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Article ; Online: Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

van Gennep, Sara / Fung, Ivan C N / de Jong, Djuna C / Ramkisoen, Rishand K / Clasquin, Esmé / de Jong, Jitteke / de Vries, Leonie C S / de Jonge, Wouter J / Gecse, Krisztina B / Löwenberg, Mark / Woolcott, John C / Mookhoek, Aart / D'Haens, Geert R

Journal of Crohn's & colitis

2024

Abstract: Background and aims: Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor.: Methods: Forty UC patients ... ...

Abstract	Background and aims: Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. Methods: Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, Tyrosine kinase 2 (TYK2) and total signal transducer and activator of transcription (STAT) 1-6 were assessed using immunohistochemistry (IHC). Results: At baseline, the median RHI was 14 (interquartile range (IQR) 10-19). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior anti-TNF treatment. At week 8, 15 patients (38%) had HEMI, 23 patients (58%) histological remission and 34 (85%) histological response. RHI decreased by a median of 14 points (IQR 9-21) in responders (p<0.001) and by 6 points (IQR 0-13) in non-responders (p=0.002). STAT1, STAT3 and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower week 8 STAT1 expression levels compared to non-responders (0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p=0.001), suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders (2.7%, IQR 0.1-7.7) compared to responders (0.4%, IQR 0.1-2.1). Conclusions: Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjae031
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Article ; Online: A nationwide database study on colectomy and colorectal cancer in ulcerative colitis: what is the role of appendectomy?

Stellingwerf, M E / Bemelman, W A / Löwenberg, M / Ponsioen, C Y / D'Haens, G R / van Dieren, S / Buskens, C J

Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland

2020 Volume 23, Issue 1, Page(s) 64–73

Abstract: ... with no appendectomy [hazard ratio (HR) 0.16, 95% C: 0.04-0.66, P = 0.011], and the same nonsignificant ...

Abstract	Aim: Although has been suggested that an appendectomy has a positive effect on the disease course in patients with ulcerative colitis (UC), recent studies indicate a potential increase in risk of colectomy and colorectal cancer (CRC). This study aimed to evaluate the rates of colectomy and CRC after appendectomy in UC patients using a nationwide prospective database [the Initiative on Crohn and Colitis Parelsnoer Institute - Inflammatory Bowel Disease (ICC PSI-IBD) database]. Method: All UC patients were retrieved from the ICC PSI-IBD database between January 2007 and May 2018. Primary outcomes were colectomy and CRC. Outcomes were compared in patients with and without appendectomy, with a separate analysis for timing of appendectomy (before or after UC diagnosis). Results: A total of 826 UC patients (54.7% female; median age 46 years, range 18-89 years) were included. Sixty-three (7.6%) patients had previously undergone appendectomy: 24 (38.1%) before and 33 (52.4%) after their diagnosis of UC. In multivariate analysis, appendectomy after UC diagnosis was associated with a significantly lower colectomy rate compared with no appendectomy [hazard ratio (HR) 0.16, 95% C: 0.04-0.66, P = 0.011], and the same nonsignificant trend was seen in patients with an appendectomy before UC diagnosis (HR 0.35, 95% CI 0.08-1.41, P = 0.138). Appendectomy was associated with delayed colectomy, particularly when it was performed after diagnosis of UC (P = 0.009). No significant differences were found in the CRC rate between patients with and without appendectomy (1.6% vs 1.2%; P = 0.555). Conclusion: Appendectomy in established UC is associated with an 84% decreased risk of colectomy and a delay in surgery. Since the colon is in situ for longer, the risk of developing CRC remains, which underscores the importance of endoscopic surveillance programmes.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Appendectomy ; Colectomy ; Colitis, Ulcerative/epidemiology ; Colitis, Ulcerative/surgery ; Colorectal Neoplasms/epidemiology ; Colorectal Neoplasms/etiology ; Colorectal Neoplasms/surgery ; Female ; Humans ; Male ; Middle Aged ; Risk Factors ; Young Adult
Language	English
Publishing date	2020-07-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1440017-0
ISSN	1463-1318 ; 1462-8910
ISSN (online)	1463-1318
ISSN	1462-8910
DOI	10.1111/codi.15184
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Zs.A 5799: Show issues

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Article ; Online: A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML.

Chen, Lanpeng / Pronk, Eline / van Dijk, Claire / Bian, Yujie / Feyen, Jacqueline / van Tienhoven, Tim / Yildirim, Meltem / Pisterzi, Paola / de Jong, Madelon M E / Bastidas, Alejandro / Hoogenboezem, Remco M / Wevers, Chiel / Bindels, Eric M / Löwenberg, Bob / Cupedo, Tom / Sanders, Mathijs A / Raaijmakers, Marc H G P

Blood cancer discovery

2023 Volume 4, Issue 5, Page(s) 394–417

Abstract: Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor ... ...

Abstract	Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted single-cell RNA sequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPC) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+ stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors are predicted to repress high-output hematopoietic stem cell subsets in NPM1-mutated acute myeloid leukemia (AML), with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcomes after chemotherapy across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment. Significance: Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcomes in human AML. See related commentary by Lisi-Vega and Méndez-Ferrer, p. 349. This article is featured in Selected Articles from This Issue, p. 337.
MeSH term(s)	Humans ; Hematopoietic Stem Cells ; Bone Marrow ; Leukemia, Myeloid, Acute/genetics ; Hematopoiesis/genetics ; Stromal Cells
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3028898-8
ISSN	2643-3249 ; 2643-3230
ISSN (online)	2643-3249
ISSN	2643-3230
DOI	10.1158/2643-3230.BCD-23-0043
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Article ; Online: mRNA-1273 vaccinated inflammatory bowel disease patients receiving TNF inhibitors develop broad and robust SARS-CoV-2-specific CD8

van den Dijssel, Jet / Duurland, Mariël C / Konijn, Veronique Al / Kummer, Laura Yl / Hagen, Ruth R / Kuijper, Lisan H / Wieske, Luuk / van Dam, Koos Pj / Stalman, Eileen W / Steenhuis, Maurice / Geerdes, Dionne M / Mok, Juk Yee / Kragten, Angela Hm / Menage, Charlotte / Koets, Lianne / Veldhuisen, Barbera / Verstegen, Niels Jm / van der Schoot, C Ellen / van Esch, Wim Je /

D'Haens, Geert Ram / Löwenberg, Mark / Volkers, Adriaan G / Rispens, Theo / Kuijpers, Taco W / Eftimov, Filip / van Gisbergen, Klaas Pjm / van Ham, S Marieke / Ten Brinke, Anja / van de Sandt, Carolien E

Journal of autoimmunity

2024 Volume 144, Page(s) 103175

Abstract: SARS-CoV-2-specific ... ...

Abstract	SARS-CoV-2-specific CD8
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes ; SARS-CoV-2 ; 2019-nCoV Vaccine mRNA-1273 ; Tumor Necrosis Factor Inhibitors ; COVID-19 ; Vaccination ; Antibodies ; Inflammatory Bowel Diseases/drug therapy ; Antibodies, Viral
Chemical Substances	2019-nCoV Vaccine mRNA-1273 (EPK39PL4R4) ; Tumor Necrosis Factor Inhibitors ; Antibodies ; Antibodies, Viral
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2024.103175
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Zs.A 2368: Show issues

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Article ; Online: Thermally-Induced Shape-Memory Behavior of Degradable Gelatin-Based Networks

Axel T. Neffe / Candy Löwenberg / Konstanze K. Julich-Gruner / Marc Behl / Andreas Lendlein

International Journal of Molecular Sciences, Vol 22, Iss 5892, p

2021 Volume 5892

Abstract: ... the material presented here could be applied, e.g., as self-anchoring devices mechanically resembling ... Hydrogels had storage moduli of 0.27–23 kPa and Young’s moduli of 215–360 kPa at 4 °C. The hydrogels were ... hydrolytically degradable, with full degradation to water-soluble products within one week at 37 °C and pH = 7.4 ...

Abstract	Shape-memory hydrogels (SMH) are multifunctional, actively-moving polymers of interest in biomedicine. In loosely crosslinked polymer networks, gelatin chains may form triple helices, which can act as temporary net points in SMH, depending on the presence of salts. Here, we show programming and initiation of the shape-memory effect of such networks based on a thermomechanical process compatible with the physiological environment. The SMH were synthesized by reaction of glycidylmethacrylated gelatin with oligo(ethylene glycol) (OEG) α,ω-dithiols of varying crosslinker length and amount. Triple helicalization of gelatin chains is shown directly by wide-angle X-ray scattering and indirectly via the mechanical behavior at different temperatures. The ability to form triple helices increased with the molar mass of the crosslinker. Hydrogels had storage moduli of 0.27–23 kPa and Young’s moduli of 215–360 kPa at 4 °C. The hydrogels were hydrolytically degradable, with full degradation to water-soluble products within one week at 37 °C and pH = 7.4. A thermally-induced shape-memory effect is demonstrated in bending as well as in compression tests, in which shape recovery with excellent shape-recovery rates R r close to 100% were observed. In the future, the material presented here could be applied, e.g., as self-anchoring devices mechanically resembling the extracellular matrix.
Keywords	shape-memory hydrogel ; active polymer ; biopolymer ; mechanical properties ; degradation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease.

Berends, Sophie E / Strik, Anne S / Van Selm, Juliet C / Löwenberg, Mark / Ponsioen, Cyriel Y / DʼHaens, Geert R / Mathôt, Ron A

Therapeutic drug monitoring

2018 Volume 40, Issue 2, Page(s) 202–211

Abstract: Background: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. ... ...

Abstract	Background: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice. The aim of this study was to evaluate PK of ADL in patients with CD and to identify factors that influence PK of ADL. Methods: In a retrospective cohort study, the authors reviewed the charts of 96 patients with CD receiving ADL induction and maintenance treatment. This patient cohort was used for external validation of population pharmacokinetic models of ADL available from literature. In addition, a novel population PK model was developed using nonlinear mixed-effects modeling. Results: None of the literature models properly described the PK of ADL in our cohort. Therefore, a novel population pharmacokinetic model was developed. Clearance of ADL increased 4-fold in the presence of anti-ADL antibodies. Patients who received ADL every week had a 40% higher clearance compared with patients receiving ADL every other week. Conclusions: Clearance of ADL increased in the presence of anti-ADL antibodies and was associated with weekly ADL administrations. In clinical practice, the decision to intensify ADL treatment to weekly administrations is primarily based on disease activity. Increased disease activity may be the result of lower drug concentrations due to higher clearance. However, increased disease activity may also increase clearance due to increased target engagement. The causal relationship between these factors remains to be elucidated.
MeSH term(s)	Adalimumab/pharmacokinetics ; Adalimumab/therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/therapeutic use ; Child ; Crohn Disease/drug therapy ; Crohn Disease/metabolism ; Female ; Humans ; Individuality ; Male ; Middle Aged ; Retrospective Studies ; Young Adult
Chemical Substances	Antibodies, Monoclonal ; Adalimumab (FYS6T7F842)
Language	English
Publishing date	2018-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	424443-6
ISSN	1536-3694 ; 0163-4356
ISSN (online)	1536-3694
ISSN	0163-4356
DOI	10.1097/FTD.0000000000000494
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Zs.A 1503: Show issues

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Article ; Online: Prospective validation of the prognostic relevance of CD34+CD38- AML stem cell frequency in the HOVON-SAKK132 trial.

Ngai, Lok Lam / Hanekamp, Diana / Janssen, Fleur / Carbaat-Ham, Jannemieke / Hofland, Maaike A M A / Fayed, Mona M H E / Kelder, Angèle / Oudshoorn-van Marsbergen, Laura / Scholten, Willemijn J / Snel, Alexander N / Bachas, Costa / Tettero, Jesse M / Breems, Dimitri A / Fischer, Thomas / Gjertsen, Bjørn T / Griškevičius, Laimonas / Juliusson, Gunnar / van de Loosdrecht, Arjan A / Maertens, Johan A /

Manz, Markus G / Pabst, Thomas / Passweg, Jakob R / Porkka, Kimmo / Valk, Peter J M / Gradowska, Patrycja / Löwenberg, Bob / de Leeuw, David C / Janssen, Jeroen J W M / Ossenkoppele, Gert J / Cloos, Jacqueline

Blood

2023 Volume 141, Issue 21, Page(s) 2657–2661

MeSH term(s)	Humans ; Prognosis ; Antigens, CD34 ; ADP-ribosyl Cyclase 1 ; Leukemia, Myeloid, Acute ; Stem Cells ; Neoplastic Stem Cells ; Flow Cytometry
Chemical Substances	Antigens, CD34 ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
Language	English
Publishing date	2023-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022019160
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Platelet-vessel wall interaction in health and disease.

Löwenberg, E C / Meijers, J C M / Levi, M

The Netherlands journal of medicine

2010 Volume 68, Issue 6, Page(s) 242–251

Abstract: Upon vessel wall injury platelets rapidly adhere to the exposed subendothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins such as von Willebrand factor, collagen and ... ...

Abstract	Upon vessel wall injury platelets rapidly adhere to the exposed subendothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins such as von Willebrand factor, collagen and fibrinogen. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates forming a stable platelet plug. In addition, activated platelets form a strong link between primary and secondary haemostasis as they provide the phospholipid surface that is necessary for the assembly of activated coagulation factor complexes required for thrombin generation. Other than the physiological function acting as a first line of defence against bleeding, platelets may also contribute to pathological thrombus formation. Platelets play an important role in thromboembolic diseases and may contribute to the formation of occlusive thrombi which can lead to severe complications such as stroke or myocardial infarction. Improved understanding of the respective roles of the various cellular receptors, adhesive proteins and regulatory proteins involved in platelet-vessel wall interaction and subsequent thrombus formation, both under physiological and pathological conditions, has led to the development and investigation of a broad range of antiplatelet drugs. This review provides an overview of the current knowledge on the mechanisms involved in the interaction between platelets and vascular endothelium and discusses recent advancements in the development of drugs interfering with platelet-vessel wall interaction at various stages of thrombus formation.
MeSH term(s)	Blood Platelets/drug effects ; Blood Platelets/pathology ; Blood Platelets/physiology ; Blood Vessels/injuries ; Blood Vessels/physiology ; Blood Vessels/physiopathology ; Humans ; Platelet Adhesiveness ; Platelet Aggregation ; Thrombosis/blood ; Thrombosis/pathology
Language	English
Publishing date	2010-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	193149-0
ISSN	1872-9061 ; 0300-2977
ISSN (online)	1872-9061
ISSN	0300-2977
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Zs.A 576: Show issues

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Article ; Online: Correction: Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis.

Birnie, Emma / Koh, Gavin C K W / Löwenberg, Ester C / Meijers, Joost C M / Maude, Rapeephan R / Day, Nicholas P J / Peacock, Sharon J / van der Poll, Tom / Wiersinga, W Joost

PLoS neglected tropical diseases

2020 Volume 14, Issue 9, Page(s) e0008722

Abstract: This corrects the article DOI: 10.1371/journal.pntd.0005468.]. ...

Abstract	[This corrects the article DOI: 10.1371/journal.pntd.0005468.].
Language	English
Publishing date	2020-09-01
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0008722
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Article ; Online: Longitudinal humoral response after SARS-CoV-2 vaccination in ocrelizumab treated MS patients: To wait and repopulate?

Multiple sclerosis and related disorders

2021 Volume 57, Page(s) 103416

Abstract: Objective: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination ... ...

Abstract	Objective: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count. Methods: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70. Results: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL). Conclusions: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.
MeSH term(s)	Antibodies, Monoclonal, Humanized ; COVID-19 ; COVID-19 Vaccines ; Humans ; Multiple Sclerosis ; SARS-CoV-2 ; Vaccination
Chemical Substances	Antibodies, Monoclonal, Humanized ; COVID-19 Vaccines ; ocrelizumab (A10SJL62JY)
Language	English
Publishing date	2021-11-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2021.103416
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