Mesenchymal stem or stromal cells (MSC) are under investigation as a potential immunotherapy. MSC are usually administered via intravenous infusion, after which they are trapped in the lungs and die ...and disappear within a day. The fate of MSC after their disappearance from the lungs is unknown and it is unclear how MSC realize their immunomodulatory effects in their short lifespan. We examined immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it. Tracking viable and dead human umbilical cord MSC (ucMSC) in mice using Qtracker beads (contained in viable cells) and Hoechst33342 (staining all cells) revealed that viable ucMSC were present in the lungs immediately after infusion. Twenty‐four hours later, the majority of ucMSC were dead and found in the lungs and liver where they were contained in monocytic cells of predominantly non‐classical Ly6Clow phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14++/CD16‐ classical monocytes polarized toward a non‐classical CD14++CD16+CD206+ phenotype after phagocytosis of ucMSC and expressed programmed death ligand‐1 and IL‐10, while TNF‐α was reduced. ucMSC‐primed monocytes induced Foxp3+ regulatory T cell formation in mixed lymphocyte reactions. These results demonstrate that infused MSC are rapidly phagocytosed by monocytes, which subsequently migrate from the lungs to other body sites. Phagocytosis of ucMSC induces phenotypical and functional changes in monocytes, which subsequently modulate cells of the adaptive immune system. It can be concluded that monocytes play a crucial role in mediating, distributing, and transferring the immunomodulatory effect of MSC. Stem Cells 2018;36:602–615
Overview of the interaction of monocytic cells with infused mesenchymal stem or stromal cells (MSCs). Umbilical cord MSC (ucMSC) get entrapped in the lungs after intravenous infusion and are rapidly cleared from the system through phagocytosis by neutrophils, lung resident macrophages, and circulating monocytes. Monocytes containing ucMSC migrate via the blood stream to other sites, in particular to the liver. In addition, debris of ucMSC ends up in the liver where it is phagocytosed by liver‐resident Kupffer cells. Phagocytosis of ucMSC induces an immunomodulatory phenotype in monocytes and ucMSC‐primed monocytes induces Foxp3+CD25hiCD127‐CD4+ regulatory T cells.
Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and ...cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.
It is unclear whether cemented or uncemented hemiarthroplasty is the best treatment option in elderly patients with displaced femoral neck fractures. Previous randomized trials comparing cemented and ...uncemented hemiarthroplasty have conflicting results. We conducted a randomized controlled trial to compare cemented and uncemented hemiarthroplasty.
This multicenter parallel-randomized controlled trial included patients of 70 years and older with a displaced femoral neck fracture (Garden type III or IV). Inclusion was between August 2008 and June 2012. Patients were randomized between a cemented hemiarthroplasty, type Müller Straight Stem or an uncemented hemiarthroplasty, type DB-10. Primary outcomes were complications, operation time, functional outcome (measured by Timed-Up-and-Go (TUG) and Groningen Activity Restriction Scale (GARS)) and mid-thigh pain. Health Related Quality of Life (HRQoL, expressed with the SF-12) was measured as an secondary outcome. Follow up was 1 year.
In total 201 patients were included in the study (91 uncemented, 110 cemented hemiarthroplasties) The uncemented group showed more major local complications (intra- and postoperative fractures and dislocations) odds ratio (95% confidence interval) 3.36 (1.40 to 8.11). There was no difference in mean operation time (57.3 vs 55.4 min). There were no differences in functional outcomes (TUG 12.8 (9.4) vs. 13.9 (9.0), GARS 43.2 (19.7) vs. 39.2 (16.5)) and mid-thigh pain (18.6 vs 21.6%). Physical component SF-12 HRQoLwas lower in the uncemented group (30.3 vs. 35.3 p < 0.05 after six weeks, 33.8 vs 38.5 p < 0.05 after 12 weeks).
A cemented hemiarthroplasty in elderly patients with a displaced femoral neck fracture results in less complications compared to an uncemented hemiarthroplasty.
Netherlands Trial Registry; NTR 1508 , accepted date 27 okt 2008.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Aims Volumetric laser endomicroscopy (VLE) is an advanced imaging system that provides a near-microscopic resolution scan of the esophageal wall layers up to 3-mm deep. VLE has the ...potential to improve detection of early neoplasia in Barrett’s esophagus (BE). However, interpretation of VLE images is complex because of the large amount of data that need to be interpreted in real time. The aim of this study was to investigate the feasibility of a computer algorithm to identify early BE neoplasia on ex vivo VLE images. Methods We used 60 VLE images from a database of high-quality ex vivo VLE-histology correlations, obtained from BE patients ± neoplasia (30 nondysplastic BE NDBE and 30 high-grade dysplasia/early adenocarcinoma images). VLE features from a recently developed clinical VLE prediction score for BE neoplasia served as input for the algorithm: (1) higher VLE surface than subsurface signal and (2) lack of layering. With this input, novel clinically inspired algorithm features were developed, based on signal intensity statistics and grayscale correlations. For comparison, generic image analysis methods were examined for their performance to detect neoplasia. For classification of the images in the NDBE or neoplastic group, several machine learning methods were evaluated. Leave-1-out cross-validation was used for algorithm validation. Results Three novel clinically inspired algorithm features were developed. The feature “layering and signal decay statistics” showed the optimal performance compared with the other clinically features (“layering” and “signal intensity distribution”) and generic image analyses methods, with an area under the receiver operating characteristic curve (AUC) of .95. Corresponding sensitivity and specificity were 90% and 93%, respectively. In addition, the algorithm showed a better performance than the clinical VLE prediction score (AUC .81). Conclusions This is the first study in which a computer algorithm for BE neoplasia was developed based on VLE images with direct histologic correlates. The algorithm showed good performance to detect BE neoplasia in ex vivo VLE images compared with the performance of a recently developed clinical VLE prediction score. This study suggests that an automatic detection algorithm has the potential to assist endoscopists in detecting early neoplasia on VLE. Future studies on in vivo VLE scans are needed to further validate the algorithm.
Control of slippage with tunable bubble mattresses Karatay, Elif; Haase, A. Sander; Visser, Claas Willem ...
Proceedings of the National Academy of Sciences - PNAS,
05/2013, Letnik:
110, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Tailoring the hydrodynamic boundary condition is essential for both applied and fundamental aspects of drag reduction. Hydrodynamic friction on superhydrophobic substrates providing gas–liquid ...interfaces can potentially be optimized by controlling the interface geometry. Therefore, establishing stable and optimal interfaces is crucial but rather challenging. Here we present unique superhydrophobic microfluidic devices that allow the presence of stable and controllable microbubbles at the boundary of microchannels. We experimentally and numerically examine the effect of microbubble geometry on the slippage at high resolution. The effective slip length is obtained for a wide range of protrusion angles, θ , of the microbubbles into the flow, using a microparticle image velocimetry technique. Our numerical results reveal a maximum effective slip length, corresponding to a 23% drag reduction at an optimal θ ≈ 10°. In agreement with the simulation results, our measurements correspond to up to 21% drag reduction when θ is in the range of −2° to 12°. The experimental and numerical results reveal a decrease in slip length with increasing protrusion angles when θ ≳ 10°. Such microfluidic devices with tunable slippage are essential for the amplified interfacial transport of fluids and particles.
The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are ...characterized by an abrogation of plasmablast formation and induction of regulatory B cells (Bregs). It is, however, unknown how MSC interact with B cells under inflammatory conditions. In this study, adipose tissue-derived MSC were pretreated with 50 ng/ml IFN-γ for 96 h (MSC-IFN-γ) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43
selection. B cells were co-cultured with MSC and stimulated with anti-IgM, anti-CD40, and IL-2; and after 7 days, B cell proliferation, phenotype, Immunoglobulin-G (IgG), and IL-10 production were analyzed. MSC did not inhibit B cell proliferation but increased the percentage of CD38
CD24
B cells (Bregs) and IL-10 production, while MSC-IFN-γ significantly reduced B cell proliferation and inhibited IgG production by B cells in a more potent fashion but did not induce Bregs or IL-10 production. Both MSC and MSC-IFN-γ required proximity to target cells and being metabolically active to exert their effects. Indoleamine 2,3 dioxygenase expression was highly induced in MSC-IFN-γ and was responsible of the anti-proliferative and Breg reduction since addition of tryptophan (TRP) restored MSC properties. Immunological conditions dictate the effect of MSC on B cell function. Under immunological quiescent conditions, MSC stimulate Breg induction; whereas, under inflammatory conditions, MSC inhibit B cell proliferation and maturation through depletion of TRP. This knowledge is useful for customizing MSC therapy for specific purposes by appropriate pretreatment of MSC.
The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce ...remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (
< 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (
< 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.
Expected survival is a major factor influencing extent of treatment for symptomatic spinal bone metastases (SBM). Predictive models have been developed, but their use can lead to over- or ...undertreatment.. The study objective was to identify prognostic factors associated with survival in patients with symptomatic SBM and to create a validated risk stratification model.
All patients who were treated for symptomatic SBM between 2001 and 2010 were included in this single center retrospective study. Medical records were reviewed for type of primary cancer, performance status, presence of visceral, brain and bone metastases, number and location of spinal metastases, and neurological functioning. Performance status was assessed with the Karnofsky performance score and neurological functioning with the Frankel scale. Analysis was performed using Kaplan-Meier curves, univariate log-rank tests, Cox regression models, and Harrell's C statistic.
A total of 1 043 patients were studied. The most prevalent tumors were those of breast (n = 299), lung (n = 250), and prostate (n = 215). Median follow-up duration was 6.6 years, and 6 patients were lost to follow-up. Based on the results of the uni- and multivariate analyses, 4 categories were created. Median survival in category A was 31.2 months (95% CI, 25.2-37.3 months), 15.4 months (95% CI, 11.9-18.2 months) for category B, 4.8 months (95% CI, 4.1-5.4 months) for category C, and 1.6 months (95% CI, 1.4-1.9 months) for category D. Harrell's C statistic was calculated after the model was applied to an external dataset, yielding a result of 0.69.
Assessing patients according to the presented model results in 4 categories with significantly different survival times.
Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet ...unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways.
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