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4 results on '"Philipp Rosenstiel"'

1. Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells

Author

Lisa-Marie Rieckmann, Michael Spohn, Lisa Ruff, David Agorku, Lisa Becker, Alina Borchers, Jenny Krause, Roisin O’Reilly, Jurek Hille, Janna-Lisa Velthaus-Rusik, Niklas Beumer, Armin Günther, Lena Willnow, Charles D. Imbusch, Peter Iglauer, Ronald Simon, Sören Franzenburg, Hauke Winter, Michael Thomas, Carsten Bokemeyer, Nicola Gagliani, Christian F. Krebs, Martin Sprick, Olaf Hardt, Sabine Riethdorf, Andreas Trumpp, Nikolas H. Stoecklein, Sven Peine, Philipp Rosenstiel, Klaus Pantel, Sonja Loges, and Melanie Janning

Subjects
Circulating tumor cells, Non-small cell lung cancer, Single cell RNA sequencing, Intratumor heterogeneity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA’s full potential, this study introduces a novel approach for CTC enrichment from DLAs. Methods DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. Results Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. Conclusions In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.

Published
2024
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2. Induction of periimplantitis in dental implants

Author

Olga Gavrilova, Benedicta Beck-Broichsitter, Stephan T. Becker, Jörg Wiltfang, Hendrik Bolte, Marc Föge, and Philipp Rosenstiel

Subjects
Male, X-ray microtomography, medicine.medical_treatment, Observation period, Dentistry, Pilot Projects, Oral cavity, Mice, Medicine, Animals, Ligature, Special diet, Ligation, Dental Implants, Titanium, business.industry, Dental Implantation, Endosseous, Histology, General Medicine, X-Ray Microtomography, Peri-Implantitis, Mice, Inbred C57BL, Disease Models, Animal, Otorhinolaryngology, Surgery, Implant, business
Abstract

Development, progression, and therapy of periimplantitis are nonresolved emerging problems. The aim of this pilot study was to establish a model for periimplantitis in mice to have a base for tests with immune-deficient knockout organisms to improve the knowledge about development and progression of periimplantitis and to develop further therapeutic options.In 8 mice, titanium implants were inserted in the median of the palate. Four of these implants had ligatures (periimplantitis group). After 2 weeks, the animals received a special diet enriched with sugar and flavor. After 9 weeks, micro-computed tomography (micro-CT) examinations to evaluate the periimplant tissue and histologies were performed.Dental implant insertions within the oral cavity are possible in living mice. Implants with ligatures showed significantly larger periimplant bone defects than controls. The radiologic findings were confirmed by histology. At the end of the observation period, the portion of implants lost was higher in the ligature group.This is the first publication to describe the insertion of dental implants in living mice. In addition, it is the first time that periimplant infection could be induced in that species. This model will pave the way to study knockout mice with reduced or even enhanced resistance to periimplantitis.

Published
2013

3. Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma

Author

Stefan Schreiber, Jo Vandesompele, Stefanie Schlierf, Philipp Rosenstiel, Alexander Schramm, Sven Rahmann, Pieter Mestdagh, Marcel Martin, Johannes H. Schulte, Theresa Thor, Tobias Marschall, and Angelika Eggert

Subjects
Small RNA, Molecular Sequence Data, BIOGENESIS, PATHOGENESIS, Medizin, Biology, Deep sequencing, Transcriptome, Neuroblastoma, microRNA, Gene expression, RNA Precursors, Genetics, Humans, TUMOR-SUPPRESSOR, Gene Library, Base Sequence, IDENTIFICATION, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Gene Expression Profiling, Chromosome Mapping, RNA, food and beverages, Biology and Life Sciences, MIRNA EXPRESSION, GENE, CANCER, Gene expression profiling, MicroRNAs, RNA editing, DISCOVERY, RNA Editing, STEM-CELLS
Abstract

Small non-coding RNAs, in particular microRNAs(miRNAs), regulate fine-tuning of gene expression and can act as oncogenes or tumor suppressor genes. Differential miRNA expression has been reported to be of functional relevance for tumor biology. Using next-generation sequencing, the unbiased and absolute quantification of the small RNA transcriptome is now feasible. Neuroblastoma(NB) is an embryonal tumor with highly variable clinical course. We analyzed the small RNA transcriptomes of five favorable and five unfavorable NBs using SOLiD next-generation sequencing, generating a total of > 188 000 000 reads. MiRNA expression profiles obtained by deep sequencing correlated well with real-time PCR data. Cluster analysis differentiated between favorable and unfavorable NBs, and the miRNA transcriptomes of these two groups were significantly different. Oncogenic miRNAs of the miR17-92 cluster and the miR-181 family were overexpressed in unfavorable NBs. In contrast, the putative tumor suppressive microRNAs, miR-542-5p and miR-628, were expressed in favorable NBs and virtually absent in unfavorable NBs. In-depth sequence analysis revealed extensive post-transcriptional miRNA editing. Of 13 identified novel miRNAs, three were further analyzed, and expression could be confirmed in a cohort of 70 NBs.

Published
2010

4. Regulation der proteolytischen Aktivität der Metalloproteasen Meprin α und Meprin β im Kontext pathologischer Konditionen

Author

Jäckle, Felix, Becker-Pauly, Christoph, Rosenstiel, Philip, Prof. Dr. Christoph Becker-Pauly, and Prof. Dr. Philipp Rosenstiel

Subjects
Inhibitoren, TMPRSS6, Abschlussarbeit, Enzymologie, Fibrose, Meprin β, Faculty of Medicine, Matriptase 2, Meprin α, doctoral thesis, Inhibition proteolytischer Aktivität, Metalloproteasen, Medizinische Fakultät, Astacin, Regulation proteolytischer Aktivität, Astacin, Degradom, Enzymologie, Fibrose, Inhibition proteolytischer Aktivität, Inhibitoren, Kollagen, Matriptase 2, Meprin α, Meprin β, Metalloproteasen, Proteolyse, Regulation proteolytischer Aktivität, TMPRSS6, TTSP, ddc:610, Degradom, Kollagen, ddc:6XX, Proteolyse, TTSP
Abstract

Meprin α und Meprin β sind Zink abhängige Metalloendoproteasen, die zur Astacin Peptidasenfamilie zählen. Meprine sind in humanen Pathologien wie Fibrose und der Generierung von Amyloid β Peptiden relevant. Um Meprine in Erkrankungen als therapeutische Moleküle einzusetzen, ist das Verständnis der Regulation ihrer proteolytischen Aktivität bedeutsam. Erstmals wurde in dieser Arbeit nachgewiesen, dass membrangebundenes Promeprin β nicht durch lösliche Proteasen aktiviert werden kann. Trypsin, der potenteste bekannte Meprin Aktivator, konnte membrangebundenes Promeprin β nicht maturieren. Somit bestätigte sich die initial aus der Meprin β Kristallstruktur entwickelte Hypothese, dass lösliche Aktivatoren keinen Zugang zur nahe der Zellmembran gelegenen Propeptid Spaltstelle erhalten und eine membrangebundene Protease zur Aktivierung notwendig ist. Es wurde Matriptase 2 als erster membrangebundener Aktivator von Promeprin β identifiziert. Dies wurde in Meprin β und Matriptase 2 Ko-Transfektionsansätzen mittels Immunoblots sowie Bestimmung der spezifischen proteolytischen Meprin β Aktivität an der Zelloberfläche validiert. Massenspektrometrische Untersuchungen identifizierten die Spaltstelle im Meprin β Propeptid an Position Arg 61/ Asn 62. In Überexpressionsstudien wurde die Kolokalisation von Meprin β und Matriptase 2 auf der Membran detektiert. Promeprin α wird nicht durch Matriptase 2 aktiviert. Zudem konnte von humanen Fibroblasten exprimiertes Prokollagen I als Meprin Substrat validiert werden. Deshalb wurde die proteolytische Meprin Aktivität mit selektierten Inhibitoren in humanen dermalen Fibroblasten reguliert. Dies resultierte in einer reduzierten Prokollagen I Maturierung im Zelllysat. Die Ergebnisse eröffnen interessante Perspektiven für zukünftige Forschungsprojekte. Es könnte die Beteiligung der Matriptase 2 bei Meprin β induzierten Pathologien und die Applikation selektiver Meprin Inhibitoren in geeigneten in vivo Fibrose Modellen analysiert werden.

Published
2018

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