anna-Luisa / Urban, Hans / Schröder, Jan-Hendrik / Steinbach, Joachim P / Münch, Christian / Ronellenfitsch, Michael W

Cell death discovery

2024 Volume 10, Issue 1, Page(s) 8

Abstract: Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investigating targeted therapy with inhibitors of the kinase mTOR have produced ambiguous results. Especially combination of mTOR inhibition with standard ... ...

Abstract	Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investigating targeted therapy with inhibitors of the kinase mTOR have produced ambiguous results. Especially combination of mTOR inhibition with standard temozolomide radiochemotherapy has resulted in reduced survival in a phase II clinical trial. To date, this phenomenon is only poorly understood. To recreate the therapeutic setting in vitro, we exposed glioblastoma cell lines to co-treatment with rapamycin and temozolomide and assessed cell viability, DNA damage and reactive oxygen species. Additionally, we employed a novel translatomic based mass spectrometry approach ("mePROD") to analyze acute changes in translated proteins. mTOR inhibition with rapamycin protected glioblastoma cells from temozolomide toxicity. Following co-treatment of temozolomide with rapamycin, an increased translation of reactive oxygen species (ROS)-detoxifying proteins was detected by mass spectrometry. This was accompanied by improved ROS-homeostasis and reduced DNA damage. Additionally, rapamycin induced the expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT) in glioblastoma cells with an unmethylated MGMT gene promotor. Inhibition of mTOR antagonized the cytotoxic effects of temozolomide in vitro. The induction of antioxidant defences and MGMT are two underlying candidate mechanisms. Further functional experiments in vitro and in vivo are warranted to characterize this effect that appears relevant for combinatorial therapeutic strategies.
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-023-01779-2
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Article ; Online: Red blood cell transfusion in patients undergoing elective primary glioblastoma resection.

Neef, Vanessa / König, Sven / Becker, Hendrik / Dubinski, Daniel / Flinspach, Armin / Raimann, Florian J / Weber, Katharina / Ronellenfitsch, Michael W / Konczalla, Juergen / Hattingen, Elke / Czabanka, Marcus / Senft, Christian / Zacharowski, Kai / Baumgarten, Peter

Blood transfusion = Trasfusione del sangue

2024

Abstract: Background: Red blood cell (RBC) transfusion in patients undergoing major elective cranial surgery is associated with increased postoperative morbidity and mortality. This study aims to identify the clinical outcome of transfused glioblastoma patients ... ...

Abstract	Background: Red blood cell (RBC) transfusion in patients undergoing major elective cranial surgery is associated with increased postoperative morbidity and mortality. This study aims to identify the clinical outcome of transfused glioblastoma patients undergoing primary surgical tumor resection and identify risk factors for RBC transfusion. Material and methods: Between 2009 and 2019, 406 patients underwent elective primary glioblastoma resection. For multivariate analysis to assess risk factors for RBC transfusion, logistic regression was conducted. The impact of RBC transfusion on overall survival was assessed using Kaplan-Meier analysis. Results: In total, 36 (8.9%) patients received RBC transfusion. Preoperative anemia rate was significantly higher in transfused patients compared to patients without RBC transfusion (33.3 vs 6.5%; p<0.0001). Postoperative complications as well as hospital length of stay (LOS) (p<0.0001) were significantly increased in transfused patients compared to non-transfused patients. After multivariate analysis, risk factors for RBC transfusion were preoperative anemia (p<0.0001), intraoperative blood loss (p<0.0001), female gender (p=0.0056) and radiation (p=0.0064). Kaplan-Meier curves revealed that RBC transfusion and being elderly (age ≥75 years) were relevant for overall survival. Discussion: RBC transfusion is associated with increased postoperative morbidity and mortality in patients undergoing elective primary glioblastoma resection. Preoperative anemia and intraoperative blood loss are major risk factors for RBC transfusion. Preoperative anemia management and blood conservation strategies are crucial in patients undergoing elective primary glioblastoma resection.
Language	English
Publishing date	2024-01-11
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2135732-8
ISSN	2385-2070 ; 0041-1787 ; 1723-2007
ISSN (online)	2385-2070
ISSN	0041-1787 ; 1723-2007
DOI	10.2450/BloodTransfus.613
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Zs.A 798: Show issues

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Article ; Online: Intrathecal IgM synthesis as a diagnostic marker in patients with suspected CNS lymphoma.

Reinecke, Raphael / Jahnke, Kolja / Foltyn-Dumitru, Martha / Lachner, Karsten / Armbrust, Moritz / Weber, Katharina J / Zeiner, Pia S / Czabanka, Marcus / Brunnberg, Uta / Hartmann, Sylvia / Steinbach, Joachim P / Ronellenfitsch, Michael W

Journal of neurochemistry

2024

Abstract: For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the ... ...

Abstract	For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study.
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Journal Article
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.16069
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Article ; Online: A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Zhao, Kai / Braun, Madita / Meyer, Leonie / Otte, Katharina / Raifer, Hartmann / Helmprobst, Frederik / Möschl, Vincent / Pagenstecher, Axel / Urban, Hans / Ronellenfitsch, Michael W / Steinbach, Joachim P / Pesek, Jelena / Watzer, Bernhard / Nockher, Wolfgang A / Taudte, R Verena / Neubauer, Andreas / Nimsky, Christopher / Bartsch, Jörg W / Rusch, Tillmann

Cells

2024 Volume 13, Issue 7

Abstract: Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family ... ...

Abstract	Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo
MeSH term(s)	Animals ; Mice ; Temozolomide/pharmacology ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Methotrexate/pharmacology ; Methotrexate/therapeutic use ; Cytarabine/pharmacology ; Cytarabine/therapeutic use ; Antineoplastic Agents, Alkylating/pharmacology ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Apoptosis ; Amides ; Pyrimidines ; Sulfonamides ; Bridged Bicyclo Compounds, Heterocyclic
Chemical Substances	Temozolomide (YF1K15M17Y) ; Methotrexate (YL5FZ2Y5U1) ; venetoclax (N54AIC43PW) ; Cytarabine (04079A1RDZ) ; Eltanexor ; Antineoplastic Agents, Alkylating ; Antineoplastic Agents ; Amides ; Pyrimidines ; Sulfonamides ; Bridged Bicyclo Compounds, Heterocyclic
Language	English
Publishing date	2024-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13070632
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Article ; Online: Single-shot bevacizumab for cerebral radiation injury.

Voss, Martin / Wenger, Katharina J / Fokas, Emmanouil / Forster, Marie-Thérèse / Steinbach, Joachim P / Ronellenfitsch, Michael W

BMC neurology

2021 Volume 21, Issue 1, Page(s) 77

Abstract: Background: Cerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to ... ...

Abstract	Background: Cerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations. Methods: We performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks. Results: We identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months. Conclusions: Single-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.
MeSH term(s)	Adult ; Aged ; Angiogenesis Inhibitors/administration & dosage ; Angiogenesis Inhibitors/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Bevacizumab/administration & dosage ; Bevacizumab/therapeutic use ; Brain/pathology ; Brain Edema/diagnostic imaging ; Brain Edema/drug therapy ; Brain Edema/etiology ; Brain Injuries/diagnostic imaging ; Brain Injuries/drug therapy ; Brain Injuries/etiology ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/secondary ; Breast Neoplasms/pathology ; Dexamethasone/therapeutic use ; Dose-Response Relationship, Drug ; Female ; Glioma/radiotherapy ; Glucocorticoids/therapeutic use ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Necrosis ; Radiation Injuries/drug therapy ; Retrospective Studies ; Treatment Outcome ; Young Adult
Chemical Substances	Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Glucocorticoids ; Bevacizumab (2S9ZZM9Q9V) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2021-02-17
Publishing country	England
Document type	Journal Article
ISSN	1471-2377
ISSN (online)	1471-2377
DOI	10.1186/s12883-021-02103-0
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Article: Inhibition of mTOR signaling protects human glioma cells from hypoxia-induced cell death in an autophagy-independent manner.

Divé, Iris / Klann, Kevin / Michaelis, Jonas B / Heinzen, Dennis / Steinbach, Joachim P / Münch, Christian / Ronellenfitsch, Michael W

Cell death discovery

2022 Volume 8, Issue 1, Page(s) 409

Abstract: Although malignant gliomas frequently show aberrant activation of the mammalian target of rapamycin (mTOR), mTOR inhibitors have performed poorly in clinical trials. Besides regulating cell growth and translation, mTOR controls the initiation of ... ...

Abstract	Although malignant gliomas frequently show aberrant activation of the mammalian target of rapamycin (mTOR), mTOR inhibitors have performed poorly in clinical trials. Besides regulating cell growth and translation, mTOR controls the initiation of autophagy. By recycling cellular components, autophagy can mobilize energy resources, and has thus been attributed cancer-promoting effects. Here, we asked whether the activation of autophagy represents an escape mechanism to pharmacological mTOR inhibition in glioma cells, and explored co-treatment with mTOR and autophagy inhibitors as a therapeutic strategy. Mimicking conditions of the glioma microenvironment, glioma cells were exposed to nutrient starvation and hypoxia. We analyzed autophagic activity, cell growth, viability and oxygen consumption following (co-)treatment with the mTOR inhibitors torin2 or rapamycin, and autophagy inhibitors bafilomycin A1 or MRT68921. Changes in global proteome were quantified by mass spectrometry. In the context of hypoxia and starvation, autophagy was strongly induced in glioma cells and further increased by mTOR inhibition. While torin2 enhanced glioma cell survival, co-treatment with torin2 and bafilomycin A1 failed to promote cell death. Importantly, treatment with bafilomycin A1 alone also protected glioma cells from cell death. Mechanistically, both compounds significantly reduced cell growth and oxygen consumption. Quantitative proteomics analysis showed that bafilomycin A1 induced broad changes in the cellular proteome. More specifically, proteins downregulated by bafilomycin A1 were associated with the mitochondrial respiratory chain and ATP synthesis. Taken together, our results show that activation of autophagy does not account for the cytoprotective effects of mTOR inhibition in our in vitro model of the glioma microenvironment. Our proteomic findings suggest that the pharmacological inhibition of autophagy induces extensive changes in the cellular proteome that can support glioma cell survival under nutrient-deplete and hypoxic conditions. These findings provide a novel perspective on the complex role of autophagy in gliomas.
Language	English
Publishing date	2022-10-06
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-022-01195-y
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