Showing papers by "University of Tübingen published in 2012"
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Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
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Conrad L. Schoch1, Keith A. Seifert, Sabine M. Huhndorf2, Vincent Robert3 +157 more•Institutions (59)
TL;DR: Among the regions of the ribosomal cistron, the internal transcribed spacer (ITS) region has the highest probability of successful identification for the broadest range of fungi, with the most clearly defined barcode gap between inter- and intraspecific variation.
Abstract: Six DNA regions were evaluated as potential DNA barcodes for Fungi, the second largest kingdom of eukaryotic life, by a multinational, multilaboratory consortium. The region of the mitochondrial cytochrome c oxidase subunit 1 used as the animal barcode was excluded as a potential marker, because it is difficult to amplify in fungi, often includes large introns, and can be insufficiently variable. Three subunits from the nuclear ribosomal RNA cistron were compared together with regions of three representative protein-coding genes (largest subunit of RNA polymerase II, second largest subunit of RNA polymerase II, and minichromosome maintenance protein). Although the protein-coding gene regions often had a higher percent of correct identification compared with ribosomal markers, low PCR amplification and sequencing success eliminated them as candidates for a universal fungal barcode. Among the regions of the ribosomal cistron, the internal transcribed spacer (ITS) region has the highest probability of successful identification for the broadest range of fungi, with the most clearly defined barcode gap between inter- and intraspecific variation. The nuclear ribosomal large subunit, a popular phylogenetic marker in certain groups, had superior species resolution in some taxonomic groups, such as the early diverging lineages and the ascomycete yeasts, but was otherwise slightly inferior to the ITS. The nuclear ribosomal small subunit has poor species-level resolution in fungi. ITS will be formally proposed for adoption as the primary fungal barcode marker to the Consortium for the Barcode of Life, with the possibility that supplementary barcodes may be developed for particular narrowly circumscribed taxonomic groups.
4,116 citations
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McGill University1, German Cancer Research Center2, Montreal Children's Hospital3, National Research Council4, Russian Academy5, Semmelweis University6, University of Debrecen7, University of Tübingen8, Boston Children's Hospital9, Augsburg College10, University of Würzburg11, Martin Luther University of Halle-Wittenberg12, Heidelberg University13, University of Toronto14, University of Düsseldorf15, University of Cambridge16, University Hospital Heidelberg17
TL;DR: The presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles, suggesting that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
2,091 citations
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German Cancer Research Center1, Heidelberg University2, McGill University3, Montreal Children's Hospital4, University of Düsseldorf5, University of Tübingen6, Virginia Commonwealth University7, Augsburg College8, Boston Children's Hospital9, University of Colorado Denver10, Cincinnati Children's Hospital Medical Center11, University of Würzburg12, Martin Luther University of Halle-Wittenberg13, Hannover Medical School14, Medical University of Łódź15, Memorial Hospital of South Bend16, Semmelweis University17, University of Debrecen18, University of Toronto19, University of Amsterdam20, Henry Ford Health System21, University of Texas MD Anderson Cancer Center22, University of Cambridge23
TL;DR: It is demonstrated that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup.
1,557 citations
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TL;DR: This work summarizes studies of structure and nucleation of amyloid and relate these to observations on amyloids polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility.
1,487 citations
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TL;DR: Dendroscope 3 is a new program for working with rooted phylogenetic trees and networks that provides a number of methods for drawing and comparingRoot phylogenetic networks, and for computing them from rooted trees.
Abstract: Dendroscope 3 is a new program for working with rooted phylogenetic trees and networks. It provides a number of methods for drawing and comparing rooted phylogenetic networks, and for computing them from rooted trees. The program can be used interactively or in command-line mode. The program is written in Java, use of the software is free, and installers for all 3 major operating systems can be downloaded from www.dendroscope.org. [Phylogenetic trees; phylogenetic networks; software.].
1,396 citations
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TL;DR: The Double Chooz experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations, and an observed-to-predicted ratio of events of 0.944±0.016 and a deficit can be interpreted as a nonzero value of the still unmeasured neutrinos mixing parameter sin(2)2θ(13).
Abstract: The Double Chooz experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. An observed-to-predicted ratio of events of 0.944±0.016(stat)±0.040(syst) was obtained in 101 days of running at the Chooz nuclear power plant in France, with two 4.25GWth reactors. The results were obtained from a single 10m3 fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 flux measurement after correction for differences in core composition. The deficit can be interpreted as an indication of a nonzero value of the still unmeasured neutrino mixing parameter sin22θ13. Analyzing both the rate of the prompt positrons and their energy spectrum, we find sin22θ13=0.086±0.041(stat)±0.030(syst), or, at 90% C.L., 0.017
1,214 citations
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TL;DR: It is proposed that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.
Abstract: Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the interactions between brain regions during cognitive processes by assessing correlations between neuronal oscillations in different regions of the primate cerebral cortex. These studies have opened a new window onto the large-scale circuit mechanisms underlying sensorimotor decision-making and top-down attention. We propose that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.
1,149 citations
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TL;DR: This work found that spontaneous oscillatory neuronal activity exhibited frequency-specific spatial correlation structure in the human brain and developed an analysis approach that discounts spurious correlation of signal power caused by the limited spatial resolution of electrophysiological measures.
Abstract: Little is known about the brain-wide correlation of electrophysiological signals. We found that spontaneous oscillatory neuronal activity exhibited frequency-specific spatial correlation structure in the human brain. We developed an analysis approach that discounts spurious correlation of signal power caused by the limited spatial resolution of electrophysiological measures. We applied this approach to source estimates of spontaneous neuronal activity reconstructed from magnetoencephalography. Overall, correlation of power across cortical regions was strongest in the alpha to beta frequency range (8–32 Hz) and correlation patterns depended on the underlying oscillation frequency. Global hubs resided in the medial temporal lobe in the theta frequency range (4–6 Hz), in lateral parietal areas in the alpha to beta frequency range (8–23 Hz) and in sensorimotor areas for higher frequencies (32–45 Hz). Our data suggest that interactions in various large-scale cortical networks may be reflected in frequency-specific power envelope correlations.
966 citations
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TL;DR: The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes, suggesting a strong bias in present clinical syndrome descriptions.
964 citations
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TL;DR: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma and MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.
Abstract: Summary Background Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m 2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Findings Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, p non-inferiority =0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, p non-inferiority =0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding Merck Sharp & Dohme.
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TL;DR: The CRESST-II cryogenic Dark Matter search, aiming at detection of WIMPs via elastic scattering off nuclei in CaWO4 crystals, completed 730 kg days of data taking in 2011 as mentioned in this paper.
Abstract: The CRESST-II cryogenic Dark Matter search, aiming at detection of WIMPs via elastic scattering off nuclei in CaWO4 crystals, completed 730 kg days of data taking in 2011. We present the data collected with eight detector modules, each with a two-channel readout; one for a phonon signal and the other for coincidently produced scintillation light. The former provides a precise measure of the energy deposited by an interaction, and the ratio of scintillation light to deposited energy can be used to discriminate different types of interacting particles and thus to distinguish possible signal events from the dominant backgrounds.
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University of Helsinki1, University of Tübingen2, University of Göttingen3, Heidelberg University4, Technische Universität München5, Ludwig Maximilian University of Munich6, University of Duisburg-Essen7, University of Cologne8, University of Gothenburg9, University of Bergen10, University of Oulu11, Aalto University12, Lund University13
TL;DR: Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo and overall survival of GIST patients with a high risk of Gist recurrence.
Abstract: Context Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo. Objective To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery. Design, Setting, and Patients Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria. Intervention Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery. Main Outcome Measures The primary end point was RFS; the secondary end points included overall survival and treatment safety. Results Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P Conclusion Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence. Trial Registration clinicaltrials.gov Identifier: NCT00116935
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TL;DR: Among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival are identified.
Abstract: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.
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University of Freiburg1, University of Tübingen2, University of Trento3, Graz University of Technology4, University of California, San Diego5, École Polytechnique Fédérale de Lausanne6, Imperial College London7, University of Washington8, University of Hamburg9, University of Arkansas for Medical Sciences10, Institute of Science and Technology Austria11, Technical University of Berlin12, University College London13
TL;DR: The BCI competition IV stands in the tradition of prior BCI competitions that aim to provide high quality neuroscientific data for open access to the scientific community and it is the hope that winning entries may enhance the analysis methods of future BCIs.
Abstract: The BCI competition IV stands in the tradition of prior BCI competitions that aim to provide high quality neuroscientific data for open access to the scientific community. As experienced already in prior competitions not only scientists from the narrow field of BCI compete, but scholars with a broad variety of backgrounds and nationalities. They include high specialists as well as students. The goals of all BCI competitions have always been to challenge with respect to novel paradigms and complex data. We report on the following challenges: (1) asynchronous data, (2) synthetic, (3) multi-class continuous data, (4) session-to-session transfer, (5) directionally modulated MEG, (6) finger movements recorded by ECoG. As after past competitions, our hope is that winning entries may enhance the analysis methods of future BCIs.
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26 Jun 2012TL;DR: In this paper, the authors investigate a family of poisoning attacks against Support Vector Machines (SVM) and demonstrate that an intelligent adversary can predict the change of the SVM's decision function due to malicious input and use this ability to construct malicious data.
Abstract: We investigate a family of poisoning attacks against Support Vector Machines (SVM). Such attacks inject specially crafted training data that increases the SVM's test error. Central to the motivation for these attacks is the fact that most learning algorithms assume that their training data comes from a natural or well-behaved distribution. However, this assumption does not generally hold in security-sensitive settings. As we demonstrate, an intelligent adversary can, to some extent, predict the change of the SVM's decision function due to malicious input and use this ability to construct malicious data.
The proposed attack uses a gradient ascent strategy in which the gradient is computed based on properties of the SVM's optimal solution. This method can be kernelized and enables the attack to be constructed in the input space even for non-linear kernels. We experimentally demonstrate that our gradient ascent procedure reliably identifies good local maxima of the non-convex validation error surface, which significantly increases the classifier's test error.
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TL;DR: Comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes, and indicates a specific role of sleep in the formation of immunological memory.
Abstract: Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep–wake cycle showed that immune parameters like numbers of undifferentiated naive T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations.
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TL;DR: It is demonstrated that an intelligent adversary can, to some extent, predict the change of the SVM's decision function due to malicious input and use this ability to construct malicious data.
Abstract: We investigate a family of poisoning attacks against Support Vector Machines (SVM). Such attacks inject specially crafted training data that increases the SVM's test error. Central to the motivation for these attacks is the fact that most learning algorithms assume that their training data comes from a natural or well-behaved distribution. However, this assumption does not generally hold in security-sensitive settings. As we demonstrate, an intelligent adversary can, to some extent, predict the change of the SVM's decision function due to malicious input and use this ability to construct malicious data. The proposed attack uses a gradient ascent strategy in which the gradient is computed based on properties of the SVM's optimal solution. This method can be kernelized and enables the attack to be constructed in the input space even for non-linear kernels. We experimentally demonstrate that our gradient ascent procedure reliably identifies good local maxima of the non-convex validation error surface, which significantly increases the classifier's test error.
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TL;DR: In this paper, the authors review current understanding of disk-planet interactions, focusing in particular on physical processes that determine the speed and direction of migration of the planet, and examine the influence of Lindblad and corotation torques as a function of disk properties.
Abstract: As planets form and grow within gaseous protoplanetary disks, the mutual gravitational interaction between the disk and planet leads to the exchange of angular momentum and migration of the planet. We review current understanding of disk-planet interactions, focusing in particular on physical processes that determine the speed and direction of migration. We describe the evolution of low-mass planets embedded in protoplanetary disks and examine the influence of Lindblad and corotation torques as a function of the disk properties. The role of the disk in causing the evolution of eccentricities and inclinations is also discussed. We describe the rapid migration of intermediate-mass planets that may occur as a runaway process and examine the transition to gap formation and slower migration driven by the viscous evolution of the disk for massive planets. The roles and influence of disk self-gravity and magnetohydrodynamic turbulence are discussed in detail, as a function of the planet mass, as is the evolution...
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Society for Immunotherapy of Cancer1, National Institutes of Health2, University of Paris3, French Institute of Health and Medical Research4, University of Bern5, Providence Portland Medical Center6, University of Mainz7, Cornell University8, University of Erlangen-Nuremberg9, Medical University of Graz10, Karolinska Institutet11, Harvard University12, CEU San Pablo University13, Memorial Sloan Kettering Cancer Center14, Lund University15, University of Southampton16, Innsbruck Medical University17, University Health Network18, Princess Margaret Cancer Centre19, Keio University20, Yamaguchi University21, Kindai University22, Cancer Research Institute23, University of Tübingen24, Loyola University Chicago25, University of Manchester26, Université de Montréal27, Georgia Regents University28, Royal Melbourne Hospital29, University of Melbourne30, Sapporo Medical University31, Kurume University32, Umeå University33, Radboud University Nijmegen34, Xi'an Jiaotong University35, Dorset County Hospital NHS Foundation Trust36, University of Texas MD Anderson Cancer Center37, Mayo Clinic38, University of Chicago39, Oregon Health & Science University40
TL;DR: Evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy, into traditional classification of cancer, designated TNM-I (TNM-Immune), and introduction of this parameter as a biomarker to classify cancers will facilitate clinical decision-making.
Abstract: Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
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Selidji T Agnandji1, Selidji T Agnandji2, Bertrand Lell2, Bertrand Lell1 +165 more•Institutions (14)
TL;DR: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants.
Abstract: BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
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University of Turin1, Masaryk University2, University of Münster3, Sapienza University of Rome4, Monash University5, Medical University of Vienna6, Medical University of Warsaw7, University of Tübingen8, Casa Sollievo della Sofferenza9, University of Bologna10, Medical University of Białystok11, Ankara University12, Charles University in Prague13, Dresden University of Technology14, University of Ulm15, Celgene16, National and Kapodistrian University of Athens17
TL;DR: MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age.
Abstract: The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P <0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P = 0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P = 0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. Conclusions MPR-R significantly prolonged progression-free survival in patients with newly di agnosed multiple myeloma who were ineligible for transplantation, with the great est benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.)
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University of Alabama1, California State University, Bakersfield2, Field Museum of Natural History3, University of Bristol4, University of Texas at Austin5, University of Chicago6, University of Nebraska–Lincoln7, University of California, Berkeley8, University of Tokyo9, American Museum of Natural History10, University of Tübingen11, North Carolina Museum of Natural Sciences12, North Carolina State University13, Instituto Butantan14, Dartmouth College15, University of North Carolina at Wilmington16, University College London17, University of California, Santa Cruz18, Humboldt University of Berlin19, Southern Methodist University20, University of Calgary21
TL;DR: A specimen-based protocol for selecting and documenting relevant fossils is presented and future directions for evaluating and utilizing phylogenetic and temporal data from the fossil record are discussed, to establish the best practices for justifying fossils used for the temporal calibration of molecular phylogenies.
Abstract: At this time, no abstract is available. SciVerse Scopus has content delivery agreements in place with each publisher and currently contains 30 million records with an abstract. An abstract may not be present due to incomplete data, as supplied by the publisher, or is still in the process of being indexed.
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TL;DR: Specialized templates that allow normalization algorithms to be applied to stroke-aged populations are introduced and a MRI template is derived that approximately matches the shape of the CT template.
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Heidelberg University1, Charité2, Ludwig Maximilian University of Munich3, University of Düsseldorf4, University of Würzburg5, University of Regensburg6, Ruhr University Bochum7, Technische Universität München8, University of Ulm9, University of Erlangen-Nuremberg10, Goethe University Frankfurt11, University of Tübingen12, Hannover Medical School13, University of Münster14, Leipzig University15, University of Rostock16, University of Göttingen17
TL;DR: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Abstract: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Seropositive patients were found to be predominantly female (p 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
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Max Planck Society1, Free University of Berlin2, University of Colorado Boulder3, Royal Berkshire NHS Foundation Trust4, University of Ioannina5, University of Oxford6, Harvard University7, Mayo Clinic8, University of Miami9, University of Tübingen10, German Center for Neurodegenerative Diseases11, Boston University12, Emory University13, University of British Columbia14, Indiana University15, Wadsworth Center16, University College London17, VU University Amsterdam18, University of Lübeck19, University of Chicago20, University of Toulouse21, Centre national de la recherche scientifique22, National Institutes of Health23, Kobe University24, deCODE genetics25, University of Washington26, University of Münster27, Centers for Disease Control and Prevention28, University of Mainz29
TL;DR: This study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
Abstract: More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson’s disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ,27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Metaanalyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P,5610 28 ) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3 ,P ARK16,SNCA, STK39 ,a ndSYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P=1.3610 28 ). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
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TL;DR: The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases, and treatment with vemurafenib should be investigated in patients with malignant BRAf(V 600E) histiocytosis.
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University of Cologne1, Charles University in Prague2, Heidelberg University3, Masaryk University4, University of Tübingen5, University of Ulm6, Charité7, Ludwig Maximilian University of Munich8, University of Würzburg9, University of Hamburg10, University of Duisburg-Essen11, Leipzig University12, University of Münster13, University of Salzburg14, University Hospital Regensburg15, Saarland University16
TL;DR: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen, and should be the treatment of choice for advanced stage Hodgkin's lymphoma.
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TL;DR: In this paper, the authors explore whether the link between gender diversity and firm performance follows a U-shape and find evidence for gender diversity to at first negatively affect firm performance and, after a critical mass of about 30 percent women has been reached, to be associated with higher firm performance than completely male boards.
Abstract: The under-representation of women on boards is a heavily discussed topic – not only in Germany. Based on critical mass theory and with the help of a hand-collected panel data set of 151 listed German firms for the years 2000-2005, we explore whether the link between gender diversity and firm performance follows a U-shape. Controlling for reversed causality, we find evidence for gender diversity to at first negatively affect firm performance and – only after a “critical mass” of about 30 percent women has been reached – to be associated with higher firm performance than completely male boards. Given our sample firms, the critical mass of 30 percent women translates into an absolute number of about three women on the board and hence supports recent studies on a corresponding “magic number” of women in the boardroom.