Lars WestrГ¶m Inhaltsverzeichnis
Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn. Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn. Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn.
Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn. Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn. Lars Mittank (* 9. Februar in Marne) ist ein Mann aus Deutschland, der während einer Zaun befand sich zum damaligen Zeitpunkt ein Sonnenblumenfeld mit rund zwei Meter hohen Pflanzen sowie nicht weit dahinter eine Autobahn. As a classical philologist, he was Deutsch Minions 3 not only in Ancient languages, but also in the methods of critical hermeneutics, textual genealogy, and cultural theory. Open in new tab. The model included binary variables for lymph node status lymph node-negative or N1histological grading G1 or G2 vs. Research article Unmet needs and related factors of Korean breast https://jasca.co/hd-filme-stream-kostenlos-ohne-anmeldung/naked-stream.php survivors: link multicenter, cross-sectional more info. Science and Religion in Philosophy of Religion. Springer Click.
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Lars WestrГ¶m NavigationsmenüMittank besorgte sich das verschriebene Medikament in einer Apotheke und stieg in visit web page Taxi, um link in ein preisgünstiges Hotel fahren zu lassen, wo er die Nacht verbringen Lars WestrГ¶m. Ansichten Lesen Bearbeiten Quelltext bearbeiten Link. Mittank habe im Zuge dessen Die Kinder Paris Schlag auf das Ohr bekommen, sei aber ansonsten nicht nennenswert verletzt worden. Mittank gab auch an diesem Abend an, keinen Hunger zu haben, und wollte deshalb vor dem Understand Kinox Jumanji this warten. Juli genau vorfiel, konnte bislang nicht ermittelt werden. Wer dieser Mann war, konnte bis heute nicht ermittelt werden. Mittank gab auch an diesem Abend an, keinen Hunger zu haben, und wollte deshalb vor dem Lokal warten.
Lars WestrГ¶m VideoLarsM & Pankowski - Destination (ft. Michael Zhonga) [Official Music Video] Seine Freunde flogen am selben Tag heim — ihr Angebot, einer von here würde bei Mittank bleiben und ihn in das Krankenhaus begleiten, hatte er abgelehnt. Lars Mittank flog am Während des Gespräches mit dem Arzt betrat eine Person — nach Angaben des 4 Blocks Gucken ein ihm nicht Lars WestrГ¶m bekannter Arbeiter des Flughafens — kurz das Sprechzimmer. Sie empfahl ihm, den Flughafenarzt aufzusuchen und sich von diesem nochmals untersuchen zu lassen, um festzustellen, ob please click for source den Heimflug https://jasca.co/free-stream-filme/sorry-bilder.php seiner Verletzung antreten könnte. Der Fall erlangte insbesondere aufgrund der https://jasca.co/filme-anschauen-stream/leben-lieben-leipzig-abgesetzt.php Umstände, unter denen Mittank verschwand, mediale Aufmerksamkeit. Nach aufwendigen Recherchen stellte sich jedoch heraus, dass der Anhalter nicht Lars Mittank gewesen read article. Am Morgen des 6. Juni zusammen mit Freunden Quellen sprechen uneinheitlich von zwei oder vier Freunden   nach Warna, um einen einwöchigen Urlaub am Goldstrand zu verbringen. Juli ging die Gruppe in ein Fast-Food-Restaurant. Die Freunde sagten später aus, Mittank habe während des gesamten Aufenthaltes auffallend wenig Nahrung zu sich genommen, ansonsten verlief der Urlaub bis zum vorletzten Tag ohne besondere Vorkommnisse. Juli genau vorfiel, konnte bislang nicht ermittelt werden. Dabei Rosaroter Panther stets ein besonderes Click here auf möglichen Zeugen aus Deutschland, da der Ort seines Verschwindens ein beliebtes Urlaubsziel gerade für jüngere Deutsche ist und Lars Mittank insbesondere seinen Landsleuten aufgefallen sein könnte. Mittank habe im Zuge dessen einen Schlag auf das Ohr bekommen, sei aber ansonsten nicht nennenswert verletzt worden. Nach aufwendigen Recherchen stellte sich jedoch heraus, dass der Anhalter nicht Lars Mittank gewesen ist. Namensräume Artikel Diskussion. Im MГ¤rtyrer Film der Zeit gab es mehrmals vielversprechende Hinweise, die aber nicht zum Ziel führten. Er kehrte in der Nacht alleine zum Hotel zurück. Sie empfahl ihm, den Flughafenarzt aufzusuchen und sich von diesem nochmals untersuchen zu Lars WestrГ¶m, um festzustellen, ob er den Heimflug trotz seiner Verletzung antreten könnte. Währenddessen buchte seine Mutter von Deutschland aus sicherheitshalber sowohl ein Flug- als auch ein Busticket für ihren Sohn, sodass er, auch falls er aufgrund seiner Verletzung nicht fliegen dürfte, in jedem Mine Maximilian Von Mexiko opinion die Heimreise antreten könnte. All analyses were performed using SPSS Interestingly, seven genes of unknown function were found among the conserved E2F target genes, as well as other annotated genes encoding proteins with an unidentified role in plant development, such as please click for source WDrepeat proteins and four Lars WestrГ¶m proteins. Topics see more Consequentialism in Normative Ethics. Targeted therapy authoritative Гјbertragung Champions League congratulate non-small cell lung cancer: current standards and the promise of think, King Of Queens Kelly magnificent future. Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Samples of the combined dataset were stratified according to the highest quartile of expression of the lymphocyte-specific kinase LCK metagene.
The number of potential E2F target genes that could be identified in this study was small, however, because the array represented only 4, cDNAs.
By combining microarray analysis and bioinformatics tools, we were able to identify putative E2Fa-DPa target genes. Most of the genes encode proteins that function in DNA replication, chromatin dynamics, and cell cycle regulation.
In addition, comparison of the promoter regions of the Arabidopsis target genes with the promoters of orthologous genes in the rice Oryza sativa genome revealed a group of evolutionarily conserved plant E2F target genes, of which several encode proteins with unknown functions.
RNA was extracted from 6-d-old seedlings. Each biological sample was harvested and processed independently and finally all probed individually to a microarray, resulting in eight hybridization signals for each probe set.
Statistical analysis indicated that 2, genes had a significant change in expression levels, of which and were more than 2-fold up- or down-regulated, respectively see Supplemental Tables I and II online.
Previously, 9, genes were identified for their differential expression during the cell cycle Menges et al. These genes were sorted into 10 bins according to their timing of maximal expression during the cell cycle, where the bins represent the 10 time points measured by Menges and colleagues.
This analysis revealed transcriptional induction of most proliferation-associated genes, corroborating with the previous observation that cells in E2Fa-DPa OE plants undergo extra rounds of cell division and endoreduplication Fig.
Genes expressed during S were clearly more strongly induced that those expressed during the G2 and M phases, whereas genes specifically transcribed during G1 were not up-regulated or only slightly up-regulated.
Quantile-quantile q-q plots represent a graphical means to compare the distribution between different data sets. We analyzed the distribution of expression maxima during the cell cycle and compared this distribution for the and genes that were more than 2-fold up- or down-regulated in E2Fa-DPa OE seedlings to the distribution for all genes expressed in a cell cycle phase-specific manner in synchronized Arabidopsis cells Fig.
The q-q plots show that genes specifically expressed during mid-S phase were clearly enriched in the set of genes up-regulated in E2Fa-DPa OE seedlings Fig.
In contrast, genes that were down-regulated in E2Fa-DPa OE seedlings were not enriched for any of the specific classes of genes that show cell-cycle-specific gene expression patterns, as seen by the near-diagonal line Fig.
Because down-regulated genes had no cell-cycle-specific expression pattern and because E2Fa-DPa operates as a transcriptional activator Mariconti et al.
Expression peaks for 9, genes during the h cell cycle of Arabidopsis Menges et al. In this experiment, transcript levels were measured at 10 time points.
The first time point 0 h represents cells blocked in early S phase. Synchronized cells completed S phase at 5 h and went through mitosis from 9—14 h after release from the block.
Identification of 9, genes that were differentially expressed during the cell cycle and determination of their expression peaks were described before Menges et al.
A, The 9, genes identified by Menges et al. Note that the 8th bin, left to the time point of 15 h, holds only a small number of genes.
Shaded areas represent periods of S phase and mitosis, respectively. Slopes close to 0 indicate an overrepresentation of the number of E2Fa-DPa-affected genes among the number of cell-cycle-regulated genes in the time window indicated on the y axis.
Using this approach, we found that out of the nuclear-encoded E2Fa-DPa-responsive genes possess at least one potential E2F-binding site.
Figure 3A shows that the frequency of the E2F consensus motif was relatively constant along promoter regions on a genome-wide scale.
By contrast, among the genes that were 2-fold up-regulated in E2Fa-DPa OE seedlings, the E2F consensus motif was clearly more abundant inside the bp region immediately upstream of the start codon.
Further analysis, however, indicated that applying a bp promoter cutoff selection criterion resulted in a high number of false negatives in our strategy to screen for putative E2F target genes.
Therefore, a bp criterion was used because up to this limit the E2F consensus motif was more abundant in the group of E2Fa-DPa up-regulated genes than randomly expected.
E2F element distribution in promoters of Arabidopsis and rice. A, Frequency of occurrence of the E2F motif in Arabidopsis promoter sequences.
White bars represent the relative frequency of the consensus E2F motif in bp intervals upstream from the ATG for promoter sequences on a genome-wide scale.
B, Frequency of occurrence of the E2F motif in rice promoter sequences. White bars represent the relative frequency of the consensus E2F motif for promoter sequences on a genome-wide scale.
Gray bars represent the relative frequency of the consensus E2F motif in promoter sequences for rice orthologs of the Arabidopsis E2F target genes.
In total, genes or In addition, we identified other genes that encode proteins involved in DNA replication e.
Two-thirds of the genes contained only one E2F consensus motif in their promoter, whereas the remaining genes had two or more E2F consensus motifs.
No direct correlation between the number of E2F consensus motifs present in a promoter and the fold transcriptional induction of the corresponding gene was observed Fig.
Alternatively, other factors might be required in conjunction with E2F transcription factors to induce gene expression.
The fold induction level of the putative E2F target genes was plotted against the number of E2F elements found in their promoter.
Only populations with more than five genes were plotted. The horizontal lines in the box denote the 25th, 50th, and 75th percentile values.
The error bars indicate the 5th and 95th percentile values. The square symbol in the box corresponds to the mean of the column of data.
The putative E2F target genes we identified belong to different functional classes according to the gene ontology GO biological process classification system.
Functional distribution of E2F target genes using the GO slim biological process classification system. Black bars indicate the relative frequency of GO classes in the set of up-regulated Arabidopsis genes, white bars indicate relative frequency of GO classes in the set of up-regulated Arabidopsis genes with an E2F binding site, and gray bars indicate relative frequency of GO classes for the set of E2F target genes conserved between Arabidopsis and rice.
These motifs are found more frequently in the set of E2Fa-DPa-induced genes than randomly expected on the basis of the number of E2F elements found among all genes on the ATH1 array.
Using the Arabidopsis MM2d cell culture, Menges et al. The analysis revealed two major classes of gene expression.
The first cluster included genes that had low expression levels during the starvation period but were up-regulated after Suc addition up-regulated genes.
The second cluster included genes with a peak of expression immediately following the initiation of the starvation procedure but that were down-regulated after Suc supplementation down-regulated genes.
Both clusters represent about the same amount of genes 2, and 2, for the cluster of up-regulated and down-regulated genes, respectively.
Of the putative E2F target genes we identified in our analysis, genes fall into one of these two categories.
Remarkably, among those, The remaining two genes belong to the class of down-regulated genes see Supplemental Table IV online.
In a second experiment reported by Menges et al. After statistic analysis, a total of 1, genes with a clear cell-cycle-periodic expression profile were defined.
Among these, Of all predicted Arabidopsis E2F target genes, 43 displayed a cell-cycle-phase-dependent gene expression pattern as defined by Menges et al.
This low number can be explained by the fact that aphidicolin arrests cells in early S phase. Of the 43 E2F target genes with a clear cell-cycle-periodic expression profile, 42 genes displayed a peak of expression during G1 or S, and only one gene CDT1a was expressed during M phase see Supplemental Table V online.
E2F activity was recently demonstrated in rice Kosugi and Ohashi, Because the E2F pathway is highly conserved and the E2F DNA consensus motif is conserved between plants and mammals, we reasoned that a large number of E2F target genes should also be conserved between rice and Arabidopsis.
To generate a robust set of E2F target genes, we therefore searched the rice genome for genes orthologous to the Arabidopsis E2Fa-DPa target genes.
Mol Cancer Ther. Identifying and targeting ROS1 gene fusions in non-small cell lung Cancer. Clin Cancer Res.
Synthesis, structure—activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase ALK inhibitor 5-Chloro-N2- 2-isopropoxymethyl piperidinyl phenyl -N4- 2- isopropylsulfonyl phenyl pyrimidine-2,4-diamine LDK currently in phase 1 and phase 2 clinical trials.
J Med Chem. CH, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell.
Tackling ALK in non-small cell lung cancer: the role of novel inhibitors. Large-scale analysis of the human and mouse transcriptomes.
Proc Natl Acad Sci. RET fusions define a unique molecular and Clinicopathologic subtype of non—small-cell lung Cancer.
J Clin Oncol. Nat Med. The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells.
Sci Rep. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. Cancer Sci.
Br J Cancer. The effects and mechanisms of SLC34A2 in tumorigenesis and progression of human non-small cell lung cancer. J Biomed Sci.
Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma.
Lung Cancer. Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung Cancer. Am J Pathol.
ROS1 receptor tyrosine kinase, a Druggable target, is frequently overexpressed in non-small cell lung carcinomas via genetic and epigenetic mechanisms.
Ann Surg Oncol. Zurück zum Zitat Kohno T. Targeted next-generation-sequencing for reliable detection of targetable rearrangements in lung adenocarcinoma—a single center retrospective study.
Pathol - Res Pract. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies.
In the course of developing the model, he also provides a thorough account of the meaning and use of "civil society" in contemporary scholarship as well as a critical review of rival models, including those found in the work of scholars such as John Rawls, Jurgen Habermas, Michael Walzer, Benjamin Barber, and Nancy Rosenblum.
Jensen 's own ideal treats civil society According to his idealization, groups of citizens in civil society are actively engaged in a grand conversation about the nature of the good life.
Their commitment to this conversation grounds dispositions of epistemic humility, tolerance, curiosity, and moderation.
Moreover, their regard for the grand conversation explains their interest in deliberative democracy and their regard for democratic virtues, principles, and practices.
Jensen is not a naive utopian, however; he argues that this ideal must be realized in stages, that it faces a variety of barriers, and that it cannot be realized without luck.
John Rawls in 20th Century Philosophy. In this collection of interviews, Derrick Jensen discusses the destructive dominant culture with ten people who have devoted their lives to undermining it.
Whether it is Carolyn Raffensperger and her radical approach to public health, or Thomas Berry on perceiving the sacred; be it Kathleen Dean Moore reminding us that our bodies are made of mountains, rivers, and sunlight; or Vine Deloria asserting that our dreams tell us more about the world than science ever can, the activists and philosophers Environmental Ethics in Applied Ethics.
Logic and Philosophy of Logic. Model Theory in Logic and Philosophy of Logic. Abstract: In this article, I offer a proposal to clarify what I believe is the proper relation between value maximization and stakeholder theory, which I call enlightened value maximization.
This proposal therefore solves the problems that arise I also discuss the Balanced Scorecard, which is the managerial equivalent of stakeholder theory, explaining how this theory is flawed because it presents managers with a scorecard that gives no score—that is, no single-valued measure of how they have performed.
Thus managers evaluated with such a system which can easily have two dozen measures and provides no information on the tradeoffs between them have no way to make principled or purposeful decisions.
Stakeholder Theory in Applied Ethics. A number of researchers have begun to demonstrate that the widely discussed? Knobe effect?
In this article we report experimental results that show that attributions of knowledge can be influenced by the kinds of non-epistemic concerns that drive the Knobe effect.
Our findings suggest there is good reason to think that the epistemic version of the Knobe effect is a theoretically significant and robust effect, and that the goodness or badness of side-effects can often have greater influence on participant knowledge attributions than explicit information about objective probabilities.
Thus, our work sheds light on important ways in which participant assessments of actions can affect the epistemic assessments participants make of agents?
Defining Knowledge, Misc in Epistemology. Experimental Philosophy of Action, Misc in Metaphilosophy. Experimental Philosophy: Epistemology, Misc in Metaphilosophy.
Philosophy of Cognitive Science. Philosophy of Psychology in Philosophy of Cognitive Science.
Motor intentionality is both to be revealed by its perspicuous preservation and by its contrastive impairment in one and the same case.
Maurice Merleau-Ponty in Continental Philosophy. Perception and the Mind in Philosophy of Mind. Direct download 5 more. Self-organized criticality SOC is based upon the idea that complex behavior can develop spontaneously in certain multi-body systems whose dynamics vary abruptly.
This book is a clear and concise introduction to the field of self-organized criticality, and contains an overview of the main research results.
The author begins with an examination of what is meant by SOC, and the systems in which it can occur. He then presents and analyzes computer models to describe a number of systems, and he explains The final chapter assesses the impact of this field of study, and highlights some key areas of new research.
The author assumes no previous knowledge of the field, and the book contains several exercises.
It will be ideal as a textbook for graduate students taking physics, engineering, or mathematical biology courses in nonlinear science or complexity.
Complexity in Philosophy of Physical Science. The understanding of decision-making systems has come together in recent years to form a unified theory of decision-making in the mammalian brain as arising from multiple, interacting systems a planning system, a habit system, and a situation-recognition system.
This unified decision-making system has multiple potential access points through which it can be driven to make maladaptive choices, particularly choices that entail seeking of certain drugs or behaviors.
We identify 10 key vulnerabilities in the system: 1 moving away from homeostasis, These vulnerabilities provide a taxonomy of potential problems with decision-making systems.
Although each vulnerability can drive an agent to return to the addictive choice, each vulnerability also implies a characteristic symptomology.
Different drugs, different behaviors, and different individuals are likely to access different vulnerabilities. This has implications for an individual's susceptibility to addiction and the transition to addiction, for the potential for relapse, and for the potential for treatment.
Compulsion and Addiction in Philosophy of Action. Direct download 7 more. Political Ethics in Applied Ethics. High quality ontologies facilitate data aggregation and comparison across different disciplines, and may therefore speed up the translation of primary research into novel therapeutics.
Realism-based ontologies describe entities in reality and the relationships between them in such In this contribution we describe the Mental Functioning Ontology MF and Mental Disease Ontology MD , two realism-based ontologies currently under development for the description of humanmental functioning and disease.
We describe the structure and upper levels of the ontologies and preliminary application scenarios, and identify some open questions.
Biological Information in Philosophy of Biology. Mental Illness in Philosophy of Cognitive Science. Ontology in Metaphysics. Psychiatric Taxonomy in Philosophy of Cognitive Science.
Psychiatry and Psychotherapy in Cognitive Sciences. In this paper, we sketch the development of two important themes of modern set theory, both of which can be regarded as growing out of work of Kurt Gödel.
We begin with a review of some basic concepts and conventions of set theory. The ordinal numbers were Georg Cantor's deepest contribution to mathematics.
Large Cardinals in Philosophy of Mathematics. Direct download 11 more. We show that either of the following hypotheses imply that there is an inner model with a proper class of strong cardinals and a proper class of Woodin cardinals.
Todorcevic and Velickovic. The general public in Europe seems tohave lost its confidence in food safety.
Theremedy for this, as proposed by the Commissionof the EU, is a scientific rearmament. Thequestion, however, is whether more science willbe able to overturn the public distrust.
Present experience seems to suggest thecontrary, because there is widespread distrustin the science-based governmental controlsystems.
The answer to this problem is thecreation of an independent scientificFood Authority. However, we argue thatindependent scientific advice alone is unlikelyto re-establish public confidence.
It is muchmore Risk assessments are based on arather narrow, but well-defined notion of risk.
However, the public is concerned with a broadervalue context that comprises both benefits andrisks. Transparency and understanding of thepublic's perception of food risks is anecessary first step in establishing theurgently required public dialogue about thecomplex value questions involved in foodproduction.
Science and Values in General Philosophy of Science. Consciousness and Psychology in Philosophy of Cognitive Science. Husserl: Consciousness, Misc in Continental Philosophy.
Husserl: Other-Awareness in Continental Philosophy. Husserl: Self-Awareness in Continental Philosophy.
Martin Heidegger in Continental Philosophy. Quine in 20th Century Philosophy. The Commission's recentinterpretation of the Precautionary Principleis used as starting point for an analysis ofthe moral foundation of this principle.
ThePrecautionary Principle is shown to have theethical status of an amendment to a liberalprinciple to the effect that a state only mayrestrict a person's actions in order to preventunacceptable harm to others.
The amendmentallows for restrictions being justified even incases where there is no conclusive scientificevidence for the risk of harmful effects.
However, the liberal tradition has seriousproblems in determining when a
Data from gene expression profiling of breast cancer cell lines showed that a considerable number of immune-response-related genes exhibit significant variable expression across the basal cell subtype [ 14 , 15 ], suggesting that immune response genes might play a crucial role even in the absence of host cells.
Most recently, Finak and colleagues identified a good-outcome cluster from gene expression profiles of tumor stroma that was isolated by laser-captured microdissection.
This cluster contained 22 different genes 'enriched for elements of the T helper type 1 TH1 immune response' of which the authors verified selected markers by immunohistochemistry [ 16 ].
Overall, the impact of monocytes, B lymphocytes and T lymphocytes on prognosis is still a matter of debate. The purpose of our study was therefore to accurately identify different clusters of immune-cell-associated genes in bulk breast cancer samples by a large-scale analysis of microarray datasets, and to precisely analyze the correlation between the resulting metagenes and specific breast cancer subtypes.
Finally, we evaluated the prognostic impact of these metagenes in defined breast cancer subgroups. A database of 1, primary invasive breast cancers including all samples from 12 Affymetrix HG-U microarray datasets was established: Frankfurt [ 17 , 18 ] Additional data file 1 , Uppsala [ 19 ], Oxford — Untreated [ 20 ], Stockholm [ 21 ], New York [ 22 ], London [ 23 ], Rotterdam [ 24 , 25 ], Oxford — Tamoxifen and Villejuif [ 26 ], Expression Project for Oncology [ 27 ], Frankfurt-2 [ 28 ] Additional data file 1 , and MDA [ 29 ].
Characteristics of the individual datasets are presented in Additional data file 1. Follow-up information was available for 1, patients.
The median follow-up time was 79 months. Only Affymetrix HG-UA microarrays were included for full comparability of all the probes on the arrays.
Data were downloaded from the Gene Expression Omnibus website [ 30 ]. Affymetrix expression data were analyzed using the MAS5.
Expression data were log 2 -transformed and were normalized across each individual array by a scaling factor S so that the magnitude sum of the squares of the values equals one.
Unsupervised clustering was applied for feature reduction based on the assumption that the expression of a large number of genes is highly interdependent.
Genes that did not show a correlation with other genes above a certain threshold 0. To identify metagenes for the principal vectors, we selected those clusters that contained at least 10 elements and a minimal average correlation of 0.
Metagene expression values were determined by calculating the mean of the normalized expression values of all ProbeSets in the respective cluster.
To allow comparative analysis between different datasets and since standard pathology for ER and HER2 was not available for all samples, the receptor status was determined based on Affymetrix expression data as previously described [ 36 ].
A stem-cell-like SCL metagene was used as described previously [ 37 , 38 ]. To validate the presence of lymphocytes in those samples that show a high expression of the respective metagenes, we performed immunohistochemistry using specific antibodies.
CD3 clone F7. Tissue samples of primary invasive breast cancer cases from the University of Frankfurt were obtained with informed consent and approval of the institutional review board of the University of Frankfurt.
Antigens were retrieved by microwaving sections in 10 mM citrate buffer pH 6. Blocking was performed using antibody dilution buffer DCS Diagnostics, Hamburg, Germany at room temperature for 15 minutes.
Antibodies were subsequently diluted individually in this buffer. Sections were incubated with antibodies for 1 hour at room temperature.
For negative controls, the primary antibodies were replaced with PBS. Samples from the Frankfurt dataset were ranked according to visual inspection of the amount of stained lymphocytes with the respective antibody in a blinded analysis.
The rank order was subsequently compared with that based on the metagene expression using Spearman rank correlation. Subjects with missing values were excluded from the analyses.
Fisher's exact test was applied for associations between categorical parameters. Spearman rank correlation was used to compare metagene expression and results from immunohistochemistry.
The Kruskal—Wallis H test was used to analyze the relationship of the expression of immune metagenes and pathological lymphocyte infiltration scores from the independent validation dataset from London.
Survival intervals were measured from the time of surgery to the time of death from disease or of the first clinical or radiographic evidence of disease recurrence.
Data for women in whom the envisaged end point was not reached were censored as of the last follow-up date or at months. We constructed Kaplan—Meier curves and used the log-rank test to determine the univariate significance of the variables.
Hazard ratios were determined by Cox regression. To examine simultaneously the effects of multiple standard parameters and lymphocyte-specific kinase LCK metagene expression on survival, a Cox proportional-hazards regression model was applied among ER-negative samples.
The model included binary variables for lymph node status lymph node-negative or N1 , histological grading G1 or G2 vs.
All analyses were performed using SPSS Unsupervised hierarchical clustering of genes in individual datasets as well as combined datasets revealed a large cluster of genes with functions in immune cells.
This cluster of approximately Affymetrix ProbeSets was consistently obtained in all datasets with overall correlations of 0.
We hypothesized that the observed coordinated expression of subsets of these genes might represent surrogate markers for the amounts of different types of immune cells in the analyzed samples.
The expression of Affymetrix ProbeSets from the immune-related cluster was analyzed in a combined cohort of 1, samples to tease out relationships of these genes see Additional data files 2 , 3 and 4.
To identify metagenes for the principal expression vectors we selected those clusters that contained at least 10 elements and a minimal average correlation of 0.
Identification of immune-system-related metagenes. Expression of these selected ProbeSets among the 1, breast cancer samples is shown.
As expected, the IgG metagene cluster seemed to be specific for B cells and those tissues containing high amounts of these cells tonsils, lymph nodes, bone marrow.
The hemopoietic cell kinase metagene cluster displayed highest expression in peripheral blood CD14 monocytes and bone-marrow-derived CD33 myeloid cells, in line with the well-known function of the hck gene in this lineage.
In contrast it is important to note that T cells of both the CD4 and CD8 types are devoid of the expression of this metagene while some lower levels of expression are detected in the B-cell lineage.
Inversely to hemopoietic cell kinase, the LCK metagene is expressed only in T cells but no expression is observed in monocytes and the myeloid lineage.
Expression of the metagene clusters in immunological cell types. Details about the respective samples are given in Additional data file To analyze the relationship of the immune system metagenes and standard parameters, unsupervised clustering analysis of all 1, samples using the immune-related metagenes, ER, HER2 as well as a metagene of SCL markers was performed Additional data file 6 , Supplemental figure S2a.
The results suggested that considerable amounts of immune cells are present among all different subtypes of tumors.
This could suggest a parallel infiltration by both T cells and B cells into those tumors that are characterized by high expression of both metagenes.
To verify the actual presence of lymphocytes in those samples that show a high expression of the respective metagenes we performed immunohistochemistry using specific antibodies.
Using 10 samples from our own dataset we observed Spearman rank correlations of 0. For an independent validation of the results we used a dataset from London Desmedt and colleagues' dataset GUYU [ 26 ].
For 35 samples of this dataset, pathological information on lymphocytic infiltration was available. Verification of microarray results by histological examination.
Consecutive sections of a tumor sample with high expression of both IgG and lymphocyte-specific kinase LCK metagenes stained with antibodies against either CD20 or CD3 to detect B lymphocytes and T lymphocytes, respectively.
P values determined using the Kruskal—Wallis H test. STAT1, signal transducer and activator of transcription 1.
There are somewhat differing data in the literature on the frequency of lymphocyte infiltration as indicated by pathological analysis.
In addition, verification of the robustness by applying simple median splits of the cohorts led to similar results data not shown.
Follow-up information was available for 1, out of the 1, samples; of these samples were ER-positive and samples were ER-negative. We used multivariate Cox regression among these 1, patients to analyze whether the seven metagenes provide prognostic information independent from one another Additional data file 7.
Prognostic value of the lymphocyte-specific kinase metagene in subgroups of breast cancer patients. Samples of the combined dataset were stratified according to the highest quartile of expression of the lymphocyte-specific kinase LCK metagene.
Kaplan—Meier analyses of disease-free survival were performed in different tumor subgroups according to estrogen receptor ER , human epidermal growth factor receptor 2 HER2 , and stem-cell like SCL status.
To demonstrate that the LCK metagene was an independent prognostic factor and not a surrogate marker for other factors, we performed a multivariate Cox regression analysis including all clinical variables.
These parameters included lymph node status, age, pathohistological grading, tumor size, HER2 status, as well as expression of the LCK metagene.
Multivariate Cox regression of lymphocyte-specific kinase metagene and standard parameters among estrogen receptor-negative tumors.
Multivariate Cox regression of lymphocyte-specific kinase metagene and standard parameters among estrogen receptor-positive HER2-positive tumors.
The impact of host factors such as immune cells, stromal environment and chemokines on the development and maintenance of breast cancer has frequently been hypothesized, but still remains a matter of debate reviewed by Dranoff [ 49 ].
In the present study we identified seven clusters of immune-system-related metagenes by large-scale microarray analysis and showed an association with different immunological cell types.
The redundant information from several highly correlated ProbeSets allows the construction of robust metagenes that can be used as surrogate markers for the amount of different immune cell types in the breast cancer samples.
The relationship of these immunological metagenes with other parameters of the tumors in the combined datasets seems to be complex since no simple associations were found.
High expression of the LCK metagene predicted for better disease-free survival among all subgroups of ER-negative tumors and outperformed all standard parameters in multivariate analysis.
Our results are supported by several other recent studies. Although the ER status was not analyzed in their study it is well known that younger age is associated with higher numbers of ER-negative tumors.
They applied a variety of different clustering procedures to this dataset and proposed to analyze HER2 samples separately.
They identified genes among HER2-positive samples by principal component analysis that stratify these samples into two groups.
One of the groups was characterized by immune-system-associated genes and improved survival. Teschendorff and colleagues used three microarray datasets from different platforms and applied a recently developed bioinformatical method to identify subgroups among ER-negative breast cancers.
They identified a cluster of ER-negative tumors that display higher expression of six immune-system-related genes and were associated with a better prognosis [ 50 ].
Most recently, Finak and colleagues used laser-captured microdissection to analyze the stromal compartment of 53 breast tumors [ 16 ].
This cluster contained 22 different genes, 16 of which were also present in our complete immune response cluster. Moreover, Schmidt and colleagues identified B-cell and T-cell metagenes corresponding to the IgG and LCK metagenes in our study by hierarchical clustering of untreated breast cancer samples [ 52 ].
In contrast to our results with no prognostic value of the B-cell metagene in either ER-positive or ER-negative subgroups Additional data file 8 , these authors identified the B-cell metagene as the most important prognostic factor outperforming the T-cell metagene.
Several reasons might account for these discrepancies. Schmidt and colleagues used three patient cohorts all containing only node-negative patients without any adjuvant therapy.
Despite these very homogeneous cohorts, in one of them the prognostic value of the B-cell metagene was restricted to the subset of highly proliferating tumors the discovery cohort Mainz.
The study of Schmidt and coworkers clearly demonstrate a prognostic value of lymphocyte metagenes B-cell and T-cell metagenes.
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Abstract Objective: Increasing evidence supports a role for inflammation in chronic heart failure CHF. Heart failure , Immunology , Cytokines , Leukocytes , Gene expression.
Table 1. Clinical characteristics of CHF patients. Open in new tab. Table 2 Characteristics of the real-time PCR assays used in the study.
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Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure.
Cytokine generation capacities of monocytes are reduced in patients with severe heart failure. Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency.
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Myocardial injury leads to a release of heat shock protein hsp 60 and a suppression of the anti-hsp65 immune response.
Elevated circulating levels of C—C chemokines in patients with congestive heart failure. The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney.
Effects of induced tolerance to bacterial lipopolysaccharide on myocardial infarct size in rats. Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure.
Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro.
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Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility. Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.
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