32 results on '"Pelusi N."'
Search Results
2. The appeal of the bad boy.
- Author
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Pelusi N
- Published
- 2009
3. Good girls, bad girls.
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Pelusi N
- Published
- 2008
4. An outsize appetite, courtesy of evolution.
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Pelusi N
- Published
- 2008
5. Love's plan B.
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Pelusi N
- Published
- 2008
6. The ups and downs of ambition.
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Pelusi N
- Published
- 2008
7. Desperation with a difference.
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Pelusi N
- Published
- 2008
8. No shame on you.
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Pelusi N
- Published
- 2008
9. Grand inquisitor.
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Pelusi N
- Published
- 2008
10. The privacy paradox.
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Pelusi N
- Published
- 2007
11. When to choose is to lose.
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Pelusi N
- Published
- 2007
12. The lure of laziness.
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Pelusi N
- Published
- 2007
13. Clinging to your crew.
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Pelusi N
- Published
- 2007
14. Solutions. Getting a grip on the greenback.
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Pelusi N
- Published
- 2007
15. Parents and children in conflict.
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Pelusi N
- Published
- 2007
16. Injustice collecting:.
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Pelusi N
- Published
- 2006
17. Dealing with difficult people: our immediate urge is to jump to our own defense, but today there are smarter moves, says Nando Pelusi, Ph.D.
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Pelusi N
- Published
- 2006
18. Jealousy: a voice of possessiveness past.
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Pelusi N
- Published
- 2006
19. The right way to rock the boat.
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Pelusi N
- Published
- 2006
20. What would Freud watch? Psychology goes prime time.
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Pelusi N, Toub M, Ryan C, and Sherman M
- Published
- 2010
21. Robert Schimmel on sex and survival.
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Pelusi N
- Published
- 2008
22. Final analysis. Albert Ellis on confidence.
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Pelusi N
- Published
- 2007
23. TargetPlex FFPE-Direct DNA Library Preparation Kit for SiRe NGS panel: An international performance evaluation study
- Author
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Giancarlo Troncone, Carlos E. de Andrea, Francesco Pepe, Giovanni Tallini, Maria D. Lozano, Paul Hofman, Verena Tischler, Natalie Pelusi, Roberta Sgariglia, Sabine Merkelbach-Bruse, Pasquale Pisapia, Sara Vander Borght, Janna Siemanowski, Daniela Cabibi, Marta Castiglia, Javier Freire, Dario de Biase, Spasenija Savic, Gabriella Fontanini, Antonio Russo, Reinhard Büttner, Lukas Bubendorf, Birgit Weynand, Catherine I. Dumur, Marius Ilie, Umberto Malapelle, Tom Xu, Roberto Pappesch, Michel Bilh, Valerio Gristina, Gianluca Roma, Massimo Barberis, Mariantonia Nacchio, Malapelle U., Pepe F., Pisapia P., Sgariglia R., Nacchio M., Barberis M., Bilh M., Bubendorf L., Buttner R., Cabibi D., Castiglia M., De Andrea C.E., De Biase D., Dumur C.I., Fontanini G., Freire J., Gristina V., Hofman P., Ilie M., Lozano M.D., Merkelbach-Bruse S., Pappesch R., Pelusi N., Roma G., Russo A., Savic S., Siemanowski J., Tallini G., Tischler V., Vander Borght S., Weynand B., Xu T., Troncone G., Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Sgariglia, Roberta, Nacchio, Mariantonia, Barberis, Massimo, Bilh, Michel, Bubendorf, Luka, Büttner, Reinhard, Cabibi, Daniela, Castiglia, Marta, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Fontanini, Gabriella, Freire, Javier, Gristina, Valerio, Hofman, Paul, Ilie, Mariu, Lozano, Maria Dolore, Merkelbach-Bruse, Sabine, Pappesch, Roberto, Pelusi, Natalie, Roma, Gianluca, Russo, Antonio, Savic, Spasenija, Siemanowski, Janna, Tallini, Giovanni, Tischler, Verena, Vander Borght, Sara, Weynand, Birgit, Xu, Tom, and Troncone, Giancarlo
- Subjects
0301 basic medicine ,Library ,Computer science ,Genomics ,Computational biology ,lung neoplasms ,DNA sequencing ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Humans ,molecular biology ,molecular ,biomarkers ,pathology ,tumour ,Gene Library ,Paraffin Embedding ,Sire ,Clinical performance ,High-Throughput Nucleotide Sequencing ,General Medicine ,DNA extraction ,Paraffin embedded ,lung neoplasm ,030104 developmental biology ,Workflow ,030220 oncology & carcinogenesis ,Mutation ,biomarker - Abstract
AimNext generation sequencing (NGS) represents a key diagnostic tool to identify clinically relevant gene alterations for treatment-decision making in cancer care. However, the complex manual workflow required for NGS has limited its implementation in routine clinical practice. In this worldwide study, we validated the clinical performance of the TargetPlex FFPE-Direct DNA Library Preparation Kit for NGS analysis. Impressively, this new assay obviates the need for separate, labour intensive and time-consuming pre-analytical steps of DNA extraction, purification and isolation from formalin-fixed paraffin embedded (FFPE) specimens in the NGS workflow.MethodsThe TargetPlex FFPE-Direct DNA Library Preparation Kit, which enables NGS analysis directly from FFPE, was specifically developed for this study by TargetPlex Genomics Pleasanton, California. Eleven institutions agreed to take part in the study coordinated by the Molecular Cytopathology Meeting Group (University of Naples Federico II, Naples, Italy). All participating institutions received a specific Library Preparation Kit to test eight FFPE samples previously assessed with standard protocols. The analytical parameters and mutations detected in each sample were then compared with those previously obtained with standard protocols.ResultsOverall, 92.8% of the samples were successfully analysed with the TargetPlex FFPE-Direct DNA Library Preparation Kit on Thermo Fisher Scientific and Illumina platforms. Altogether, in comparison with the standard workflow, the TargetPlex FFPE-Direct DNA Library Preparation Kit was able to detect 90.5% of the variants.ConclusionThe TargetPlex FFPE-Direct DNA Library Preparation Kit combined with the SiRe panel constitutes a convenient, practical and robust cost-saving solution for FFPE NGS analysis in routine practice.
- Published
- 2021
24. Balance.
- Author
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Garfinkel J, Sergo P, and Pelusi N
- Published
- 2007
25. Real-world data on the prevalence of BRCA1/2 and HRR gene mutations in patients with primary and metastatic castration resistant prostate cancer.
- Author
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Hommerding M, Hommerding O, Bernhardt M, Kreft T, Sanders C, Tischler V, Basitta P, Pelusi N, Wulf AL, Ohlmann CH, Ellinger J, Ritter M, and Kristiansen G
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- Aged, Aged, 80 and over, Humans, Male, Middle Aged, Genes, BRCA1, Genes, BRCA2, Mutation, Neoplasm Metastasis, Prevalence, BRCA1 Protein genetics, BRCA2 Protein genetics, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Purpose: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer., Methods: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2)., Results: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval., Conclusion: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment., (© 2024. The Author(s).)
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- 2024
- Full Text
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26. Mass Spectrometry-Based Profiling of Histone Post-Translational Modifications in Uveal Melanoma Tissues, Human Melanocytes, and Uveal Melanoma Cell Lines - A Pilot Study.
- Author
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Herwig-Carl MC, Sharma A, Tischler V, Pelusi N, Loeffler KU, Holz FG, Zeschnigk M, Landreville S, Auw-Haedrich C, Noberini R, and Bonaldi T
- Subjects
- Humans, Histones, Pilot Projects, Melanocytes metabolism, Cell Line, Mass Spectrometry, Melanoma metabolism, Uveal Neoplasms pathology
- Abstract
Purpose: Epigenetic alterations in uveal melanoma (UM) are still neither well characterized, nor understood. In this pilot study, we sought to provide a deeper insight into the possible role of epigenetic alterations in the pathogenesis of UM and their potential prognostic relevance. To this aim, we comprehensively profiled histone post-translational modifications (PTMs), which represent epigenetic features regulating chromatin accessibility and gene transcription, in UM formalin-fixed paraffin-embedded (FFPE) tissues, control tissues, UM cell lines, and healthy melanocytes., Methods: FFPE tissues of UM (n = 24), normal choroid (n = 4), human UM cell lines (n = 7), skin melanocytes (n = 6), and uveal melanocytes (n = 2) were analyzed through a quantitative liquid chromatography-mass spectrometry (LC-MS) approach., Results: Hierarchical clustering showed a clear separation with several histone PTMs that changed significantly in a tumor compared to normal samples, in both tissues and cell lines. In addition, several acetylations and H4K20me1 showed lower levels in BAP1 mutant tumors. Some of these changes were also observed when we compared GNA11 mutant tumors with GNAQ tumors. The epigenetic profiling of cell lines revealed that the UM cell lines MP65 and UPMM1 have a histone PTM pattern closer to the primary tissues than the other cell lines analyzed., Conclusions: Our results suggest the existence of different histone PTM patterns that may be important for diagnosis and prognosis in UM. However, further analyses are needed to confirm these findings in a larger cohort. The epigenetic characterization of a panel of UM cell lines suggested which cellular models are more suitable for epigenetic investigations.
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- 2024
- Full Text
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27. Evaluation of the effectiveness of a nationwide precision medicine program for patients with advanced non-small cell lung cancer in Germany: a historical cohort analysis.
- Author
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Kästner A, Kron A, van den Berg N, Moon K, Scheffler M, Schillinger G, Pelusi N, Hartmann N, Rieke DT, Stephan-Falkenau S, Schuler M, Wermke M, Weichert W, Klauschen F, Haller F, Hummel HD, Sebastian M, Gattenlöhner S, Bokemeyer C, Esposito I, Jakobs F, von Kalle C, Büttner R, Wolf J, and Hoffmann W
- Abstract
Background: The national Network Genomic Medicine (nNGM) Lung Cancer provides comprehensive and high-quality multiplex molecular diagnostics and standardized personalized treatment recommendation for patients with advanced non-small cell lung cancer (aNSCLC) in Germany. The primary aim of this study was to investigate the effectiveness of the nNGM precision medicine program in terms of overall survival (OS) using real-world data (RWD)., Methods: A historical nationwide cohort analysis of patients with aNSCLC and initial diagnosis between 04/2019 and 06/2020 was conducted to compare treatment and OS of patients with and without nNGM-participation. Patients participating within the nNGM (nNGM group) were selected based on a prospective nNGM database. The electronic health records (EHR) of the prospective nNGM database were case-specifically linked to claims data (AOK, German health insurance). The control group was selected from claims data of patients receiving usual care without nNGM-participation (non-nNGM group). The minimum follow-up period was six months., Findings: Overall, n = 509 patients in the nNGM group and n = 7213 patients in the non-nNGM group met the inclusion criteria. Patients participating in the nNGM had a significantly improved OS compared to the non-nNGM group (median OS: 10.5 months vs. 8.7 months, p = 0.008, HR = 0.84, 95% CI: 0.74-0.95). The 1-year survival rates were 46.8% (nNGM) and 41.3% (non-nNGM). The use of approved tyrosine kinase inhibitors (TKI) in the first-line setting was significantly higher in the nNGM group than in the non-nNGM group (nNGM: 8.4% (43/509) vs. non-nNGM: 5.1% (366/7213), p = 0.001). Overall, patients receiving first-line TKI treatment had significantly higher 1-year OS rates than patients treated with PD-1/PD-L1 inhibitors and/or chemotherapy (67.2% vs. 40.2%, p < 0.001)., Interpretation: This is the first study to demonstrate a significant survival benefit and higher utilization of targeted therapies for aNSCLC patients participating within nNGM. Our data indicate that precision medicine programs can enhance collaborative personalized lung cancer care and promote the implementation of treatment innovations and the latest scientific knowledge into clinical routine care., Funding: The study was funded by the AOK Federal Association Germany., Competing Interests: AKä, nvdB, KM, and WH declare financial support from the Federal Association of the AOK, Berlin, Germany (e.g., for performing the analyses and writing the manuscript), as stated in the manuscript. MSche received institutional grants from Amgen, Bristol Myers Squibb, Dracen Pharmaceuticals Inc., Janssen, Novartis, Siemens Healthineers, personal consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, Siemens Healthineers and Takeda, honoraria or payment for educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Pfizer, Sanofi-Aventis and Takeda; received support for attending meetings and/or travel from Boehringer Ingelheim, Janssen, Pfizer, AstraZeneca; and reports participation on a Data Safety Monitoring Board at Boehringer Ingelheim, a leadership or fiduciary role (unpaid) at the ESMO Lung Cancer Faculty, ESMO Climate Change Task Force and the EORTC Lung Cancer group. DTR received payment or honoraria from Roche (Bristol Myers Squibb), Bayer and Lilly for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Bayer. MSchu received institutional grants from AstraZeneca and Bristol Myers Squibb, consulting fees from Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi-Aventis and Takeda, payment or honoraria from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Roche, Sanofi-Aventis for lectures, presentations, speakers’ bureaus, manuscript writing or educational events; received support for attending meetings and/or travel from Janssen, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Novartis, Amgen; and participated in Data Safety Monitoring Boards or Advisory Boards at Amgen, Bristol-Myers Squibb, Novartis, Sanofi-Aventis, Janssen, Tacalyx, Abalos and GlaxoSmithKline. MW received institutional grants from Roche, personal consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Amgen, Immatics, Bayer and ImCheck Therapeutics, payment or honoraria for educational events from Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT-TUD GmbH, Amgen and Novartis; he received support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Janssen, Amgen, GEMoaB, Sanofi-Aventis, Immatics, Merck Serono and Daiichi Sankyo and honoraria for participation in a Data Safety Monitoring Board or Advisory Board of ISA Pharmaceuticals. FK received payment or honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Lilly, Agilent, Bayer, Merck and Trillium for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and is a board member at the National Pathologists’ Association Germany; and received personal honoraria for lectures by AstraZeneca and Novartis and participated in an advisory board by AstraZeneca. MSe received grants from AstraZeneca and consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, Merck-Serono and GSK; received payment or honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, CureVac, BioNTech, Merck-Serono, GSK, Daiichi and Pfizer for lectures, presentations, speakers’ bureaus, manuscript writing or educational events; and received support for attending meetings and/or travel from Pfizer, Bristol-Myers Squibb and participated in a Data Safety Monitoring Board at Amgen. CB received consulting fees from the AOK NRW-Hamburg, and honoraria for participation in a Data Safety Monitoring Board or Advisory Board of AstraZeneca, Bayer Healthcare, Bristol Myers Squibb, Janssen-Cilag, Merck Serono and Sanofi-Aventis; received payment or honoraria for lectures given for Bristol Myers Squibb, Roche Pharma and Sanofi-Aventis; and received support for attending meetings and/or travel from Sanofi-Aventis, Janssen-Cilag and has an unpaid leadership or fiduciary role at DGHO, DKG-Zertifizierungskommission and CCC Netzwerk. RB received payment or honoraria for lectures and participation in advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Qiagen, Pfizer, Roche and Targos MP Inc.; and reports a leadership or fiduciary role as co-founder and co-owner of Gnothis Inc (SE) and Timer Therapeutics Inc (GE). JW received funding from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. The remaining authors declare no conflict of interest., (© 2023 The Author(s).)
- Published
- 2023
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28. Inflammatory fibroid polyp of the renal pelvis: first report at an extra-gastrointestinal site with molecular confirmation.
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Nagy D, Ellinger J, Ritter M, Pelusi N, and Kristiansen G
- Subjects
- Female, Humans, Aged, Kidney Pelvis pathology, Polyps genetics, Polyps pathology, Gastrointestinal Neoplasms pathology, Leiomyoma pathology
- Abstract
Inflammatory fibroid polyps (IFP) are rare and benign mesenchymal tumours of the gastrointestinal tract. They are submucosal spindle cell lesions with an eosinophilic-rich inflammatory infiltrate and mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. In this report, we present the case of a 74-year-old female with a solid tumour of the kidney, which presented as a bland proliferation of spindle cells with thin-walled blood vessels and an inflammatory infiltrate with eosinophilic granulocytes. Immunohistochemistry revealed a positivity for vimentin and a weak staining for CD99 and CD34 in the spindle cells. Because of the morphological similarity to IFPs of the gastrointestinal tract, a molecular pathology analysis was performed. This identified an oncogenic mutation in exon 18 of the PDGFRA gene, which is characteristic for inflammatory fibroid polyps of the gastrointestinal tract. To the best of our knowledge, this is the first case of an IFP in the urogenital tract., (© 2023. The Author(s).)
- Published
- 2023
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29. TargetPlex FFPE-Direct DNA Library Preparation Kit for SiRe NGS panel: an international performance evaluation study.
- Author
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Malapelle U, Pepe F, Pisapia P, Sgariglia R, Nacchio M, Barberis M, Bilh M, Bubendorf L, Büttner R, Cabibi D, Castiglia M, De Andrea CE, de Biase D, Dumur CI, Fontanini G, Freire J, Gristina V, Hofman P, Ilie M, Lozano MD, Merkelbach-Bruse S, Pappesch R, Pelusi N, Roma G, Russo A, Savic S, Siemanowski J, Tallini G, Tischler V, Vander Borght S, Weynand B, Xu T, and Troncone G
- Subjects
- Gene Library, Humans, Mutation, Paraffin Embedding, Genomics, High-Throughput Nucleotide Sequencing methods
- Abstract
Aim: Next generation sequencing (NGS) represents a key diagnostic tool to identify clinically relevant gene alterations for treatment-decision making in cancer care. However, the complex manual workflow required for NGS has limited its implementation in routine clinical practice. In this worldwide study, we validated the clinical performance of the TargetPlex FFPE-Direct DNA Library Preparation Kit for NGS analysis. Impressively, this new assay obviates the need for separate, labour intensive and time-consuming pre-analytical steps of DNA extraction, purification and isolation from formalin-fixed paraffin embedded (FFPE) specimens in the NGS workflow., Methods: The TargetPlex FFPE-Direct DNA Library Preparation Kit, which enables NGS analysis directly from FFPE, was specifically developed for this study by TargetPlex Genomics Pleasanton, California. Eleven institutions agreed to take part in the study coordinated by the Molecular Cytopathology Meeting Group (University of Naples Federico II, Naples, Italy). All participating institutions received a specific Library Preparation Kit to test eight FFPE samples previously assessed with standard protocols. The analytical parameters and mutations detected in each sample were then compared with those previously obtained with standard protocols., Results: Overall, 92.8% of the samples were successfully analysed with the TargetPlex FFPE-Direct DNA Library Preparation Kit on Thermo Fisher Scientific and Illumina platforms. Altogether, in comparison with the standard workflow, the TargetPlex FFPE-Direct DNA Library Preparation Kit was able to detect 90.5% of the variants., Conclusion: The TargetPlex FFPE-Direct DNA Library Preparation Kit combined with the SiRe panel constitutes a convenient, practical and robust cost-saving solution for FFPE NGS analysis in routine practice., Competing Interests: Competing interests: UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Diaceutics, GSK, Merck and AstraZeneca, unrelated to the current work. LB is has a consulting or advisory role with AstraZeneca, AbbVie, Bayer, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Takeda and F. Hoffmann-La Roche, and has received research funding (institution) from F. Hoffmann-La Roche, MSD and Sanofi. PH reports personal fees (as advisor) from Roche, Astrazeneca, BMS, MSD, Pfizer, Bayer, Amgen, Illumina, Qiagen, Thermo Fisher Scientific, Biocartis, Ed Lilly, unrelated to the current work. MI reports personal fees (as speaker bureau) from Roche, Merck & Co, AstraZeneca, Bristol-Myers Squibb and Boehringer-Ingelheim, unrelated to the current work. GR is the coinventor of the intellectual property used in the background noise suppression aspects of the TargePlex FFPE-Direct NGS Library Preparation Kit developed in collaboration with SenseCare Medicals. AR reports personal fees from Bristol, Pfizer, Bayer, Kyowa Kirin, Ambrosetti for advisory board activity and speaker honorarium from Roche Diagnostic speaker honorarium, unrelated to the submitted work. SS received personal fees from MSD, Astra Zeneca, Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb and Thermo Fisher Scientific, unrelated to the submitted work. TX is an employee and affiliate with SenseCare Medicals. GTroncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer and Bayer, unrelated to the current work.The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
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30. Cultivation of Clear Cell Renal Cell Carcinoma Patient-Derived Organoids in an Air-Liquid Interface System as a Tool for Studying Individualized Therapy.
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Esser LK, Branchi V, Leonardelli S, Pelusi N, Simon AG, Klümper N, Ellinger J, Hauser S, Gonzalez-Carmona MA, Ritter M, Kristiansen G, Schorle H, Hölzel M, and Toma MI
- Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer accounting for 80% of all renal cancers as well as the majority of renal cancer-associated deaths. During the last decade, the treatment paradigm for ccRCC has radically changed. In particular, the recent development of immune checkpoint inhibitors (ICI) has led to an increased overall survival in the metastatic setting. Moreover, novel immune therapies targeting the tumor microenvironment have been developed. In this rapidly evolving treatment landscape, precise tools for personalized cancer therapy are needed. Here, we collected fresh tissue from 42 patients who underwent surgical resection for renal cell carcinoma. Part of the tissue was used to obtain formalin-fixed, paraffin-embedded samples or RNA. The remaining tissue was minced and cultured in a collagen-based three-dimensional, air-liquid interface (ALI) culture system. The generated patient-derived tumor organoids (ALI PDOs) were characterized by immunohistochemistry staining and RNA sequencing to validate their close similarity to the matched tumor. Immune cells and stromal cells within the microenvironment could be identified. Finally, we treated 10 ALI PDOs with the commonly used targeted cancer drug cabozantinib or the ICI nivolumab. Interestingly, we observed varying responses of ALI PDOs to these treatments and future studies are needed to investigate whether the ALI PDO approach could inform about treatment responses in patients. In conclusion, this three-dimensional ccRCC culture model represents a promising, facile tool for monitoring tumor responses to different types of therapies in a controlled manner, yet, still preserves the key features of the tumor of origin., (Copyright © 2020 Esser, Branchi, Leonardelli, Pelusi, Simon, Klümper, Ellinger, Hauser, Gonzalez-Carmona, Ritter, Kristiansen, Schorle, Hölzel and Toma.)
- Published
- 2020
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31. Persistent Human KIT Receptor Signaling Disposes Murine Placenta to Premature Differentiation Resulting in Severely Disrupted Placental Structure and Functionality.
- Author
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Kaiser F, Hartweg J, Jansky S, Pelusi N, Kubaczka C, Sharma N, Nitsche D, Langkabel J, and Schorle H
- Subjects
- Animals, Female, Gene Expression Regulation, Developmental genetics, Humans, MAP Kinase Signaling System genetics, Mice, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Placenta metabolism, Placental Lactogen genetics, Pregnancy, Proto-Oncogene Proteins c-akt genetics, Trophoblasts pathology, Homeobox A10 Proteins genetics, Placentation genetics, Prolactin genetics, Proto-Oncogene Proteins c-kit genetics, Trophoblasts metabolism
- Abstract
Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KIT
D816V expression on placental development using a humanized mouse model. Placentas from KITD816V animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KITD816V -trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KITD816V -TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3-6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo.- Published
- 2020
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32. The spleen microenvironment influences disease transformation in a mouse model of KIT D816V -dependent myeloproliferative neoplasm.
- Author
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Pelusi N, Kosanke M, Riedt T, Rösseler C, Seré K, Li J, Gütgemann I, Zenke M, Janzen V, and Schorle H
- Subjects
- Animals, Bone Marrow Cells pathology, Bone Marrow Neoplasms blood, Cell Proliferation, Cell Transformation, Neoplastic genetics, Disease Models, Animal, Erythrocytes metabolism, Erythrocytes pathology, Fibrosis, GATA2 Transcription Factor metabolism, Gene Expression Regulation, Neoplastic, Hematopoiesis, Hematopoiesis, Extramedullary, Hematopoietic Stem Cells metabolism, Mice, Inbred C57BL, Phenotype, Polycythemia Vera genetics, Polycythemia Vera pathology, Signal Transduction, Spleen surgery, Splenomegaly pathology, Bone Marrow Neoplasms genetics, Bone Marrow Neoplasms pathology, Cell Transformation, Neoplastic pathology, Proto-Oncogene Proteins c-kit genetics, Spleen pathology, Tumor Microenvironment
- Abstract
Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KIT
D816V receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KITD816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KITD816V induction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KITD816V mutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis.- Published
- 2017
- Full Text
- View/download PDF
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