TY - JOUR A1 - Arnholdt, Jörg A1 - Kamawal, Yama A1 - Holzapfel, Boris Michael A1 - Ripp, Axel A1 - Rudert, Maximilian A1 - Steinert, Andre Friedrich T1 - Evaluation of implant fit and frontal plane alignment after bi-compartmental knee arthroplasty using patient-specific instruments and implants JF - Archives of Medical Science N2 - Introduction The goals of successful bi-compartmental knee arthroplasty are to achieve correct fit and positioning of the implant, while appropriately correcting the mechanical alignment of the leg after surgery. As these requirements are not always reliably fulfilled using off-the-shelf implant systems, newer approaches for bi-compartmental resurfacing have been explored. Material and methods In this article we report the radiographic results of 30 patients with anteromedial osteoarthritis (OA) who were treated with a novel patient-specific fixed-bearing bi-compartmental knee resurfacing system using custom-made implants and instruments. Utilizing standardized pre- and postoperative radiographic analyses (based on anterior-posterior and lateral, anterior-posterior weight-bearing full-length radiographs, patella skyline views and preoperative computed tomography (CT) scanning) implant fit and positioning as well as correction of the mechanical axis (hip-knee-ankle angle, HKA) were determined. Results On average, HKA was corrected from 173.4 ±3.47° preoperatively to 179.4 ±2.85° postoperatively. The coronal femoro-tibial angle was corrected on average 5.61°. The preoperative tibial slope measured on lateral views was 6.38 ±2.4°, while the average slope in the CT-based planning protocol (iView) was 6.14 ±2.40°. Postoperative lateral tibial slope was determined to be 5.77 ±1.97°. The thickness of the posterior femoral cuts was measured intraoperatively and, in all cases, corresponded well to the targeted thickness of the cuts provided by the iView. The joint line was preserved in all cases and the average Insall-Salvati index was 1.078 ±0.11 pre- and 1.072 ±0.11 postoperatively. The fit of the implant components measured by over- or underhang was excellent throughout (< 1.01 mm). Conclusions Custom-made bicompartmental knee arthroplasty can ensure optimized fitting and positioning of the implant with restoration of the leg axis. These implants could be considered as an alternative primary solution for knee surgeons treating bi-compartmental disease. KW - implant fit KW - bi-compartmental knee arthoplasty KW - bi-compartmental KW - implant positioning KW - knee osteoarthritis KW - knee arthroplasty KW - patient-specific KW - knee alignment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159668 VL - 14 IS - 6 ER - TY - JOUR A1 - Kohlmorgen, Britta A1 - Elias, Johannes A1 - Schoen, Christoph T1 - Improved performance of the artus Mycobacterium tuberculosis RG PCR kit in a low incidence setting: a retrospective monocentric study JF - Scientific Reports N2 - Tuberculosis (TB) and the spread of Mycobacterium tuberculosis complex (MTBC) strains resistant against rifampin (RIF) and isoniazid (INH) pose a serious threat to global health. However, rapid and reliable MTBC detection along with RIF/INH susceptibility testing are challenging in low prevalence countries due to the higher rate of false positives. Here, we provide the first performance data for the artus MTBC PCR assay in a low prevalence setting. We analyze 1323 respiratory and 311 non-respiratory samples with the artus MTBC PCR assay as well as by mycobacterial culture and microscopy. We propose retesting of specimens in duplicate and consideration of a determined cycle-threshold value cut-off greater than 34, as this significantly increases accuracy, specificity, and negative predictive value without affecting sensitivity. Furthermore, we tested fourteen MTBC positive samples with the GenoType MTBDRplus test and demonstrate that using an identical DNA extraction protocol for both assays does not impair downstream genotypic testing for RIF and INH susceptibility. In conclusion, our procedure optimizes the use of the artus MTB assay with workload efficient methods in a low incidence setting. Combining the modified artus MTB with the GenoType MTBDRplus assays allows rapid and accurate detection of MTBC and RIF/INH resistance. KW - laboratory techniques and procedures KW - Tuberculosis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159248 VL - 7 IS - 14127 ER - TY - JOUR A1 - Lapa, Constantin A1 - Arias-Loza, Paula A1 - Hayakawa, Nobuyuki A1 - Wakabayashi, Hiroshi A1 - Werner, Rudolf A. A1 - Chen, Xinyu A1 - Shinaji, Tetsuya A1 - Herrmann, Ken A1 - Pelzer, Theo A1 - Higuchi, Takahiro T1 - Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus JF - Scientific Reports N2 - Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake. KW - molecular medicine KW - endocrinology Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159066 VL - 7 ER - TY - JOUR A1 - Hefner, Jochen A1 - Berberich, Sara A1 - Lanvers, Elena A1 - Sanning, Maria A1 - Steimer, Ann-Kathrin A1 - Kunzmann, Volker T1 - New insights into frequency and contents of fear of cancer progression/recurrence (FOP/FCR) in outpatients with colorectal carcinoma (CRC) receiving oral capecitabine: a pilot study at a comprehensive cancer center JF - Patient Preference and Adherence N2 - Background: Fear of cancer progression/recurrence (FOP/FCR) is considered one of the most prevalent sources of distress in cancer survivors and associated with lower quality of life and functional impairment. Detailed measures of FOP/FCR are needed because little is known about the knowledge of FOP/FCR, its associations with the patient–doctor relationship, and the rate of adequate therapy. Colorectal cancer (CRC) is one of the most prevalent cancer entities, and oral capecitabine is widely prescribed as treatment. Therefore, we initiated a pilot study to expand the literature on FOP/FCR in CRC outpatients receiving capecitabine and to generate hypotheses for future investigations. Methods: This study included 58 patients treated at a comprehensive cancer center. FOP/FCR was assessed with the Fear of Progression Questionnaire (FOP-Q-SF). Satisfaction with the relationships with doctors was assessed with the Patient–Doctor Relationship Questionnaire-9 (PRDQ-9). Levels of side effects were rated by the patients on a visual analog scale. Clinical data were extracted from the charts. Results: A total of 19 out of 58 patients (36%) suffered from FOP/FCR according to our assessment. Levels of FOP/FCR seemed to be mostly moderate to high. Only four out of the 19 distressed patients (21%) were treated accordingly. Typical side effects of oncological treatment were associated with higher FOP/FCR. Satisfaction with doctor–patient relationships was not associated with FOP/FCR. Regarding single items of FOP/FCR, three out of the five most prevalent fears were associated with close relatives. Discussion: FOP/FCR occurred frequently in more than one in three patients, but was mostly untreated in this sample of consecutive outpatients with CRC receiving oral capecitabine. In detail, most fears were related to family and friends. In addition to an unmet need of patients, our data indicate sources of distress not considered thus far. If replicated in larger studies, results may help to inform intervention development and improve patient care. KW - fear of progression KW - comprehensive management KW - oral anticancer drugs KW - colorectal cancer KW - screening for distress Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158476 VL - 11 ER - TY - JOUR A1 - Lapa, Constantin A1 - Kircher, Stefan A1 - Schirbel, Andreas A1 - Rosenwald, Andreas A1 - Kropf, Saskia A1 - Pelzer, Theo A1 - Walles, Thorsten A1 - Buck, Andreas K. A1 - Weber, Wolfgang A. A1 - Wester, Hans-Juergen A1 - Herrmann, Ken A1 - Lückerath, Katharina T1 - Targeting CXCR4 with [\(^{68}\)Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma? JF - Oncotarget N2 - C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy. KW - PET KW - CXCR4 KW - [\(^{68}\)Ga] pentixafor KW - pleural mesothelioma KW - theranostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169989 VL - 8 IS - 57 ER - TY - JOUR A1 - Sunkavalli, Ushasree A1 - Aguilar, Carmen A1 - Silva, Ricardo Jorge A1 - Sharan, Malvika A1 - Cruz, Ana Rita A1 - Tawk, Caroline A1 - Maudet, Claire A1 - Mano, Miguel A1 - Eulalio, Ana T1 - Analysis of host microRNA function uncovers a role for miR-29b-2-5p in Shigella capture by filopodia JF - PLoS Pathogens N2 - MicroRNAs play an important role in the interplay between bacterial pathogens and host cells, participating as host defense mechanisms, as well as exploited by bacteria to subvert host cellular functions. Here, we show that microRNAs modulate infection by Shigella flexneri, a major causative agent of bacillary dysentery in humans. Specifically, we characterize the dual regulatory role of miR-29b-2-5p during infection, showing that this microRNA strongly favors Shigella infection by promoting both bacterial binding to host cells and intracellular replication. Using a combination of transcriptome analysis and targeted high-content RNAi screening, we identify UNC5C as a direct target of miR-29b-2-5p and show its pivotal role in the modulation of Shigella binding to host cells. MiR-29b-2-5p, through repression of UNC5C, strongly enhances filopodia formation thus increasing Shigella capture and promoting bacterial invasion. The increase of filopodia formation mediated by miR-29b-2-5p is dependent on RhoF and Cdc42 Rho-GTPases. Interestingly, the levels of miR-29b-2-5p, but not of other mature microRNAs from the same precursor, are decreased upon Shigella replication at late times post-infection, through degradation of the mature microRNA by the exonuclease PNPT1. While the relatively high basal levels of miR-29b-2-5p at the start of infection ensure efficient Shigella capture by host cell filopodia, dampening of miR-29b-2-5p levels later during infection may constitute a bacterial strategy to favor a balanced intracellular replication to avoid premature cell death and favor dissemination to neighboring cells, or alternatively, part of the host response to counteract Shigella infection. Overall, these findings reveal a previously unappreciated role of microRNAs, and in particular miR-29b-2-5p, in the interaction of Shigella with host cells. KW - hos tcells KW - Salmonellosis KW - Shigellosis KW - microRNAs KW - Shigella KW - small interfering RNAs KW - HeLa cells KW - Cell binding Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158204 VL - 13 IS - 4 ER - TY - JOUR A1 - Pieczykolan, Aleks A1 - Huestegge, Lynn T1 - Cross-modal Action Complexity: Action- and Rule-related Memory Retrieval in Dual-response Control JF - Frontiers in Psychology N2 - Normally, we do not act within a single effector system only, but rather coordinate actions across several output modules (cross-modal action). Such cross-modal action demands can vary substantially with respect to their complexity in terms of the number of task-relevant response combinations and to-be-retrieved stimulus-response (S-R) mapping rules. In the present study, we study the impact of these two types of cross-modal action complexity on dual-response costs (i.e., performance differences between single- and dual-action demands). In Experiment 1, we combined a manual and an oculomotor task, each involving four response alternatives. Crucially, one (unconstrained) condition involved all 16 possible combinations of response alternatives, whereas a constrained condition involved only a subset of possible response combinations. The results revealed that preparing for a larger number of response combinations yielded a significant, but moderate increase in dual-response costs. In Experiment 2, we utilized one common lateralized auditory (e.g., left) stimulus to trigger incompatible response compounds (e.g., left saccade and right key press or vice versa). While one condition only involved one set of task-relevant S-R rules, another condition involved two sets of task-relevant rules (coded by stimulus type: noise/tone), while the number of task-relevant response combinations was the same in both conditions. Here, an increase in the number of to-be-retrieved S-R rules was associated with a substantial increase in dual-response costs that were also modulated on a trial-by-trial basis when switching between rules. Taken together, the results shed further light on the dependency of cross-modal action control on both action- and rule-related memory retrieval processes. KW - task rules KW - cross-modal action KW - dual tasks KW - dual-response costs KW - oculomotor control Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157794 VL - 8 IS - 529 ER - TY - JOUR A1 - Schmidt, Marianne A1 - Skaf, Josef A1 - Gavril, Georgiana A1 - Polednik, Christine A1 - Roller, Jeanette A1 - Kessler, Michael A1 - Holzgrabe, Ulrike T1 - The influence of Osmunda regalis root extract on head and neck cancer cell proliferation, invasion and gene expression JF - BMC Complementary and Alternative Medicine N2 - Background: According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines. Methods: Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay. Results: O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract. Conclusion: The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients. KW - head and neck carcinoma KW - invasion KW - plant extract KW - proliferation KW - HNSCC KW - metastasis KW - gene expression KW - Osmunda regalis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158704 VL - 17 IS - 518 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Schmid, Jan S. A1 - Schirbel, Andreas A1 - Lassmann, Michael A1 - Wild, Vanessa A1 - Rudelius, Martina A1 - Kudlich, Theodor A1 - Herrmann, Ken A1 - Scheurlen, Michael A1 - Buck, Andreas K. A1 - Kropf, Saskia A1 - Wester, Hans-Jürgen A1 - Lapa, Constantin T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach JF - Theranostics N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors. KW - SSTR KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor KW - [\(^{68}\)Ga]Pentixafor KW - CXCR4 KW - chemokine receptor KW - PET/CT KW - DOTATOC KW - PRRT KW - Positronen-Emissions-Tomografie Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008 VL - 7 IS - 6 ER - TY - JOUR A1 - Emmert, Adrian A1 - Kneisel, Christof T1 - Internal structure of two alpine rock glaciers investigated by quasi-3-D electrical resistivity imaging JF - The Cryosphere N2 - Interactions between different formative processes are reflected in the internal structure of rock glaciers. Therefore, the detection of subsurface conditions can help to enhance our understanding of landform development. For an assessment of subsurface conditions, we present an analysis of the spatial variability of active layer thickness, ground ice content and frost table topography for two different rock glaciers in the Eastern Swiss Alps by means of quasi-3-D electrical resistivity imaging (ERI). This approach enables an extensive mapping of subsurface structures and a spatial overlay between site-specific surface and subsurface characteristics. At Nair rock glacier, we discovered a gradual descent of the frost table in a downslope direction and a constant decrease of ice content which follows the observed surface topography. This is attributed to ice formation by refreezing meltwater from an embedded snow bank or from a subsurface ice patch which reshapes the permafrost layer. The heterogeneous ground ice distribution at Uertsch rock glacier indicates that multiple processes on different time domains were involved in the development. Resistivity values which represent frozen conditions vary within a wide range and indicate a successive formation which includes several advances, past glacial overrides and creep processes on the rock glacier surface. In combination with the observed topography, quasi-3-D ERI enables us to delimit areas of extensive and compressive flow in close proximity. Excellent data quality was provided by a good coupling of electrodes to the ground in the pebbly material of the investigated rock glaciers. Results show the value of the quasi-3-D ERI approach but advise the application of complementary geophysical methods for interpreting the results. KW - Fernerkundung KW - Gletscher KW - Alpen KW - Struktur Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157569 VL - 11 ER - TY - JOUR A1 - Kraft, Peter A1 - Fleischer, Anna A1 - Wiedmann, Silke A1 - Rücker, Viktoria A1 - Mackenrodt, Daniel A1 - Morbach, Caroline A1 - Malzahn, Uwe A1 - Kleinschnitz, Christoph A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study JF - BMC Neurology N2 - Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital Würzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95% confidence intervals (95% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71–0.89) to 0.93 (95% CI 0.87–0.96), and κ from 0.39 (−95% CI 0.14–0.92) to 0.79 (95% CI 0.67–0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96–1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95% CI 0.40–0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies. KW - ischemic stroke KW - systolic dysfunction KW - point-of-care echocardiography KW - ejection fraction KW - stroke unit KW - feasibility KW - accuracy Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158081 VL - 17 IS - 159 ER - TY - JOUR A1 - Lagler, Charlotte A1 - El-Mesery, Mohamed A1 - Kübler, Alexander Christian A1 - Müller-Richter, Urs Dietmar Achim A1 - Stühmer, Thorsten A1 - Nickel, Joachim A1 - Müller, Thomas Dieter A1 - Wajant, Harald A1 - Seher, Axel T1 - The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent JF - PLoS ONE N2 - Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2. KW - apoptosis KW - gene expression KW - necrotic cell death KW - multiple myeloma KW - cell metabolism KW - cell cycle and cell division KW - B cells Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158993 VL - 12 IS - 10 ER - TY - JOUR A1 - Morbach, Caroline A1 - Wagner, Martin A1 - Güntner, Stefan A1 - Malsch, Carolin A1 - Oezkur, Mehmet A1 - Wood, David A1 - Kotseva, Kornelia A1 - Leyh, Rainer A1 - Ertl, Georg A1 - Karmann, Wolfgang A1 - Heuschmann, Peter U A1 - Störk, Stefan T1 - Heart failure in patients with coronary heart disease: Prevalence, characteristics and guideline implementation - Results from the German EuroAspire IV cohort JF - BMC Cardiovascular Disorders N2 - Background: Adherence to pharmacotherapeutic treatment guidelines in patients with heart failure (HF) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Our aim was to investigate prevalence and characteristics of HF in patients with coronary heart disease (CHD), and to assess the adherence to current HF guidelines in patients with HF stage C, thus identifying potential targets for the optimization of guideline implementation. Methods: Patients from the German sample of the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EuroAspire) IV survey with a hospitalization for CHD within the previous six to 36 months providing valid data on echocardiography as well as on signs and symptoms of HF were categorized into stages of HF: A, prevalence of risk factors for developing HF; B, asymptomatic but with structural heart disease; C, symptomatic HF. A Guideline Adherence Indicator (GAI-3) was calculated for patients with reduced (≤40%) left ventricular ejection fraction (HFrEF) as number of drugs taken per number of drugs indicated; beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRA) were considered. Results: 509/536 patients entered analysis. HF stage A was prevalent in n = 20 (3.9%), stage B in n = 264 (51.9%), and stage C in n = 225 (44.2%) patients; 94/225 patients were diagnosed with HFrEF (42%). Stage C patients were older, had a longer duration of CHD, and a higher prevalence of arterial hypertension. Awareness of pre-diagnosed HF was low (19%). Overall GAI-3 of HFrEF patients was 96.4% with a trend towards lower GAI-3 in patients with lower LVEF due to less thorough MRA prescription. Conclusions: In our sample of CHD patients, prevalence of HF stage C was high and a sizable subgroup suffered from HFrEF. Overall, pharmacotherapy was fairly well implemented in HFrEF patients, although somewhat worse in patients with more reduced ejection fraction. Two major targets were identified possibly suited to further improve the implementation of HF guidelines: 1) increase patients´ awareness of diagnosis and importance of HF; and 2) disseminate knowledge about the importance of appropriately implementing the use of mineralocorticoid receptor antagonists. Trial registration: This is a cross-sectional analysis of a non-interventional study. Therefore, it was not registered as an interventional trial. KW - awareness KW - heart failure KW - pharmacotherapy KW - coronary artery disease KW - coronary heart disease KW - euroaspire KW - guideline adherence KW - guideline implementation KW - mineralocorticoid antagonist KW - preserved ejection fraction Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157738 VL - 17 IS - 108 ER - TY - JOUR A1 - Wegert, Jenny A1 - Vokuh, Christian A1 - Ziegler, Barbara A1 - Ernestus, Karen A1 - Leuschner, Ivo A1 - Furtwängler, Rhoikos A1 - Graf, Norbert A1 - Gessler, Manfred T1 - TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia JF - The Journal of Pathology: Clinical Research N2 - TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87%), but this rate dropped to 26% for stages II–IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease. KW - tumour heterogeneity KW - Wilms tumour KW - nephroblastoma KW - anaplasia KW - TP53 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158302 VL - 3 ER - TY - JOUR A1 - Jessberger, Steffen A1 - Högger, Petra A1 - Genest, Franca A1 - Salter, Donald M. A1 - Seefried, Lothar T1 - Cellular pharmacodynamic effects of Pycnogenol\(^{®}\) in patients with severe osteoarthritis: a randomized controlled pilot study JF - BMC Complementary and Alternative Medicine N2 - Background: The standardized maritime pine bark extract (Pycnogenol\(^{®}\)) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol\(^{®}\) and its in vivo mechanism of action in OA patients. Methods: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol\(^{®}\) twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. Results: The oral intake of Pycnogenol\(^{®}\) downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. Conclusions: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol\(^{®}\) on symptom scores of patients suffering from OA. KW - maritime pine bark extract KW - qPCR KW - ADAMTS KW - cartilage KW - clinical study KW - osteoarthritis KW - Pycnogenol KW - serum KW - synovial fluid Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159532 VL - 17 IS - 537 ER - TY - JOUR A1 - Polat, Bülent A1 - Kaiser, Philipp A1 - Wohlleben, Gisela A1 - Gehrke, Thomas A1 - Scherzad, Agmal A1 - Scheich, Matthias A1 - Malzahn, Uwe A1 - Fischer, Thomas A1 - Vordermark, Dirk A1 - Flentje, Michael T1 - Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer JF - BMC Cancer N2 - Background: In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery. Methods: Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2). Results: A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003). Conclusions: Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact. KW - perioperative changes KW - osteopontin KW - TGFβ1 KW - head and neck cancer KW - survival Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157529 VL - 17 IS - 6 ER - TY - JOUR A1 - Sayed, Sameh A1 - Schimmer, Christoph A1 - Shade, Ina A1 - Leyh, Rainer A1 - Aleksic, Ivan T1 - Combined pulmonary and left ventricular support with veno-pulmonary ECMO and impella 5.0 for cardiogenic shock after coronary surgery JF - Journal of Cardiothoracic Surgery N2 - Background: Mechanical circulatory support is a common practice nowadays in the management of patients after cardiogenic shock due to myocardial infarction. The single or combined use of one or more devices for mechanical support depends not only on the advantage or disadvantage of these devices but also on the timing of use of these devices before the development of multi organ failure. In our case we used more than one tool for mechanical circulatory support during the prolonged and complicated course of our patient with postcardiotomy cardiogenic shock after coronary artery bypass surgery. Case Presentation: We describe the combined use of Impella 5.0 and veno- pulmonary extra corporeal membrane oxygenation (VP-ECMO) for biventricular failure in a 52 years—old man. He presented with cardiogenic shock after inferior wall ST-elevation myocardial infarction. After emergency coronary artery bypass surgery and failure to wean from extracorporeal circulation we employed V-P ECMO and consecutively Impella 5.0 to manage the primarily failing right and secondarily failing left ventricles. He remained hemodynamically stable on both Impella 5.0 and VP-ECMO until Heart Mate II left ventricular assist device implantation on the 14th postoperative day. Right sided support was weaned on 66th postoperative day. The patient remained in the intensive care unit for 77 days. During his prolonged stay, he underwent renal replacement therapy and tracheostomy with complete recovery. Six months later, he was successfully heart transplanted and has completed three and half years of unremarkable follow up. Conclusions: The combined use of VP ECMO and Impella 5.0 is effective in the management of postcardiotomy biventricular failure as a bridge for further mechanical support or heart transplantation. KW - cardiogenic shock KW - extra corporeal membrane oxygenator KW - impella 5.0 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157598 VL - 12 IS - 38 ER - TY - JOUR A1 - Döhler, Anja A1 - Schneider, Theresa A1 - Eckert, Ina A1 - Ribechini, Eliana A1 - Andreas, Nico A1 - Riemann, Marc A1 - Reizis, Boris A1 - Weih, Falk A1 - Lutz, Manfred B. T1 - RelB\(^{+}\) Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3\(^{+}\) Regulatory T Cells JF - Frontiers in Immunology N2 - Thymus-derived natural Foxp3\(^{+}\) CD4\(^{+}\) regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelB\(^{fl/fl}\) mice (RelB\(^{DCko}\)), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103\(^{-}\) Langerin\(^{-}\) dermal DCs (dDCs) and Langerhans cells but not CD103\(^{+}\) Langerin\(^{+}\) dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4\(^{+}\) CD44\(^{high}\) CD25\(^{low}\) memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelB\(^{DCko}\) mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelB\(^{DCko}\) mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2\(^{+}\) Tml frequencies during homeostasis. KW - lymph nodes KW - dendritic cells KW - RelB KW - regulatory T cells KW - IL-2 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158121 VL - 8 IS - 726 ER - TY - JOUR A1 - Langenhorst, Daniela A1 - Tabares, Paula A1 - Gulde, Tobias A1 - Becklund, Bryan R. A1 - Berr, Susanne A1 - Surh, Charles D. A1 - Beyersdorf, Niklas A1 - Hünig, Thomas T1 - Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation JF - Frontiers in Immunology N2 - In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4\(^{+}\) T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity. KW - D665 KW - regulatory T cells KW - self-reactivity KW - autoimmunity KW - CD28 superagonists KW - TGN1412 KW - TAB08 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159387 VL - 8 IS - 1985 ER - TY - JOUR A1 - Born, Dennis-Peter A1 - Zinner, Christoph A1 - Sperlich, Billy T1 - The mucosal immune function is not compromised during a period of high-intensity interval training. Is it time to reconsider an old assumption? JF - Frontiers in Physiology N2 - Purpose: The aim of the study was to evaluate the mucosal immune function and circadian variation of salivary cortisol, Immunoglobin-A (sIgA) secretion rate and mood during a period of high-intensity interval training (HIIT) compared to long-slow distance training (LSD). Methods: Recreational male runners (n = 28) completed nine sessions of either HIIT or LSD within 3 weeks. The HIIT involved 4 × 4 min of running at 90–95% of maximum heart rate interspersed with 3 min of active recovery while the LSD comprised of continuous running at 70–75% of maximum heart rate for 60–80 min. The psycho-immunological stress-response was investigated with a full daily profile of salivary cortisol and immunoglobin-A (sIgA) secretion rate along with the mood state on a baseline day, the first and last day of training and at follow-up 4 days after the last day of training. Before and after the training period, each athlete's running performance and peak oxygen uptake (V·O\(_{2peak}\)) was determined with an incremental exercise test. Results: The HIIT resulted in a longer time-to-exhaustion (P = 0.02) and increased V·O\(_{2peak}\) compared to LSD (P = 0.01). The circadian variation of sIgA secretion rate showed highest values in the morning immediately after waking up followed by a decrease throughout the day in both groups (P < 0.05). With HIIT, the wake-up response of sIgA secretion rate was higher on the last day of training (P < 0.01) as well as the area under the curve (AUC\(_{G}\)) higher on the first and last day of training and follow-up compared to the LSD (P = 0.01). Also the AUC\(_{G}\) for the sIgA secretion rate correlated with the increase in V·O\(_{2peak}\) and running performance. The AUC\(_{G}\) for cortisol remained unaffected on the first and last day of training but increased on the follow-up day with both, HIIT and LSD (P < 0.01). Conclusion: The increased sIgA secretion rate with the HIIT indicates no compromised mucosal immune function compared to LSD and shows the functional adaptation of the mucosal immune system in response to the increased stress and training load of nine sessions of HIIT. KW - high-volume training KW - periodization KW - circadian rhythm KW - cortisol KW - diurnal profile KW - endurance KW - immunoglobin-A Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158025 VL - 8 IS - 485 ER -