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Buch ; Dissertation / Habilitation: Experimentelle Kandidatengen-Analyse zum Aufschluss über die Ätiologie der posterioren Urethralklappen und des Prune-Belly-Syndroms

Thiel, Uwe

2009

Verfasserangabe	von Uwe Thiel
Sprache	Deutsch
Umfang	VIII, 123 Bl., Ill., graph. Darst., 30 cm
Erscheinungsland	Deutschland
Dokumenttyp	Buch ; Dissertation / Habilitation
Dissertation / Habilitation	Heidelberg, Univ., Diss., 2009
HBZ-ID	HT016285723
Datenquelle	Katalog ZB MED Medizin, Gesundheit

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Buch ; Online ; Dissertation / Habilitation: Enhancing CHM1319 specific TCR-transgenic T cell cytotoxic effect on Ewing sarcoma cell lines

Biele, Emilie Cécile Renée Verfasser] / [Thiel, Uwe [Akademischer Betreuer] / Thiel, Uwe [Gutachter] / Mautner, Josef [Gutachter]

2023

Verfasserangabe	Emilie Cécile Renée Biele ; Gutachter: Uwe Thiel, Josef Mautner ; Betreuer: Uwe Thiel
Schlagwörter	Medizin, Gesundheit ; Medicine, Health
Thema/Rubrik (Code)	sg610
Sprache	Englisch
Verlag	Universitätsbibliothek der TU München
Erscheinungsort	München
Dokumenttyp	Buch ; Online ; Dissertation / Habilitation
Datenquelle	Digitale Dissertationen im Internet

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Artikel: YB-1-based oncolytic virotherapy in combination with CD47 blockade enhances phagocytosis of pediatric sarcoma cells.

von Ofen, Anna Josefine / Thiel, Uwe / Eck, Jennifer / Gassmann, Hendrik / Thiede, Melanie / Hauer, Julia / Holm, Per Sonne / Schober, Sebastian J

Frontiers in oncology

2024 Band 14, Seite(n) 1304374

Abstract: Oncolytic viruses (OVs) selectively replicate in tumor cells resulting in lysis, spreading of new infectious units and induction of antitumor immune responses through abrogating an immunosuppressive tumor microenvironment (TME). Due to their mode of ... ...

Abstract	Oncolytic viruses (OVs) selectively replicate in tumor cells resulting in lysis, spreading of new infectious units and induction of antitumor immune responses through abrogating an immunosuppressive tumor microenvironment (TME). Due to their mode of action, OVs are ideal combination partners with targeted immunotherapies. One highly attractive combination is the inhibition of the 'don't-eat-me'-signal CD47, which is known to increase the phagocytic potential of tumor-associated macrophages. In this work, we analyzed the combination approach consisting of the YB-1-based oncolytic adenovirus XVir-N-31 (XVir) and the CD47 inhibitor (CD47i) B6.H12.2 concerning its phagocytic potential. We investigate phagocytosis of XVir-, adenovirus wildtype (AdWT)-, and non-infected established pediatric sarcoma cell lines by different monocytic cells. Phagocytes (immature dendritic cells and macrophages) were derived from THP-1 cells and healthy human donors. Phagocytosis of tumor cells was assessed via FACS analysis in the presence and absence of CD47i. Additional characterization of T cell-stimulatory surface receptors as well as chemo-/cytokine analyses were performed. Furthermore, tumor cells were infected and studied for the surface expression of the 'eat-me'-signal calreticulin (CALR) and the 'don't-eat-me'-signal CD47. We herein demonstrate that (1) XVir-infected tumor cells upregulate both CALR and CD47. XVir induces higher upregulation of CD47 than AdWT. (2) XVir-infection enhances phagocytosis in general and (3) the combination of XVir and CD47i compared to controls showed by far superior enhancement of phagocytosis, tumor cell killing and innate immune activation. In conclusion, the combination of CD47i and XVir causes a significant increase in phagocytosis exceeding the monotherapies considerably accompanied by upregulation of T cell-stimulatory receptor expression and inflammatory chemo/-cytokine secretion.
Sprache	Englisch
Erscheinungsdatum	2024-01-31
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2024.1304374
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Buch ; Online ; Dissertation / Habilitation: Ewing Sarcoma-Derived Extracellular Vesicles Impair Dendritic Cell Maturation and Function, and Upregulate Endogenous Retroelements

Gaßmann, Hendrik Maximilian Verfasser] / [Burdach, Stefan [Akademischer Betreuer] / Thiel, Uwe [Gutachter] / Nößner, Elfriede [Gutachter] / Staege, Martin S. [Gutachter]

2023

Verfasserangabe	Hendrik Maximilian Gaßmann ; Gutachter: Uwe Thiel, Elfriede Nößner, Martin S. Staege ; Betreuer: Stefan Burdach
Schlagwörter	Medizin, Gesundheit ; Medicine, Health
Thema/Rubrik (Code)	sg610
Sprache	Englisch
Verlag	Universitätsbibliothek der TU München
Erscheinungsort	München
Dokumenttyp	Buch ; Online ; Dissertation / Habilitation
Datenquelle	Digitale Dissertationen im Internet

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Artikel ; Online: TCR-transgenic T cells and YB-1-based oncolytic virotherapy improve survival in a preclinical Ewing sarcoma xenograft mouse model.

Schober, Sebastian J / Thiede, Melanie / Gassmann, Hendrik / von Ofen, Anna Josefine / Knoch, Pia / Eck, Jennifer / Prexler, Carolin / Kordass-Wally, Corazon / Hauer, Julia / Burdach, Stefan / Holm, Per Sonne / Thiel, Uwe

Frontiers in immunology

2024 Band 15, Seite(n) 1330868

Abstract: Background: Ewing sarcoma (EwS) is an aggressive and highly metastatic bone and soft tissue tumor in pediatric patients and young adults. Cure rates are low when patients present with metastatic or relapsed disease. Therefore, innovative therapy ... ...

Abstract	Background: Ewing sarcoma (EwS) is an aggressive and highly metastatic bone and soft tissue tumor in pediatric patients and young adults. Cure rates are low when patients present with metastatic or relapsed disease. Therefore, innovative therapy approaches are urgently needed. Cellular- and oncolytic virus-based immunotherapies are on the rise for solid cancers. Methods: Here, we assess the combination of EwS tumor-associated antigen CHM1 Results: In vitro Conclusion: Our data prove synergistic antitumor effects
Mesh-Begriff(e)	Humans ; Mice ; Animals ; Child ; Sarcoma, Ewing ; Oncolytic Virotherapy ; CD8-Positive T-Lymphocytes/pathology ; Heterografts ; Disease Models, Animal ; Animals, Genetically Modified ; Receptors, Antigen, T-Cell/genetics ; Transcription Factors
Chemische Substanzen	Receptors, Antigen, T-Cell ; YB-1 protein, mouse ; Transcription Factors
Sprache	Englisch
Erscheinungsdatum	2024-01-22
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1330868
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Prospective evaluation of multitarget treatment of pediatric patients with helical intensity-modulated radiotherapy.

Salfelder, Maria-Elena A / Kessel, Kerstin A / Thiel, Uwe / Burdach, Stefan / Kampfer, Severin / Combs, Stephanie E

Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al

2020 Band 196, Heft 12, Seite(n) 1103–1115

Abstract: Background and purpose: Radiotherapy (RT) is persistently gaining significance in the treatment of pediatric tumors. However, individual features of a growing body and multifocal stages complicate this approach. Tomotherapy offers advantages in the ... ...

Abstract	Background and purpose: Radiotherapy (RT) is persistently gaining significance in the treatment of pediatric tumors. However, individual features of a growing body and multifocal stages complicate this approach. Tomotherapy offers advantages in the treatment of anatomically complex tumors with low risks of side effects. Here we report on toxicity incidence and outcome of tomotherapy with a focus on multitarget RT (mtRT). Materials and methods: From 2008 to 2017, 38 children diagnosed with sarcoma were treated with tomotherapy. The median age was 15 years (6-19 years). Toxicity was graded according to the Common Terminology Criteria for Adverse Events v.4.03 and classified into symptoms during RT, acutely (0-6 months) and late (>6 months) after RT, and long-term sideeffects (>24 months). Results: The main histologies were Ewing sarcoma (n = 23 [61%]) and alveolar rhabdomyosarcoma (n = 5 [13%]). RT was performed with a median total dose of 54 Gy (40.5-66.0 Gy) and a single dose of 2 Gy (1.80-2.27 Gy). Twenty patients (53%) received mtRT. Median follow-up was 29.7 months (95% confidence interval 15.3-48.2 months) with a 5-year survival of 55.2% (±9.5%). The 5‑year survival rate of patients with mtRT (n = 20) was 37.1 ± 13.2%, while patients who received single-target RT (n = 18) had a 5-year survival rate of 75 ± 10.8%. Severe toxicities (grade 3 and 4) emerged in 14 patients (70%) with mtRT and 7 patients (39%) with single-target RT. Two non-hematological grade 4 toxicities occurred during RT: one mucositis and one radiodermatitis. After mtRT 5 patients had grade 3 toxicities acute and after single-target RT 4 patients. One patient had acute non-hematological grade 4 toxicities (gastritis, pericarditis, and pericardial effusion) after mtRT. Severe late effects of RT occurred in 2 patients after mtRT and in none of the single-target RT patients. No severe long-term side effects appeared. Conclusion: Our results showed acceptable levels of acute and late toxicities, considering the highly advanced diseases and multimodal treatment. Hence, tomotherapy is a feasible treatment method for young patients with anatomically complex tumors or multiple targets. Especially mtRT is a promising and innovative treatment approach for pediatric sarcomas, delivering unexpectedly high survival rates for patients with multifocal Ewing sarcomas in this study, whereby the limited number of patients should invariably be considered in the interpretation.
Mesh-Begriff(e)	Adolescent ; Bone Neoplasms/radiotherapy ; Child ; Female ; Follow-Up Studies ; Humans ; Male ; Prospective Studies ; Radiodermatitis/etiology ; Radiotherapy, Intensity-Modulated/adverse effects ; Radiotherapy, Intensity-Modulated/methods ; Rhabdomyosarcoma, Alveolar/radiotherapy ; Sarcoma/radiotherapy ; Sarcoma, Ewing/radiotherapy ; Young Adult
Sprache	Englisch
Erscheinungsdatum	2020-08-03
Erscheinungsland	Germany
Dokumenttyp	Journal Article
ZDB-ID	84983-2
ISSN	1439-099X ; 0179-7158 ; 0039-2073
ISSN (online)	1439-099X
ISSN	0179-7158 ; 0039-2073
DOI	10.1007/s00066-020-01670-4
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles.

The Journal of clinical investigation

2024 Band 134, Heft 9

Abstract: Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), ... ...

Abstract	Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.
Mesh-Begriff(e)	Humans ; Extracellular Vesicles/metabolism ; Extracellular Vesicles/genetics ; DNA Damage ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Transcriptional Regulator ERG/genetics ; Transcriptional Regulator ERG/metabolism ; Male ; RNA-Binding Protein EWS/genetics ; RNA-Binding Protein EWS/metabolism ; Proto-Oncogene Protein c-fli-1/genetics ; Proto-Oncogene Protein c-fli-1/metabolism ; Sarcoma, Ewing/genetics ; Sarcoma, Ewing/pathology ; Sarcoma, Ewing/metabolism ; Sarcoma, Ewing/immunology ; Cell Line, Tumor ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/metabolism ; Mice ; Animals ; Heterochromatin/metabolism ; Heterochromatin/genetics
Chemische Substanzen	Oncogene Proteins, Fusion ; Transcriptional Regulator ERG ; RNA-Binding Protein EWS ; ERG protein, human ; Proto-Oncogene Protein c-fli-1 ; RNA, Neoplasm ; EWS-FLI fusion protein ; Heterochromatin
Sprache	Englisch
Erscheinungsdatum	2024-03-26
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI169470
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Buch ; Online ; Dissertation / Habilitation: Viro-immunotherapy against Ewing sarcoma: synergistic antitumor effects of the oncolytic adenovirus XVir-N-31 with T cell receptor-transgenic T cells and cell cycle inhibition

Schober, Sebastian Johannes [Verfasser] / Burdach, Stefan E. G. [Akademischer Betreuer] / Thiel, Uwe [Gutachter] / Holm, Per Sonne [Gutachter] / Kochanek, Stefan [Gutachter]

2022

Verfasserangabe	Sebastian Johannes Schober ; Gutachter: Uwe Thiel, Per Sonne Holm, Stefan Kochanek ; Betreuer: Stefan E. G. Burdach
Schlagwörter	Medizin, Gesundheit ; Medicine, Health
Thema/Rubrik (Code)	sg610
Sprache	Englisch
Verlag	Universitätsbibliothek der TU München
Erscheinungsort	München
Dokumenttyp	Buch ; Online ; Dissertation / Habilitation
Datenquelle	Digitale Dissertationen im Internet

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Artikel ; Online: The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma.

Schober, Sebastian Johannes / Schoening, Caroline / Eck, Jennifer / Middendorf, Charlotte / Lutsch, Julia / Knoch, Pia / von Ofen, Anna Josefine / Gassmann, Hendrik / Thiede, Melanie / Hauer, Julia / Kolk, Andreas / Mantwill, Klaus / Gschwend, Jürgen E / Burdach, Stefan E G / Nawroth, Roman / Thiel, Uwe / Holm, Per Sonne

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Band 29, Heft 10, Seite(n) 1996–2011

Abstract: Purpose: Ewing sarcoma (EwS) is a highly malignant pediatric tumor characterized by a non-T-cell-inflamed immune-evasive phenotype. When relapsed or metastasized, survival is poor, emphasizing the need for novel treatment strategies. Here, we analyze ... ...

Abstract	Purpose: Ewing sarcoma (EwS) is a highly malignant pediatric tumor characterized by a non-T-cell-inflamed immune-evasive phenotype. When relapsed or metastasized, survival is poor, emphasizing the need for novel treatment strategies. Here, we analyze the novel combination approach using the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition to augment EwS immunogenicity. Experimental design: In vitro, viral toxicity, replication, and immunogenicity were studied in several EwS cell lines. In vivo tumor xenograft models with transient humanization were applied to evaluate tumor control, viral replication, immunogenicity, and dynamics of innate as well as human T cells after treatment with XVir-N-31 combined with CDK4/6 inhibition. Furthermore, immunologic features of dendritic cell maturation and T-cell-stimulating capacities were assessed. Results: The combination approach significantly increased viral replication and oncolysis in vitro, induced HLA-I upregulation, and IFNγ-induced protein 10 expression and enhanced maturation of monocytic dendritic cells with superior capacities to stimulate tumor antigen-specific T cells. These findings were confirmed in vivo showing tumor infiltration by (i) monocytes with antigen-presenting capacities and M1 macrophage marker genes, (ii) TReg suppression in spite of adenovirus infection, (iii) superior engraftment, and (iv) tumor infiltration by human T cells. Consequently, survival was improved over controls with signs of an abscopal effect after combination treatment. Conclusions: The joint forces of the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition induce therapeutically relevant local and systemic antitumor effects. Innate as well as adaptive immunity against EwS is boosted in this preclinical setting, pointing toward high therapeutic potential in the clinic.
Mesh-Begriff(e)	Child ; Humans ; Sarcoma, Ewing/pathology ; Adenoviridae/genetics ; Oncolytic Virotherapy ; Cell Line, Tumor ; Adenoviridae Infections ; Adaptive Immunity ; Oncolytic Viruses/genetics ; Xenograft Model Antitumor Assays ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism
Chemische Substanzen	CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Sprache	Englisch
Erscheinungsdatum	2023-03-09
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-1961
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: T Cells Directed against the Metastatic Driver Chondromodulin-1 in Ewing Sarcoma: Comparative Engineering with CRISPR/Cas9 vs. Retroviral Gene Transfer for Adoptive Transfer.

Xue, Busheng / von Heyking, Kristina / Gassmann, Hendrik / Poorebrahim, Mansour / Thiede, Melanie / Schober, Kilian / Mautner, Josef / Hauer, Julia / Ruland, Jürgen / Busch, Dirk H / Thiel, Uwe / Burdach, Stefan E G

Cancers

2022 Band 14, Heft 22

Abstract: Ewing sarcoma (EwS) is a highly malignant sarcoma of bone and soft tissue with early metastatic spread and an age peak in early puberty. The prognosis in advanced stages is still dismal, and the long-term effects of established therapies are severe. ... ...

Abstract	Ewing sarcoma (EwS) is a highly malignant sarcoma of bone and soft tissue with early metastatic spread and an age peak in early puberty. The prognosis in advanced stages is still dismal, and the long-term effects of established therapies are severe. Efficacious targeted therapies are urgently needed. Our previous work has provided preliminary safety and efficacy data utilizing T cell receptor (TCR) transgenic T cells, generated by retroviral gene transfer, targeting HLA-restricted peptides on the tumor cell derived from metastatic drivers. Here, we compared T cells engineered with either CRISPR/Cas9 or retroviral gene transfer. Firstly, we confirmed the feasibility of the orthotopic replacement of the endogenous TCR by CRISPR/Cas9 with a TCR targeting our canonical metastatic driver chondromodulin-1 (CHM1). CRISPR/Cas9-engineered T cell products specifically recognized and killed HLA-A*02:01+ EwS cell lines. The efficiency of retroviral transduction was higher compared to CRISPR/Cas9 gene editing. Both engineered T cell products specifically recognized tumor cells and elicited cytotoxicity, with CRISPR/Cas9 engineered T cells providing prolonged cytotoxic activity. In conclusion, T cells engineered with CRISPR/Cas9 could be feasible for immunotherapy of EwS and may have the advantage of more prolonged cytotoxic activity, as compared to T cells engineered with retroviral gene transfer.
Sprache	Englisch
Erscheinungsdatum	2022-11-08
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14225485
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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