7 results on '"Hetzer, J."'
Search Results
2. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1.
- Author
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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
- Full Text
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3. Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.
- Author
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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
- Subjects
- 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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4. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
- Author
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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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5. 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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6. Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia.
- Author
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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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7. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
- Author
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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
- Subjects
- 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
- Full Text
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