36 results on '"Michaelis, L."'
Search Results
2. P524: PHASE 1B/2 STUDY ON SAFETY, PK, PD, AND PRELIMINARY EFFICACY OF THE SELECTIVE SYK INHIBITOR LANRAPLENIB IN COMBINATION WITH THE FLT3 INHIBITOR GILTERITINIB, IN FLT3-MUTATED R/R AML (KB-LANRA 1001)
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Stein, E. M., primary, Patel, A., additional, Michaelis, L. C., additional, Schiller, G., additional, Swords, R., additional, Carvajal, L. A., additional, Bray, G., additional, DiMartino, J., additional, and Levy, M. Y., additional
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- 2022
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3. P35: ACID‐BASED FORMULA WITH SYNBIOTICS MODIFIES GUT MICROBIOTA IN NON‐IGE MEDIATED COW’S MILK ALLERGIC INFANTS
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Fox, A, van Ampting, M, Nijhuis, MO, Wopereis, H, Butt, A, Peroni, D, Vandenplas, Y, Candy, D, Shah, N, West, C, Garssen, J, Knol, J, Harthoorn, L, and Michaelis, L
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- 2017
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4. Safety of ruxolitinib therapy prior to allogeneic hematopoietic stem-cell transplantation for myeloproliferative neoplasms
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Hanif, A, Hari, P N, Atallah, E, Carlson, K-SB, Pasquini, M C, and Michaelis, L C
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- 2016
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5. Randomised controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood: O.9
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Zolkipli, Z., Roberts, G., Cornelius, V., Michaelis, L. J., Djukanovic, R., Kurukulaaratchy, R., and Arshad, S. H.
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- 2015
6. Acid-based formula with synbiotics modifies gut microbiota in non-ige mediated cow's milk allergic infants
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Fox, A., van Ampting, M., Nijhuis, M. O., Wopereis, H., Butt, A., Peroni, D., Vandenplas, Y., Candy, D., Shah, N., West, Christina, Garssen, J., Knol, J., Harthoorn, L., Michaelis, L., Fox, A., van Ampting, M., Nijhuis, M. O., Wopereis, H., Butt, A., Peroni, D., Vandenplas, Y., Candy, D., Shah, N., West, Christina, Garssen, J., Knol, J., Harthoorn, L., and Michaelis, L.
- Abstract
Supplement: 5, Special Issue: SI, Meeting Abstract: P35
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- 2017
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7. Amino acid-based formula including specific synbiotics modifies the gut microbiota and reduces clinical symptoms in non-IgE mediated cow's milk allergic infants
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Fox, A. T., Wopereis, H., Van Ampting, M. T., Oude, Nijhuis M. M., Butt, A. M., Peroni, D. G., Vandenplas, Y., Candy, Dc, Shah, N., West, Christina E., Garssen, J., Harhoorn, L. F., Knol, J., Michaelis, L. J., Fox, A. T., Wopereis, H., Van Ampting, M. T., Oude, Nijhuis M. M., Butt, A. M., Peroni, D. G., Vandenplas, Y., Candy, Dc, Shah, N., West, Christina E., Garssen, J., Harhoorn, L. F., Knol, J., and Michaelis, L. J.
- Abstract
Supplement: 103, Special Issue: SI, Meeting Abstract: 0122
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- 2017
8. P35: AMINO ACID-BASED FORMULA WITH SYNBIOTICS MODIFIES GUT MICROBIOTA IN NON-IGE MEDIATED COW’S MILK ALLERGIC INFANTS
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Fox, A, primary, van Ampting, M, additional, Nijhuis, MO, additional, Wopereis, H, additional, Butt, A, additional, Peroni, D, additional, Vandenplas, Y, additional, Candy, D, additional, Shah, N, additional, West, C, additional, Garssen, J, additional, Knol, J, additional, Harthoorn, L, additional, and Michaelis, L, additional
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- 2017
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9. Plasmodium vivax infection: atypical memory B cells are expanded and associated with the persistence of Duffy binding protein II (DBPII) antibody response
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Kano, Flora S, primary, Lima, Barbara AS, additional, Tang, Michaelis L, additional, Costa, Pedro AC, additional, Fontes, Cor JF, additional, Sanchez, Bruno M, additional, Rocha, Roberto S, additional, Soares, Irene S, additional, Brito, Cristiana FA, additional, Antonelli, Lis, additional, and Carvalho, Luzia H, additional
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- 2014
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10. Distinct HLA class II alleles influence antibody response to the Plasmodium vivax Duffy binding protein
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Kano, Flora S, primary, Souza-Silva, Flávia A, additional, Sousa, Taís N, additional, Alves, Jéssica RS, additional, Tang, Michaelis L, additional, Rocha, Roberto S, additional, Brito, Cristiana FA, additional, Sell, Ana Maria, additional, and Carvalho, Luzia H, additional
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- 2014
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11. Plasmodium vivax infection: atypical memory B cells are expanded and associated with the persistence of Duffy binding protein II (DBPII) antibody response
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Pedro Ac Costa, Irene S. Soares, Lis Ribeiro do Valle Antonelli, C. F. A. Brito, Barbara As Lima, Cor Jf Fontes, Flora S. Kano, Michaelis L Tang, Bruno Antonio Marinho Sanchez, Luzia H. Carvalho, and Roberto S. Rocha
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Plasmodium vivax ,Biology ,medicine.disease ,biology.organism_classification ,Virology ,Persistence (computer science) ,Serology ,Infectious Diseases ,medicine.anatomical_structure ,Parasitology ,Immunity ,parasitic diseases ,Immunology ,Poster Presentation ,medicine ,biology.protein ,Antibody ,B cell ,Malaria - Abstract
Antibody responses generated during malaria infection represent an important component of acquired clinical immunity. Despite that, B cell subpopulations induced by the Plasmodium vivax (Pv) infection remains largely unknown. Here, we demonstrated that activated as well as “atypical” memory B cells (MBCs) are expanded in peripheral blood of Pv-exposed individuals, but their frequencies were not associated with acute infection. Aiming to investigate the association between peripheral B cells subsets and Pv-specific antibodies, we further followed-up 34 individuals exposed to P. vivax in the Brazilian Amazon area, an area of markedly unstable malaria transmission; after three cross-sectional survey (at 6-months intervals), ELISA-detected specific IgG (AMA-1, MSP1-19, DBPII) allowed the classification of those individuals as non-responder (NR), temporary (TR) or persistent responder (PR). For AMA-1 and MSP1-19 serological groups, the frequencies of MBCs (classical and atypical) and plasma cells (PCs) were similar among the groups. For DBPII group, we found a trend toward decreases classical MBCs according to the antibody response (NR>TR>PR). On the other hand, the frequencies of atypical MBCs increased according to the presence and persistence of DBPII antibody response (PR>TR>NR). Altogether, these results showed that atypical MBCs are expanded in Pv-exposed individuals (infected and non-infected), and it seems to be associated with the persistence of DBPII antibody response. Although preliminary, these results suggest that atypical MBCs contribute in generation of malarial antibody responses and provide insight into the role of atypical MBCs in P. vivax malaria immunity.
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- 2014
12. Weak Agonistic LPS Restores Intestinal Immune Homeostasis
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Tobias Münzner, Kerstin Fuchs, Antonio Molinaro, Lena Michaelis, Flaviana Di Lorenzo, Thorsten Kliem, Alex Steimle, Bernd J. Pichler, Ingo B. Autenrieth, Kerstin Gronbach, Raphael Parusel, Andrea I. Schäfer, Julia-Stefanie Frick, Anna Lange, Alba Silipo, Hasan Halit Öz, Jan K. Maerz, Steimle, A., Michaelis, L., DI LORENZO, Flaviana, Kliem, T., Munzner, T., Maerz, J. K., Schafer, A., Lange, A., Parusel, R., Gronbach, K., Fuchs, K., Silipo, A., Oz, H. H., Pichler, B. J., Autenrieth, I. B., Molinaro, A., and Frick, J. -S.
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Lipopolysaccharides ,Receptor complex ,Lipopolysaccharide ,Context (language use) ,Inflammation ,Inflammatory bowel disease ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,inflammatory bowel disease ,Drug Discovery ,Genetics ,medicine ,Animals ,Homeostasis ,Humans ,Intestinal Mucosa ,Receptor ,Molecular Biology ,Immunity, Mucosal ,intestinal immune homeostasi ,030304 developmental biology ,Pharmacology ,Mice, Knockout ,0303 health sciences ,lipopolysaccharide ,intestinal immune homeostasis ,medicine.disease ,Colitis ,Inflammatory Bowel Diseases ,CD11c Antigen ,Gastrointestinal Microbiome ,Disease Models, Animal ,Lipid A ,chemistry ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Immunology ,TLR4 ,Molecular Medicine ,Original Article ,medicine.symptom ,Biomarkers - Abstract
Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases., Lipopolysaccharides (LPSs), as one of the most potent immunomodulatory substances in the gut, usually promote a pro-inflammatory response. In this study, Steimle et al. demonstrate that LPS from the common gut commensal Bacteroides vulgatus can rather help to diminish intestinal inflammation in mice due to its weak agonistic activity.
- Published
- 2019
13. A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.
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Murthy GSG, Saliba AN, Szabo A, Harrington A, Abedin S, Carlson K, Michaelis L, Runaas L, Baim A, Hinman A, Maldonado-Schmidt S, Venkatachalam A, Flatten KS, Peterson KL, Schneider PA, Litzow M, Kaufmann SH, and Atallah E
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- Humans, Male, Middle Aged, Female, Aged, Adult, Naphthyridines therapeutic use, Naphthyridines administration & dosage, Recurrence, Treatment Outcome, Drug Resistance, Neoplasm, Aged, 80 and over, Cyclopentanes, Sulfonamides therapeutic use, Sulfonamides administration & dosage, Azacitidine administration & dosage, Azacitidine therapeutic use, Azacitidine adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Pyrimidines administration & dosage, Pyrimidines therapeutic use, Pyrimidines adverse effects
- Abstract
Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
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- 2024
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14. MeDaX: A Knowledge Graph on FHIR.
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Mazein I, Gebhardt T, Zinkewitz F, Michaelis L, Braun S, Waltemath D, Henkel R, and Wodke JAH
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- Humans, Health Level Seven, Germany, Databases, Factual, Electronic Health Records
- Abstract
In Germany, the standard format for exchange of clinical care data for research is HL7 FHIR. Graph databases (GDBs), well suited for integrating complex and heterogeneous data from diverse sources, are currently gaining traction in the medical field. They provide a versatile framework for data analysis which is generally challenging for raw FHIR-formatted data. For generation of a knowledge graph (KG) for clinical research data, we tested different extract-transform-load (ETL) approaches to convert FHIR into graph format. We designed a generalised ETL process and implemented a prototypic pipeline for automated KG creation and ontological structuring. The MeDaX-KG prototype is built from synthetic patient data and currently serves internal testing purposes. The presented approach is easy to customise to expand to other data types and formats.
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- 2024
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15. [FAIR health data in the national and international data space].
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Waltemath D, Beyan O, Crameri K, Dedié A, Gierend K, Gröber P, Inau ET, Michaelis L, Reinecke I, Sedlmayr M, Thun S, and Krefting D
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- Humans, Germany, Internationality, National Health Programs, Electronic Health Records
- Abstract
Health data are extremely important in today's data-driven world. Through automation, healthcare processes can be optimized, and clinical decisions can be supported. For any reuse of data, the quality, validity, and trustworthiness of data are essential, and it is the only way to guarantee that data can be reused sensibly. Specific requirements for the description and coding of reusable data are defined in the FAIR guiding principles for data stewardship. Various national research associations and infrastructure projects in the German healthcare sector have already clearly positioned themselves on the FAIR principles: both the infrastructures of the Medical Informatics Initiative and the University Medicine Network operate explicitly on the basis of the FAIR principles, as do the National Research Data Infrastructure for Personal Health Data and the German Center for Diabetes Research.To ensure that a resource complies with the FAIR principles, the degree of FAIRness should first be determined (so-called FAIR assessment), followed by the prioritization for improvement steps (so-called FAIRification). Since 2016, a set of tools and guidelines have been developed for both steps, based on the different, domain-specific interpretations of the FAIR principles.Neighboring European countries have also invested in the development of a national framework for semantic interoperability in the context of the FAIR (Findable, Accessible, Interoperable, Reusable) principles. Concepts for comprehensive data enrichment were developed to simplify data analysis, for example, in the European Health Data Space or via the Observational Health Data Sciences and Informatics network. With the support of the European Open Science Cloud, among others, structured FAIRification measures have already been taken for German health datasets., (© 2024. The Author(s).)
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- 2024
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16. Confounder or Confederate? The Interactions Between Drugs and the Gut Microbiome in Psychiatric and Neurological Diseases.
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Michaelis L, Berg L, and Maier L
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- Humans, Brain, Psychotropic Drugs pharmacology, Gastrointestinal Microbiome physiology, Nervous System Diseases drug therapy
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The gut microbiome is emerging as an important factor in signaling along the gut-brain axis. The intimate physiological connection between the gut and the brain allows perturbations in the microbiome to be directly transmitted to the central nervous system and thereby contribute to psychiatric and neurological diseases. Common microbiome perturbations result from the ingestion of xenobiotic compounds including pharmaceuticals such as psychotropic drugs. In recent years, a variety of interactions between these drug classes and the gut microbiome have been reported, ranging from direct inhibitory effects on gut bacteria to microbiome-mediated drug degradation or sequestration. Consequently, the microbiome may play a critical role in influencing the intensity, duration, and onset of therapeutic effects, as well as in influencing the side effects that patients may experience. Furthermore, because the composition of the microbiome varies from person to person, the microbiome may contribute to the frequently observed interpersonal differences in the response to these drugs. In this review, we first summarize the known interactions between xenobiotics and the gut microbiome. Then, for psychopharmaceuticals, we address the question of whether these interactions with gut bacteria are irrelevant for the host (i.e., merely confounding factors in metagenomic analyses) or whether they may even have therapeutic or adverse effects., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2024
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17. Identifying Credible Sources of Health Information in Social Media: Phase 2-Considerations for Non-Accredited Nonprofit Organizations, For-Profit Entities, and Individual Sources.
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Burstin H, Curry S, Ranney ML, Arora V, Wachler BB, Chou WS, Correa R, Cryer D, Dizon D, Flores EJ, Harmon G, Jain A, Johnson K, Laine C, Leininger L, McMahon G, Michaelis L, Minhas R, Mularski R, Oldham J, Padman R, Pinnock C, Rivera J, Southwell B, Villarruel A, and Wallace K
- Abstract
Competing Interests: Similar to Phase 1, in order to minimize conflicts of interest, CMSS, WHO, and NAM took steps to ensure the independence and objectivity of the advisory committee and this paper, in that authors were required to disclose financial and non-financial conflicts of interest (Kington et al., 2021). This paper represents the opinions of the authors and does not reflect a consensus position of CMSS; NAM; the National Academies of Sciences, Engineering, and Medicine; WHO; or the authors' organizations. The advisory committee did not receive payment for their contributions to this paper.Conflict-of-Interest Disclosures: Megan L. Ranney discloses receiving financial compensation from the National Opioid Abatement Trust II. Vineet Arora discloses receiving honoraria from the Journal of Hospital Medicine and UpToDate and receiving royalties from McGraw Hill. Don Dizon discloses receiving financial compensation from AstraZeneca and Clovis and stock options from Midi. Efrén J. Flores discloses receiving honoraria from Medscape and financial compensation from Journal of the American College of Radiology. Anjali Jain discloses sole proprietorship of Anjali Jain Research & Consulting, LLC. Richard Mularski discloses receiving grants from Gilead Sciences, Merck, and Pfizer. Claude Pinnock discloses former employment at Meta/Facebook.
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- 2023
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18. Insights into the FAIRness of the German Network University Medicine: A Survey.
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Michaelis L, Poyraz RA, Muzoora MR, Gierend K, Bartschke A, Dieterich C, Johann T, Krefting D, Waltemath D, and Thun S
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- Humans, Universities, Pandemics, Software, COVID-19 epidemiology, Medicine
- Abstract
The need to harness large amounts of data, possibly within a short period of time, became apparent during the Covid-19 pandemic outbreak. In 2022, the Corona Data Exchange Platform (CODEX), which had been developed within the German Network University Medicine (NUM), was extended by a number of common components, including a section on FAIR science. The FAIR principles enable research networks to evaluate how well they comply with current standards in open and reproducible science. To be more transparent, but also to guide scientists on how to improve data and software reusability, we disseminated an online survey within the NUM. Here we present the outcomes and lessons learnt.
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- 2023
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19. The MeDaX Knowledge Graph Prototype.
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Wodke JAH, Michaelis L, and Henkel R
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- Humans, Pattern Recognition, Automated, Information Dissemination, Knowledge, Medical Informatics, Biomedical Research
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Data sharing is sustainable for several reasons, including minimising economical and human costs or maximising knowledge gain. Still, reuse of biomedical (research) data is often hampered by the diverse technical, juridical, and scientific requirements for biomedical data handling and specifically sharing. We are building a toolbox for automated generation of knowledge graphs (KGs) from diverse sources, for data enrichment, and for data analysis. Into the MeDaX KG prototype, we integrated data from the core data set of the German Medical Informatics Initiative (MII) with ontological and provenance information. This prototype is currently used for internal concept and method testing only. In subsequent versions it will be expanded by including more meta-data and relevant data sources as well as further tools, including a user interface.
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- 2023
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20. Transient Retention of Photoreceptor Outer Segments in Matrigel-Embedded Retinal Organoids.
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Berber P, Bondarenko S, Michaelis L, and Weber BHF
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- Organoids, Retina physiology, Cell Differentiation, Photoreceptor Cells, Retinal Pigment Epithelium metabolism, Induced Pluripotent Stem Cells
- Abstract
Retinal organoids (ROs) are three-dimensional retinal tissues, which are differentiated in vitro from induced pluripotent stem cells (iPSC), ultimately forming all main retinal cell types under defined culture conditions. ROs show several highly specialized retinal features, including the outgrowth of photoreceptor outer segments (OSs). In vivo, the photoreceptor OSs are enveloped and maintained by protrusions of retinal pigment epithelium (RPE) cells, the so-called apical microvilli, while ROs fail to recapitulate this critical interaction in culture development. Here, we define specific co-culture conditions aiming to compensate for the missing physical proximity of RPE and OSs in RO development. Accordingly, functional RPE cells and ROs were differentiated simultaneously from the same iPSC clone, the former resulting in byproduct RPE or bRPE cells. While some co-culture approaches indicated a temporary functional interaction between bRPE and RO photoreceptors, they did not improve the photoreceptor histoarchitecture. In contrast, embedding ROs in a basement membrane extract without bRPE cells showed a robust improvement in the rate of photoreceptor OS retention. RO embedding is a quick and easy method that greatly enhances the preservation of photoreceptor OSs, an important structure for modelling retinal diseases with the involvement of photoreceptors.
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- 2022
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21. Shorter Interval between Treatment and COVID Immunization Is Associated With Poor Seroconversion in Patients with Hematological Malignancies.
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Mohan M, Nagavally S, Shah N NN, Michaelis L, Chhabra S, Souza AD, Abedin S, Runaas L, Guru Murthy GS, Longo W, Hamadani M, Dhakal B, Hari P, and Fenske TS
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- Humans, Immunization, Seroconversion, Vaccination, COVID-19 prevention & control, Hematologic Neoplasms therapy
- Published
- 2022
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22. A Pilot Clinical Study to Investigate the Hypomethylating Properties of Freeze-dried Black Raspberries in Patients with Myelodysplastic Syndrome or Myeloproliferative Neoplasm.
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Dong A, Pan X, Lin CW, Huang YW, Krause H, Pan P, Baim A, Thomas MJ, Chen X, Yu J, Michaelis L, Liu P, Wang LS, and Atallah E
- Abstract
Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are bone marrow disorders characterized by cytopenias and progression to acute myeloid leukemia. Hypomethylating agents (HMAs) are Food and Drug Administration-approved therapies for MDS and MDS/MPN patients. HMAs have improved patients' survival and quality of life when compared with other therapies. Although HMAs are effective in MDS and MDS/MPN patients, they are associated with significant toxicities that place a large burden on patients. Our goal is to develop a safer and more effective HMA from natural products. We previously reported that black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice. In addition, BRBs exert hypomethylating effects in patients with colorectal cancer and familial adenomatous polyposis. In the current study, we conducted a pilot clinical trial to evaluate the hypomethylating effects of BRBs in patients with low-risk MDS or MDS/MPN. Peripheral blood mononuclear cells (PBMCs) were isolated before and after three months of BRB intervention. CD45
+ cells were isolated from PBMCs for methylation analysis using a reduced-representation bisulfite sequencing assay. Each patient served as their own matched control, with their measurements assessed before intervention providing a baseline for post-intervention results. Clinically, our data showed that BRBs were well-tolerated with no side effects. When methylation data was combined, BRBs significantly affected methylation levels of 477 promoter regions. Pathway analysis suggests that BRB-induced intragenic hypomethylation drives leukocyte differentiation. A randomized, placebo-controlled clinical trial of BRB use in low-risk MDS or MDS/MPN patients is warranted., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2022 Korean Society of Cancer Prevention.)- Published
- 2022
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23. Influence of caries and molar incisor hypomineralization on oral health-related quality of life in children.
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Michaelis L, Ebel M, Bekes K, Klode C, and Hirsch C
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- Child, Cross-Sectional Studies, Dental Caries Susceptibility, Humans, Prevalence, Quality of Life, Dental Caries epidemiology, Dental Enamel Hypoplasia epidemiology
- Abstract
Objectives: This study was aimed to compare the impact of caries and molar incisor hypomineralization (MIH) on oral health-related quality of life (OHRQoL) in children., Material and Methods: A total of 528 German children aged 7 to 10 years were recruited, half affected by caries and the other half affected by MIH. Both groups were matched according to age, sex, and social status and divided into 3 categories according to severity. The German version of the Child Perceptions Questionnaire for 8- to 10 years old (CPQ-G8-10) was used to analyze the impact on OHRQoL by applying ANOVA models., Results: Patients with MIH showed a mean CPQ score of 10.7 (± 9.3). This was significantly higher compared to the caries group with 8.1 (± 9.8). The score increased linearly from the low severity category to the high severity category in both groups (caries, 4.1 to 13.8; MIH, 5.2 to 17.7, respectively)., Conclusion: With increasing severity, both clinical conditions showed a greater negative impact on OHRQoL. MIH was associated with more impairments., Clinical Relevance: Currently, the focus in pediatric dentistry is placed on the prevention and treatment of caries. Both diseases may have a negative influence on OHRQoL. Since children perceive the impairments by MIH as worse and the prevalence is equal to that of caries, which focus might be shifted in the future., (© 2021. The Author(s).)
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- 2021
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24. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.
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Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, Godwin JE, Arellano ML, Sweet KL, Emadi A, Ravandi F, Erba HP, Byrne M, Michaelis L, Topp MS, Vey N, Ciceri F, Carrabba MG, Paolini S, Huls GA, Jongen-Lavrencic M, Wermke M, Chevallier P, Gyan E, Récher C, Stiff PJ, Pettit KM, Löwenberg B, Church SE, Anderson E, Vadakekolathu J, Santaguida M, Rettig MP, Muth J, Curtis T, Fehr E, Guo K, Zhao J, Bakkacha O, Jacobs K, Tran K, Kaminker P, Kostova M, Bonvini E, Walter RB, Davidson-Moncada JK, Rutella S, and DiPersio JF
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytokine Release Syndrome chemically induced, Cytokine Release Syndrome drug therapy, Dose-Response Relationship, Immunologic, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Follow-Up Studies, Hematopoiesis drug effects, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Maximum Tolerated Dose, Middle Aged, Nausea chemically induced, Protein Interaction Maps, Survival Rate, Antineoplastic Agents, Immunological therapeutic use, Immunotherapy, Leukemia, Myeloid, Acute therapy, Salvage Therapy
- Abstract
Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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25. Gut Commensal-Induced IκBζ Expression in Dendritic Cells Influences the Th17 Response.
- Author
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Michaelis L, Treß M, Löw HC, Klees J, Klameth C, Lange A, Grießhammer A, Schäfer A, Menz S, Steimle A, Schulze-Osthoff K, and Frick JS
- Subjects
- Animals, Autoimmune Diseases immunology, Bacteroides immunology, CD4-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Cells, Cultured, Colitis immunology, Cytokines immunology, Escherichia coli immunology, Female, Inflammation immunology, Interleukin-10 immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Adaptor Proteins, Signal Transducing immunology, Dendritic Cells immunology, Gastrointestinal Microbiome immunology, Th17 Cells immunology
- Abstract
Intestinal commensal bacteria can have a large impact on the state of health and disease of the host. Regulation of Th17 cell development by gut commensals is known to contribute to their dichotomous role in promoting gut homeostasis and host defense, or development of autoimmune diseases. Yet, the underlying mechanisms remain to be fully elucidated. One candidate factor contributing to Th17 differentiation, and the expression of which could be influenced by commensals is the atypical nuclear IκB protein IκBζ. IκBζ acts as a transcriptional regulator of the expression of Th17-related secondary response genes in many cell types including dendritic cells (DCs). Insights into the regulation of IκBζ in DCs could shed light on how these immune sentinel cells at the interface between commensals, innate and adaptive immune system drive an immune-tolerogenic or inflammatory Th17 cell response. In this study, the influence of two gut commensals of low ( Bacteroides vulgatus ) or high ( Escherichia coli ) immunogenicity on IκBζ expression in DCs and its downstream effects was analyzed. We observed that the amount of IκBζ expression and secretion of Th17-inducing cytokines correlated with the immunogenicity of these commensals. However, under immune-balanced conditions, E. coli also strongly induced an IκBζ-dependent secretion of anti-inflammatory IL-10, facilitating a counter-regulative Treg response as assessed in in vitro CD4
+ T cell polarization assays. Yet, in an in vivo mouse model of T cell-induced colitis, prone to inflammatory and autoimmune conditions, administration of E. coli promoted an expansion of rather pro-inflammatory T helper cell subsets whereas administration of B. vulgatus resulted in the induction of protective T helper cell subsets. These findings might contribute to the development of new therapeutic strategies for the treatment of autoimmune diseases using commensals or commensal-derived components., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Michaelis, Treß, Löw, Klees, Klameth, Lange, Grießhammer, Schäfer, Menz, Steimle, Schulze-Osthoff and Frick.)- Published
- 2021
- Full Text
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26. Improving Outcomes of Acute Promyelocytic Leukemia in the Current Era: Analysis of the SEER Database.
- Author
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Guru Murthy GS, Szabo A, Michaelis L, Carlson KS, Runaas L, Abedin S, and Atallah E
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers, Tumor antagonists & inhibitors, Female, Follow-Up Studies, Humans, Incidence, Kaplan-Meier Estimate, Leukemia, Promyelocytic, Acute diagnosis, Leukemia, Promyelocytic, Acute epidemiology, Male, Middle Aged, Molecular Targeted Therapy methods, Prognosis, Retrospective Studies, Risk Factors, SEER Program statistics & numerical data, Sex Factors, United States epidemiology, Young Adult, Biomarkers, Tumor analysis, Leukemia, Promyelocytic, Acute therapy, Neoplasms, Second Primary epidemiology, Palliative Care methods, Salvage Therapy methods
- Abstract
Background: Outcomes of acute promyelocytic leukemia (APL) have significantly improved with the availability of targeted agents. It remains unclear whether the population-level outcomes of APL have improved over time., Methods: Using the SEER database, we identified patients aged ≥20 years with pathologically confirmed APL diagnosed in 2000 through 2014 and who were actively followed. Patients were stratified by diagnosis period into 3 groups (2000-2004, 2005-2009, and 2010-2014) to assess the temporal trends in overall survival (OS), cause-specific survival (CSS), and other outcomes., Results: A total of 2,962 patients with a median age of 48 years (range, 20-96 years) were included. Hispanic patients constituted 21.5% of the cohort and the largest proportion (47.9%) of uninsured patients. The incidence of APL was 0.33 cases per 100,000 population per year. Incidence varied significantly by age, sex, race/ethnicity, and diagnosis period. Survival was significantly higher for patients diagnosed in 2010 through 2014 compared with those diagnosed in 2005 through 2009 and in 2000 through 2004 (4-year OS, 73.4% vs 65.6% vs 57.3%, respectively; 4-year CSS, 78.3% vs 70.8% vs 60.8%, respectively). Early mortality improved significantly over time (2000-2004, 25.3%; 2005-2009, 20.6%; 2010-2014, 17.1%) and was higher in men and Hispanic patients. According to multivariate analysis, diagnosis before 2010 and unmarried status were associated with a higher mortality risk. Uninsured patients had a significantly higher early mortality without a significant difference in post-30-day CSS. No significant changes were noted in risk of secondary malignancies., Conclusions: Population-level outcomes of APL have continued to improve over time. However, significant discrepancies in disease outcomes continue to exist, highlighting the need for more research.
- Published
- 2020
- Full Text
- View/download PDF
27. Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses.
- Author
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Maerz JK, Trostel C, Lange A, Parusel R, Michaelis L, Schäfer A, Yao H, Löw HC, and Frick JS
- Subjects
- Animals, Antigens, Bacterial immunology, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Immunologic Memory, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, B-Lymphocytes, Regulatory immunology, Bacteroides physiology, Bacteroides Infections immunology, Dendritic Cells immunology, Escherichia coli physiology, Escherichia coli Infections immunology, Inflammatory Bowel Diseases immunology, Microbiota immunology, T-Lymphocytes, Regulatory immunology, Th2 Cells immunology
- Abstract
B cells fulfill multifaceted functions that influence immune responses during health and disease. In autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, depletion of functional B cells results in an aggravation of disease in humans and respective mouse models. This could be due to a lack of a pivotal B cell subpopulation: regulatory B cells (Bregs). Although Bregs represent only a small proportion of all immune cells, they exhibit critical properties in regulating immune responses, thus contributing to the maintenance of immune homeostasis in healthy individuals. In this study, we report that the induction of Bregs is differentially triggered by the immunogenicity of the host microbiota. In comparative experiments with low immunogenic Bacteroides vulgatus and strong immunogenic Escherichia coli , we found that the induction and longevity of Bregs depend on strong Toll-like receptor activation mediated by antigens of strong immunogenic commensals. The potent B cell stimulation via E. coli led to a pronounced expression of suppressive molecules on the B cell surface and an increased production of anti-inflammatory cytokines like interleukin-10. These bacteria-primed Bregs were capable of efficiently inhibiting the maturation and function of dendritic cells (DCs), preventing the proliferation and polarization of T helper (Th)1 and Th17 cells while simultaneously promoting Th2 cell differentiation in vitro . In addition, Bregs facilitated the development of regulatory T cells (Tregs) resulting in a possible feedback cooperation to establish immune homeostasis. Moreover, the colonization of germfree wild type mice with E. coli but not B. vulgatus significantly reduced intestinal inflammatory processes in dextran sulfate sodium (DSS)-induced colitis associated with an increase induction of immune suppressive Bregs. The quantity of Bregs directly correlated with the severity of inflammation. These findings may provide new insights and therapeutic approaches for B cell-controlled treatments of microbiota-driven autoimmune disease., (Copyright © 2020 Maerz, Trostel, Lange, Parusel, Michaelis, Schäfer, Yao, Löw and Frick.)
- Published
- 2020
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28. Weak Agonistic LPS Restores Intestinal Immune Homeostasis.
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Steimle A, Michaelis L, Di Lorenzo F, Kliem T, Münzner T, Maerz JK, Schäfer A, Lange A, Parusel R, Gronbach K, Fuchs K, Silipo A, Öz HH, Pichler BJ, Autenrieth IB, Molinaro A, and Frick JS
- Subjects
- Animals, Biomarkers, CD11c Antigen metabolism, Colitis etiology, Colitis metabolism, Colitis pathology, Disease Models, Animal, Gastrointestinal Microbiome immunology, Homeostasis drug effects, Humans, Inflammatory Bowel Diseases diagnostic imaging, Inflammatory Bowel Diseases etiology, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases pathology, Intestinal Mucosa drug effects, Lipid A immunology, Lipopolysaccharides pharmacology, Mice, Mice, Knockout, Positron-Emission Tomography, Homeostasis immunology, Immunity, Mucosal, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Lipopolysaccharides immunology
- Abstract
Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c
+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
29. Flagellin hypervariable region determines symbiotic properties of commensal Escherichia coli strains.
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Steimle A, Menz S, Bender A, Ball B, Weber ANR, Hagemann T, Lange A, Maerz JK, Parusel R, Michaelis L, Schäfer A, Yao H, Löw HC, Beier S, Tesfazgi Mebrhatu M, Gronbach K, Wagner S, Voehringer D, Schaller M, Fehrenbacher B, Autenrieth IB, Oelschlaeger TA, and Frick JS
- Subjects
- Animals, Colitis chemically induced, Colitis immunology, Disease Models, Animal, Escherichia coli genetics, Escherichia coli Infections microbiology, Escherichia coli Proteins genetics, Female, Flagellin metabolism, Intestinal Mucosa, Intestines, Male, Mice, Mice, Inbred C57BL, Signal Transduction immunology, Symbiosis physiology, Toll-Like Receptor 5 metabolism, Escherichia coli metabolism, Flagellin genetics, Symbiosis genetics
- Abstract
Escherichia coli represents a classical intestinal gram-negative commensal. Despite this commensalism, different E. coli strains can mediate disparate immunogenic properties in a given host. Symbiotic E. coli strains such as E. coli Nissle 1917 (EcN) are attributed beneficial properties, e.g., promotion of intestinal homeostasis. Therefore, we aimed to identify molecular features derived from symbiotic bacteria that might help to develop innovative therapeutic alternatives for the treatment of intestinal immune disorders. This study was performed using the dextran sodium sulphate (DSS)-induced colitis mouse model, which is routinely used to evaluate potential therapeutics for the treatment of Inflammatory Bowel Diseases (IBDs). We focused on the analysis of flagellin structures of different E. coli strains. EcN flagellin was found to harbor a substantially longer hypervariable region (HVR) compared to other commensal E. coli strains, and this longer HVR mediated symbiotic properties through stronger activation of Toll-like receptor (TLR)5, thereby resulting in interleukin (IL)-22-mediated protection of mice against DSS-induced colitis. Furthermore, using bone-marrow-chimeric mice (BMCM), CD11c+ cells of the colonic lamina propria (LP) were identified as the main mediators of these flagellin-induced symbiotic effects. We propose flagellin from symbiotic E. coli strains as a potential therapeutic to restore intestinal immune homeostasis, e.g., for the treatment of IBD patients., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
- Full Text
- View/download PDF
30. Early Fluorescence in situ Hybridization Assessment during Acute Myeloid Leukemia Induction Chemotherapy.
- Author
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Schneidewend R, Hosking P, Brazauskas R, Peterson J, Beaudin C, Michaelis L, Atallah E, Hari P, and Carlson K
- Subjects
- Adult, Aged, Biomarkers, Tumor, Female, Genetic Markers, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Odds Ratio, Young Adult, In Situ Hybridization, Fluorescence, Leukemia, Myeloid, Acute genetics
- Published
- 2018
- Full Text
- View/download PDF
31. Phytyl fatty acid esters in vegetables pose a risk for patients suffering from Refsum's disease.
- Author
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Krauß S, Michaelis L, and Vetter W
- Subjects
- Gas Chromatography-Mass Spectrometry, Humans, Risk Factors, Fatty Acids metabolism, Phytanic Acid metabolism, Refsum Disease metabolism, Vegetables metabolism
- Abstract
Patients suffering from Refsum's disease show mutations in the enzyme necessary for the degradation of phytanic acid. Accumulation of this tetramethyl-branched fatty acid in inner organs leads to severe neurological and cardiac dysfunctions which can even result in death. Thus, patients with Refsum's disease have to follow a specific diet resigning foods with high levels of phytanic acid and trans-phytol like products from ruminant animals with a tolerable daily intake (TDI) of ≤ 10 mg/d. We recently reported the occurrence of phytyl fatty acid esters (PFAE, trans-phytol esterified with a fatty acid) in bell pepper with trans-phytol amounts of up to 5.4 mg/100 g fresh weight (FW). In this study we carried out in vitro-digestion experiments of PFAE with artificial digestion fluids. Our results demonstrate that PFAE actually are a source for bioavailable trans-phytol and thus add to the TDI. Eating only one portion of bell pepper (∼150 g) could therefore lead to exploitation of the TDI of up to 81%. Analysis of additional vegetable matrices showed that also rocket salad with up to 4.2 mg/100 g FW trans-phytol bound in PFAE represents a risk-relevant food for patients with Refsum's disease and should therefore be taken into account.
- Published
- 2017
- Full Text
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32. A Fatal Case of Erdheim-Chester Disease with Hepatic Involvement.
- Author
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Balasubramanian G, Modiri A, Affi M, Hagen CE, Batdorf B, Oshima K, Michaelis L, and Saeian K
- Abstract
Erdheim-Chester disease (ECD) is a rare form of systemic histiocytosis, typically presenting with striking osseous involvement characterized by bilateral osteosclerosis and involvement of organs such as the lung, pituitary gland, heart, and brain. Liver involvement with ECD is extremely uncommon. We report a 56-year-old woman presenting with newly diagnosed cirrhosis and signs concerning for intra-abdominal malignancy, including omental caking and peritoneal thickening. Liver biopsy demonstrated xanthogranulomatous infiltration from ECD. The patient showed initial improvement with interferon therapy, but she developed severe depression, which led to the discontinuation of the treatment. Shortly afterward, she died from progressive liver dysfunction resulting in hepatorenal syndrome.
- Published
- 2017
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33. Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation.
- Author
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Kanate AS, Hari PN, Pasquini MC, Visotcky A, Ahn KW, Boyd J, Guru Murthy GS, Rizzo JD, Saber W, Drobyski W, Michaelis L, Atallah E, Carlson KS, D'Souza A, Fenske TS, Cumpston A, Bunner P, Craig M, Horowitz MM, and Hamadani M
- Subjects
- Adult, Aged, Allografts, Disease-Free Survival, Female, Humans, Male, Methotrexate administration & dosage, Middle Aged, Prospective Studies, Survival Rate, Tacrolimus administration & dosage, Atorvastatin administration & dosage, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Immunologic Factors administration & dosage
- Abstract
Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
34. Symbiotic gut commensal bacteria act as host cathepsin S activity regulators.
- Author
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Steimle A, Gronbach K, Beifuss B, Schäfer A, Harmening R, Bender A, Maerz JK, Lange A, Michaelis L, Maurer A, Menz S, McCoy K, Autenrieth IB, Kalbacher H, and Frick JS
- Subjects
- Animals, Bacteroides immunology, Bacteroides physiology, Bacteroides Infections immunology, Bacteroides Infections microbiology, Benzopyrans pharmacology, Blotting, Western, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Bone Marrow Cells microbiology, Carbamates pharmacology, Cathepsins antagonists & inhibitors, Cathepsins genetics, Cells, Cultured, Colitis immunology, Colitis metabolism, Cytokines immunology, Cytokines metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells microbiology, Gastrointestinal Microbiome physiology, Gene Expression immunology, Host-Pathogen Interactions immunology, Immune Tolerance immunology, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Reactive Oxygen Species immunology, Reactive Oxygen Species metabolism, Reverse Transcriptase Polymerase Chain Reaction, Bacteria immunology, Cathepsins immunology, Gastrointestinal Microbiome immunology, Symbiosis immunology
- Abstract
Cathepsin S (CTSS) is a lysosomal protease whose activity regulation is important for MHC-II signaling and subsequent activation of CD4
+ T cell mediated immune responses. Dysregulation of its enzymatic activity or enhanced secretion into extracellular environments is associated with the induction or progression of several autoimmune diseases. Here we demonstrate that commensal intestinal bacteria influence secretion rates and intracellular activity of host CTSS and that symbiotic bacteria, i.e. Bacteroides vulgatus mpk, may actively regulate this process and help to maintain physiological levels of CTSS activities in order to prevent from induction of pathological inflammation. The symbiont-controlled regulation of CTSS activity is mediated by anticipating reactive oxygen species induction in dendritic cells which, in turn, maintains cystatin C (CysC) monomer binding to CTSS. CysC monomers are potent endogenous CTSS inhibitors. This Bacteroides vulgatus caused and CysC dependent CTSS activity regulation is involved in the generation of tolerant intestinal dendritic cells contributing to prevention of T-cell mediated induction of colonic inflammation. Taken together, we demonstrate that symbionts of the intestinal microbiota regulate host CTSS activity and secretion and might therefore be an attractive approach to deal with CTSS associated autoimmune diseases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
35. Randomized controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood.
- Author
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Zolkipli Z, Roberts G, Cornelius V, Clayton B, Pearson S, Michaelis L, Djukanovic R, Kurukulaaratchy R, and Arshad SH
- Subjects
- Administration, Oral, Animals, Dermatophagoides farinae immunology, Dermatophagoides pteronyssinus immunology, Double-Blind Method, Female, Humans, Infant, Male, Primary Prevention, Allergens therapeutic use, Antigens, Dermatophagoides therapeutic use, Hypersensitivity prevention & control, Immunotherapy adverse effects
- Abstract
Background: Children born to atopic parents are at increased risk of sensitization to environmental allergens., Objective: We sought to demonstrate proof of concept for oral immunotherapy to high-dose house dust mite (HDM) allergen in infancy in the prevention of allergen sensitization and allergic diseases., Methods: This was a prospective, randomized, double-blind, placebo-controlled, proof-of-concept study involving 111 infants less than 1 year of age at high risk of atopy (≥ 2 first-degree relatives with allergic disease) but with negative skin prick test responses to common allergens at randomization. HDM extract (active) and appropriate placebo solution were administered orally twice daily for 12 months, and children were assessed every 3 months. Coprimary outcomes were cumulative sensitization to HDM and sensitization to any common allergen during treatment, whereas development of eczema, wheeze, and food allergy were secondary outcomes. All adverse events were recorded., Results: There was a significant (P = .03) reduction in sensitization to any common allergen (16.0%; 95% CI, 1.7% to 30.4%) in the active (5 [9.4%]) compared with placebo (13 [25.5%]) treatment groups. There was no treatment effect on the coprimary outcome of HDM sensitization and the secondary outcomes of eczema, wheeze, and food allergy. The intervention was well tolerated, with no differences between active and placebo treatments in numbers or nature of adverse events., Conclusion: Prophylactic HDM oral immunotherapy is well tolerated in children at high heredity risk. The results met the trial's prespecified criteria for proof of concept in reducing sensitization to any allergen; however, no significant preventive effect was observed on HDM sensitization or allergy-related symptoms., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
36. Dietary restriction causing iodine-deficient goitre.
- Author
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Cheetham T, Plumb E, Callaghan J, Jackson M, and Michaelis L
- Subjects
- Child, Preschool, Diet, Food Hypersensitivity diet therapy, Humans, Iodine administration & dosage, Male, Diet, Protein-Restricted adverse effects, Goiter etiology, Iodine deficiency
- Abstract
Iodine-deficient goitre was common in some parts of the UK prior to the introduction of salt iodisation. Many contemporary salt preparations do not contain much iodine, and there are renewed concerns about the iodine status of the population. We present a boy with severe allergy who developed goitre and significant thyroid dysfunction in association with an iodine-deficient 'food-restricted' diet. The case highlights the importance of a comprehensive nutritional assessment in all children on multiple food restrictions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
- Full Text
- View/download PDF
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