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Book ; Online ; Thesis: Organotypische Schnittkulturen aus Glioblastomgewebe als präklinisches Testsystem

Hähnel, Susann [Verfasser]

2023

Author's details	Susann Hähnel
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	German
Publisher	Universitätsbibliothek Leipzig
Publishing place	Leipzig
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level

Haehnel, Susann / Rade, Michael / Kaiser, Nicole / Reiche, Kristin / Horn, Andreas / Loeffler, Dennis / Blumert, Conny / Rapp, Felicitas / Horn, Friedemann / Meixensberger, Juergen / Renner, Christof / Mueller, Wolf / Gaunitz, Frank / Bechmann, Ingo / Winter, Karsten

FEBS Open Bio. 2022 Feb., v. 12, no. 2

2022

Abstract: One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that ... ...

Abstract	One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with poor prognosis and little is known about its genetic background and heterogeneity regarding therapy success. In this study, tissue from the tumors of 25 patients with primary GBM was processed into slice cultures and treated with standard therapy (irradiation and temozolomide). Total RNA sequencing and automated histochemistry were performed to enable analysis of treatment effects at a transcriptional and histological level. Slice cultures from long‐term survivors (overall survival [OS] > 24 months) exhibited more apoptosis than cultures from patients with shorter OS. Proliferation within these slices was slightly increased in contrast to other groups, but not significantly. Among all samples, 58 protein‐coding genes were upregulated and 32 downregulated in treated vs. untreated slice cultures. In general, an upregulation of DNA damage‐related and cell cycle checkpoint genes as well as enrichment of genotoxicity pathways and p53‐dependent signaling was found after treatment. Overall, the current study reproduces knowledge from former studies regarding the feasibility of transcriptomic analyses and automated histology in tissue slice cultures. We further demonstrate that the experimental data merge with the clinical follow‐up of the patients, which improves the applicability of our model system.
Keywords	DNA ; RNA ; apoptosis ; automation ; brain neoplasms ; cell cycle checkpoints ; genetic background ; genotoxicity ; glioblastoma ; histochemistry ; humans ; irradiation ; models ; patients ; prognosis ; therapeutics ; transcription (genetics) ; transcriptome ; transcriptomics
Language	English
Dates of publication	2022-02
Size	p. 480-493.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2651702-4
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13353
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level.

FEBS open bio

2021 Volume 12, Issue 2, Page(s) 480–493

Abstract	One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with poor prognosis and little is known about its genetic background and heterogeneity regarding therapy success. In this study, tissue from the tumors of 25 patients with primary GBM was processed into slice cultures and treated with standard therapy (irradiation and temozolomide). Total RNA sequencing and automated histochemistry were performed to enable analysis of treatment effects at a transcriptional and histological level. Slice cultures from long-term survivors (overall survival [OS] > 24 months) exhibited more apoptosis than cultures from patients with shorter OS. Proliferation within these slices was slightly increased in contrast to other groups, but not significantly. Among all samples, 58 protein-coding genes were upregulated and 32 downregulated in treated vs. untreated slice cultures. In general, an upregulation of DNA damage-related and cell cycle checkpoint genes as well as enrichment of genotoxicity pathways and p53-dependent signaling was found after treatment. Overall, the current study reproduces knowledge from former studies regarding the feasibility of transcriptomic analyses and automated histology in tissue slice cultures. We further demonstrate that the experimental data merge with the clinical follow-up of the patients, which improves the applicability of our model system.
MeSH term(s)	Brain Neoplasms/genetics ; Glioblastoma/metabolism ; Humans ; Sequence Analysis, RNA ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Whole Exome Sequencing
Chemical Substances	Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2021-12-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2651702-4
ISSN	2211-5463 ; 2211-5463
ISSN (online)	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13353
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level

Haehnel, Susann / Rade, Michael / Kaiser, Nicole / Reiche, Kristin / Horn, Andreas / Löffler, Dennis / Blumert, Conny / Rapp, Felicitas / Horn, Friedemann / Meixensberger, Jürgen / Renner, Christof / Mueller, Wolf / Gaunitz, Frank / Bechmann, Ingo / Winter, Karsten

2022

Abstract: 480 ... 493 ... One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was ... ...

Abstract	480 493 One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with poor prognosis and little is known about its genetic background and heterogeneity regarding therapy success. In this study, tissue from the tumors of 25 patients with primary GBM was processed into slice cultures and treated with standard therapy (irradiation and temozolomide). Total RNA sequencing and automated histochemistry were performed to enable analysis of treatment effects at a transcriptional and histological level. Slice cultures from long-term survivors (overall survival [OS] > 24 months) exhibited more apoptosis than cultures from patients with shorter OS. Proliferation within these slices was slightly increased in contrast to other groups, but not significantly. Among all samples, 58 protein-coding genes were upregulated and 32 downregulated in treated vs. untreated slice cultures. In general, an upregulation of DNA damage-related and cell cycle checkpoint genes as well as enrichment of genotoxicity pathways and p53-dependent signaling was found after treatment. Overall, the current study reproduces knowledge from former studies regarding the feasibility of transcriptomic analyses and automated histology in tissue slice cultures. We further demonstrate that the experimental data merge with the clinical follow-up of the patients, which improves the applicability of our model system. 12 2
Keywords	Gliablastoma multiforme ; radiochemotherapy ; differential RNA sequencing ; tissue slice cultures ; 610 ; 620
Subject code	610
Language	English
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of X-irradiation on microglia.

Menzel, Franziska / Kaiser, Nicole / Haehnel, Susann / Rapp, Felicitas / Patties, Ina / Schöneberg, Nina / Haimon, Zhana / Immig, Kerstin / Bechmann, Ingo

Glia

2018 Volume 66, Issue 1, Page(s) 15–33

Abstract: Irradiation is widely used to treat brain tumors, and also to create bone marrow (BM) chimeras. BM chimeras are widely used to dissect functions and origin of microglia and blood-derived mononuclear cells under homeostatic or pathological conditions. ... ...

Abstract	Irradiation is widely used to treat brain tumors, and also to create bone marrow (BM) chimeras. BM chimeras are widely used to dissect functions and origin of microglia and blood-derived mononuclear cells under homeostatic or pathological conditions. This is facilitated by the fact that microglia survive irradiation and are thus regarded radio-resistant. In this study, we tested whether microglia are indeed radio-resistant and looked for potential mechanisms that might explain this phenomenon. We analyzed the radio-resistance of microglia independently of their physiological brain environment compared to other mononuclear cells from spleen and brain after X-irradiation with 7 Gy or 30 Gy. Furthermore, we investigated long-term effects of X-irradiation on microglia using organotypic hippocampal slice cultures (OHSCs). We found a significant higher survival rate of isolated microglia 4 hr after X-irradiation with 30 Gy accompanied by a decreased proliferation rate. Investigations of apoptosis-related genes revealed no regulation of a specific antiapoptotic pathway but ataxia telangiectasia mutated (ATM), a DNA-repair-related gene, was significantly upregulated in isolated microglia 4 hr after 30 Gy. Irradiation of OHSCs with 7 and 30 Gy revealed a highly and significantly decreased cell number, morphological changes and an increase in migration velocity of microglia. Furthermore, cell loss, increased soma size and process length of microglia was also found in BM chimeras irradiated with 9.5 Gy 5 weeks after irradiation. Here, we present new evidence implying that microglia are not a homogeneous population of radio-resistant cells and report on long-term alterations of microglia that survived irradiation.
MeSH term(s)	Animals ; Apoptosis/radiation effects ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Brain/metabolism ; Brain/radiation effects ; CX3C Chemokine Receptor 1/genetics ; CX3C Chemokine Receptor 1/metabolism ; Calcium-Binding Proteins/metabolism ; Cell Proliferation/genetics ; Cell Proliferation/radiation effects ; Cell Size/radiation effects ; Cell Survival/radiation effects ; Gene Expression Regulation/genetics ; Gene Expression Regulation/radiation effects ; Glial Fibrillary Acidic Protein/metabolism ; Hippocampus/cytology ; Ki-67 Antigen/metabolism ; Leukocyte Common Antigens/metabolism ; Leukocytes, Mononuclear ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Microglia/radiation effects ; Spleen/metabolism ; Spleen/radiation effects ; Time Factors ; X-Rays
Chemical Substances	Aif1 protein, mouse ; CX3C Chemokine Receptor 1 ; Calcium-Binding Proteins ; Cx3cr1 protein, mouse ; Glial Fibrillary Acidic Protein ; Ki-67 Antigen ; Microfilament Proteins ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1) ; Leukocyte Common Antigens (EC 3.1.3.48)
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.23239
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 2345: Show issues

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Conference proceedings: Human organotypic glioblastoma tissue slices for therapy improvement can be analyzed by transcriptome-wide next-generation sequencing, whole slice immunochemical analysis and immunoblotting

Haehnel, Susann / Reiche, Kristin / Oppermann, Henry / Winter, Karsten / Meixensberger, Jürgen / Bechmann, Ingo / Gaunitz, Frank

2017 , Page(s) Mi.13.01

Event/congress	68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS); Magdeburg; ; Society of British Neurological Surgeons; 2017
Keywords	Medizin, Gesundheit
Publishing date	2017-06-09
Publisher	German Medical Science GMS Publishing House; Düsseldorf
Document type	Conference proceedings
DOI	10.3205/17dgnc446
Database	German Medical Science

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Article ; Online: Deep sequencing and automated histochemistry of human tissue slice cultures improve their usability as preclinical model for cancer research.

Haehnel, Susann / Reiche, Kristin / Loeffler, Dennis / Horn, Andreas / Blumert, Conny / Puppel, Sven-Holger / Kaiser, Nicole / Rapp, Felicitas / Rade, Michael / Horn, Friedemann / Meixensberger, Juergen / Bechmann, Ingo / Gaunitz, Frank / Winter, Karsten

Scientific reports

2019 Volume 9, Issue 1, Page(s) 19961

Abstract: Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often ... ...

Abstract	Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often limited to histology. Here, we demonstrate that slices are also suitable for whole transcriptome sequencing and present a method for automated histochemistry of whole slices. Tumor and peritumoral tissue from a patient with glioblastoma was processed to slice cultures, which were treated with standard therapy including temozolomide and X-irradiation. Then, RNA sequencing and automated histochemistry were performed. RNA sequencing was successfully accomplished with a sequencing depth of 243 to 368 x 10
MeSH term(s)	Gene Expression Profiling/methods ; Glioblastoma/genetics ; Glioblastoma/pathology ; High-Throughput Nucleotide Sequencing/methods ; Histocytochemistry/methods ; Humans ; Immunohistochemistry/methods ; Sequence Analysis, RNA ; Transcriptome
Language	English
Publishing date	2019-12-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-56509-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Deep sequencing and automated histochemistry of human tissue slice cultures improve their usability as preclinical model for cancer research

Haehnel, Susann / Reiche, Kristin / Löffler, Dennis / Horn, Andreas / Blumert, Conny / Puppel, Sven Holger / Kaiser, Nicole / Rapp, Felicitas / Rade, Michael / Horn, Friedemann / Meixenberger, Jürgen / Bechmann, Ingo / Gaunitz, Frank / Winter, Karsten

2019

Abstract: Art. 19961, 15 S. ... Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of ... ...

Abstract	Art. 19961, 15 S. Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often limited to histology. Here, we demonstrate that slices are also suitable for whole transcriptome sequencing and present a method for automated histochemistry of whole slices. Tumor and peritumoral tissue from a patient with glioblastoma was processed to slice cultures, which were treated with standard therapy including temozolomide and X-irradiation. Then, RNA sequencing and automated histochemistry were performed. RNA sequencing was successfully accomplished with a sequencing depth of 243 to 368 x 106 reads per sample. Comparing tumor and peritumoral tissue, we identified 1888 genes significantly downregulated and 2382 genes upregulated in tumor. Treatment significantly downregulated 2017 genes, whereas 1399 genes were upregulated. Pathway analysis revealed changes in the expression profile of treated glioblastoma tissue pointing towards downregulated proliferation. This was confirmed by automated analysis of whole tissue slices stained for Ki67. In conclusion, we demonstrate that RNA sequencing of tissue slices is possible and that histochemical analysis of whole tissue slices can be automated which increases the usability of this preclinical model. 9
Keywords	610 ; 620
Subject code	616
Language	English
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Individual Susceptibility Analysis Using Patient-derived Slice Cultures of Colorectal Carcinoma.

Sönnichsen, Rasmus / Hennig, Laura / Blaschke, Vera / Winter, Karsten / Körfer, Justus / Hähnel, Susann / Monecke, Astrid / Wittekind, Christian / Jansen-Winkeln, Boris / Thieme, René / Gockel, Ines / Grosser, Kerstin / Weimann, Arved / Kubick, Christoph / Wiechmann, Volker / Aigner, Achim / Bechmann, Ingo / Lordick, Florian / Kallendrusch, Sonja

Clinical colorectal cancer

2017 Volume 17, Issue 2, Page(s) e189–e199

Abstract: Background: Nonresponse to chemotherapy in colorectal carcinoma (CRC) is still a clinical problem. For most established treatment regimens, no predictive biomarkers are available. Patient-derived tumor slice culture may be a promising ex vivo technology ...

Abstract	Background: Nonresponse to chemotherapy in colorectal carcinoma (CRC) is still a clinical problem. For most established treatment regimens, no predictive biomarkers are available. Patient-derived tumor slice culture may be a promising ex vivo technology to assess the drug susceptibility in individual tumors. Methods: Patient-derived slice cultures of CRC specimens were prepared according to a standardized protocol and treated with different concentrations of 5-fluorouracil (5-FU) and an adapted FOLFOX regimen (5-FU and oxaliplatin) to investigate histologic response. Additionally, a semi-automatized readout using fluorescent stain-specific segmentation algorithms for Image J was established to quantify changes in tumor proliferation. Nonresponse to chemotherapy was defined as persisting tumor cell proliferation. Results: Slices treated with 5-FU showed lower tumor cell fractions and dose-dependent alterations of proliferating tumor cells compared with controls (1 μM, Δ +3%; 10 μM, Δ -9%; 100 μM, Δ -15%). Individual tumor samples were examined and differences in chemotherapy susceptibility could be observed. Untreated slice cultures contained an average tumor cell fraction of 31% ± 7%. For all samples, the histopathologic characteristics exhibited some degree of intratumoral heterogeneity with regard to tumor cell morphology and distribution. The original tumor matched the features found in slices at baseline and after 3 days of cultivation. Conclusions: Patient-derived slice cultures may help to predict response to clinical treatment in individual patients with CRC. Future studies need to address the problem of tumor heterogeneity and evolution. Prospective correlation of ex vivo results with the clinical course of treated patients is warranted.
MeSH term(s)	Adenocarcinoma ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Proliferation/drug effects ; Colorectal Neoplasms ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor/methods ; Fluorouracil/pharmacology ; Humans ; Leucovorin/pharmacology ; Organ Culture Techniques/methods ; Organoplatinum Compounds/pharmacology ; Precision Medicine/methods
Chemical Substances	Organoplatinum Compounds ; Leucovorin (Q573I9DVLP) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2017-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112638-0
ISSN	1938-0674 ; 1533-0028
ISSN (online)	1938-0674
ISSN	1533-0028
DOI	10.1016/j.clcc.2017.11.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 5798: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 435: Show issues

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