The intestinal epithelium serves as a barrier to discriminate the outside from the inside and is in constant exchange with the luminal contents, including nutrients and the microbiota. Pathogens have evolved mechanisms to overcome the multiple ways of defense in the mucosa, while several members of the microbiota can exhibit pathogenic features once the healthy barrier integrity of the epithelium is disrupted. This not only leads to symptoms accompanying the acute infection but may also contribute to long-term injuries such as genomic instability, which is linked to mutations and cancer. While for Helicobacter pylori a link between infection and cancer is well established, many other bacteria and their virulence factors have only recently been linked to gastrointestinal malignancies through epidemiological as well as mechanistic studies. This review will focus on those pathogens and members of the microbiota that have been linked to genotoxicity in the context of gastric or colorectal cancer. We will address the mechanisms by which such bacteria establish contact with the gastrointestinal epithelium-either via an existing breach in the barrier or via their own virulence factors as well as the mechanisms by which they interfere with host genomic integrity.Weniger anzeigen
Campylobacter concisus is a human-pathogenic bacterium of the gastrointestinal tract. This study aimed at the contribution of the mucosal immune system in the context of intestinal epithelial barrier dysfunction induced by C. concisus. As an experimental leaky gut model, we used in vitro co-cultures of colonic epithelial cell monolayers (HT-29/B6-GR/MR) with M1-macrophage-like THP-1 cells on the basal side. Forty-eight hours after C. concisus infection, the decrease in the transepithelial electrical resistance in cell monolayers was more pronounced in co-culture condition and 22 ± 2% (p < 0.001) higher than the monoculture condition without THP-1 cells. Concomitantly, we observed a reduction in the expression of the tight junction proteins occludin and tricellulin. We also detected a profound increase in 4 kDa FITC-dextran permeability in C. concisus-infected cell monolayers only in co-culture conditions. This is explained by loss of tricellulin from tricellular tight junctions (tTJs) after C. concisus infection. As an underlying mechanism, we observed an inflammatory response after C. concisus infection through pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) released from THP-1 cells in the co-culture condition. In conclusion, the activation of subepithelial immune cells exacerbates colonic epithelial barrier dysfunction by C. concisus through tricellulin disruption in tTJs, leading to increased antigen permeability (leaky gut concept).Weniger anzeigen
Reconstruction of segmental bone defects by autologous bone grafting is still the standard of care but presents challenges including anatomical availability and potential donor site morbidity. The process of 3D bioprinting, the application of 3D printing for direct fabrication of living tissue, opens new possibilities for highly personalized tissue implants, making it an appealing alternative to autologous bone grafts. One of the most crucial hurdles for the clinical application of 3D bioprinting is the choice of a suitable cell source, which should be minimally invasive, with high osteogenic potential, with fast, easy expansion. In this study, mesenchymal progenitor cells were isolated from clinically relevant human bone biopsy sites (explant cultures from alveolar bone, iliac crest and fibula; bone marrow aspirates; and periosteal bone shaving from the mastoid) and 3D bioprinted using projection-based stereolithography. Printed constructs were cultivated for 28 days and analyzed regarding their osteogenic potential by assessing viability, mineralization, and gene expression. While viability levels of all cell sources were comparable over the course of the cultivation, cells obtained by periosteal bone shaving showed higher mineralization of the print matrix, with gene expression data suggesting advanced osteogenic differentiation. These results indicate that periosteum-derived cells represent a highly promising cell source for translational bioprinting of bone tissue given their superior osteogenic potential as well as their minimally invasive obtainability.Weniger anzeigen
The butenolide molecule, karrikin (KAR), emerging in smoke of burned plant material, enhances light responses such as germination, inhibition of hypocotyl elongation, and anthocyanin accumulation in Arabidopsis. The KAR signaling pathway consists of KARRIKIN INSENSITIVE 2 (KAI2) and MORE AXILLARY GROWTH 2 (MAX2), which, upon activation, act in an SCF E3 ubiquitin ligase complex to target the downstream signaling components SUPPRESSOR OF MAX2 1 (SMAX1) and SMAX1-LIKE 2 (SMXL2) for degradation. How degradation of SMAX1 and SMXL2 is translated into growth responses remains unknown. Although light clearly influences the activity of KAR, the molecular connection between the two pathways is still poorly understood. Here, we demonstrate that the KAR signaling pathway promotes the activity of a transcriptional module consisting of ELONGATED HYPOCOTYL 5 (HY5), B-BOX DOMAIN PROTEIN 20 (BBX20), and BBX21. The bbx20 bbx21 mutant is largely insensitive to treatment with KAR2, similar to a hy5 mutant, with regards to inhibition of hypocotyl elongation and anthocyanin accumulation. Detailed analysis of higher order mutants in combination with RNA-sequencing analysis revealed that anthocyanin accumulation downstream of SMAX1 and SMXL2 is fully dependent on the HY5-BBX module. However, the promotion of hypocotyl elongation by SMAX1 and SMXL2 is, in contrast to KAR2 treatment, only partially dependent on BBX20, BBX21, and HY5. Taken together, these results suggest that light- and KAR-dependent signaling intersect at the HY5-BBX transcriptional module.Weniger anzeigen
A series of experiments is carried out to identify the contribution of interface and bulk antiferromagnetic (AFM) spins to exchange bias (EB) in ultrathin epitaxial ferromagnetic (FM)/AFM bilayer samples. These are single-crystalline AFM Ni𝑥Mn100−𝑥 and ferromagnetic Co layers on Cu3Au(001), deposited under ultrahigh vacuum conditions, in which structural or chemical defects are deliberately introduced by controlled Ar ion sputtering at the surface of the AFM layer or at a certain depth inside the AFM layer. Comparison of the magnetic properties measured by magneto-optical Kerr effect for sputtered and nonsputtered parts of the same sample then allows a precise determination of the influence of sputtering on the AFM layer during the sample preparation, whereas all other parameters are kept identical. The results show that the creation of defects in the bulk of the AFM layer enhances the magnitude of EB and its blocking temperature, but not the creation of defects at the interface. It is also observed that the deeper the insertion of defects in the AFM layer, the higher the value of the EB field and the larger the coercivity, These findings are discussed as the effect of additional pinning centers in the bulk of the AFM layer.Weniger anzeigen
Zinc and cadmium atoms from laser ablation of the metals and mercury atoms ablated from a dental amalgam target react with HCN in excess argon during deposition at 5 K to form the MCN and MNC molecules and CN radicals. UV irradiation decreases the higher energy ZnNC isomer in favor of the lower energy ZnCN product. Cadmium and mercury atoms produce analogous MCN primary molecules. Laser ablation of metals also produces plume radiation which initiates H-atom detachment from HCN. The freed H atom can add to CN radical to produce the HNC isomer. The argon matrix also traps the higher energy but more intensely absorbing isocyanide molecules. Further reactions with H atoms generate HMCN and HMNC hydrides, which can be observed by virtue of their C−N stretches and intense M−H stretches. Computational modeling of IR spectra and relative energies guides the identification of reaction products by providing generally reliable frequency differences within the Zn, Cd and Hg family of products, and estimating isotopic shifts using to 13C and 15N isotopic substitution for comparison with experimental data.Weniger anzeigen
Wet-chemical generation of pores in graphene is a challenging synthetic task. Although graphene oxide is available in large quantities and chemically diverse, extended lattice defects already present from synthesis hamper the controlled growth of pores. However, membrane, energy, or nanoelectronic applications essentially require uniform pores in applications. Here, oxo-functionalized graphene (oxoG), a type of graphene oxide with a controlled density of vacancy defects, is used as starting material. Pores in graphene are generated from potassium permanganate treated oxoG and heating from room temperature to 400 °C. With etching time, the size of pores increases and pore-diameters of, for example, 100–200 nm in majority become accessible. The experiments are conducted on the single-layer level on Si/SiO2 wafers. Flakes remain stable on the µm scale and do not fold. The process leads to rims of pores, which are functionalized by carbonyl groups in addition to hydroxyl and carboxyl groups. In addition, it is found that heterostructures with intrinsically n-doped MoS2 can be fabricated and photoluminescence (PL) measurements reveal a 10-fold increased PL. Thus, graphene with pores is a novel highly temperature-stable electron-accepting 2D material to be integrated into van der Waals heterostructures.Weniger anzeigen
Tetracene is an archetypal material undergoing singlet fission—the generation of a pair of triplet excitons from one singlet exciton. Here, using time-resolved electron spin resonance, we show how the spin dynamics in tetracene crystals are influenced by temperature and morphology. Upon cooling from 300 to 200 K, we observe a switch between singlet fission and intersystem crossing generated triplets, manifesting as an inversion in transient spin polarization. We extract a spin dephasing time of approximately 40 ns for fission-generated triplets at room temperature, nearly 100 times shorter than the dephasing time that we measure for triplets localized on isolated tetracene molecules. These results highlight the importance of morphology and thermal activation in singlet fission systems.Weniger anzeigen
Background: Pituitary pars intermedia dysfunction (PPID), a neurodegenerative disease leading to reduced dopamine production, is a common disease in aged horses. The treatment is based on administration of the dopamine agonist pergolide. This drug has been related to valvular fibrosis in humans, but the cardiovascular effect of this drug has not yet been investigated in horses.
Objectives: To determine whether pergolide induces valvular disease in horses or affects the cardiac function.
Methods: Standard, tissue Doppler (TDE) and two-dimensional speckle tracking (STE) echocardiography were performed in horses with diagnosed PPID based on adrenocorticotropic hormone dosage. Measurements taken in horses treated with pergolide were compared with those from untreated horses with nonparametric t-tests. Furthermore, measurements from follow-up examinations performed at least three months after the initial exam were compared with a Wilcoxon signed rank test for repeated measurements in each group.
Results: Twenty-three horses were included. None of the 12 horses under treatment developed valvular regurgitation. Furthermore, no differences in the measurements of the left ventricular systolic or diastolic function could be seen between the group of horses with treatment and those without treatment. Measurements taken in the follow-up exam did not differ compared to those taken in the initial exam in both groups.
Conclusions: No changes of the left ventricular function assessed by TDE and STE could be shown in a small population of horses with confirmed PPID. Treatment with pergolide did not affect the ventricular function nor induce valvular disease.Weniger anzeigen
Soft law instruments such as recommendations, guidelines or communications do not entail jurisdictional control, but produce important legal and practical effects. The literature on soft law frequently praises these instruments for enhancing governance efficiency through flexible problem solving. On the other hand critiques stress a lack of legitimacy as soft law is typically adopted outside the legislative arena. Yet, relatively little is known about concrete effects it takes at the national level. On the basis of case study evidence from Germany, this chapter shows that despite being non-binding, EU soft law is frequently implemented. Comparing implementation of nine soft law instruments in financial market regulation, social and environmental policy the chapter highlights that actors implement soft EU instruments either in the form of soft or hard law. Efficiency gains are frequently a main driver of implementation, while legitimacy and accountability become a concern where responsibilities are blurred during implementation.Weniger anzeigen
This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.Weniger anzeigen
We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.Weniger anzeigen
Amid the COVID-19 pandemic, digital health literacy (DHL) has become a significant public health concern. This research aims to assess information seeking behavior, as well as the ability to find relevant information and deal with DHL among university students in Pakistan. An online-based cross-sectional survey, using a web-based interviewing technique, was conducted to collect data on DHL. Simple bivariate and multivariate linear regression was performed to assess the association of key characteristics with DHL. The results show a high DHL related to COVID-19 in 54.3% of students. Most of the Pakistani students demonstrated similar to 50% DHL in all dimensions, except for reliability. Multivariate findings showed that gender, sense of coherence and importance of information were found to be significantly associated with DHL. However, a negative association was observed with students ' satisfaction with information. This led to the conclusion that critical operational and navigations skills are essential to achieve COVID-19 DHL and cope with stress, particularly to promote both personal and community health. Focused interventions and strategies should be designed to enhance DHL amongst university students to combat the pandemic.Weniger anzeigen
Objectives: We aimed to assess the impact of image context information on the accuracy of deep learning models for tooth classification on panoramic dental radiographs. Methods: Our dataset contained 5008 panoramic radiographs with a mean number of 25.2 teeth per image. Teeth were segmented bounding-box-wise and classified by one expert; this was validated by another expert. Tooth segments were cropped allowing for different context; the baseline size was 100% of each box and was scaled up to capture 150%, 200%, 250% and 300% to increase context. On each of the five generated datasets, ResNet-34 classification models were trained using the Adam optimizer with a learning rate of 0.001 over 25 epochs with a batch size of 16. A total of 20% of the data was used for testing; in subgroup analyses, models were tested only on specific tooth types. Feature visualization using gradient-weighted class activation mapping (Grad-CAM) was employed to visualize salient areas. Results: F1-scores increased monotonically from 0.77 in the base-case (100%) to 0.93 on the largest segments (300%; p = 0.0083; Mann-Kendall-test). Gains in accuracy were limited between 200% and 300%. This behavior was found for all tooth types except canines, where accuracy was much higher even for smaller segments and increasing context yielded only minimal gains. With increasing context salient areas were more widely distributed over each segment; at maximum segment size, the models assessed minimum 3-4 teeth as well as the interdental or inter-arch space to come to a classification. Conclusions: Context matters; classification accuracy increased significantly with increasing context.Weniger anzeigen
The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu2+ inhibited the cell proliferation (inhibitory concentration 50 (IC50) of DSF and DSF/Cu2+ were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were <1). DSF or DSF/Cu2+ abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu2+ reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu2+, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu2+ enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.Weniger anzeigen
Background: Stress and depression are known to contribute to coronary artery disease (CAD) with catecholamines (CA), altering the balance to a pro- and anti-inflammatory stetting and potentially playing a key role in the underlying pathophysiology. This study aimed to elucidate the impact of social stress on the CA system and inflammation markers in patients suffering from CAD and depression. Methods: 93 subjects were exposed to the Trier Social Stress Test (TSST). Based on the results of the depression subscale of the Hospital Anxiety and Depression Scale (HADS, German Version) and the presence/absence of CAD, they were divided into four groups. A total of 21 patients suffered from CAD and depression (+D+CAD), 26 suffered from CAD alone (-D+CAD), and 23 suffered from depression only (+D-CAD); another 23 subjects served as healthy controls (-D-CAD). Subjects were registered at 09:00 AM at the laboratory. A peripheral venous catheter was inserted, and after a 60-min-resting period, the TSST was applied. Prior to and 5, 15, 30, and 60 min after the stress test, plasma epinephrine, norepinephrine, and dopamine concentrations (High Performance Liquid Chromatography (HPLC)) were measured together with the inflammation markers interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). High-sensitive C-reactive protein (hs-CRP, Enzyme-linked Immunosorbent Assay (ELISA)) was measured prior to TSST. Results: (+D-CAD) and (+D+CAD) patients showed significantly lower epinephrine and dopamine levels compared to the (-D+CAD) and (-D-CAD) participants at baseline (prior to TSST). Over the whole measurement period after the TSST, no inter-group difference was detected. Partial correlation (controlling for age, gender and Body Mass Index (BMI)) revealed a significant direct relation between MCP-1 and norepinephrine (r = 0.47, p = 0.03) and MCP-1 and epinephrine (r = 0.46, p = 0.04) in patients with -D+CAD at rest. Conclusions: The stress response of the CA system was not affected by depression or CAD, whereas at baseline we detected a depression-related reduction of epinephrine and dopamine release independent of CAD comorbidity. Reduced norepinephrine and dopamine secretion in the central nervous system in depression, known as 'CA-deficit hypothesis', are targets of antidepressant drugs. Our results point towards a CA-deficit in the peripheral nervous system in line with CA-deficit of the central nervous system and CA exhaustion in depression. This might explain somatic symptoms such as constipation, stomach pain, diarrhoea, sweating, tremor, and the influence of depression on the outcome of somatic illness such as CAD.Weniger anzeigen
Background: periacetabular osteotomy (PAO) is known as the gold standard surgical treatment in young adults with symptomatic hip dysplasia. With the aim of reducing soft tissue trauma, we developed a new rectus and sartorius sparing (RASS) approach. We hypothesized that this new PAO technique was equal regarding acetabular reorientation, complication rate, and short-term clinical outcome parameters, compared to our conventional, rectus sparing (RS) approach. Patients and Methods: we retrospectively assessed all PAO procedures performed by a single surgeon between 2016 and 2019 (n = 239 hips in 217 patients). The cases in which the new RASS technique were used (n = 48) were compared to the RS cases for acetabular orientation parameters, surgical time, perioperative reduction of hemoglobin level, and length of hospital stay (LOHS). Inclusion criteria were a lateral center-edge angle (LCEA) <25 degrees and osteoarthritis Tonnis grade ≤1. Patients with acetabular retroversion or additional femoral osteotomy were excluded. Results: the mean patient age at the time of surgery was 29 years (14 to 50, SD ± 8.5). Females accounted for 79.5% in this series. The mean preoperative LCEA were 16 degrees (7 to 24 degrees, SD ± 4.4) and 15 degrees (0 to 23 degrees, SD ± 6) in the RASS and the RS group, respectively (p = 0.96). The mean preoperative acetabular index (AI) angles were 14 degrees (2 to 25 degrees, SD ± 4) and 14 degrees (7 to 29 degrees, SD ± 4.3), respectively (p = 0.67). The mean postoperative LCEA were significantly improved to 31 degrees (25 to 37 degrees, SD ± 3.5, p < 0.001) and 30.2 degrees (20 to 38 degrees, SD ± 4, p < 0.001), respectively. The mean postoperative AI angles improved to 2.8 degrees (-3 to 13 degrees, SD ± 3.3, p < 0.001) and 3 degrees (-2 to 15 degrees, SD ± 3.3, p < 0.001), respectively. There were no significant differences between the RASS and the RS group for surgical time, perioperative reduction in hemoglobin level, and LOHS. No blood transfusions were necessary perioperatively in either group. No major perioperative complication occurred in either group. We observed one surgical site infection (SSI) requiring superficial debridement in the RS group. Conclusion: the RASS approach for PAO showed to be a safe procedure with equivalent acetabular reorientation and equivalent clinical outcome parameters compared to the RS approach. Additionally, patients have fewer postoperative restrictions in mobilization with the RASS approach.Weniger anzeigen
Diaphragmatic hernia (DH) after a liver resection (LR) is an uncommon but potentially severe complication. In this retrospective study, we aim to share our experience with DH in our hepatic surgery center. We retrospectively analyzed 3107 patients who underwent a liver resection between January 2012 and September 2019. The diagnosis of DH was based on clinical examination and radiological imaging and confirmed by intraoperative findings during surgical repair. Five out of 3107 (0.16%) patients after LR developed DH. Especially, all five DH patients had a major right-sided LR before (n = 716, 0.7%). The mean time interval between initial LR and occurrence of DH was 30 months (range 15 to 44 months). DH exclusively occurred after a right or extended right hepatectomy. Two patients underwent emergency surgery, three were asymptomatic, and DH was diagnosed in follow-up imaging. Three of these five treated patients (60%) developed DH recurrence: two of three (67%) patients after suture repair alone and the only patient after suture repair in combination with an absorbable mesh. The patient who was treated with a composite mesh implant did not show any signs of DH recurrence after 52 months of follow-up. In patients who develop DH after liver surgery, a mesh augmentation with nonresorbable material is generally recommended. In order to diagnose these patients in an early state, we recommend that special attention be paid and a prompt and targeted diagnostic examination of patients with abdominal complaints after right-sided liver resections take place.Weniger anzeigen
Background and Objectives: The programs of enhanced recovery after surgery are the new revolution in surgical departments; however, features of this concept have not been systematically explored. Therefore, the purpose of this study was to explore Enhanced recovery after surgery (ERAS)-related research using bibliometric analysis. Materials and Methods: The search strategy of ERAS programs was conducted in the Web of Science database. Bibliometric analysis was further performed by Excel and Bibliometrix software. The relationship between citation counts and Mendeley readers was assessed by linear regression analysis. Results: 8539 studies from 1994-2019 were included in the present research, with reporting studies originating from 91 countries using 18 languages. The United States (US) published the greatest number of articles. International cooperation was discovered in 82 countries, with the most cooperative country being the United Kingdom. Henrik Kehlet was found to have published the highest number of studies. The journal Anesthesia and Analgesia had the largest number of articles. Linear regression analysis presented a strong positive correlation between citations and Mendeley readers. Most research was related to gastrointestinal surgery in this field. Conclusion: This bibliometric analysis shows the current status of ERAS programs from multiple perspectives, and it provides reference and guidance to scholars for further research.Weniger anzeigen
Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes-key features of RA-and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup.Weniger anzeigen