38 results on '"Sobottka B"'
Search Results
2. MA12.04 SAKK 16/14: CD8 T Cell Positioning Correlates with Survivalin Stage IIIA(N2) NSCLC After Neoadjuvant Immunotherapy
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Sobottka, B., primary, Tochtermann, G., additional, Trueb, M., additional, Nowack, M., additional, Alborelli, I., additional, Leonards, K., additional, Manzo, M., additional, Keller, E., additional, Herzig, P., additional, Schmid, D., additional, Eboulet, E.I., additional, Hayoz, S., additional, Godar, G., additional, Schneider, M., additional, Jermann, P., additional, Savic Prince, S., additional, König, D., additional, Pless, M., additional, Zippelius, A., additional, Rothschild, S.I., additional, and Koelzer, V.H., additional
- Published
- 2022
- Full Text
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3. SAKK 16/14: CD8 T Cell Positioning Correlates with Survival in Stage IIIA (N2) NSCLC After Neoadjuvant Immunotherapy
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Sobottka, B, Tochtermann, G, Trueb, M, Nowack, M, Kölzer, Viktor, et al, and University of Zurich
- Subjects
10049 Institute of Pathology and Molecular Pathology ,610 Medicine & health - Published
- 2022
4. Induced oligodendrocyte death does not elicit anti-myelin autoimmunity: W21.007
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Buch, T., Wörtge, S., Locatelli, G., Ingold, B., Frommer, F., Sobottka, B., Krüger, M., Heppner, F., Waisman, A., and Becher, B.
- Published
- 2012
5. Molekulare Tumordiagnostik – aktuelle Methoden, Anwendungsbeispiele und Ausblick
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Sobottka, B., primary and Weber, A., additional
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- 2020
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6. Messinstrumente zur Verlaufsbeurteilung pathologischen PC-/Internet-Gebrauchs
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Sobottka, B, additional, Feindel, H, additional, Meinke, A, additional, Vogelgesang, M, additional, and Fischer, T, additional
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- 2017
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7. Ergebnisse einer Einjahreskatamnese nach stationärer Psychotherapie bei Pathologischem PC-/Internet-Gebrauch
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Sobottka, B, primary, Feindel, H, additional, Schuhler, P, additional, Schwarz, S, additional, Vogelgesang, M, additional, and Fischer, T, additional
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- 2013
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8. CNS Live Imaging Reveals a New Mechanism of Myelination: The Liquid Croissant Model (P02.065)
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Goebels, N., primary, Sobottka, B., additional, Kaech, A., additional, Becher, B., additional, and Ziegler, U., additional
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- 2012
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9. Pathologischer PC-/ Internet-Gebrauch: Sozialmedizinische Aspekte eines neuen Krankheitsbildes
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Sobottka, B, primary and Fischer, T, additional
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- 2011
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10. Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings
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Sobottka, B., primary, Schlote, T., additional, Krumpaszky, H. G, additional, and Kreissig, I., additional
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- 1998
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11. Squamous cell carcinoma of the lung metastizing into choroid. A case report.
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Sobottka, B, primary
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- 1995
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12. 4233 Squamous cell carcinoma of the lung metastizing into choroid. A case report
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Sobottka, B., primary, Inhoffen, W., additional, Stanowsky, A., additional, and Kreissig, I., additional
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- 1995
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13. Ultrasonography of metastases and melanomas of the choroid.
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Sobottka, B and Kreissig, I
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- 1999
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14. Cell proliferation activity in posterior uveal melanoma after Ru-106 brachytherapy: an EORTC ocular oncology group study
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Pe'er, J., Stefani, F.H., Seregard, S., Kivela, T., Lommatzsch, P., Prause, J.U., Sobottka, B., Damato, B., and Chowers, I.
- Abstract
AIM: To evaluate the cell proliferation activity in posterior uveal melanomas after Ru-106 brachytherapy. METHODS: Eyes containing choroidal or ciliary body melanoma from seven ocular oncology centres, which were enucleated after first being treated by Ru-106 brachytherapy and which had enough melanoma tissue to enable histological assessment, were included. The 57 eligible specimens were divided into a group of 44 eyes that were enucleated because of tumour regrowth, and a non-recurrent group of 13 eyes that were enucleated because of complications such as neovascular glaucoma. 46 non-irradiated eyes harbouring uveal melanoma served as a control group. All specimens underwent routine processing. They were cut into 5 μm sections, and were stained with two main cell proliferation markers: PC-10 for PCNA and MIB-1 for Ki-67. The stained sections were assessed, and the cells that were positive in the immunostaining were counted in each section. The results were evaluated by various statistical methods. RESULTS: The PC-10 score showed a statistically significant difference across the three groups (p = 0.002). The control group showed the highest PC-10 score (median 31.0 PCC/HPF) followed by the tumour regrowth group (median 4.9 PCC/HPF). The lowest PC-10 scores were found in the non-recurrent tumours (median 0.05 PCC/HPF). The MIB-1 score in the control group (median 5.77 PCC/HPF) was similar to the regrowth group (median 5.4 PCC/HPF). In contrast, the MIB-1 score in the non-recurrent tumours was statistically significantly lower (median 0.42 PCC/HPF). The PC-10 and MIB-1 scores were similar in tumours composed of either spindle cells or epithelioid cells in all groups. CONCLUSIONS: The non-recurrent melanomas demonstrate significantly lower cellular proliferation activity than melanomas that showed regrowth or that were not irradiated at all. In our hands, PCNA gave more meaningful information than Ki-67. Our findings strongly support the need for treating regrowing posterior uveal melanoma either by enucleation or re-treatment by brachytherapy. On the other hand, also in the non-recurrent uveal melanomas there are viable cells with potential for proliferation, although fewer in number, with unknown capacity for metastatic spread. Therefore, the irradiated tumours should be followed for many years, probably for life.
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- 2001
15. [Changed chemosensory identity following experimental bone marrow transplantation: recognition by another species]
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Sobottka B, Frank Eggert, Ferstl R, and Müller-Ruchholtz W
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Discrimination Learning ,Smell ,Mice ,Species Specificity ,Animals ,Female ,Mice, Inbred Strains ,Rats, Inbred Strains ,Pheromones ,Bone Marrow Transplantation ,Rats - Abstract
A new paradigm was constructed using rats as trained animals in order to examine changes appearing in the scent of mice after a fully allogeneic bone marrow transplantation (BMT). Two rats (CAP), deprived of water 20 hours before each training session, were trained in an olfactometer to discriminate two fully allogeneic mice strains (C3H, C57) via their urine odors. Reinforcement for identification of the St was provided by a drop of water. After discrimination was built-up, the reinforcement schedule was reduced stepwise in defined blocks of trials, in order to allow transfer-of-training tests, to which urine samples of allogeneic reconstituted BMT-chimeras (C57----C3H and C3H----C57) were submitted. It was confirmed that the strain-specific urine odors of the recipients were changed by a fully allogeneic BMT. The results also showed that the urine odors of allogeneic reconstituted chimeras differed from the specific urine odor of the donor strain.
- Published
- 1989
16. Immune Phenotype-Genotype Associations in Primary Clear Cell Renal Cell Carcinoma and Matched Metastatic Tissue.
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Sobottka B, Vetter V, Banaei-Esfahani A, Nowak M, Lorch A, Sirek A, Mertz KD, Brunelli M, Berthold D, de Leval L, Kahraman A, Koelzer VH, and Moch H
- Abstract
Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8
+ T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically "cold." Inflamed, pathologically "hot" PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8+ TOX+ T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8+ TOX+ T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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17. Whole-Exome Sequencing Reveals High Mutational Concordance between Primary and Matched Recurrent Triple-Negative Breast Cancers.
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Kaur J, Chandrashekar DS, Varga Z, Sobottka B, Janssen E, Gandhi K, Kowalski J, Kiraz U, Varambally S, and Aneja R
- Abstract
Purpose: Triple-negative breast cancer (TNBC) is a molecularly complex and heterogeneous breast cancer subtype with distinct biological features and clinical behavior. Although TNBC is associated with an increased risk of metastasis and recurrence, the molecular mechanisms underlying TNBC metastasis remain unclear. We performed whole-exome sequencing (WES) analysis of primary TNBC and paired recurrent tumors to investigate the genetic profile of TNBC., Methods: Genomic DNA extracted from 35 formalin-fixed paraffin-embedded tissue samples from 26 TNBC patients was subjected to WES. Of these, 15 were primary tumors that did not have recurrence, and 11 were primary tumors that had recurrence (nine paired primary and recurrent tumors). Tumors were analyzed for single-nucleotide variants and insertions/deletions., Results: The tumor mutational burden (TMB) was 7.6 variants/megabase in primary tumors that recurred ( n = 9); 8.2 variants/megabase in corresponding recurrent tumors ( n = 9); and 7.3 variants/megabase in primary tumors that did not recur ( n = 15). MUC3A was the most frequently mutated gene in all groups. Mutations in MAP3K1 and MUC16 were more common in our dataset. No alterations in PI3KCA were detected in our dataset., Conclusions: We found similar mutational profiles between primary and paired recurrent tumors, suggesting that genomic features may be retained during local recurrence.
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- 2023
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18. Biallelic ELOC-Inactivated Renal Cell Carcinoma: Molecular Features Supporting Classification as a Distinct Entity.
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Batavia AA, Rutishauser D, Sobottka B, Schraml P, Beerenwinkel N, and Moch H
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- Humans, Vascular Endothelial Growth Factor A, Elongin genetics, Von Hippel-Lindau Tumor Suppressor Protein genetics, TOR Serine-Threonine Kinases, Carcinoma, Renal Cell pathology, Kidney Neoplasms genetics, Kidney Neoplasms pathology
- Abstract
Approximately 70% of clear cell renal cell carcinoma (ccRCC) is characterized by the biallelic inactivation of von Hippel-Lindau (VHL) on chromosome 3p. ELOC-mutated (Elongin C-mutated) renal cell carcinoma containing biallelic ELOC inactivations with chromosome 8q deletions is considered a novel subtype of renal cancer possessing a morphologic overlap with ccRCC, renal cell carcinoma (RCC) with fibromyomatous stroma exhibiting Tuberous Sclerosis Complex (TSC)/mammalian Target of Rapamycin (mTOR) mutations, and clear cell papillary tumor. However, the frequency and consequences of ELOC alterations in wild-type VHL and mutated VHL RCC are unclear. In this study, we characterize 123 renal tumors with clear cell morphology and known VHL mutation status to assess the morphologic and molecular consequences of ELOC inactivation. Using OncoScan and whole-exome sequencing, we identify 18 ELOC-deleted RCCs, 3 of which contain ELOC mutations resulting in the biallelic inactivation of ELOC. Biallelic ELOC and biallelic VHL aberrations were mutually exclusive; however, 2 ELOC-mutated RCCs showed monoallelic VHL alterations. Furthermore, no mutations in TSC1, TSC2, or mTOR were identified in ELOC-mutated RCC with biallelic ELOC inactivation. Using High Ambiguity Driven biomolecular DOCKing, we report a novel ELOC variant containing a duplication event disrupting ELOC-VHL interaction alongside the frequently seen Y79C alteration. Using hyper reaction monitoring mass spectrometry, we show RCCs with biallelic ELOC alterations have significantly reduced ELOC expression but similar carbonic anhydrase 9 and vascular endothelial growth factor A expression compared with classical ccRCC with biallelic VHL inactivation. The absence of biallelic VHL and TSC1, TSC2, or mTOR inactivation in RCC with biallelic ELOC inactivation (ELOC mutation in combination with ELOC deletions on chromosome 8q) supports the notion of a novel, molecularly defined tumor entity., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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19. A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.
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Tietscher S, Wagner J, Anzeneder T, Langwieder C, Rees M, Sobottka B, de Souza N, and Bodenmiller B
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- Humans, Female, Programmed Cell Death 1 Receptor, T-Cell Exhaustion, Phenotype, CD8-Positive T-Lymphocytes, Breast Neoplasms metabolism, Antineoplastic Agents metabolism
- Abstract
Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1
high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments., (© 2023. The Author(s).)- Published
- 2023
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20. Distinct Gene Expression Profiles of Matched Primary and Metastatic Triple-Negative Breast Cancers.
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Kaur J, Chandrashekar DS, Varga Z, Sobottka B, Janssen E, Kowalski J, Kiraz U, Varambally S, and Aneja R
- Abstract
Background: Although triple-negative breast cancer (TNBC) is associated with an increased risk of recurrence and metastasis, the molecular mechanisms underlying metastasis in TNBC remain unknown. To identify transcriptional changes and genes regulating metastatic progression in TNBC, we compared the transcriptomic profiles of primary and matched metastatic tumors using massively parallel RNA sequencing. Methods: We performed gene expression profiling using formalin-fixed paraffin-embedded (FFPE) TNBC tissues of patients from two cohorts: the Zurich cohort (n = 31) and the Stavanger cohort (n = 5). Among the 31 patients in the Zurich cohort, 18 had primary TNBC tumors that did not metastasize, and 13 had primary tumors that metastasized (11 paired primary and locoregional recurrences). The Stavanger cohort included five matched primary and metastatic TNBC tumors. Significantly differentially expressed genes (DEGs; absolute fold change ≥2, p < 0.05) were identified and subjected to functional analyses. We investigated if there was any overlap between DEGs from both the cohorts with epithelial-to-mesenchymal-to-amoeboid transition (EMAT) gene signature. xCell was used to estimate relative fractions of 64 immune and stromal cell types in each RNA-seq sample. Results: In the Zurich cohort, we identified 1624 DEGs between primary TNBC tumors and matched metastatic lesions. xCell analysis revealed a significantly higher immune scores for metastatic lesions compared to paired primary tumors in the Zurich cohort. We also found significant upregulation of three MammaPrint signature genes (HRASLS, TGFB3 and RASSF7) in primary tumors that metastasized compared to primary tumors that remained metastasis-free. In the Stavanger cohort, we identified 818 DEGs between primary tumors and matched metastatic lesions. No significant differences in xCell immune scores were observed. We found that 21 and 14 DEGs from Zurich and Stavanger cohort, respectively, overlapped with the EMAT gene signature. In both cohorts, genes belonging to the MMP, FGF, and PDGFR families were upregulated in primary tumors compared to matched metastatic lesions. Conclusions: Our results suggest that distinct gene expression patterns exist between primary TNBCs and matched metastatic tumors. Further studies are warranted to explore whether these discrete expression profiles underlie or result from disease status.
- Published
- 2022
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21. Integrated Analysis Of Immunotherapy Treated Clear Cell Renal Cell Carcinomas: An Exploratory Study.
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Sobottka B, Nienhold R, Nowak M, Hench J, Haeuptle P, Frank A, Sachs M, Kahraman A, Moch H, Koelzer VH, and Mertz KD
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- B7-H1 Antigen, CD8-Positive T-Lymphocytes, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, Tumor Microenvironment, Carcinoma, Renal Cell therapy, Kidney Neoplasms therapy
- Abstract
Molecular or immunological differences between responders and nonresponders to immune checkpoint inhibitors (ICIs) of clear cell renal cell carcinomas (ccRCCs) remain incompletely understood. To address this question, we performed next-generation sequencing, methylation analysis, genome wide copy number analysis, targeted RNA sequencing and T-cell receptor sequencing, and we studied frequencies of tumor-infiltrating CD8+ T cells, presence of tertiary lymphoid structures (TLS) and PD-L1 expression in 8 treatment-naive ccRCC patients subsequently treated with ICI (3 responders, 5 nonresponders). Unexpectedly, we identified decreased frequencies of CD8+ tumor-infiltrating T cells and TLS, and a decreased expression of PD-L1 in ICI responders when compared with nonresponders. However, neither tumor-specific genetic alterations nor gene expression profiles correlated with response to ICI or the observed immune features. Our results underline the challenge to stratify ccRCC patients for immunotherapy based on routinely available pathologic primary tumor material, even with advanced technologies. Our findings emphasize the analysis of pretreated metastatic tissue in line with recent observations describing treatment effects on the tumor microenvironment. In addition, our data call for further investigation of additional parameters in a larger ccRCC cohort to understand the mechanistic implications of the observed differences in tumor-infiltrating CD8+ T cells, TLS, and PD-L1 expression., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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22. Correction: Establishing standardized immune phenotyping of metastatic melanoma by digital pathology.
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Sobottka B, Nowak M, Frei AL, Haberecker M, Merki S, Levesque MP, Dummer R, Moch H, and Koelzer VH
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- 2021
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23. Establishing standardized immune phenotyping of metastatic melanoma by digital pathology.
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Sobottka B, Nowak M, Frei AL, Haberecker M, Merki S, Levesque MP, Dummer R, Moch H, and Koelzer VH
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- Adult, Aged, Aged, 80 and over, Deep Learning, Female, Humans, Male, Melanoma immunology, Middle Aged, CD8-Positive T-Lymphocytes, Image Processing, Computer-Assisted, Immunophenotyping methods, Melanoma pathology
- Abstract
CD8+ tumor-infiltrating T cells can be regarded as one of the most relevant predictive biomarkers in immune-oncology. Highly infiltrated tumors, referred to as inflamed (clinically "hot"), show the most favorable response to immune checkpoint inhibitors in contrast to tumors with a scarce immune infiltrate called immune desert or excluded (clinically "cold"). Nevertheless, quantitative and reproducible methods examining their prevalence within tumors are lacking. We therefore established a computational diagnostic algorithm to quantitatively measure spatial densities of tumor-infiltrating CD8+ T cells by digital pathology within the three known tumor compartments as recommended by the International Immuno-Oncology Biomarker Working Group in 116 prospective metastatic melanomas of the Swiss Tumor Profiler cohort. Workflow robustness was confirmed in 33 samples of an independent retrospective validation cohort. The introduction of the intratumoral tumor center compartment proved to be most relevant for establishing an immune diagnosis in metastatic disease, independent of metastatic site. Cut-off values for reproducible classification were defined and successfully assigned densities into the respective immune diagnostic category in the validation cohort with high sensitivity, specificity, and precision. We provide a robust diagnostic algorithm based on intratumoral and stromal CD8+ T-cell densities in the tumor center compartment that translates spatial densities of tumor-infiltrating CD8+ T cells into the clinically relevant immune diagnostic categories "inflamed", "excluded", and "desert". The consideration of the intratumoral tumor center compartment allows immune phenotyping in the clinically highly relevant setting of metastatic lesions, even if the invasive margin compartment is not captured in biopsy material., (© 2021. The Author(s).)
- Published
- 2021
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24. Spatial protein heterogeneity analysis in frozen tissues to evaluate tumor heterogeneity.
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Fomitcheva-Khartchenko A, Rapsomaniki MA, Sobottka B, Schraml P, and Kaigala GV
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- Humans, Female, ErbB Receptors metabolism, ErbB Receptors genetics, Genetic Heterogeneity, Breast Neoplasms pathology, Breast Neoplasms genetics, Breast Neoplasms metabolism
- Abstract
A new workflow for protein-based tumor heterogeneity probing in tissues is here presented. Tumor heterogeneity is believed to be key for therapy failure and differences in prognosis in cancer patients. Comprehending tumor heterogeneity, especially at the protein level, is critical for tracking tumor evolution, and showing the presence of different phenotypical variants and their location with respect to tissue architecture. Although a variety of techniques is available for quantifying protein expression, the heterogeneity observed in the tissue is rarely addressed. The proposed method is validated in breast cancer fresh-frozen tissues derived from five patients. Protein expression is quantified on the tissue regions of interest (ROI) with a resolution of up to 100 μm in diameter. High heterogeneity values across the analyzed patients in proteins such as cytokeratin 7, β-actin and epidermal growth factor receptor (EGFR) using a Shannon entropy analysis are observed. Additionally, ROIs are clustered according to their expression levels, showing their location in the tissue section, and highlighting that similar phenotypical variants are not always located in neighboring regions. Interestingly, a patient with a phenotype related to increased aggressiveness of the tumor presents a unique protein expression pattern. In summary, a workflow for the localized extraction and protein analysis of regions of interest from frozen tissues, enabling the evaluation of tumor heterogeneity at the protein level is presented., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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25. Renal cell carcinoma pathology in 2021: 'new need for renal cancer immune profiling'.
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Sobottka B, Lorch A, Silina K, van den Broek M, and Moch H
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- Biomarkers, Tumor, Humans, Prognosis, Tumor Microenvironment, Carcinoma, Renal Cell, Kidney Neoplasms therapy
- Abstract
Purpose of Review: The aim of this review is to outline characteristics of the renal cell carcinoma (RCC) tumor immune microenvironment (TIME), the potential impact of tumor intrinsic alterations on the TIME and the value of metastatic tissue assessment in this context., Recent Findings: According to the latest European Association of Urology, European Society for Medical Oncology and National Comprehensive Cancer Network guidelines immune checkpoint inhibition represents a new core treatment strategy in advanced clear cell RCC (ccRCC). Despite its success, the prognosis of many RCC patients remains unsatisfactory most likely because of resistance mechanisms within the TIME. Moreover, most studies assess the primary tumor even though the advanced metastatic disease is targeted. Overall, metastatic RCC has hardly been investigated. First insights into the complexity of the genomic and immune landscape in RCC were recently provided. The functional impact of tumor intrinsic alterations on the TIME has just been described potentially contributing to therapy response in RCC., Summary: The complexity of the RCC TIME and its potential interdependence with tumor intrinsic alterations has only just been recognized. A deeper understanding of the TIME may reveal predictive and prognostic biomarkers long-awaited in RCC, improve RCC patient stratification and could possibly be most instructive if assessed in metastatic tissue., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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26. The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support.
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Irmisch A, Bonilla X, Chevrier S, Lehmann KV, Singer F, Toussaint NC, Esposito C, Mena J, Milani ES, Casanova R, Stekhoven DJ, Wegmann R, Jacob F, Sobottka B, Goetze S, Kuipers J, Sarabia Del Castillo J, Prummer M, Tuncel MA, Menzel U, Jacobs A, Engler S, Sivapatham S, Frei AL, Gut G, Ficek J, Miglino N, Aebersold R, Bacac M, Beerenwinkel N, Beisel C, Bodenmiller B, Dummer R, Heinzelmann-Schwarz V, Koelzer VH, Manz MG, Moch H, Pelkmans L, Snijder B, Theocharides APA, Tolnay M, Wicki A, Wollscheid B, Rätsch G, and Levesque MP
- Subjects
- Clinical Decision-Making methods, Computational Biology methods, Decision Support Systems, Clinical, Humans, Precision Medicine methods, Prospective Studies, Neoplasms genetics, Neoplasms metabolism
- Abstract
The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease., Competing Interests: Declaration of Interests B.S. is scientific co-founder and shareholder of Allcyte GmbH. L.P. and G.G. are listed as inventor on patents related to the 4i technology (WO 2019/207004; WO 2020/008071). G.R., K.-V.L., and S.G.S. are listed on a patent application related to single-cell analyses (European Patent Application No. 20170724.7). H.M. is on advisory boards for Bayer, Astra Zeneca, Janssen, Roche, and Merck. R.D. reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, and Alligator outside the submitted work. G.R. is cofounder and on the Scientific Advisory Board of Computomics GmbH. M.P.L. is a co-founder and shareholder of Oncobit AG and receives research funding from Novartis, Roche, and Molecular Partners. The Tumor Profiler study is jointly funded by a public-private partnership involving F. Hoffmann-La Roche Ltd., ETH Zurich, University of Zurich, University Hospital Zurich, and University Hospital Basel., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
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27. CD39 + PD-1 + CD8 + T cells mediate metastatic dormancy in breast cancer.
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Tallón de Lara P, Castañón H, Vermeer M, Núñez N, Silina K, Sobottka B, Urdinez J, Cecconi V, Yagita H, Movahedian Attar F, Hiltbrunner S, Glarner I, Moch H, Tugues S, Becher B, and van den Broek M
- Subjects
- Animals, Antigens, CD metabolism, Apyrase metabolism, Breast Neoplasms pathology, Breast Neoplasms therapy, CD8-Positive T-Lymphocytes metabolism, Cell Line, Tumor, Humans, Immunotherapy, Lung immunology, Lung pathology, Mammary Neoplasms, Experimental pathology, Mammary Neoplasms, Experimental therapy, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, Knockout, Neoplasm Metastasis, Programmed Cell Death 1 Receptor metabolism, Mice, Antigens, CD immunology, Apyrase immunology, Breast Neoplasms immunology, CD8-Positive T-Lymphocytes immunology, Mammary Neoplasms, Experimental immunology, Programmed Cell Death 1 Receptor immunology
- Abstract
Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39
+ PD-1+ CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+ PD-1+ CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+ PD-1+ CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+ PD-1+ CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+ PD-1+ CD8+ T cell response that favors metastatic dormancy in the lungs.- Published
- 2021
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28. Differential PD-1/LAG-3 expression and immune phenotypes in metastatic sites of breast cancer.
- Author
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Sobottka B, Moch H, and Varga Z
- Subjects
- Aged, Antigens, CD genetics, Breast Neoplasms genetics, Breast Neoplasms mortality, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Female, Gene Expression, Humans, Immunophenotyping, Middle Aged, Neoplasm Grading, Neoplasm Staging, Prognosis, Programmed Cell Death 1 Receptor genetics, T-Lymphocyte Subsets, Lymphocyte Activation Gene 3 Protein, Antigens, CD metabolism, Biomarkers, Tumor, Breast Neoplasms metabolism, Breast Neoplasms pathology, Programmed Cell Death 1 Receptor metabolism
- Abstract
Background: A dual blockade against the novel immune checkpoint inhibitor lymphocyte activation gene-3 (LAG-3) and programmed cell death protein-1 (PD-1) is currently considered in advanced breast cancer. Nevertheless, PD-1 or LAG-3 expression within distant metastatic breast cancer tissue remains understudied., Methods: To address this knowledge gap, we investigated the PD-1 and LAG-3 expression in combination with the CD8-based immune phenotype in intrapatient matched primary tumor distant metastases, representing 95 breast cancer patients with metastases occurring at four different anatomical locations. The immune phenotype was categorized into 2 categories: inflamed corresponding to the clinical category "hot" and exhausted or desert consistent with clinically "cold" tumors., Results: Metastases of "cold" primary tumors always remained "cold" at their matched metastatic site. Expression of PD-1/LAG-3 was associated with a "hot" immune phenotype in both the primary tumors and metastases. We could not observe any association between the immune phenotype and the breast cancer molecular subtype. Brain and soft tissue metastases were more commonly inflamed with signs of exhaustion than other anatomical sites of metastases. Taken together, (i) the immune phenotype varied between sites of distant metastases, and (ii) PD-1
+ /LAG-3+ was strongly associated with a "hot" immune phenotype and (iii) was most prevalent in brain and soft tissue metastases among distant metastases., Conclusions: Our data strongly support an integrated analysis of the immune phenotype together with the PD-1/LAG-3 expression in distant metastases to identify patients with inflamed but exhausted tumors. This may eventually improve the stratification and likelihood for advanced breast cancer patients to profit from immunotherapy.- Published
- 2021
- Full Text
- View/download PDF
29. Somatic BRCA1 mutations in clinically sporadic breast cancer with medullary histological features.
- Author
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Rechsteiner M, Dedes K, Fink D, Pestalozzi B, Sobottka B, Moch H, Wild P, and Varga Z
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Codon, Terminator, Female, Frameshift Mutation, Genetic Predisposition to Disease genetics, High-Throughput Nucleotide Sequencing methods, Humans, Middle Aged, Retrospective Studies, BRCA1 Protein genetics, Breast Neoplasms genetics, Mutation
- Abstract
Background: The role of somatic BRCA1/2 gene mutations in breast cancer is getting increasing attention in view of hereditary disease. The medullary phenotype and triple negative intrinsic subtypes are often, but not exclusively encountered in BRCA1 germline mutated breast cancer, whilst for BRCA2, no association to specific histological features are known. In this study, we addressed the relationship between morphological medullary phenotype and BRCA1/2 somatic mutations in breast cancer without known positive family anamnesis., Methods: 32 clinically sporadic breast cancers with medullary features were analyzed for somatic BRCA1/2 mutations (all coding exons) with next-generation sequencing technology. Paraffin-embedded formalin-fixed breast cancer samples from all patients were analyzed., Results: Three of 32 tumors (9%) had pathogenic (ARUP class-5) BRCA1 gene alterations. Two of these pathogenic variants exhibited deletions leading to frameshift mutations (p.Glu23fs, p.Val1234fs), and the remaining single-nucleotid-variant resulted in premature STOP codon (p.Glu60Ter). In one patient, the same pathogenic BRCA1 mutation was detected (p.Glu23fs) in normal breast tissue. Retrospective follow-up in two patients revealed a positive family history for breast cancer and consecutive germline mutation testing confirmed presence of BRCA1 mutations. No somatic pathogenic BRCA2 mutations were detected., Conclusions: BRCA1 mutation testing may be useful in clinically sporadic breast cancer patients with medullary features to identify potential mutation carriers independently from intrinsic molecular subtype. Formalin-fixed paraffin-embedded cancer tissue can undergo testing within a routine molecular-diagnostic setting as a clinical BRCA1/2 mutation screening strategy.
- Published
- 2018
- Full Text
- View/download PDF
30. Tumor biomarker conversion between primary and metastatic breast cancer: mRNA assessment and its concordance with immunohistochemistry.
- Author
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Stefanovic S, Wirtz R, Deutsch TM, Hartkopf A, Sinn P, Varga Z, Sobottka B, Sotiris L, Taran FA, Domschke C, Hennigs A, Brucker SY, Sohn C, Schuetz F, Schneeweiss A, and Wallwiener M
- Abstract
Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests. This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1 , PGR , ERBB2 , and MKI67 and the reference genes B2M and CALM2 . Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients ( p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple-negative PTs ( p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ ESR1 (81%(κ 0.51) in PT and 84%(κ 0.34) in MT, PR/ PGR (70%(κ 0.10) in PT and 78% (κ -0.32) in MT), and for HER2/ ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor., Competing Interests: CONFLICTS OF INTEREST RMW is the founder and an employee of STRATIFYER Molecular Pathology GmbH and participated in developing the RT-qPCR system. All other authors declare that they have no competing interests.
- Published
- 2017
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31. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases.
- Author
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Sobottka B, Pestalozzi B, Fink D, Moch H, and Varga Z
- Abstract
Tumor infiltrating lymphocytes in primary breast cancer (TIL) are acknowledged measures of disease free survival (DFS) in adjuvant and neoadjuvant settings. Little is known about the biology of metastasis infiltrating lymphocytes (mTIL) although the local immunity of the metastatic site may critically influence the infiltrate composite. To address this question, we compared mTIL with their matched TIL in 87 breast cancer patients and their corresponding distant metastasis at four different anatomical locations. Sections of surgical specimen were immunohistochemically analyzed for CD4(+), CD8(+) and CD20(+) lymphocytes in three different tumor compartments: intratumoral lymphocytes (iTIL) defined as lymphocytes in direct contact with breast cancer cells, stromal lymphocytes (sTIL) located within the intratumoral stromal tissue and invasive-margin lymphocytes (imTIL). Overall, we found fewer (p < 0.001) mTIL than TIL. Within the tumor compartments, imTIL were more frequent than sTIL and iTIL both within metastases and the matched primary tumors (PT) (p < 0.001). CD4(+) T cells were more numerous than CD8(+) T cells and CD20(+) B cells (p < 0.001). There was a similar pattern in PT and their corresponding metastasis. Only patients with brain metastases differed from the others displaying less CD20(+) B cells at the infiltrative margin of the PT (p < 0.05). In summary, mTIL were significantly reduced within metastases but still mirrored the infiltrate pattern of the PT, interestingly regardless of the metastatic anatomical locations investigated. Our results suggest that the PT assigns the infiltrating lymphocyte pattern resumed at the metastatic site.
- Published
- 2016
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32. Primary oligodendrocyte death does not elicit anti-CNS immunity.
- Author
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Locatelli G, Wörtge S, Buch T, Ingold B, Frommer F, Sobottka B, Krüger M, Karram K, Bühlmann C, Bechmann I, Heppner FL, Waisman A, and Becher B
- Subjects
- Animals, Cell Death immunology, Cells, Cultured, Gene Knock-In Techniques, Mice, Mice, Transgenic, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Oligodendroglia immunology, Oligodendroglia pathology
- Abstract
Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes. However, even conditions favoring autoimmunity-bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies-did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.
- Published
- 2012
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33. CNS live imaging reveals a new mechanism of myelination: the liquid croissant model.
- Author
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Sobottka B, Ziegler U, Kaech A, Becher B, and Goebels N
- Subjects
- Animals, Axons chemistry, Axons ultrastructure, Cell Differentiation physiology, Cerebellum ultrastructure, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal methods, Microscopy, Electron methods, Myelin Sheath chemistry, Myelin Sheath ultrastructure, Nerve Fibers, Myelinated chemistry, Nerve Fibers, Myelinated ultrastructure, Neurogenesis physiology, Organ Culture Techniques methods, Time-Lapse Imaging methods, Axons physiology, Cerebellum growth & development, Models, Neurological, Myelin Sheath physiology, Nerve Fibers, Myelinated physiology
- Abstract
The overall morphology and with it associated the formation of myelin is generally thought to be resolved. Based on electron microscopic findings more than half a century ago, the current model of myelination describes all myelin membranes to run in parallel with the longitudinal axis of the axon and to form a smooth surface, reminiscent of a rolled up carpet. However, different studies in the past demonstrated a distinct myelin morphology with an uneven myelin surface contour that challenges the established concept. Even though the current model of myelination has since been recognized as insufficient, CNS myelin formation has not yet been investigated in real-time with the requisite technique and resolution. We therefore traced myelin growth in murine organotypic cerebellar slice cultures using high-resolution confocal live imaging, light and electron microscopy and assessed myelin morphology in young and adult mice by confocal microscopy. Our data verify that the myelin surface is indeed not smooth but runs in a bidirectional, regularly spaced coil along the axon in both young and adult mice. Time-lapse imaging revealed that the growth of coiled myelin turns emerges during myelin formation. We therefore propose the "liquid croissant" model as a new concept of myelination that overcomes not only some of the incongruences of previous myelination theories, but potentially also explains the development of certain myelin pathologies observed in remyelination and axonopathies., (Copyright © 2011 Wiley‐Liss, Inc.)
- Published
- 2011
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34. Separation of fast from slow anabolism by site-specific PEGylation of insulin-like growth factor I (IGF-I).
- Author
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Metzger F, Sajid W, Saenger S, Staudenmaier C, van der Poel C, Sobottka B, Schuler A, Sawitzky M, Poirier R, Tuerck D, Schick E, Schaubmar A, Hesse F, Amrein K, Loetscher H, Lynch GS, Hoeflich A, De Meyts P, and Schoenfeld HJ
- Subjects
- Animals, Cell Line, Dogs, Half-Life, Humans, Hypoglycemia chemically induced, Hypoglycemia metabolism, Insulin-Like Growth Factor Binding Proteins metabolism, Insulin-Like Growth Factor I chemistry, Insulin-Like Growth Factor I pharmacology, Muscle, Skeletal pathology, Musculoskeletal Diseases metabolism, Musculoskeletal Diseases pathology, Polyethylene Glycols chemistry, Polyethylene Glycols pharmacology, Receptor, Insulin metabolism, Insulin-Like Growth Factor I pharmacokinetics, Muscle, Skeletal metabolism, Musculoskeletal Diseases drug therapy, Polyethylene Glycols pharmacokinetics, Receptor, Insulin agonists
- Abstract
Insulin-like growth factor I (IGF-I) has important anabolic and homeostatic functions in tissues like skeletal muscle, and a decline in circulating levels is linked with catabolic conditions. Whereas IGF-I therapies for musculoskeletal disorders have been postulated, dosing issues and disruptions of the homeostasis have so far precluded clinical application. We have developed a novel IGF-I variant by site-specific addition of polyethylene glycol (PEG) to lysine 68 (PEG-IGF-I). In vitro, this modification decreased the affinity for the IGF-I and insulin receptors, presumably through decreased association rates, and slowed down the association to IGF-I-binding proteins, selectively limiting fast but maintaining sustained anabolic activity. Desirable in vivo effects of PEG-IGF-I included increased half-life and recruitment of IGF-binding proteins, thereby reducing risk of hypoglycemia. PEG-IGF-I was equipotent to IGF-I in ameliorating contraction-induced muscle injury in vivo without affecting muscle metabolism as IGF-I did. The data provide an important step in understanding the differences of IGF-I and insulin receptor contribution to the in vivo activity of IGF-I. In addition, PEG-IGF-I presents an innovative concept for IGF-I therapy in diseases with indicated muscle dysfunction.
- Published
- 2011
- Full Text
- View/download PDF
35. Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss.
- Author
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Sobottka B, Harrer MD, Ziegler U, Fischer K, Wiendl H, Hünig T, Becher B, and Goebels N
- Subjects
- Animals, Autoantigens immunology, Axons immunology, Axons pathology, Mice, Mice, Transgenic, Multiple Sclerosis etiology, Multiple Sclerosis pathology, Oligodendroglia immunology, Oligodendroglia pathology, Oligodendroglia ultrastructure, Organ Culture Techniques, Autoimmunity, CD8-Positive T-Lymphocytes immunology, Central Nervous System immunology, Central Nervous System pathology, Cytotoxicity, Immunologic, Multiple Sclerosis immunology, Myelin Sheath immunology, Myelin Sheath pathology
- Abstract
Permanent disability of patients suffering from central nervous system (CNS) inflammation such as multiple sclerosis, the most common chronic inflammatory disorder of the CNS, originates mainly from demyelination and axonal damage. Although many studies in the past focused on the role of CD4(+) T cells, several recent findings postulate the relevance of autoaggressive, cytotoxic CD8(+) T cells in the effector phase of multiple sclerosis. Yet, it remains unresolved whether axonal injury is the result of a CD8(+) T cell-targeted hit against the axon itself or the consequence of an attack against the myelin structure. To address this issue of CD8-mediated tissue damage in CNS inflammation, we performed continuous confocal imaging of autoaggressive, cytotoxic CD8(+) T cells in living organotypic cerebellar brain slices. We observed that loading brain slices with the cognate peptide antigen caused CD8-mediated damage of myelinated axons. To exclude the possibility that the cognate peptide loaded onto the brain slices was presented by axons directly, we restricted the cognate antigen expression exclusively to the cytosol of oligodendrocytes. Aside from vast myelin damage, extensive axonal bystander injury occurred. Using this model system of inflammatory CNS injury, we visualize that axonal loss can be the consequence from "collateral bystander damage" by autoaggressive, cytotoxic CD8(+) T cells, targeting their cognate antigen processed and presented by oligodendrocytes.
- Published
- 2009
- Full Text
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36. ProNGF inhibits NGF-mediated TrkA activation in PC12 cells.
- Author
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Sobottka B, Reinhardt D, Brockhaus M, Jacobsen H, and Metzger F
- Subjects
- Animals, Caspases metabolism, Dose-Response Relationship, Drug, Drug Interactions, Mitogen-Activated Protein Kinase Kinases genetics, Mitogen-Activated Protein Kinase Kinases metabolism, Mutation, PC12 Cells, Rats, Receptor, trkA genetics, Signal Transduction drug effects, Time Factors, Transfection methods, Nerve Growth Factor pharmacology, Nerve Growth Factors pharmacology, Protein Precursors pharmacology, Receptor, trkA metabolism
- Abstract
Degeneration of cholinergic basal forebrain neurons (CBFN) is a hallmark in the pathology of Alzheimer's disease (AD). Critically depending upon the neurotrophic support through nerve growth factor (NGF), CBFN in the AD brain face elevated concentrations of the pro-form of NGF (proNGF) and suffer from an imbalance between TrkA and p75(NTR) expression. Research for the underlying mechanisms of CBFN death suggested a pro-apoptotic activity of proNGF. However, this finding could not be confirmed by all investigators and other studies even observed a neurotrophic function of proNGF. In the presence of these controversial findings we investigated the activity of proNGF in PC12 cells with specific emphasis on its neurotoxic versus neurotrophic action. In this study, we show that proNGF can mediate TrkA receptor signaling directly, yet in the manner of a partial agonist with a lower maximum activity than NGF. A pro-apoptotic activity of proNGF could not be confirmed in our cellular system. Interestingly and surprisingly, pre-incubation with proNGF at low, sub-active concentrations inhibited TrkA-mediated neurotrophic NGF signaling in PC12 cells. Our data support a novel hypothesis for the role of elevated proNGF levels in CBFN pathology in AD. Thus, proNGF can indirectly contribute to the slow neurodegeneration in AD by reducing NGF-mediated trophic support.
- Published
- 2008
- Full Text
- View/download PDF
37. [Carcinoma-associated retinopathy: a review with clinical examples].
- Author
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Sobottka B, Schlote T, Besch D, Djelebova T, Wilhelm H, and Zrenner E
- Subjects
- Aged, Autoantibodies blood, Breast Neoplasms diagnosis, Breast Neoplasms immunology, Calcium-Binding Proteins immunology, Carcinoma diagnosis, Carcinoma immunology, Diagnosis, Differential, Electroretinography, Female, Hippocalcin, Humans, Male, Middle Aged, Optic Neuritis diagnosis, Optic Neuritis immunology, Paraneoplastic Syndromes immunology, Recoverin, Retinal Diseases immunology, Uterine Neoplasms diagnosis, Uterine Neoplasms immunology, Eye Proteins, Lipoproteins, Nerve Tissue Proteins, Paraneoplastic Syndromes diagnosis, Retinal Diseases diagnosis
- Abstract
Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome. In this survey we report about two further patients with CAR, who were referred to the University Eye Hospital of Tuebingen within a few months. The most common primary tumor associated with CAR is small cell carcinoma of the lung. Case reports about rhabdomyosarcoma, carcinoma of the endometrium, prostate and mamma were also described. The exact pathogenesis of CAR is still unknown. Specific autoantibodies were found against the photoreceptor protein recovering (23-kd retinal CAR antigen). However, this reaction is not present in all patients, and probably other antigens are also involved. Most of the patients experience symptoms of CAR before the primary tumor is detected. Besides glare sensitivity and flashing lights, a rapidly progressive, often asymmetric visual loss may occur. Although paracentral and mid-peripheral scotomas can be found frequently, visual field defects are often quite heterogeneous. Typically, the responses in the electroretinogram (ERG) are markedly reduced, but normal ERGs were also described. The fundus picture in CAR shows sheathing of the retinal vessels, narrowing of the arterioles and clumbing of the retinal pigment epithelium. The prognosis is poor. Frequently there is progression to bilateral loss of vision within a few months. Treatment of the primary tumor does not seem to alter the ocular prognosis. Systemic corticosteroids may be helpful in some patients. Nevertheless, no proven therapeutic regimen is currently available.
- Published
- 2000
- Full Text
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38. Cataract surgery at the end of the 19th century at Tübingen.
- Author
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Schlote T, Sobottka B, Kreutzer B, Thiel HJ, and Rohrbach JM
- Subjects
- Cataract Extraction methods, Germany, History, 19th Century, Humans, Cataract Extraction history
- Abstract
Cataract extraction with a Graefe knife incision was the most important development in cataract surgery during the 19th century. To determine the indications, visual outcome, complications, and problems of cataract surgery performed a century ago, we reviewed patient records from the year 1895. With use of Graefe's technique of cataract extraction, the early postoperative visual acuity was 20/200 or better in 63% and 20/40 or better in 5%. A secondary cataract developed in about 30% of eyes. A flat anterior chamber persisted for more than two days in about 20% of eyes. Astigmatism was not regularly measured, but was markedly increased after surgery. Surgery for secondary cataract was performed in only 20 eyes. There was a complication rate of nearly 50% in secondary cataracts. These results demonstrate some of the major problems of cataract surgery 100 years ago: secondary cataract, insufficient wound closure, high astigmatism, and aphakia as a refractive problem.
- Published
- 1997
- Full Text
- View/download PDF
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