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Piffkó, András ; Broggini, Thomas ; Harms, Christoph ; Adams, Ralf Heinrich ; Vajkoczy, Peter ; Czabanka, Marcus Alexander
Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.
Riecke, Kerstin ; Müller, Volkmar ; Weide, Rudolf ; Schmidt, Marcus ; Park-Simon, Tjoung-Won ; Möbus, Volker ; Mundhenke, Christoph ; Polasik, Arkadius ; Lübbe, Kristina ; Hesse, Tobias ; Laakmann, Elena ; Thill, Marc ; Fasching, Peter Andreas ; Denkert, Carsten ; Fehm, Tanja ; Nekljudova, Valentina ; Rey, Julia ; Loibl, Sibylle ; Witzel, Isabell
Simple Summary: The incidence of brain metastases from breast cancer is increasing and the treatment is still a major challenge. Several scores have been developed in order to estimate the prognosis of patients with brain metastases by objective criteria. Here, we validated all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer patients with brain metastases in the Brain Metastases in the German Breast Cancer (BMBC) registry. Although all three available GPA-scores were associated with OS, they all show limitations mainly in predicting short-term (below 3 months) survival but also in long-term (above 12 months) survival. We discuss the test performances of all scores in our work and provide evidence how physicians should use them as a tool to select patients for different treatment options.
Abstract: Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.
Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases
(2020)
Laakmann, Elena ; Witzel, Isabell ; Neunhöffer, Tanja ; Weide, Rudolf ; Schmidt, Marcus ; Park-Simon, Tjoung-Won ; Möbus, Volker ; Mundhenke, Christoph ; Polasik, Arkadius ; Lübbe, Kristina ; Hesse, Tobias ; Riecke, Kerstin ; Thill, Marc ; Fasching, Peter Andreas ; Denkert, Carsten ; Fehm, Tanja ; Nekljudova, Valentina ; Rey, Julia ; Loibl, Sibylle ; Müller, Volkmar
Simple Summary: The prognosis for patients with breast cancer that has spread to the brain is poor, and survival for these women hasn’t improved over the last few decades. We do not currently test for asymptomatic brain metastases in breast cancer patients, although this does happen in some other types of cancer. In this study we wanted to find out more about breast cancer that has spread to the brain and in particular to see whether there might be any advantage to spotting brain metastases before the development of neurological symptoms. Overall, our results suggest that women could be better off if their brain metastases are diagnosed before they begin to cause symptoms. We now need to carry out a clinical trial to see what happens if we screen high-risk breast cancer patients for brain metastases. This will verify whether doing so could increase survival, symptom control or quality of life.
Abstract: Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
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 ; 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
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 (ΔT>2 K) leads to evaporation of the UTTC, while rapid cooling (ΔT<−2 K) leads to destabilization of the particles with the potential for significant dehydration below the cloud.
Haase, Peter ; Tonkin, Jonathan D. ; Stoll, Stefan ; Burkhard, Benjamin ; Frenzel, Mark ; Geijzendorffer, Ilse R. ; Häuser, Christoph L. ; Klotz, Stefan ; Kühn, Ingolf ; McDowell, William H. ; Mirtl, Michael ; Müller, Felix ; Musche, Martin ; Penner, Johannes ; Zacharias, Steffen ; Schmeller, Dirk S.
Global change effects on biodiversity and human wellbeing call for improved long-term environmental data as a basis for science, policy and decision making, including increased interoperability, multifunctionality, and harmonization. Based on the example of two global initiatives, the International Long-Term Ecological Research (ILTER) network and the Group on Earth Observations Biodiversity Observation Network (GEO BON), we propose merging the frameworks behind these initiatives, namely ecosystem integrity and essential biodiversity variables, to serve as an improved guideline for future site-based long-term research and monitoring in terrestrial, freshwater and coastal ecosystems. We derive a list of specific recommendations of what and how to measure at a monitoring site and call for an integration of sites into co-located site networks across individual monitoring initiatives, and centered on ecosystems. This facilitates the generation of linked comprehensive ecosystem monitoring data, supports synergies in the use of costly infrastructures, fosters cross-initiative research and provides a template for collaboration beyond the ILTER and GEO BON communities.
Grammatikos, Georgios ; Dietz, Julia ; Ferreirós Bouzas, Nerea ; Koch, Alexander ; Dultz, Georg ; Bon, Dimitra ; Karakasiliotis, Ioannis ; Lutz, Thomas ; Knecht, Gaby ; Gute, Peter ; Herrmann, Eva ; Zeuzem, Stefan ; Mavromara, Penelope ; Sarrazin, Christoph ; Pfeilschifter, Josef
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.
Sarabhai, Theresia ; Peter, Christoph ; Bär, Anne-Kathrin ; Windolf, Joachim ; Relja, Borna ; Wesselborg, Sebastian ; Wahlers, Thorsten ; Paunel-Görgülü, Adnana-Nicoleta
Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.
Atkinson, Andrew ; Zwahlen, Marcel ; Barger, Diana ; d’Arminio Monforte, Antonella ; Wit, Stephane de ; Girardi, Enrico ; Svedhem, Veronica ; Morlat, Philippe ; Mussini, Cristina ; Noguera-Julian, Antoni ; Stephan, Christoph ; Touloumi, Giota ; Kirk, Ole ; Mocroft, Amanda ; Reiss, Peter ; Miró, Jose Maria ; Carpenter, James R. ; Furrer, Hansjakob
Background: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count.
Methods: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring.
Results: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6–1.1; P = .2).
Conclusions: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.
Dultz, Georg ; Kronenberger, Bernd ; Azizi, Alireza ; Mihm, Ulrike ; Vogl, Thomas J. ; Sarrazin, Ulrike ; Sarrazin, Christoph ; Zeuzem, Stefan ; Hofmann, Wolf-Peter
Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim.
Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago.
Results: During hospitalization, the platelet count was measured above 330,000/μl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved.
Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.
Depprich, Rita ; Zipprich, Holger ; Ommerborn, Michelle ; Naujoks, Christian ; Wiesmann, Hans-Peter ; Kiattavorncharoen, Sirichai ; Lauer, Hans-Christoph ; Meyer, Ulrich ; Kübler, Norbert ; Handschel, Jörg
Background Titanium and titanium alloys are widely used for fabrication of dental implants. Since the material composition and the surface topography of a biomaterial play a fundamental role in osseointegration, various chemical and physical surface modifications have been developed to improve osseous healing. Zirconia-based implants were introduced into dental implantology as an altenative to titanium implants. Zirconia seems to be a suitable implant material because of its tooth-like colour, its mechanical properties and its biocompatibility. As the osseointegration of zirconia implants has not been extensively investigated, the aim of this study was to compare the osseous healing of zirconia implants with titanium implants which have a roughened surface but otherwise similar implant geometries. Methods Forty-eight zirconia and titanium implants were introduced into the tibia of 12 minipigs. After 1, 4 or 12 weeks, animals were sacrificed and specimens containing the implants were examined in terms of histological and ultrastructural techniques. Results Histological results showed direct bone contact on the zirconia and titanium surfaces. Bone implant contact as measured by histomorphometry was slightly better on titanium than on zirconia surfaces. However, a statistically significant difference between the two groups was not observed. Conclusion The results demonstrated that zirconia implants with modified surfaces result in an osseointegration which is comparable with that of titanium implants.
Mollenhauer, Hannes ; Kasner, Max ; Haase, Peter ; Peterseil, Johannes ; Wohner, Christoph ; Frenzel, Mark ; Mirtl, Michael ; Schima, Robert ; Bumberger, Jan ; Zacharias, Steffen
The challenges posed by climate and land use change are increasingly complex, with ever-increasing and accelerating impacts on the global environmental system. The establishment of an internationally harmonized, integrated, and long-term operated environmental monitoring infrastructure is one of the major challenges of modern environmental research. Increased efforts are currently being made in Europe to establish such a harmonized pan-European observation infrastructure, and the European network of Long-Term Ecological Research sites – LTER-Europe – is of particular importance. By evaluating 477 formally accredited LTER-Europe sites, this study gives an overview of the current distribution of these infrastructures and the present condition of long-term environmental research in Europe. We compiled information on long-term biotic and abiotic observations and measurements and examined the representativeness in terms of continental biogeographical and socio-ecological gradients. The results were used to identify gaps in both measurements and coverage of the aforementioned gradients. Furthermore, an overview of the current state of the LTER-Europe observation strategies is given. The latter forms the basis for investigating the comparability of existing LTER-Europe monitoring concepts both in terms of observational design as well as in terms of the scope of the environmental compartments, variables and properties covered.
Unique features of a global human ectoparasite identified through sequencing of the bed bug genome
(2016)
Benoit, Joshua B. ; Adelman, Zach N. ; Reinhardt, Klaus ; Dolan, Amanda ; Poelchau, Monica ; Jennings, Emily C. ; Szuter, Elise M. ; Hagan, Richard W. ; Gujar, Hemant ; Shukla, Jayendra Nath ; Zhu, Fang ; Mohan, Muthugounder ; Nelson, David R. ; Rosendale, Andrew J. ; Derst, Christian ; Resnik, Valentina ; Wernig, Sebastian ; Menegazzi, Pamela ; Wegener, Christian ; Peschel, Nicolai ; Hendershot, Jacob M. ; Blenau, Wolfgang ; Predel, Reinhard ; Johnston, Paul R. ; Ioannidis, Panagiotis ; Waterhouse, Robert M. ; Nauen, Ralf ; Schorn, Corinna ; Ott, Mark-Christoph ; Maiwald, Frank ; Johnston, J. Spencer ; Gondhalekar, Ameya D. ; Scharf, Michael E. ; Peterson, Brittany F. ; Raje, Kapil R. ; Hottel, Benjamin A. ; Armisén, David ; Crumière, Antonin Jean Johan ; Refki, Peter Nagui ; Santos, Maria Emilia ; Sghaier, Essia ; Viala, Séverine ; Khila, Abderrahman ; Ahn, Seung-Joon ; Childers, Christopher ; Lee, Chien-Yueh ; Lin, Han ; Hughes, Daniel S. T. ; Duncan, Elizabeth J. ; Murali, Shwetha C. ; Qu, Jiaxin ; Dugan, Shannon ; Lee, Sandra L. ; Chao, Hsu ; Dinh, Huyen ; Han, Yi ; Doddapaneni, Harshavardhan ; Worley, Kim C. ; Muzny, Donna Marie ; Wheeler, David ; Panfilio, Kristen A. ; Vargas Jentzsch, Iris M. ; Vargo, Edward L. ; Booth, Warren ; Friedrich, Markus ; Weirauch, Matthew T. ; Anderson, Michelle A. ; Jones, Jeffery W. ; Mittapalli, Omprakash ; Zhao, Chaoyang ; Zhou, Jing-Jiang ; Evans, Jay D. ; Attardo, Geoffrey M. ; Robertson, Hugh M. ; Zdobnov, Evgeny M. ; Ribeiro, José M. C. ; Gibbs, Richard A. ; Werren, John H. ; Palli, Subba Reddy ; Schal, Coby ; Richards, Stephen
The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host–symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human–bed bug and symbiont–bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.
Stevic, Ines ; Müller, Volkmar ; Weber, Karsten E. ; Fasching, Peter Andreas ; Karn, Thomas ; Marmé, Frederic ; Schem, Christian ; Stickeler, Elmar ; Denkert, Carsten Michael ; Mackelenbergh, Marion Tina van ; Salat, Christoph ; Schneeweiss, Andreas ; Pantel, Klaus ; Loibl, Sibylle ; Untch, Michael ; Schwarzenbach, Heidi
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Mirtl, Michael ; Borer, Elizabeth T. ; Djukic, Ika ; Forsius, Martin ; Haubold, Herbert ; Hugo, Wim ; Jourdan, Jonas ; Lindenmayer, David ; McDowell, William H. ; Muraoka, Hiroyuki ; Orenstein, Daniel E. ; Pauw, Johan C. ; Peterseil, Johannes ; Shibata, Hideaki ; Wohner, Christoph ; Yu, Xiubo ; Haase, Peter
Since its founding in 1993 the International Long-term Ecological Research Network (ILTER) has gone through pronounced development phases. The current network comprises 44 active member LTER networks representing 700 LTER Sites and ~ 80 LTSER Platforms across all continents, active in the fields of ecosystem, critical zone and socio-ecological research. The critical challenges and most important achievements of the initial phase have now become state-of-the-art in networking for excellent science. At the same time increasing integration, accelerating technology, networking of resources and a strong pull for more socially relevant scientific information have been modifying the mission and goals of ILTER. This article provides a critical review of ILTER's mission, goals, development and impacts. Major characteristics, tools, services, partnerships and selected examples of relative strengths relevant for advancing ILTER are presented. We elaborate on the tradeoffs between the needs of the scientific community and stakeholder expectations. The embedding of ILTER in an increasingly collaborative landscape of global environmental observation and ecological research networks and infrastructures is also reflected by developments of pioneering regional and national LTER networks such as SAEON in South Africa, CERN/CEOBEX in China, TERN in Australia or eLTER RI in Europe. The primary role of ILTER is currently seen as a mechanism to investigate ecosystem structure, function, and services in response to a wide range of environmental forcings using long-term, place-based research. We suggest four main fields of activities and advancements for the next decade through development/delivery of a: (1) Global multi-disciplinary community of researchers and research institutes; (2) Strategic global framework and strong partnerships in ecosystem observation and research; (3) Global Research Infrastructure (GRI); and (4) a scientific knowledge factory for societally relevant information on sustainable use of natural resources.
Ablyazimov, Timur O. ; Aichelin, Jörg ; Andreev, V. V. ; Avdejchikov, V. V. ; Averianov, A. V. ; Avramenko, S. V. ; Akishina, Valentina ; Akishin, Pavel G. ; Aksinenko, V. D. ; Alfeev, A. V. ; Alfeev, V. S. ; Babkin, Vadim A. ; Baginyan, S. A. ; Balandin, V. P. ; Baranova, A. V. ; Barznat, M. I. ; Basylev, S. N. ; Belyakov, Dmitry V. ; Bogdanova, G. A. ; Boguslavsky, I. V. ; Bolshakova, I. A. ; Boos, E. E. ; Bratkovskaya, Elena L. ; Cassing, Wolfgang ; Chernenko, Sergey P. ; Davkov, V. ; Davkov, K. ; Demidova, V. I. ; Deng, Z. ; Derenovskaya, Olga ; Donskov, S. V. ; Dunin, V. B. ; Ershov, A. A. ; Fateev, Oleg V. ; Fedorov, Yu. I. ; Gapienko, V. A. ; Gavrishuk, O. P. ; Genchev, S. G. ; Golovatyuk, V. M. ; Golochvastov, A. I. ; Golovnya, S. N. ; Grigalashvili, N. ; Guber, Fedor ; Gudima, K. K. ; Gumen, S. ; Gurchin, Yu. V. ; Hartnack, Christoph ; Hayduchok, V. ; Heuser, J. ; Huang, X. ; Ivanov, V. V. ; Ivashkin, Alexander ; Ierusalimov, Alexander P. ; Ilgenfritz, Ernst-Michael ; Isupov, A. Yu. ; Ivanets, V. ; Janek, M. ; Karachuk, Yu.-T. ; Karmanov, D. E. ; Kekelidze, V. D. ; Kekelidze, G. D. ; Khabarov, V. S. ; Khabarov, S. V. ; Kholodenko, Anatoli G. ; Khrenov, A. N. ; Kireev, V. I. ; Kiryushin, Yu. T. ; Kisel, P. I. ; Kisel, Ivan ; Kogut, I. ; Kokoulina, E. S. ; Kolesnikov, Vadim I. ; Konchakovski, V. ; Kopko, B. ; Korolev, M. G. ; Korotkova, A. M. ; Kost, Y. ; Kovaljova, N. ; Kovtun, Volodymyr E. ; Kozachenko, L. ; Kravets, M. ; Kugler, Andrej ; Kurbatov, E. O. ; Kurepin, Alexey B. ; Kurilkin, Aleksey K. ; Kurilkin, Pavel K. ; Kushpil, V. ; Kutov, A. Yu. ; Kuznezov, A. V. ; Kuzmin, N. A. ; Ladygin, Evgeny A. ; Ladygin, Vladimir P. ; Ladygina, N. B. ; Lebedev, A. A. ; Lenok, V. V. ; Levchenko, A. ; Li, Y. ; Linnyk, Olena ; Lipchinski, D. ; Litvinenko, E. P. ; Lobastov, S. P. ; Lokhtin, Igor P. ; Lukstins, Juris ; Lyashchenko, V. N. ; Madigozhin, D. T. ; Makido, O. ; Maksimenko, N. V. ; Malakhov, Aleksandr I. ; Malinina, Liudmila ; Martinska, M. ; Merkin, M. M. ; Mikhaylov, Yu. V. ; Mialkovsky, V. V. ; Moroz, A. ; Murin, Yu. N. ; Nagorny, S. N. ; Nakalov, Y. ; Nikitin, Vladimir A. ; Nomokonov, Petr V. ; Okhrimenko, O. V. ; Palynyak, I. ; Pavljuchkov, V. V. ; Parfenov, A. N. ; Petukhov, Yu. P. ; Pechenov, Vladimir N. ; Pechenova, Olga Yu. ; Peshekhonov, V. D. ; Piyadin, S. M. ; Polyakov, V. A. ; Popovichi, J. ; Radkov, I. S. ; Radnev, S. V. ; Rakhlin, L. ; Raportirenko, A. M. ; Rashevski, G. ; Reva, S. N. ; Reznikov, S. G. ; Riadovikov, V. N. ; Rukoyatkin, P. A. ; Rufanov, I. A. ; Sadovsky, Alexander ; Semak, A. A. ; Senger, Peter ; Shabunov, A. V. ; Shapovalov, H. ; Shejnast, V. ; Shkilyov, A. L. ; Shurygin, F. ; Shutov, A. V. ; Slepnev, V. M. ; Slepnev, I. V. ; Snigirev, Alexander M. ; Sushko, I. ; Suzdalev, V. I. ; Svoboda, Ondřej ; Syschenko, V. V. ; Sychkov, S. Yu. ; Terekhin, Arkadiy A. ; Terlezky, A. V. ; Teryaev, O. V. ; Tiflov, V. V. ; Tikhomirov, V. V. ; Tlustý, Pavel ; Topilin, N. D. ; Trpisova, B. ; Tsupa, Yu. P. ; Turchin, A. A. ; Tymoshyn, S. ; Ukhanov, M. N. ; Usenko, Evgeny A. ; Urban, J. ; Vasendina, V. A. ; Vasiliev, Taras A. ; Vassiliev, Iouri ; Vladimirova, N. M. ; Vishnevsky, A. V. ; Vnukov, I. E. ; Vokal, Stanislav ; Volgin, S. V. ; Volkov, Vasily ; Vorobiev, A. P. ; Voronin, A. G. ; Voronyuk, Vadym V. ; Voroshylo, H. ; Wang, J. ; Wang, Y. ; Yerashok, V. ; Yukaev, A. I. ; Zagachevskyi, Y. ; Zaljyubovsky, I. I. ; Zanevsky, Yuri V. ; Zenkov, A. ; Zhu, X. ; Zinchenko, A. P. ; Zrelov, P. V. ; Zryuev, V. N.
It is proposed to install an experimental setup in the fixed-target hall of the Nuclotron with the final goal to perform a research program focused on the production of strange matter in heavyion collisions at beam energies between 2 and 6 A GeV. The basic setup will comprise a large acceptance dipole magnet with inner tracking detector modules based on double-sided Silicon micro-strip sensors and GEMs. The outer tracking will be based on the drift chambers and straw tube detector. Particle identification will be based on the time-of-flight measurements. This setup will be sufficient perform a comprehensive study of strangeness production in heavy-ion collisions, including multi-strange hyperons, multi-strange hypernuclei, and exotic multi-strange heavy objects. These pioneering measurements would provide the first data on the production of these particles in heavy-ion collisions at Nuclotron beam energies, and would open an avenue to explore the third (strangeness) axis of the nuclear chart. The extension of the experimental program is related with the study of in-medium effects for vector mesons decaying in hadronic modes. The studies of the NN and NA reactions for the reference is assumed.
Tombach, Bernd ; Bohndorf, Klaus ; Brodtrager, Wolfgang ; Claussen, Claus D. ; Düber, Christoph ; Galanski, Michael ; Grabbe, Eckhardt ; Gortenuti, Giacomo ; Kuhn, Michael ; Gross-Fengels, Walter ; Hammerstingl, Renate Maria ; Happel, Brigitte ; Heinz-Peer, Gertraud ; Jung, Gregor ; Kittner, Thomas ; Lagalla, Roberto ; Lengsfeld, Philipp ; Loose, Reinhard ; Oyen, Raymond H. G. ; Pavlica, Pietro ; Pering, Christiane ; Pozzi-Mucelli, Roberto ; Persigehl, Thorsten ; Reimer, Peter ; Renken, Nomdo S. ; Richter, Götz M. ; Rummeny, Ernst J. ; Schäfer, Fritz ; Szczerbo-Trojanowska, Malgorzata ; Urbanik, Andrzej ; Vogl, Thomas J. ; Hajek, Paul
The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.
It has been shown that certain chemokine receptor polymorphisms may correspond to certain complications after organ transplantation. Ischemic-type biliary lesion (ITBL) encounters for major morbidity and mortality in liver transplant recipients. So far, the exact cause for ITBL remains unclear. Certain risk factors for the development of ITBL like donor age and cold ischemic time are well described. In a previous study, a 32-nucleotide deletion of the chemokine receptor-5Delta32 (CCR-5Delta32) was strongly associated with the incidence of ITBL in adult liver transplantation. This study re-evaluates the association of CCR-5Delta32 gene polymorphism and the incidence of ITBL. 169 patients were included into this retrospective analysis. 134 patients were homozygous for wild-type CCR-5, 33 patients heterozygous, and 2 patients were homozygous for CCR-5Delta32 mutation. There were no major differences in donor or recipients demographics. No association was found between CCR-5Delta32 mutation and the development of ITBL.We conclude that CCR-5Delta32 is no risk factor for the development of ITBL in our patient cohort.
Praktiknjo, Michael ; Monteiro, Sofia ; Grandt, Josephine ; Kimer, Nina ; Madsen, Jan L. ; Werge, Mikkel P. ; William, Peter ; Brol, Maximilian ; Turco, Laura ; Schierwagen, Robert ; Chang, Johannes ; Klein, Sabine ; Uschner, Frank Erhard ; Welsch, Christoph ; Moreau, Richard ; Schepis, Filippo ; Bendtsen, Flemming ; Gluud, Lise L. ; Møller, Søren ; Trebicka, Jonel
Background & Aims: Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis.
Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL‐33 receptor (sIL‐33R). Patients were divided according to CI (<3.2; 3.2‐4.2; >4.2 L/min/m2) in hypo‐ (n = 84), normo‐ (n = 69) and hyperdynamic group (n = 55). After a median follow‐up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL‐6 was an independent predictor of fatal ACLF development.
Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.
Wilke, Jan ; Mohr, Lisa ; Tenforde, Adam S. ; Edouard, Pascal ; Fossati, Chiara ; González-Gross, Marcela ; Sánchez Ramírez, Celso ; Laiño, Fernando ; Tan, Benedict ; Pillay, Julian David ; Pigozzi, Fabio ; Jimenez-Pavon, David ; Novak, Bernhard ; Jaunig, Johannes ; Zhang, Mandy ; Poppel, Mireille van ; Heidt, Christoph ; Willwacher, Steffen ; Yuki, Gustavo ; Lieberman, Daniel E. ; Vogt, Lutz ; Verhagen, Evert ; Hespanhol, Luiz ; Hollander, Karsten Peter
Governments have restricted public life during the COVID-19 pandemic, inter alia closing sports facilities and gyms. As regular exercise is essential for health, this study examined the effect of pandemic-related confinements on physical activity (PA) levels. A multinational survey was performed in 14 countries. Times spent in moderate-to-vigorous physical activity (MVPA) as well as in vigorous physical activity only (VPA) were assessed using the Nordic Physical Activity Questionnaire (short form). Data were obtained for leisure and occupational PA pre- and during restrictions. Compliance with PA guidelines was calculated based on the recommendations of the World Health Organization (WHO). In total, n = 13,503 respondents (39 ± 15 years, 59% females) were surveyed. Compared to pre-restrictions, overall self-reported PA declined by 41% (MVPA) and 42.2% (VPA). Reductions were higher for occupational vs. leisure time, young and old vs. middle-aged persons, previously more active vs. less active individuals, but similar between men and women. Compared to pre-pandemic, compliance with WHO guidelines decreased from 80.9% (95% CI: 80.3–81.7) to 62.5% (95% CI: 61.6–63.3). Results suggest PA levels have substantially decreased globally during the COVID-19 pandemic. Key stakeholders should consider strategies to mitigate loss in PA in order to preserve health during the pandemic.