Benchmarking in the SWISSspine Registry: results of 52 Dynardi lumbar total disc replacements compared with the data pool of 431 other lumbar disc prostheses

The SWISSspine registry is the first mandatory registry of its kind in the history of Swiss orthopaedics and it follows the principle of "coverage with evidence development”. Its goal is the generation of evidence for a decision by the Swiss federal office of health about reimbursement of the concerned technologies and treatments by the basic health insurance of Switzerland. Recently, developed and clinically implemented, the Dynardi total disc arthroplasty (TDA) accounted for 10% of the implanted lumbar TDAs in the registry. We compared the outcomes of patients treated with Dynardi to those of the recipients of the other TDAs in the registry. Between March 2005 and October 2009, 483 patients with single-level TDA were documented in the registry. The 52 patients with a single Dynardi lumbar disc prosthesis implanted by two surgeons (CE and OS) were compared to the 431 patients who received one of the other prostheses. Data were collected in a prospective, observational multicenter mode. Surgery, implant, 3-month, 1-year, and 2-year follow-up forms as well as comorbidity, NASS and EQ-5D questionnaires were collected. For statistical analyses, the Wilcoxon signed-rank test and chi-square test were used. Multivariate regression analyses were also performed. Significant and clinically relevant reduction of low back pain and leg pain as well as improvement in quality of life was seen in both groups (P<0.001 postop vs. preop). There were no inter-group differences regarding postoperative pain levels, intraoperative and follow-up complications or revision procedures with a new hospitalization. However, significantly more Dynardi patients achieved a minimum clinically relevant low back pain alleviation of 18 VAS points and a quality of life improvement of 0.25 EQ-5D points. The patients with Dynardi prosthesis showed a similar outcome to patients receiving the other TDAs in terms of postoperative low back and leg pain, complications, and revision procedures. A higher likelihood for achieving a minimum clinically relevant improvement of low back pain and quality of life in Dynardi patients was observed. This difference might be due to the large number of surgeons using other TDAs compared to only two surgeons using the Dynardi TDA, with corresponding variations in patient selection, patient-physician interaction and other factors, which cannot be assessed in a registry stud

CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner

Fundamental Valuation of Extra-Financial Information

We augment seminal models based on Ohlson (1995) by integrating the value impact of ratings related to three different extra-financial categories, i. e. corporate governance, human capital, and innovation capital. By integrating extra-financial information in valuation models, we examine whether current market values can be better estimated and future stock performance better predicted when considering this information. For a sample of large Euro-pean public firms, we find that a model including human capital information and analysts’ earnings forecasts best explains current stock prices. Our model based on human capital in-formation (without analysts’ forecasts) best identifies under- and overvalued companies

Probing spacetime and accretion model for the Galactic Center: Comparison of Kerr and dilaton black hole shadows

In the vicinity of black holes, the influence of strong gravity, plasma physics, and emission processes govern the behavior of the system. Since observations such as those carried out by the EHT are not yet able to unambiguously constrain models for astrophysical and gravitational properties, it is imperative to explore the accretion models, particle distribution function, and description of the spacetime geometry. Our current understanding of these properties is often based on the assumption that the spacetime is well-described by by the Kerr solution to general relativity, combined with basic emission and accretion models. We explore alternative models for each property performing general relativistic magnetohydrodynamic and radiative transfer simulations. By choosing a Kerr solution to general relativity and a dilaton solution to Einstein-Maxwell-dilaton-axion gravity as exemplary black hole background spacetimes, we aim to investigate the influence of accretion and emission models on the ability to distinguish black holes in two theories of gravity. We carry out three-dimensional general relativistic magnetohydrodynamics simulations of both black holes, matched at their innermost stable circular orbit, in two distinct accretion scenarios. Using general-relativistic radiative transfer calculations, we model the thermal synchrotron emission and in the next step apply a non-thermal electron distribution function, exploring representative parameters to compare with multiwavelength observations. We further consider Kerr and dilaton black holes matched at their unstable circular photon orbits, as well as their event horizons. From multiwavelength emission and spectral index analysis, we find that accretion model and spacetime have only a small impact on the spectra compared to the choice of emission model

Detection of Marker Associated with CTC in Colorectal Cancer in Mononuclear Cells of Patients with Benign Inflammatory Intestinal Diseases

Colorectal carcinoma (CRC) belongs to the most common tumor entities in western countries. Circulating tumor cells (CTC) in blood of CRC patients are a powerful prognostic and predictive biomarker. However, whether CTC-associated markers can also be used for early CRC detection and discrimination from benign diseases is not known. This study investigated the presence of CTC-associated markers CK20, PLS3, LAD1, and DEFA5 in blood of patients with benign inflammatory intestinal disease (IID) and their correlation with malignancy. The detection rate of CK20 and DEFA5 significantly differed between diseased patients and healthy controls. LAD1 and PLS3 were detected in all samples with clear differences in gene expression. DEFA5 expression was higher in CRC and IID patients compared to healthy donors, while CK20 and PLS3 were lower in CRC compared to IID patients or healthy controls. Overall, all CTC-associated markers were detectable in blood of IID patients, but not correlating with inflammation severity. Finally, PLS3 emerged as a suitable marker for differentiation between malignant and non-malignant intestinal diseases or healthy controls, however its suitability for early CRC detection needs to be further validated

Emotional startle modulation in male patients with recent-onset schizophrenia

Patients with schizophrenia suffer from both cognitive as well as emotional disturbances, leading to reduced social functioning and quality of life. This study investigated the ongoing emotional states of medicated and antipsychotic-free patients and healthy controls using an emotional startle paradigm. During positive, neutral and negative emotional pictures, aversive acoustic startle stimuli were presented at 4 different probe latencies (300, 800, 1300 and 3800 ms) from picture onset. In both patients and controls, positive pictures, and more specifically erotic pictures, elicited significantly smaller eye blinks compared with startle stimuli presented during neutral and negative pictures. With regard to the subjective ratings, medicated patients rated erotic pictures significantly less pleasant and the adventure, nature, and household pictures as significantly more arousing than healthy control subjects. The present results indicate the need to further investigate emotional responding to specific picture contents, with specific focus on the sexual needs and expectations of schizophrenic patients, so as to eventually improve the quality of life in these patients

Protein Profiling of Serum Extracellular Vesicles Reveals Qualitative and Quantitative Differences After Differential Ultracentrifugation and ExoQuickTM Isolation

Solid tumor biopsies are the current standard for precision medicine. However, the procedure is invasive and not always feasible. In contrast, liquid biopsies, such as serum enriched for extracellular vesicles (EVs) represent a non-invasive source of cancer biomarkers. In this study, we compared two EV isolation methods in the context of the protein biomarker detection in inflammatory bowel disease (IBD) and colorectal cancer (CRC). Using serum samples of a healthy cohort as well as CRC and IBD patients, EVs were isolated by ultracentrifugation and ExoQuickTM in parallel. EV associated protein profiles were compared by multiplex-fluorescence two-dimensional difference gel electrophoresis (2D-DIGE) and subsequent identification by mass spectrometry. Validation of gelsolin (GSN) was performed using fluorescence-quantitative western blot. 2D-DIGE resolved 936 protein spots in all serum-enriched EVs isolated by ultracentrifugation or ExoQuickTM. Hereof, 93 spots were differently expressed between isolation approaches. Higher levels of GSN in EVs obtained with ExoQuickTM compared to ultracentrifugation were confirmed by western blot (p = 0.0006). Although patient groups were distinguishable after both EV isolation approaches, sample preparation strongly influences EVs' protein profile and thus impacts on inter-study reproducibility, biomarker identification and validation. The results stress the need for strict SOPs in EV research before clinical implementation can be reached

Synthesis of tumor-associated MUC1-glycopeptides and their multivalent presentation by functionalized gold colloids

The mucin MUC1 is a glycoprotein involved in fundamental biological processes, which can be found over-expressed and with a distinctly altered glycan pattern on epithelial tumor cells; thus it is a promising target structure in the quest for effective carbohydrate-based cancer vaccines and immunotherapeutics. Natural glycopeptide antigens indicate only a low immunogenicity and a T-cell independent immune response; however, this major drawback can be overcome by coupling of glycopeptide antigens multivalently to immunostimulating carrier platforms. In particular, gold nanoparticles are well suited as templates for the multivalent presentation of glycopeptide antigens, due to their remarkably high surface-to-volume ratio in combination with their high biostability. In this work the synthesis of novel MUC1-glycopeptide antigens and their coupling to gold nanoparticles of different sizes are presented. In addition, the development of a new dot-blot immunoassay to test the potential antigen-antibody binding is introduced

Longitudinal Analysis of Circulating Tumor Cells in Colorectal Cancer Patients by a Cytological and Molecular Approach: Feasibility and Clinical Application

Introduction Liquid biopsies allowing for individualized risk stratification of cancer patients have become of high significance in individualized cancer diagnostics and treatment. The detection of circulating tumor cells (CTC) has proven to be highly relevant in risk prediction, e.g., in colorectal cancer (CRC) patients. In this study, we investigate the clinical relevance of longitudinal CTC detection over a course of follow-up after surgical resection of the tumor and correlate these findings with clinico-pathological characteristics. Methods In total, 49 patients with histologically proven colorectal carcinoma were recruited for this prospective study. Blood samples were analyzed for CTC presence by two methods: first by marker-dependent immunofluorescence staining combined with automated microscopy with the NYONE® cell imager and additionally, indirectly, by semi-quantitative Cytokeratin-20 (CK20) RT-qPCR. CTC quantification data were compared and correlated with the clinico-pathological parameters. Results Detection of CTC over a post-operative time course was feasible with both applied methods. In patients who were pre-operatively negative for CTCs with the NYONE® method or below the cut-off for relative CK20 mRNA expression after analysis by PCR, a statistically significant rise in the immediate post-operative CTC detection could be demonstrated. Further, in the cohort analyzed by PCR, we detected a lower CTC load in patients who were adjuvantly treated with chemotherapy compared to patients in the follow-up subgroup. This finding was contrary to the same patient subset analyzed with the NYONE® for CTC detection. Conclusion Our study investigates the occurrence of CTC in CRC patients after surgical resection of the primary tumor and during postoperative follow-up. The resection of the tumor has an impact on the CTC quantity and the longitudinal CTC analysis supports the significance of CTC as a prognostic biomarker. Future investigations with an even more extended follow-up period and larger patient cohorts will have to validate our results and may help to define an optimal longitudinal sampling scheme for liquid biopsies in the post-operative monitoring of cancer patients to enable tailored therapy concepts for precision medicine