23 results on '"Hetzer, J."'
Search Results
2. PCR31 Assessment of Pain, Stiffness, and Physical Functioning Pre and During Burosumab Among Adults with X-Linked Hypophosphatemia: Results from a Multinational, Long-Term, Prospective Outcomes Disease Monitoring Program
- Author
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Yang, E., Chen, Z., Hetzer, J., Kruger, E., and Skrinar, A.
- Published
- 2023
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3. Notfallstrumektomie bei thyreotoxischer Krise mit Multiorganversagen
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Mödl, B., Pfafferott, C., Terfloth, R., Hitzler, H.-J., Wirtzfeld, A., Hetzer, J., and Linder, M. M.
- Published
- 1999
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4. 25 - CC-486 (Oral Azacitidine) Induces Responses in Patients with Hematological Malignancies Who had Failed Prior Treatment with Injectable Hypomethylating Agents (HMAS)
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Garcia-Manero, G., Savona, M.R., Gore, S.D., Scott, B.L., Cogle, C.R., Boyd, T., Conkling, P., Hetzer, J., Dong, Q., Kumar, K., Ukrainskyj, S.M., and Skikne, B.S.
- Published
- 2017
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5. Seifen, Waschmittel
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Cox, H. E., Evers, N., Hetzer, J., Smither, F. W., Divine, R. E., Long, C. P., Sheely, M. L., Trevithick, H. P., Walker, P. H., Knigge, G., Bergell, C., Korennowa, A., Bolschakowa, M. T., Randa, E., Spasskij, N., Pleschkowa, S., Chernitschkina, A., American Chemical Society, and American Oil Chemist Society
- Published
- 1939
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6. Textilindustrie
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Cerbaro, E., Baroni, G., Cappelli, A., Tuffi, R., Ruthing, A., Christoph, H., and Hetzer, J.
- Published
- 1940
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7. 99 CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS)-DEFINED HIGHER-RISK MYELODYSPLASTIC SYNDROMES (MDS)
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Garcia-Manero, G., Savona, M.R., Gore, S.D., Cogle, C.R., Conkling, P., Hetzer, J., Dong, Q., Ukrainskyj, S.M., and Skikne, B.S.
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- 2015
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8. Chemische Grundlagen der Schaum-, Wasch-, Netz- und Dispergiermittel.
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Hetzer, J.
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- 1942
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9. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1.
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Gallage S, Ali A, Barragan Avila JE, Seymen N, Ramadori P, Joerke V, Zizmare L, Aicher D, Gopalsamy IK, Fong W, Kosla J, Focaccia E, Li X, Yousuf S, Sijmonsma T, Rahbari M, Kommoss KS, Billeter A, Prokosch S, Rothermel U, Mueller F, Hetzer J, Heide D, Schinkel B, Machauer T, Pichler B, Malek NP, Longerich T, Roth S, Rose AJ, Schwenck J, Trautwein C, Karimi MM, and Heikenwalder M
- Subjects
- Animals, Humans, Mice, Male, Intracellular Signaling Peptides and Proteins metabolism, Liver metabolism, Liver pathology, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Signal Transduction, Intermittent Fasting, PPAR alpha metabolism, Fasting, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Liver Neoplasms pathology, Liver Neoplasms metabolism, Mice, Inbred C57BL, Phosphoenolpyruvate Carboxykinase (GTP) metabolism
- Abstract
The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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10. Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.
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Giugliani R, Gonzalez-Meneses A, Scarpa M, Burton B, Wang R, Martins E, Oussoren E, Hennermann JB, Chabrol B, Grant CL, Sun A, Durand C, Hetzer J, Malkus B, Marsden D, and Merritt Ii JL
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- Humans, Male, Child, Preschool, Female, Child, Infant, Longitudinal Studies, Adolescent, Mucopolysaccharidosis VII drug therapy, Glucuronidase therapeutic use, Glucuronidase metabolism, Enzyme Replacement Therapy methods, Recombinant Proteins therapeutic use, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects
- Abstract
Background: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII., Methods: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022., Results: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died., Conclusions: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing., (© 2024. The Author(s).)
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- 2024
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11. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
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Funk MC, Gleixner JG, Heigwer F, Vonficht D, Valentini E, Aydin Z, Tonin E, Del Prete S, Mahara S, Throm Y, Hetzer J, Heide D, Stegle O, Odom DT, Feldmann A, Haas S, Heikenwalder M, and Boutros M
- Subjects
- Mice, Animals, Stem Cells, Phenotype, Inflammation, Intestines, Intestinal Mucosa
- Abstract
Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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12. Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer.
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Yousuf S, Qiu M, Voith von Voithenberg L, Hulkkonen J, Macinkovic I, Schulz AR, Hartmann D, Mueller F, Mijatovic M, Ibberson D, AlHalabi KT, Hetzer J, Anders S, Brüne B, Mei HE, Imbusch CD, Brors B, Heikenwälder M, Gaida MM, Büchler MW, Weigert A, Hackert T, and Roth S
- Subjects
- Humans, Multiomics, Single-Cell Analysis, Tumor Microenvironment, Pancreatic Neoplasms, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal therapy, Carcinoma, Pancreatic Ductal drug therapy, Immune System Diseases, Adenocarcinoma of Lung
- Abstract
Background & Aims: As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach., Methods: We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level., Results: We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition., Conclusions: Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia.
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Weber TJ, Imel EA, Carpenter TO, Peacock M, Portale AA, Hetzer J, Merritt JL, and Insogna K
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- Adult, Humans, Phosphates, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Familial Hypophosphatemic Rickets drug therapy, Genetic Diseases, X-Linked drug therapy
- Abstract
Context: Burosumab was developed as a treatment option for patients with the rare, lifelong, chronically debilitating, genetic bone disease X-linked hypophosphatemia (XLH)., Objective: Collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab., Methods: UX023-CL203 (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. The long-term UX023-CL203 study (January 5, 2015 through November 30, 2018) provided data up to 184 weeks. Participants in UX023-CL203 received burosumab based on the last dose in the prior KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12, burosumab could be titrated upward/downward to achieve fasting serum phosphate levels within the normal range. Primary objectives included long-term safety, the proportion of subjects achieving fasting serum phosphate in the normal range, changes in bone turnover markers, patient-reported outcomes for pain and stiffness, and measures of mobility., Results: Fasting serum phosphate levels at the midpoint of the dosing interval (2 weeks postdose, the time of peak effect) were within the normal range in 85% to 100% of subjects. Measures of phosphate metabolism and bone biomarkers generally improved with burosumab therapy, approaching or reaching their respective normal ranges by study end. Improvements in patient-reported outcomes and mobility were sustained throughout the observation period. No new safety findings emerged with longer-term burosumab treatment., Conclusion: These data support the conclusion that burosumab therapy may be a safe and effective long-term treatment option for adult patients with XLH., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2022
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14. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
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Crouchet E, Bandiera S, Fujiwara N, Li S, El Saghire H, Fernández-Vaquero M, Riedl T, Sun X, Hirschfield H, Jühling F, Zhu S, Roehlen N, Ponsolles C, Heydmann L, Saviano A, Qian T, Venkatesh A, Lupberger J, Verrier ER, Sojoodi M, Oudot MA, Duong FHT, Masia R, Wei L, Thumann C, Durand SC, González-Motos V, Heide D, Hetzer J, Nakagawa S, Ono A, Song WM, Higashi T, Sanchez R, Kim RS, Bian CB, Kiani K, Croonenborghs T, Subramanian A, Chung RT, Straub BK, Schuppan D, Ankavay M, Cocquerel L, Schaeffer E, Goossens N, Koh AP, Mahajan M, Nair VD, Gunasekaran G, Schwartz ME, Bardeesy N, Shalek AK, Rozenblatt-Rosen O, Regev A, Felli E, Pessaux P, Tanabe KK, Heikenwälder M, Schuster C, Pochet N, Zeisel MB, Fuchs BC, Hoshida Y, and Baumert TF
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- Animals, Carcinogenesis pathology, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Chemoprevention, Cohort Studies, Cyclic AMP metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Disease Models, Animal, Gene Expression Regulation, Neoplastic drug effects, HEK293 Cells, Hepacivirus physiology, Hepatitis C genetics, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Humans, Immunologic Surveillance drug effects, Inflammation pathology, Liver drug effects, Liver metabolism, Liver Cirrhosis pathology, Liver Neoplasms pathology, Macrophages drug effects, Macrophages metabolism, Macrophages pathology, Male, Mice, Knockout, Nizatidine pharmacology, Prognosis, Signal Transduction drug effects, Transcriptome genetics, Mice, Drug Discovery, Liver pathology, Models, Biological
- Abstract
Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2
+ , CLEC5Ahigh , MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., (© 2021. The Author(s).)- Published
- 2021
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15. Publisher Correction: Inhibition of LTβR signalling activates WNT-induced regeneration in lung.
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Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, Ertüz Z, Lopez MA, Ansari M, Strunz M, Mayr C, Angelidis I, Ciminieri C, Costa R, Kohlhepp MS, Guillot A, Günes G, Jeridi A, Funk MC, Beroshvili G, Prokosch S, Hetzer J, Verleden SE, Alsafadi H, Lindner M, Burgstaller G, Becker L, Irmler M, Dudek M, Janzen J, Goffin E, Gosens R, Knolle P, Pirotte B, Stoeger T, Beckers J, Wagner D, Singh I, Theis FJ, de Angelis MH, O'Connor T, Tacke F, Boutros M, Dejardin E, Eickelberg O, Schiller HB, Königshoff M, Heikenwalder M, and Yildirim AÖ
- Published
- 2021
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16. Inhibition of LTβR signalling activates WNT-induced regeneration in lung.
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Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, Ertüz Z, Lopez MA, Ansari M, Strunz M, Mayr C, Angelidis I, Ciminieri C, Costa R, Kohlhepp MS, Guillot A, Günes G, Jeridi A, Funk MC, Beroshvili G, Prokosch S, Hetzer J, Verleden SE, Alsafadi H, Lindner M, Burgstaller G, Becker L, Irmler M, Dudek M, Janzen J, Goffin E, Gosens R, Knolle P, Pirotte B, Stoeger T, Beckers J, Wagner D, Singh I, Theis FJ, de Angelis MH, O'Connor T, Tacke F, Boutros M, Dejardin E, Eickelberg O, Schiller HB, Königshoff M, Heikenwalder M, and Yildirim AÖ
- Subjects
- Adaptive Immunity, Aging metabolism, Alveolar Epithelial Cells cytology, Alveolar Epithelial Cells drug effects, Alveolar Epithelial Cells metabolism, Animals, Apoptosis drug effects, Emphysema metabolism, Female, Humans, Immunity, Innate, Lung metabolism, Lymphotoxin beta Receptor metabolism, Mice, Mice, Inbred C57BL, NF-kappa B metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Smoke adverse effects, Stem Cells drug effects, Stem Cells metabolism, Wnt Proteins metabolism, beta Catenin metabolism, Lung drug effects, Lung physiology, Lymphotoxin beta Receptor antagonists & inhibitors, Regeneration drug effects, Signal Transduction drug effects, Wnt Proteins agonists
- Abstract
Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures
1,2 , which are associated with severe chronic inflammatory diseases that span several organ systems3-6 . How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.- Published
- 2020
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17. Confronting an individual-based simulation model with empirical community patterns of grasslands.
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Taubert F, Hetzer J, Schmid JS, and Huth A
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- Population Dynamics, Grassland, Models, Statistical, Residence Characteristics
- Abstract
Grasslands contribute to global biogeochemical cycles and can host a high number of plant species. Both-species dynamics and biogeochemical fluxes-are influenced by abiotic and biotic environmental factors, management and natural disturbances. In order to understand and project grassland dynamics under global change, vegetation models which explicitly capture all relevant processes and drivers are required. However, the parameterization of such models is often challenging. Here, we report on testing an individual- and process-based model for simulating the dynamics and structure of a grassland experiment in temperate Europe. We parameterized the model for three species and confront simulated grassland dynamics with empirical observations of their monocultures and one two-species mixture. The model reproduces general trends of vegetation patterns (vegetation cover and height, aboveground biomass and leaf area index) for the monocultures and two-species community. For example, the model simulates well an average annual grassland cover of 70% in the species mixture (observed cover of 77%), but also shows mismatches with specific observation values (e.g. for aboveground biomass). By a sensitivity analysis of the applied inverse model parameterization method, we demonstrate that multiple vegetation attributes are important for a successful parameterization while leaf area index revealed to be of highest relevance. Results of our study pinpoint to the need of improved grassland measurements (esp. of temporally higher resolution) in close combination with advanced modelling approaches., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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18. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice.
- Author
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Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García-Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze-Bergkamen H, and Köhler BC
- Subjects
- Adolescent, Adult, Aged, Animals, Carbon Tetrachloride, Cell Nucleus, Cell Proliferation, Cells, Cultured, Cysteine Endopeptidases genetics, Deubiquitinating Enzyme CYLD, Dicarbethoxydihydrocollidine, Epithelial Cells metabolism, Female, Fibrosis, Gene Knockdown Techniques, Humans, Liver pathology, Liver Cirrhosis chemically induced, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Lymphotoxin beta Receptor agonists, Lymphotoxin-beta metabolism, Male, Mice, Middle Aged, Parenchymal Tissue pathology, Protein Transport, Proto-Oncogene Mas, RNA, Messenger metabolism, Transcription Factor RelB genetics, Young Adult, Bile Ducts metabolism, Bile Ducts pathology, Cholangitis, Sclerosing metabolism, Cytokines genetics, Liver Diseases metabolism, Transcription Factor RelB metabolism
- Abstract
Background & Aims: Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction., Methods: We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin β (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the cylindromatosis (CYLD) lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (Cyld
ΔLPC mice and Cyld/RelbΔLPC mice) and compared them with C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or standard chow diets to induce biliary injury or were given injections of CCl4 to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time polymerase chain reaction. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist, and transfected with small interfering RNAs to knock down RELB., Results: In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C virus, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts compared with control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated with exposure to LTB. The phenotype of CyldΔLPC mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/RelbΔLPC mice. Compared with livers from control mice, livers from CyldΔLPC mice (but not Cyld/RelbΔLPC mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and tumor necrosis factor superfamily [TNFSF] members TNFSF11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]) produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl4 exposure. CyldΔLPC mice and Cyld/RelbΔLPC mice had improved liver function on the DDC diet compared with control mice fed the DDC diet., Conclusion: Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in CyldΔLPC mice. Deletion of RELB and CYLD from LPCs protects mice from DDC-induced cholestatic liver fibrosis., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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19. CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes.
- Author
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de Lima M, Oran B, Champlin RE, Papadopoulos EB, Giralt SA, Scott BL, William BM, Hetzer J, Laille E, Hubbell B, Skikne BS, and Craddock C
- Subjects
- Adult, Aged, Allografts, Disease-Free Survival, Female, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Graft vs Host Disease prevention & control, Humans, Male, Middle Aged, Survival Rate, Azacitidine administration & dosage, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Maintenance Chemotherapy, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Myelodysplastic Syndromes therapy
- Abstract
Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.)., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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20. CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia.
- Author
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Garcia-Manero G, Scott BL, Cogle CR, Boyd TE, Kambhampati S, Hetzer J, Dong Q, Kumar K, Ukrainskyj SM, Beach CL, and Skikne BS
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Azacitidine adverse effects, Female, Hemorrhage blood, Hemorrhage chemically induced, Humans, Male, Middle Aged, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes pathology, Platelet Count, Thrombocytopenia blood, Thrombocytopenia pathology, Azacitidine administration & dosage, Myelodysplastic Syndromes drug therapy, Thrombocytopenia drug therapy
- Abstract
Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 10
9 /L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109 /L and 198 × 109 /L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 109 /L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, then increased thereafter. Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
21. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies.
- Author
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Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, Kumar K, Skikne B, and MacBeth KJ
- Subjects
- Administration, Oral, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic blood, Antimetabolites, Antineoplastic therapeutic use, Area Under Curve, Azacitidine blood, Azacitidine therapeutic use, DNA Methylation, Dose-Response Relationship, Drug, Drug Administration Schedule, Epigenesis, Genetic, Half-Life, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic mortality, Leukemia, Myelomonocytic, Chronic pathology, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes pathology, Survival Analysis, Antimetabolites, Antineoplastic pharmacokinetics, Azacitidine pharmacokinetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myelomonocytic, Chronic drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Unlabelled: CC-486 (oral azacitidine) is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05) reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle), with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle., Trial Registration: ClinicalTrials.gov NCT00528983.
- Published
- 2015
- Full Text
- View/download PDF
22. Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes.
- Author
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Seymour JF, Bennett JM, List AF, Mufti GJ, Gore SD, Fenaux P, Santini V, Hetzer J, Songer S, Skikne BS, and Beach CL
- Subjects
- Aged, Aged, 80 and over, Biopsy, Humans, Middle Aged, Myelodysplastic Syndromes mortality, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Bone Marrow pathology, Drug Tolerance, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes pathology
- Abstract
The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of <30% cellularity were considered hypocellular with data evaluable from 299 patients (azacitidine n = 154, CCR n = 145); 13% (n = 39) hypocellular, 87% (n = 260) non-hypocellular. Patient characteristics were balanced between cellularity and treatment groups. Most patients (90-100%) had 2-3 cytopenias at baseline. Median (range) azacitidine treatment cycle lengths were 35·5 (28-54) and 33·0 (15-75) d in hypocellular and non-hypocellular groups, respectively. At 33 months, median OS was not reached (NR) [95% confidence interval (CI): 19·2, NR] in hypocellular patients receiving azacitidine versus 16·9 months (95% CI: 11·1, 19·3) with CCR (P = 0·001); and in non-hypocellular patients, it was 21·1 months (95% CI: 16·2, 34·7) versus 15·3 months (95% CI: 9·3, 17·6) (P = 0·012). Azacitidine tolerance was similar regardless of cellularity. Grade 3-4 thrombocytopenia and neutropenia occurred similarly in hypocellular patients treated with azacitidine versus CCR (80% vs. 92% and 88% vs. 75%). Azacitidine OS results are consistent with those from AZA-001, regardless of cellularity, and demonstrate its safety and efficacy in higher-risk myelodysplasia with hypocellular BM., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
23. Cyclic-GMP enhances light-induced excitation and induces membrane currents in Drosophila retinal photoreceptors.
- Author
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Bacigalupo J, Bautista DM, Brink DL, Hetzer JF, and O'Day PM
- Subjects
- Animals, Cyclic GMP analogs & derivatives, Cyclic GMP pharmacology, Darkness, Drosophila, Electric Conductivity, Membranes physiology, Photoreceptor Cells, Invertebrate drug effects, Photoreceptor Cells, Invertebrate radiation effects, Photosensitizing Agents pharmacology, Pupa, Reaction Time, Retina drug effects, Retina physiology, Retina radiation effects, Cyclic GMP physiology, Light, Photoreceptor Cells, Invertebrate physiology
- Abstract
Phototransduction in the Drosophila retina appears to require the phosphoinositide signaling cascade following receptor/G-protein activation. Subsequent opening of membrane cationic channels causes excitation. The biochemical events underlying channel opening and regulation of sensitivity remain largely unknown. Evidence is mounting that phototransduction in Drosophila and other invertebrate species may additionally involve the second messenger, cyclic-GMP (cGMP). We report that exogenous cGMP influenced Drosophila retinal phototransduction in two ways. In whole cell tight-seal voltage-clamp experiments, membrane permeant cGMP analog, 8-bromo-cyclic-GMP (8-Br-cGMP), induced membrane currents and dramatically enhanced light-induced currents. The currents induced by 8-Br-cGMP possessed reversal potentials similar to those induced by light. The magnitudes of cGMP-induced currents exhibited marked dependence on intensity of background illumination. Potential direct or modulatory roles of cGMP in Drosophila phototransduction are discussed.
- Published
- 1995
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