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Article ; Online: The

Cornillet, Martin / Villard, Christina / Rorsman, Fredrik / Molinaro, Antonio / Nilsson, Emma / Kechagias, Stergios / von Seth, Erik / Bergquist, Annika

EClinicalMedicine

2024 Volume 70, Page(s) 102526

Abstract: Background: Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools ...

Abstract	Background: Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. Methods: We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Findings: Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. Interpretation: We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040. Funding: This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.
Language	English
Publishing date	2024-03-11
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2024.102526
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Article ; Online: Dysregulated peripheral proteome reveals NASH-specific signatures identifying patient subgroups with distinct liver biology.

Stiglund, Natalie / Hagström, Hannes / Stål, Per / Cornillet, Martin / Björkström, Niklas K

Frontiers in immunology

2023 Volume 14, Page(s) 1186097

Abstract: Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and ... ...

Abstract	Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking. Methods: The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis. Results: We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients. Conclusion: NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology.
MeSH term(s)	Humans ; Non-alcoholic Fatty Liver Disease/pathology ; Proteome ; Liver Neoplasms ; Biology
Chemical Substances	Proteome
Language	English
Publishing date	2023-06-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1186097
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Article ; Online: Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features.

Cornillet, Martin / Zemack, Helen / Jansson, Hannes / Sparrelid, Ernesto / Ellis, Ewa / Björkström, Niklas K

Cells

2023 Volume 12, Issue 12

Abstract: Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all ... ...

Abstract	Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.
MeSH term(s)	Humans ; alpha 1-Antitrypsin/genetics ; alpha 1-Antitrypsin/metabolism ; alpha 1-Antitrypsin Deficiency/complications ; alpha 1-Antitrypsin Deficiency/diagnosis ; alpha 1-Antitrypsin Deficiency/epidemiology ; alpha 1-Antitrypsin Deficiency/genetics ; Biliary Tract Neoplasms/etiology ; Biliary Tract Neoplasms/genetics ; Phenotype ; Prevalence
Chemical Substances	alpha 1-Antitrypsin
Language	English
Publishing date	2023-06-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12121663
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Article ; Online: Tissue-specific nonheritable influences drive endometrial immune system variation.

Bister, Jonna / Filipovic, Iva / Sun, Dan / Crona-Guterstam, Ylva / Cornillet, Martin / Ponzetta, Andrea / Michaëlsson, Jakob / Gidlöf, Sebastian / Ivarsson, Martin A / Strunz, Benedikt / Björkström, Niklas K

Science immunology

2024 Volume 9, Issue 94, Page(s) eadj7168

Abstract: Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The ... ...

Abstract	Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.
MeSH term(s)	Female ; Humans ; Twins, Dizygotic/genetics ; Twins, Monozygotic/genetics ; Endometrium ; Uterus ; Immune System
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adj7168
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Article: Are antibodies to fine specificities of citrullinated peptides/proteins useful for stratification of rheumatoid arthritis patients?

Nogueira, Leonor / Parra, Emilie / Larrieu, Margaux / Verrouil, Evelyne / Cornillet, Martin

Clinical & translational immunology

2021 Volume 10, Issue 7, Page(s) e1288

Abstract: Background: In rheumatoid arthritis (RA), antibodies to citrullinated protein (ACPA) are believed to be heterogeneous and patient stratification by antibody profiling raised clinical interest for patient management. However, heterogeneity might be ... ...

Abstract	Background: In rheumatoid arthritis (RA), antibodies to citrullinated protein (ACPA) are believed to be heterogeneous and patient stratification by antibody profiling raised clinical interest for patient management. However, heterogeneity might be partially artificial because of the use of heterogeneous methods for ACPA detection. In recent work instead, we found that ACPA were mainly directed towards a single fibrin-derived peptide, β60-74BiotNt, but a comparative analysis with the presence of other ACPA specificities is still lacking. Objectives: To present an overview of RA patients' stratification based on the detection of the main ACPA fine specificities with the same method as compared to that of anti-β60-74BiotNt antibodies. Methods: Over 4500 measurements were performed with more than 22 standardised ELISAs, sera from 180 RA patients and 200 to 436 non-RA rheumatic disease controls. Results: Four to 81% of RA patients had ACPA towards various targets, confirming the heterogeneity of ACPA specificities. However, the subgroups of patients overlapped up to 97% with ACPA levels of correlation coefficients up to 0.8, showing redundancy of some targets. Multiplexing decreased diagnostic specificity from 95% to 64%. Instead, anti-β60-74BiotNt detection identified almost all ACPA-positive patients. Conclusions: Antibodies to citrullinated protein multiplexing shows some degree of redundancy and is not suitable for diagnostic purposes. ACPA fine specificities might be less heterogeneous than perceived by sera testing on multiple peptides. Patient stratification largely depends on detection methods and requires standardisation.
Language	English
Publishing date	2021-07-05
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2694482-0
ISSN	2050-0068
ISSN	2050-0068
DOI	10.1002/cti2.1288
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Article ; Online: Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features

Martin Cornillet / Helen Zemack / Hannes Jansson / Ernesto Sparrelid / Ewa Ellis / Niklas K. Björkström

Cells, Vol 12, Iss 1663, p

2023 Volume 1663

Abstract	Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.
Keywords	alpha-1 antitrypsin deficiency ; biliary tract cancer ; survival ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.

Pertsinidou, Eleftheria / Saevarsdottir, Saedis / Manivel, Vivek Anand / Klareskog, Lars / Alfredsson, Lars / Mathsson-Alm, Linda / Hansson, Monika / Cornillet, Martin / Serre, Guy / Holmdahl, Rikard / Skriner, Karl / Jakobsson, Per-Johan / Westerlind, Helga / Askling, Johan / Rönnelid, Johan

Annals of the rheumatic diseases

2024 Volume 83, Issue 3, Page(s) 277–287

Abstract: Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.: Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated ... ...

Abstract	Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis. Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline. Results: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained. Conclusion: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria.
MeSH term(s)	Humans ; Rheumatoid Factor ; Arthritis, Rheumatoid ; Inflammation ; Autoantibodies ; Peptides, Cyclic ; Immunoglobulin G ; Immunoglobulin M ; Immunoglobulin A
Chemical Substances	Rheumatoid Factor (9009-79-4) ; Autoantibodies ; Peptides, Cyclic ; Immunoglobulin G ; Immunoglobulin M ; Immunoglobulin A
Language	English
Publishing date	2024-02-15
Publishing country	England
Document type	Journal Article
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/ard-2023-224728
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Article ; Online: Phenotypic diversity of human adipose tissue-resident NK cells in obesity.

Haugstøyl, Martha E / Cornillet, Martin / Strand, Kristina / Stiglund, Natalie / Sun, Dan / Lawrence-Archer, Laurence / Hjellestad, Iren D / Busch, Christian / Mellgren, Gunnar / Björkström, Niklas K / Fernø, Johan

Frontiers in immunology

2023 Volume 14, Page(s) 1130370

Abstract: Natural killer (NK) cells have emerged as key mediators of obesity-related adipose tissue inflammation. However, the phenotype of NK cell subsets residing in human adipose tissue are poorly defined, preventing a detailed understanding of their role in ... ...

Abstract	Natural killer (NK) cells have emerged as key mediators of obesity-related adipose tissue inflammation. However, the phenotype of NK cell subsets residing in human adipose tissue are poorly defined, preventing a detailed understanding of their role in metabolic disorders. In this study, we applied multicolor flow cytometry to characterize CD56
MeSH term(s)	Humans ; CD56 Antigen/metabolism ; Killer Cells, Natural/metabolism ; Phenotype ; Adipose Tissue/metabolism ; Obesity/metabolism
Chemical Substances	CD56 Antigen
Language	English
Publishing date	2023-02-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1130370
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Article: Preoperative immunological plasma markers TRAIL, CSF1 and TIE2 predict survival after resection for biliary tract cancer.

Jansson, Hannes / Cornillet, Martin / Sun, Dan / Filipovic, Iva / Sturesson, Christian / O'Rourke, Colm J / Andersen, Jesper B / Björkström, Niklas K / Sparrelid, Ernesto

Frontiers in oncology

2023 Volume 13, Page(s) 1169537

Abstract: Introduction: Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing ... ...

Abstract	Introduction: Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank. Methods: Expression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts. Results: Three preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells. Discussion: In conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.
Language	English
Publishing date	2023-06-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1169537
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Article ; Online: Så skapades covid-19-biobanken.

Ljunggren, Hans-Gustaf / Strålin, Kristoffer / Chen, Puran / Cornillet, Martin / Rooijackers, Olav / I Eriksson, Lars / Aleman, Soo / Björkström, Niklas

Lakartidningen

2021 Volume 118

Abstract: Biobanks function as important repositories for biological samples collected in health care. As such, they play an important role in enabling important medical research over time. In response to the covid-19 outbreak in Stockholm, Sweden, a group of ... ...

Title translation	Insights from creating a covid-19 biobank in Sweden.
Abstract	Biobanks function as important repositories for biological samples collected in health care. As such, they play an important role in enabling important medical research over time. In response to the covid-19 outbreak in Stockholm, Sweden, a group of specialists in intensive care, infectious diseases, and clinical microbiology, as well as scientists with experience in immunology and viral diseases, rapidly gathered. The group discussed how to cope with the prevailing situation, both from a clinical and a research-oriented perspective. Among strategies decided was an attempt to rapidly organize a biological sample collection organized in a biobank for immediate but also long-term research purposes. Given the pandemic conditions with a new virus, the biobank project and associated immediate immunological research tasks turned out to be challenging. In the following months, many lessons were learned from the systematic collection of clinical samples and associated immunological research. Many insights were gained of value for future pandemic preparedness.
MeSH term(s)	Biological Specimen Banks ; Biomedical Research ; COVID-19 ; Humans ; SARS-CoV-2 ; Sweden
Language	Swedish
Publishing date	2021-12-15
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	391010-6
ISSN	1652-7518 ; 0023-7205
ISSN (online)	1652-7518
ISSN	0023-7205
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