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Koch, Agnes Antonia Sophie ; Sponholz, Stefan ; Trainer, Stephan ; Stratmann, Jan Alexander ; Sebastian, Martin ; Rauch, Maximilian ; Wolff, Robert ; Steinbach, Joachim Peter ; Ronellenfitsch, Michael Wilfried ; Urban, Hans
Brain metastases are a common finding upon initial diagnosis of otherwise locally limited non-small cell lung cancer. We present a retrospective case series describing three cases of patients with symptomatic, synchronous brain metastases and resectable lung tumors. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab. Afterwards, resection of the pulmonary lesion with curative intent was performed. One patient showed progressive disease 12 months after initial diagnosis, and passed away 31 months after initial diagnosis. Two of the patients are still alive and maintain a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, illustrating the potential of novel combinatorial treatment approaches.
Mäder, Lisa ; Blank, Anna-Eva ; Capper, David ; Jansong, Janina ; Baumgarten, Peter ; Wirsik, Naita M. ; Zachskorn, Cornelia ; Ehlers, Jakob ; Seifert, Michael ; Klink, Barbara ; Liebner, Stefan ; Niclou, Simone P. ; Naumann, Ulrike ; Harter, Patrick Nikolaus ; Mittelbronn, Michel Guy André
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.
We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.
Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.
In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.
Hau, Peter ; Frappaz, Didier ; Hovey, Elizabeth ; McCabe, Martin G. ; Pajtler, Kristian Wilfried ; Wiestler, Benedikt ; Seidel, Clemens ; Combs, Stephanie ; Dirven, Linda ; Klein, Martin ; Anazodo, Antoinette ; Hattingen, Elke ; Hofer, Silvia ; Pfister, Stefan ; Zimmer, Claus ; Kortmann, Rolf-Dieter ; Sunyach, Marie-Pierre ; Tanguy, Ronan ; Effeney, Rachel ; Deimling, Andreas von ; Sahm, Felix ; Rutkowski, Stefan ; Berghoff, Anna ; Franceschi, Enrico ; Pineda, Estela ; Beier, Dagmar ; Peeters, Ellen ; Gorlia, Thierry ; Vanlancker, Maureen ; Bromberg, Jacoline E. C. ; Gautier, Julien ; Ziegler, David S. ; Preusser, Matthias ; Wick, Wolfgang ; Weller, Michael
Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
Capper, David ; Deimling, Andreas von ; Brandes, Alba ; Carpentier, Antoine F. ; Kesari, Santosh ; Sepulveda-Sanchez, Juan M. ; Wheeler, Helen Rippier ; Chinot, Olivier ; Cher, Lawrence ; Steinbach, Joachim Peter ; Specenier, Pol ; Rodon, Jordi ; Cleverly, Ann ; Smith, Claire ; Gueorguieva, Ivelina ; Miles, Colin ; Guba, Susan ; Desaiah, Durisala ; Estrem, Shawn T. ; Lahn, Michael ; Wick, Wolfgang
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.
Arvaniti, Eirini ; Fricker, Kim S. ; Moret, Michael ; Rupp, Niels Jan Felix ; Hermanns, Thomas ; Fankhauser, Christian D. ; Wey, Norbert ; Wild, Peter Johannes ; Rüschoff, Jan Hendrik ; Claassen, Manfred
The Gleason grading system remains the most powerful prognostic predictor for patients with prostate cancer since the 1960s. Its application requires highly-trained pathologists, is tedious and yet suffers from limited inter-pathologist reproducibility, especially for the intermediate Gleason score 7. Automated annotation procedures constitute a viable solution to remedy these limitations. In this study, we present a deep learning approach for automated Gleason grading of prostate cancer tissue microarrays with Hematoxylin and Eosin (H&E) staining. Our system was trained using detailed Gleason annotations on a discovery cohort of 641 patients and was then evaluated on an independent test cohort of 245 patients annotated by two pathologists. On the test cohort, the inter-annotator agreements between the model and each pathologist, quantified via Cohen’s quadratic kappa statistic, were 0.75 and 0.71 respectively, comparable with the inter-pathologist agreement (kappa = 0.71). Furthermore, the model’s Gleason score assignments achieved pathology expert-level stratification of patients into prognostically distinct groups, on the basis of disease-specific survival data available for the test cohort. Overall, our study shows promising results regarding the applicability of deep learning-based solutions towards more objective and reproducible prostate cancer grading, especially for cases with heterogeneous Gleason patterns.
Adam, Elisabeth ; Schmid, Benedikt ; Sonntagbauer, Michael ; Kranke, Peter ; Zacharowski, Kai ; Meybohm, Patrick
Rothweiler, Florian ; Michaelis, Martin ; Brauer, Peter ; Otte, Jürgen ; Weber, Kristoffer ; Fehse, Boris ; Doerr, Hans Wilhelm ; Wiese, Michael ; Kreuter, Jörg ; Abed, Yousef al- ; Nicoletti, Ferdinando ; Cinatl, Jindrich
The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
Leeuwen, Tessa M. van ; Sauer, Andreas ; Jurjut, Anna-Maria ; Wibral, Michael ; Uhlhaas, Peter J. ; Singer, Wolf ; Melloni, Lucia
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors—introduced during the hysteresis experiment—lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Bernatz, Simon ; Monden, Daniel ; Geßler, Florian ; Radić, Tijana ; Hattingen, Elke ; Senft, Christian ; Seifert, Volker ; Ronellenfitsch, Michael Wilfried ; Plate, Karl ; Harter, Patrick Nikolaus ; Baumgarten, Peter
Higher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.
Parvini, Puria ; Saminsky, Michael ; Stanner, Julia ; Klum, Matthias ; Nickles, Katrin ; Eickholz, Peter
Objective: To compare discomfort/pain following periodontal probing around teeth and peri‐implant probing around implants with or without platform switching.
Methods: Two dentists recruited and examined 65 patients, each of them exhibiting a dental implant with a contralateral tooth. Only two types of implants were included: one with and one without platform switching. Periodontal and peri‐implant probing depths (PPD) and probing attachment level (PAL) were assessed. Whether implant or tooth was measured first was randomly assigned. Immediately after probing, patients scored discomfort/pain using a visual analogue scale (VAS). The emergence profiles of implant crowns were assessed as angles between interproximal surfaces on radiographs.
Results: Sixty‐five patients (age 69; 63/76 years [median; lower/upper quartile]; 38 females, 11 smokers) were examined. With the exception of mean PPD and PAL (p < .05) clinical parameters (PPD, PAL, bleeding on probing, suppuration) were well balanced between implants and teeth. Peri‐implant probing (VAS: 10; 0.75/16.25) caused significantly (p < .001) more discomfort/pain than periodontal probing (4; 0/10). Logistic regression analysis identified a larger difference between discomfort/pain for peri‐implant and periodontal probing in the maxilla than the mandible (p = .003). Comparing discomfort/pain between implants maxilla (p = .006) and emergence profile (p = .015) were associated with discomfort/pain. Type of implant (with/without platform switching) had no significant effect on discomfort/pain.
Conclusions: Peri‐implant probing caused significantly more discomfort/pain than periodontal probing. Implant design with/without platform switching failed to have a significant effect on discomfort/pain.
Brenneis, Christian ; Sisignano, Marco ; Coste, Ovidiu ; Altenrath, Kai ; Fischer, Michael ; Angioni, Carlo Federico ; Fleming, Ingrid ; Brandes, Ralf ; Reeh, Peter Werner ; Woolf, Clifford J. ; Geisslinger, Gerd ; Scholich, Klaus
Background
Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
Results
In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
Conclusion
Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
Gossel, Leonie D. H. ; Heim, Catrin Birgit ; Pfeffermann, Lisa-Marie ; Moser, Laura M. ; Bönig, Halvard-Björn ; Klingebiel, Thomas ; Bader, Peter ; Wels, Winfried ; Merker, Michael ; Rettinger, Eva
The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
Merker, Michael ; Wagner, Juliane ; Kreyenberg, Hermann ; Heim, Catrin Birgit ; Moser, Laura M. ; Wels, Winfried ; Bönig, Halvard-Björn ; Ullrich, Evelyn ; Klingebiel, Thomas ; Bader, Peter ; Rettinger, Eva
High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13–35 days after intravenous tumor cell injection, as shown by in vivo bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56–66 days, n = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS.
Ablikim, Medina ; Achasov, Mikhail N. ; Adlarson, Patrik ; Ahmed, Samer ; Albrecht, Malte ; Amoroso, Antonio ; An, Qi ; Anita ; Bai, Yu ; Bakina, Olga ; Baldini Ferroli, Rinaldo ; Balossino, Ilaria ; Ban, Yong ; Begzsuren, Khurelbaatar ; Bennett, Jake V. ; Berger, Niklaus ; Bertani, Monica ; Bettoni, Diego ; Bianchi, Fabrizio ; Biernat, Jacek ; Bloms, Johannes ; Bortone, Alberto ; Boyko, Igor R. ; Briere, Roy A. ; Cai, Hao ; Cai, Xiao ; Calcaterra, Alessandro ; Cao, G. F. ; Cao, N. ; Çetin, Serkant Ali ; Chang, Jinfan ; Chang, W. L. ; Chelkov, Gueorgui A. ; Chen, D. Y. ; Chen, G. ; Chen, Hesheng ; Chen, M. L. ; Chen, S. J. ; Chen, X. R. ; Chen, Yuanbo ; Cheng, W. ; Cibinetto, Gianluigi ; Cossio, Fabio ; Cui, X. F. ; Dai, Hongliang ; Dai, J. P. ; Dai, Xinchen ; Dbeyssi, Alaa ; de Boer, R. B. ; Dedovich, Dmitri V. ; Deng, Ziyan ; Denig, Achim ; Denysenko, Igor ; Destefanis, Marco Giovanni Maria ; De Mori, Francesca ; Ding, Yanchun ; Dong, C. ; Dong, J. ; Dong, Liaoyuan ; Dong, Mingyi ; Du, Shuxian ; Fang, J. ; Fang, Shuangshi ; Fang, Y. ; Farinelli, Riccardo ; Fava, Luciano ; Feldbauer, Florian ; Felici, Giulietto ; Feng, C. Q. ; Fritsch, Miriam ; Fu, Chengdong ; Fu, Y. ; Gao, X. L. ; Gao, Y. ; Gao, Y. ; Gao, Y. G. ; Garzia, Isabella ; Gersabeck, Evelina ; Gilman, A. ; Götzen, Klaus ; Gong, L. ; Gong, Wenxuan ; Gradl, Wolfgang ; Greco, M. ; Gu, L. M. ; Gu, Minhao ; Gu, S. ; Gu, Y. T. ; Guan, C. Y. ; Guo, Aiqiang ; Guo, L. B. ; Guo, R. P. ; Guo, Yuping ; Guo, Yuping ; Guskov, Alexey ; Han, S. ; Han, T. T. ; Han, T. Z. ; Hao, Xiqing ; Harris, Frederick Allan ; He, K. L. ; Heinsius, Fritz-Herbert ; Held, T. ; Heng, Yuekun ; Himmelreich, Mathilde ; Holtmann, Tobias ; Hou, Y. R. ; Hou, Zhilong ; Hu, Haiming ; Hu, J. F. ; Hu, T. ; Hu, Y. ; Huang, G. S. ; Huang, L. Q. ; Huang, X. T. ; Huang, Z. ; Huesken, Nils ; Hussain, Tahir ; Ikegami Andersson, Walter ; Imoehl, William ; Irshad, M. ; Jaeger, S. ; Janchiv, S. ; Ji, Quan ; Ji, Qingping ; Ji, X. B. ; Ji, X. L. ; Jiang, H. B. ; Jiang, Xiaoshan ; Jiang, X. Y. ; Jiao, J. B. ; Jiao, Z. ; Jin, Shan ; Jin, Y. ; Johansson, Tord ; Kalantar-Nayestanaki, Nasser ; Kang, X. S. ; Kappert, Rosa ; Kavatsyuk, Myroslav O. ; Ke, B. C. ; Keshk, I. K. ; Khoukaz, Alfons ; Kiese, P. ; Kiuchi, R. ; Kliemt, Ralf ; Koch, L. ; Kolcu, Onur Bugra ; Kopf, Bertram ; Kuemmel, M. ; Küßner, Meike ; Kupsc, Andrzej ; Kurth, M. G. ; Kühn, Wolfgang ; Lane, John Jake ; Lange, Jens Sören ; Larin, Paul ; Lavezzi, Lia ; Leithoff, Hans Heinrich ; Lellmann, Max ; Lenz, Thomas ; Li, C. ; Li, C. H. ; Li, Cheng ; Li, D. M. ; Li, F. ; Li, G. ; Li, Haibo ; Li, H. J. ; Li, J. L. ; Li, J. Q. ; Li, Ke ; Li, L. K. ; Li, Lei ; Li, P. L. ; Li, P. R. ; Li, S. Y. ; Li, Weidong ; Li, Weiguo ; Li, X. H. ; Li, Xing Long ; Li, Z. B. ; Li, Z. Y. ; Liang, H. ; Liang, H. ; Liang, Y. F. ; Liang, Y. T. ; Liao, L. Z. ; Libby, J. ; Lin, C. X. ; Liu, B. ; Liu, B. J. ; Liu, C. X. ; Liu, D. ; Liu, D. Y. ; Liu, Fu-Hu ; Liu, Fang ; Liu, Feng ; Liu, H. B. ; Liu, H. M. ; Liu, Huanhuan ; Liu, Huihui ; Liu, J. B. ; Liu, J. Y. ; Liu, K. ; Liu, K. Y. ; Liu, Ke ; Liu, L. ; Liu, L. Y. ; Liu, Q. ; Liu, S. B. ; Liu, T. ; Liu, X. ; Liu, Y. B. ; Liu, Zhen-An ; Liu, Z. Q. ; Long, Y. F. ; Lou, Xinchou ; Lu, H. J. ; Lu, J. D. ; Lu, Junguang ; Lu, X. L. ; Lu, Y. ; Lu, Yunpeng ; Luo, Chenglin ; Luo, M. X. ; Luo, P. W. ; Luo, T. ; Luo, X. L. ; Lusso, S. ; Lyu, Xiao-Rui ; Ma, Fengcai ; Ma, H. L. ; Ma, Lianliang ; Ma, M. M. ; Ma, Qiumei ; Ma, R. Q. ; Ma, R. T. ; Ma, X. N. ; Ma, X. X. ; Ma, Xiaoyan ; Ma, Y. M. ; Maas, Frank E. ; Maggiora, Marco ; Maldaner, Stephan ; Malde, Sneha ; Malik, Qadeer Afzal ; Mangoni, Alessio ; Mao, Yajun ; Mao, Zepu ; Marcello, Simonetta ; Meng, Z. X. ; Messchendorp, Johannes Gerhardus ; Mezzadri, Giulio ; Min, T. J. ; Mitchell, Ryan Edward ; Mo, Xiaohu ; Mo, Y. J. ; Muchnoi, Nikolai Yu. ; Muramatsu, Hajime ; Nakhoul, Simon ; Nefedov, Yury ; Nerling, Frank ; Nikolaev, Ivan Borisovich ; Ning, Z. ; Nisar, Shabana ; Olsen, Stephen L. ; Ouyang, Qun ; Pacetti, Simone ; Pan, Y. ; Papenbrock, Michael ; Pathak, A. ; Patteri, Piero ; Pelizäus, Marc ; Peng, H. P. ; Peters, Klaus ; Pettersson, J. ; Ping, J. L. ; Ping, R. G. ; Pitka, A. ; Poling, Ronald ; Prasad, Vindhyawasini ; Qi, H. ; Qi, H. R. ; Qi, Ming ; Qi, T. Y. ; Qian, S. ; Qian, W.-B. ; Qiao, Congfeng ; Qin, L. Q. ; Qin, X. P. ; Qin, X. S. ; Qin, Zhonghua ; Qiu, Jinfa ; Qu, S. Q. ; Rashid, K. H. ; Ravindran, Krishnakumar ; Redmer, Christoph Florian ; Rivetti, Angelo ; Rodin, Viktor ; Da Rocha Rolo, Manuel Dionisio ; Rong, Gang ; Rosner, Christoph ; Rump, Marcel Andre ; Sarantsev, Andrei V. ; Savrié, Mauro ; Schelhaas, Yasemin ; Schnier, Claudius ; Schönning, Karin ; Shan, Wei ; Shan, Xinyu ; Shao, M. ; Shen, C. P. ; Shen, P. X. ; Shen, X. 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We report a measurement of the observed cross sections of e+ e− → J/ψX based on 3.21 fb − 1 of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686) → J/ψX) = (64.4 ± 0.6 ± 1.6)% and B(ψ(3770) → J/ψX) = (0.5 ± 0.2 ± 0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ (3686) → J/ψX and ψ(3770) → J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→ J/ψX. Under this assumption, we extracted the R (3760) mass M R (3760 ) = 3766.2 ± 3.8 ± 0.4 MeV/c2, total width Γ tot R ( 3760 ) = 22.2 ± 5.9 ± 1.4 MeV, and product of leptonic width and decay branching fraction
ΓeeR(3760) B[R(3760) → J/ψX] = (79.4 ± 85.5 ± 11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.
Laban, Hebatullah ; Weigert, Andreas ; Zink, Joana Miriam ; Elgheznawy, Amro ; Schürmann, Christoph ; Günther, Lea ; Abdel Malik, Randa ; Bothur, Sabrina ; Wingert, Susanne ; Bremer, Rolf ; Rieger, Michael A. ; Brüne, Bernhard ; Brandes, Ralf ; Fleming, Ingrid ; Benz, Peter M.
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP−/− mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair. Importantly, VASP deletion in bone marrow–derived cells was sufficient to mimic the increased blood flow recovery of global VASP−/− mice. In chemotaxis experiments, VASP−/− neutrophils/monocytes were significantly more responsive to M1-related chemokines than wild-type controls. Mechanistically, VASP formed complexes with the chemokine receptor CCR2 and β-arrestin-2, and CCR2 receptor internalization was significantly reduced in VASP−/− leukocytes. Our data indicate that VASP is a major regulator of leukocyte recruitment and polarization in postischemic revascularization and support a novel role of VASP in chemokine receptor trafficking.
Rezende Felipe, Flávia Figueiredo de ; Moll, Franziska ; Walter, Maria ; Helfinger, Valeska ; Hahner, Fabian ; Janetzko, Patrick ; Ringel, Christian ; Weigert, Andreas ; Fleming, Ingrid ; Weißmann, Norbert ; Künne, Carsten Tobias ; Looso, Mario ; Rieger, Michael A. ; Nawroth, Peter ; Fleming, Thomas ; Brandes, Ralf ; Schröder, Katrin
Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
Background: The evaluation of local mental health care remains difficult. For this reason systematic development of appropriate services is barely possible.
Methods: We examined involuntary hospitalization in the city of Frankfurt/Main with regard to diagnoses, socio-demographic data, complementary psychosocial outpatient care, and circumstances of hospitalization. There are four psychiatric clinics, each serving a catchment area of more than 165.000 inhabitants. These clinics are responsible for all psychiatric in-patient treatments regardless of the admission modus. During a one year period, 677 patients were involuntarily hospitalized. Statistical analyses were performed subsequent to pooling the data.
Results: During a period of one year, 103 out of 100.000 inhabitants of Frankfurt/Main were admitted involuntarily. The rate of involuntary admissions related to all admissions was 10.98 percent. Any complementary psychosocial care was missing in more than 70 percent of patients admitted involuntarily. Only about 10 percent of patients were examined by a physician before reaching the hospital and in disappointing 1.3 percent the municipal mental health service had been consulted prior to involuntarily admission.
Conclusion: Our results show that a systematic improvement of precautionary complementary psychosocial care for risk patients is needed as well as the obligation of psychiatric emergency consultation before involuntary hospitalization.
Peter, Thomas ; Luo, Beiping ; Wirth, Martin ; Kiemle, Christoph ; Flentje, Harald ; Yushkov, Vladimir A. ; Khattatov, Vyacheslav ; Rudakov, Vladimir V. ; Thomas, Andreas ; Borrmann, Stephan ; Toci, Guido ; Mazzinghi, Piero ; Beuermann, Jürgen ; Schiller, Cornelius ; Cairo, Francesco ; Di Donfrancesco, Guido ; Adriani, Alberto ; Volk, C.-Michael ; Strom, Johan ; Noone, Kevin ; Mitev, Valentin ; MacKenzie, Robert A. ; Carslaw, Kenneth S. ; Trautmann, Thomas ; Santacesaria, Vincenzo ; Stefanutti, Leopoldo
Subvisible cirrus clouds (SVCs) may contribute to dehydration close to the tropical tropopause. The higher and colder SVCs and the larger their ice crystals, the more likely they represent the last efficient point of contact of the gas phase with the ice phase and, hence, the last dehydrating step, before the air enters the stratosphere. The first simultaneous in situ and remote sensing measurements of SVCs were taken during the APE-THESEO campaign in the western Indian ocean in February/March 1999. The observed clouds, termed Ultrathin Tropical Tropopause Clouds (UTTCs), belong to the geometrically and optically thinnest large-scale clouds in the Earth´s atmosphere. Individual UTTCs may exist for many hours as an only 200--300 m thick cloud layer just a few hundred meters below the tropical cold point tropopause, covering up to 105 km2. With temperatures as low as 181 K these clouds are prime representatives for defining the water mixing ratio of air entering the lower stratosphere.
Luo, Beiping ; Peter, Thomas ; Wernli, Heini ; Fueglistaler, Stephan ; Wirth, Martin ; Kiemle, Christoph ; Flentje, Harald ; Yushko, Vladimir A. ; Khattatov, Vyacheslav ; Rudakov, Vladimir V. ; Thomas, Andreas ; Borrmann, Stephan ; Toci, Guido ; Mazzinghi, Piero ; Beuermann, Jürgen ; Schiller, Cornelius ; Cairo, Francesco ; Di Donfrancesco, Guido ; Adriani, Alberto ; Volk, C.-Michael ; Strom, Johan ; Noone, Kevin ; Mitev, Valentin ; MacKenzie, Robert A. ; Carslaw, Kenneth S. ; Trautmann, Thomas ; Santacesaria, Vincenzo ; Stefanutti, Leopoldo
Mechanisms by which subvisible cirrus clouds (SVCs) might contribute to dehydration close to the tropical tropopause are not well understood. Recently Ultrathin Tropical Tropopause Clouds (UTTCs) with optical depths around 10-4 have been detected in the western Indian ocean. These clouds cover thousands of square kilometers as 200-300 m thick distinct and homogeneous layer just below the tropical tropopause. In their condensed phase UTTCs contain only 1-5% of the total water, and essentially no nitric acid. A new cloud stabilization mechanism is required to explain this small fraction of the condensed water content in the clouds and their small vertical thickness. This work suggests a mechanism, which forces the particles into a thin layer, based on upwelling of the air of some mm/s to balance the ice particles, supersaturation with respect to ice above and subsaturation below the UTTC. In situ measurements suggest that these requirements are fulfilled. The basic physical properties of this mechanism are explored by means of a single particle model. Comprehensive 1-D cloud simulations demonstrate this stabilization mechanism to be robust against rapid temperature fluctuations of +/- 0.5 K. However, rapid warming (Delta T > 2 K) leads to evaporation of the UTTC, while rapid cooling (Delta T < -2 K) leads to destabilization of the particles with the potential for significant dehydration below the cloud