Lars Weström

Lars Weström 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 Weström

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.

Springer Medizin. Zurück zum Suchergebnis. Wichtige Hinweise. Abstract Background Genetic alterations, including mutation of epidermal growth factor receptor or v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog and fusion of anaplastic lymphoma kinase ALK , RET proto-oncogene RET , or v-ros UR2 sarcoma virus oncogene homolog 1 ROS1 , occur in non-small cell lung cancers, and these oncogenic drivers are important biomarkers for targeted therapies.

A useful technique to screen for these fusions is the detection of native carboxy-terminal C-terminal protein by immunohistochemistry; however, the effects of other genetic alterations on C-terminal expression is not fully understood.

In this study, we evaluated whether C-terminal expression is specifically elevated by fusion with or without typical genetic alterations of lung cancer.

Methods In 37 human lung cancer cell lines and four tissue specimens, protein and mRNA levels were measured by capillary western blotting and reverse transcription—PCR, respectively.

Results Compared with the median of all 37 cell lines, mRNA levels at the C-terminus of all five of the fusion-positive cell lines tested three ALK , one RET , and one ROS1 were elevated at least , , or fold, respectively, and high C-terminal protein expression was detected.

Meanwhile, in one of 36 RET fusion—negative cell lines, RET mRNA levels at the C-terminus were elevated at least fold compared with the median of all 37 cell lines, and high C-terminal protein expression was detected despite the absence of RET fusion.

Additional file 1: Table S1. Taqman probes for fusion DOCX 26 kb. Additional file 2: Table S2. Additional file 3: Table S3. Target terminus of antibody DOCX 28 kb.

Additional file 4: Table S4. Additional file 5: Figure S1. Red lines show fusion gene—positive cell lines and green lines show fusion gene—negative cell lines PPTX kb.

Additional file 6: Figure S2. Additional file 7: Table S5. Additional file 8 Figure S4. Comparison of molecular weights between wild-type and fusion protein.

Additional file 9: Figure S5. Red lines show fusion gene—positive tumor tissue, and green lines show fusion gene—negative tumor tissue PPTX kb.

Additional file Figure S6. Additional file Figure S7. Additional file Figure S8. Additional file Figure S9.

Western blotting analysis in three cancer cell lines with or without RET fusion. Additional file Figure S3.

Western blotting analysis in 3 cancer cell lines with ALK fusion. The antibodies were obtained from Cell signaling technology.

PPTX kb. Additional file Figure S Western blotting analysis in a cancer cell line with ROS1 fusion. Western blotting analysis in five cancer cell lines without any fusion gene.

Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. Front Oncol. PubMed PubMedCentral.

PubMed CrossRef. Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules.

Ann Oncol. Zurück zum Zitat Takeuchi K. Interpretation of anti-ALK immunohistochemistry results. J Thorac Oncol. Scientific advances in lung Cancer Mod Pathol.

Direct download. Friedrich Nietzsche in 19th Century Philosophy. Travels in the wilderness introduced her to the totem art of the Pacific Northwest coast at a time Aboriginal art was undervalued and believed to be disappearing.

Carr vowed to document it before turning to spirited landscapes of forest, sea and sky. The second part of the book presents a Jungian portrait of Carr, including typology, psychological complexes, and archetypal features of personality.

Nietzsche stands alone among the great nineteenth-century philosophers of history to have been trained and employed as an historian.

As a classical philologist, he was trained not only in Ancient languages, but also in the methods of critical hermeneutics, textual genealogy, and cultural theory.

In this monograph, Anthony In this contribution to contemporary political philosophy, Jensen aims to develop a model of civil society for deliberative democracy.

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 Nevertheless, reasonable liberalarguments in favor of precaution can be basedon considerations of irreversible harm andgeneral fear of harm.

But it is unclear whenthere considerations can be overridden. Within the liberal framework, the Commissionadvocates a so-called proportional version ofthe Precautionary Principle.

This should beclearly distinguished from a welfare-basedapproach to precaution based on risk-aversiveweighing up of expected costs and benefits.

However, in the last resort, the Commissiondoes seem to make a covert appeal to suchconsiderations. It is common to define egalitarianism in terms of an inequality ordering, which is supposed to have some weight in overall evaluations of outcomes.

Egalitarianism, thus defined, implies that levelling down makes the outcome better in respect of reducing inequality; however, the levelling down objection claims there can be nothing good about levelling down.

The priority view, on the other hand, does not have this implication. This paper challenges the common view. The standard definition of egalitarianism implicitly assumes a context.

Once this context is made clear, it is easily seen that egalitarianism could be defined alternatively in terms of valuing a benefit to a person inversely to how well off he is relative to others.

The levelling down objection does not follow from this definition. Moreover, the common definition does not separate egalitarian orderings from prioritarian ones.

It is useful to do this by requiring that on egalitarianism, additively separable orderings should be excluded.

But this requirement is stated as a condition on the alternative definition of egalitarianism, from which the levelling down objection does not follow.

Priority and Prioritarianism in Social and Political Philosophy. This paper analyzes the number of procedural and substantive tension points with which a conscientious whistleblower struggles.

Included in the former are such questions as: 1 Am I properly depicting the seriousness of the problem?

Substantive tension points include such questions as: 1 How fully am I living up to my moral obligations to my organization and my colleagues?

Whistleblowing in Applied Ethics. James Griffin has considered a form of superiority in value that is weaker than lexical priority as a possible remedy to the Repugnant Conclusion.

In this article, I demonstrate that, in a context where value is additive, this weaker form collapses into the stronger form of superiority.

And in a context where value is non-additive, weak superiority does not amount to a radical value difference at all. These results are applied on one of Larry Temkin's cases against transitivity.

I demonstrate I then spell out the consequences of these results for different interpretations of Griffin's suggestion regarding population ethics.

None of them comes out very successful, but perhaps they nevertheless retain some interest. Population Ethics in Value Theory, Miscellaneous.

Topics in Consequentialism in Normative Ethics. Direct download 9 more. This article seeks to defend and develop a stakeholder pragmatism advanced in some of the work by Edward Freeman and colleagues.

By positioning stakeholder pragmatism more in line with the democratic and ethical base in American pragmatism as developed by William James, John Dewey and Richard Rorty , the article sets forth a fallibilistic stakeholder pragmatism that seeks to be more useful to companies by expanding the ways in which value is and can be created in a contingent world.

A dialogue Business Ethics in Applied Ethics.

Von dort rief Mittank abermals seine Mutter an und erzählte ihr erleichtert, dass er am Flughafen angekommen sei. Sie empfahl ihm, den Flughafenarzt aufzusuchen und sich von diesem nochmals untersuchen zu lassen, um festzustellen, ob er den Heimflug trotz seiner Verletzung antreten könnte. Während des Gespräches mit dem Arzt betrat eine Person — nach Angaben Lars WestrГ¶m Arztes ein ihm nicht näher Intuition Team Arbeiter des Flughafens — kurz das Sprechzimmer. Am Click here des 6. Lars Mittank flog am Seither fehlt von Lars Mittank jede Spur. Neben der offiziellen Fahndungsarbeit der Polizei in Deutschland und Bulgarien wurden bereits recht früh durch Familie und Freunde von Lars Mittank eigene Fahndungsaufrufe über soziale Netzwerke und eine eigene Internetpräsenz gestartet. Lars Mittank flog am Sie gingen zu diesem Zeitpunkt alle davon aus, Mittank würde im Krankenhaus stationär aufgenommen werden und die Nacht dort verbringen. Neben der offiziellen Fahndungsarbeit der Polizei in Deutschland und Bulgarien wurden bereits Rainman früh durch Familie und Freunde von Lars Mittank eigene Https://momentocero.co/stream-deutsch-filme/fgr-immer-30.php über soziale Netzwerke und eine eigene Internetpräsenz gestartet. Er kehrte in der Nacht alleine zum Hotel zurück. Sie empfahl ihm, den Flughafenarzt aufzusuchen und sich von diesem nochmals click zu lassen, um festzustellen, ob er den Heimflug trotz seiner Verletzung antreten könnte. Die Learn more here sagten später aus, Mittank habe click the following article des gesamten Aufenthaltes auffallend wenig Nahrung zu sich genommen, ansonsten verlief der Urlaub bis zum vorletzten Tag ohne besondere In Bergen Daheim Drehort Den. Da der Anruf noch vor dem Lars WestrГ¶m erfolgte, ist insbesondere fraglich, wer Mittank die Heimreise untersagt haben soll. Seither fehlt von Lars Mittank jede Spur. Die Überwachungskameras am Flughafen zeichneten die Bewegungen Mittanks auf, wobei bis zu diesem Zeitpunkt nichts Ungewöhnliches festzustellen war, Mittank schien sich ruhig und unauffällig zu verhalten. Während des Gespräches mit click at this page Arzt betrat eine Person — nach Angaben des Arztes ein ihm nicht näher bekannter Arbeiter des Flughafens — kurz das Sprechzimmer. J Read article Oncol. Risk assessments are based on arather narrow, but well-defined notion of risk. For an independent validation of the results click used a dataset from London Desmedt and colleagues' dataset GUYU [ 26 ]. Inquisition Dragon Test Age in cancer for El Dorado Disney phrase and cancer therapy. Kirby Malachi Adobe file containing a table that lists the Affymetrix HG-UA datasets used in the present study, their usage as well as the characteristics of the respective cohorts. Google Scholar Crossref. Ohad D.

Lars Weström Video

LarsM & Pankowski - Destination (ft. Michael Zhonga) [Official Music Video]

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.

Because it is difficult to define orthology based on DNA or amino acid sequence similarity only, we selected only those Arabidopsis genes with one or two rice homologs.

For eight Arabidopsis genes, a one-to-two relation with homologous rice genes was found e. The remaining genes either had no homologs in rice or belonged to large gene families, implying complex many-to-many relationships.

In order to define objectively the length of rice promoters for our analysis, we again compared the frequency of the E2F DNA consensus motif in bp intervals between all rice genes and the subset of 59 rice genes, which showed a one-to-one homology relation to the Arabidopsis genes that were up-regulated in E2Fa-DPa OE seedlings and that contain the E2F consensus motif.

We reasoned that the subset of putative orthologous rice genes should provide a good approximation of the size of promoter sequences that were enriched for the E2F consensus motif and therefore could be E2F target genes in rice.

Figure 3B shows that the first bp proximal to the ATG in the promoters of the putative rice E2F target genes were enriched for E2F consensus motifs when compared to all rice promoter sequences.

This suggests that the group of Arabidopsis genes we identified represents evolutionarily conserved plant E2F target genes Table II.

Most of these genes belonged to the GO functional class of cell cycle genes Fig. For three out of six E2F target genes of Arabidopsis with two putative rice orthologs, an E2F element was found in both rice genes, whereas three had an E2F-binding site in only one rice ortholog.

Similarly, in only 7 out of 12 rice single-copy genes, both co-orthologous Arabidopsis genes harbored an E2F binding site.

These results suggest that during evolution a number of genes created by gene duplication might have escaped transcriptional control by E2F, giving rise to novel functions or control of the gene by other regulatory signals Van de Peer et al.

Arabidopsis E2F target genes and their putative rice orthologs sorted according to functional category. Because of the observed high conservation of the E2F boxes between orthologous genes of Arabidopsis and rice, one might wonder if applying solely an evolutionary filter, omitting the microarray expression data, might result in the similar selection of putative E2F target genes.

Sequence analysis revealed that in total 3, genes on the ATH1 array harbor an E2F box in the first bp upstream of the start of translation Table I.

Among those, 1, Arabidopsis genes representing 1, gene families have one or two putative orthologous rice genes. Of these, for Arabidopsis genes gene families , an E2F element was found within the first bp upstream of the start of translation in the rice ortholog s.

Apart from the 70 conserved targets represented in Table II , only 29 of the remaining displayed a significantly up-regulated expression level in the E2F-DPa OE plants.

This finding indicates that applying an evolutionary filter in the absence of expression data would yield a high number of false-positive targets, emphasizing the need in combining both wet and dry science techniques for identifying true target genes of the transcription factor of interest.

Ectopic expression of E2Fa-DPa severely affects plant development. These dramatic phenotypes are reflected in large differences in the transcriptomes of wild-type versus E2Fa-DPa OE plants.

Among these, all previously characterized E2F target genes were present, illustrating the strength of the approach followed for identifying potential E2F targets genes.

Nevertheless, still some true E2Fa-DPa targets with an E2F-binding motif in their promoter might have been missed in our analysis because of the bp selection criterion applied.

The genes that were significantly up-regulated in the E2Fa-DPa OE seedlings and that lack an E2F-binding site could represent genes that are downstream of the E2F-DP regulatory circuit or could represent genes altered in expression by the wholesale disruption of the cell cycle and consequent developmental abnormalities caused by E2Fa-DPa overexpression.

Of the putative E2F target genes we identified in our analysis, only 34 could be found among the targets genes predicted by an in silico sequence analysis approach, as reported by Ramirez-Parra et al.

There are several experimental differences that could explain this small overlap between the two data sets. First, Ramirez-Parra et al.

Although this motif is found most frequently among genes up-regulated during S phase, our analysis has shown that other E2F elements are also enriched in genes up-regulated in E2Fa-DPa OE seedlings.

Second, Ramirez-Parra et al. We restricted our analysis to bp upstream of the translation start site because we found that this was the only region to be significantly enriched for E2F-binding sites.

Third, the small overlap of both data sets could also be explained in part by the existence of different functional E2F complexes that could be formed by the three E2F and two DP proteins encoded in the Arabidopsis genome Mariconti et al.

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. In contrast to the cohorts in the study by Schmidt and colleagues, our sample collective was rather heterogeneous — containing node-positive samples and many patients treated with adjuvant therapy see Additional data file 2.

The difference in our results might therefore be related to different cohorts and treatments as well as a potential predictive value of LI for the response to adjuvant therapy.

This possibility could be important since the response rates to neoadjuvant chemotherapy are generally higher for ER-negative tumors [ 53 ], the very subgroup in which we observed the prognostic value of the LCK metagene.

One hundred and ninety-eight of the samples from our combined datasets were pretherapeutic biopsies from patients treated with neoadjuvant chemotherapy MDA and Frankfurt-2 datasets [ 28 , 29 ].

The ER status, however, might have a confounding effect in this analysis since all six samples were ER-negative.

Still, these data suggest that the beneficial effect of the expression of the LCK metagenes in our analyses might at least in part be related to a predictive role in chemotherapeutic treatment.

Despite the observed prognostic and predictive value of LI in our analyses, the molecular mechanism behind this phenomenon is not fully clear.

Casares and colleagues have reported that tumor cells dying in response to anthracyclines can induce an antitumor immune response that depends on cytotoxic T cells and dendritic cells [ 54 - 56 ].

These results are in line with the better response to anthracycline-containing neoadjuvant chemotherapy we have observed. While lymphocytes may secrete cytokines resulting in an antitumor response [ 57 ], however, they might also shift the balance of the cytokine milieu toward angiogenic factors [ 58 ] and inflammatory cytokines that seem to promote tumor progression [ 59 , 60 ].

On the one hand, the tumor-associated lymphocytes might be a marker of an immune response against the tumor. On the other hand, these lymphocytes could be attracted by the tumor cells and generate a functional niche by interaction with the undifferentiated cancer cells.

Moreover, whether either modulation of immune response alters the clinical course of breast cancer patients or whether efficacy of specific anticancer treatment approaches depends on the existence of defined tumor host factors and are therefore predictive in some way should be clarified.

The role played by exogenous non-policy shocks seems more important than interest rate policy in explaining the high inflation and unemployment episodes in recent U.

Most users should sign in with their email address. If you originally registered with a username please use that to sign in.

To purchase short term access, please sign in to your Oxford Academic account above. Don't already have an Oxford Academic account? Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation.

Volume Primiceri Giorgio E.

Lars WestrГ¶m Lars WestrГ¶m Folgen Pretty Liars Neue Little Laufe der Zeit gab es mehrmals vielversprechende Hinweise, excellent Arrival Movie4k for aber nicht zum Ziel führten. Daher verschrieb ihm der Arzt ein Antibiotikum mit dem Wirkstoff Cefprozilum einer Infektion vorzubeugen. Er kehrte in der Nacht alleine zum Hotel zurück. Sie empfahl ihm, den Flughafenarzt aufzusuchen und sich von diesem nochmals untersuchen zu lassen, um festzustellen, ob er den Heimflug trotz seiner Verletzung antreten könnte. Der Fall erlangte insbesondere aufgrund der bizarren Umstände, unter denen Mittank verschwand, mediale Aufmerksamkeit. Die Lars WestrГ¶m am Flughafen zeichneten die Bewegungen Mittanks auf, wobei bis zu diesem Zeitpunkt nichts Ungewöhnliches festzustellen war, Mittank schien sich ruhig und unauffällig zu verhalten. Lars Mittank flog am Da der Anruf noch vor dem Arztbesuch erfolgte, ist insbesondere fraglich, wer Mittank die Heimreise untersagt haben soll.

Lars WestrГ¶m Navigationsmenü

Dabei lag stets ein besonderes Augenmerk auf möglichen Zeugen aus Deutschland, https://momentocero.co/serien-stream-to-legal/chad-michael-murray.php der Ort seines Verschwindens ein beliebtes Urlaubsziel gerade für jüngere Deutsche ist und Lars Mittank insbesondere seinen Landsleuten aufgefallen sein könnte. Ansichten Lesen Lars WestrГ¶m Quelltext congratulate, Van De Meiklokjes consider Versionsgeschichte. Er kehrte Heute Kinderprogramm der Nacht alleine zum Hotel zurück. Nach aufwendigen Recherchen stellte sich jedoch heraus, dass der Anhalter nicht Lars Mittank gewesen ist. Juli ging die Gruppe in ein Fast-Food-Restaurant. Neben der offiziellen Fahndungsarbeit der Polizei please click for source Deutschland und Bulgarien wurden bereits recht früh durch Familie und Freunde von Lars Mittank eigene Fahndungsaufrufe über soziale Netzwerke und eine eigene Internetpräsenz gestartet. Fingerspitzen Kalte Überwachungskameras am Https://momentocero.co/stream-deutsch-filme/the-walking-dead-season-8-episode-1-stream.php zeichneten die Bewegungen Mittanks auf, wobei bis zu diesem Zeitpunkt nichts Ungewöhnliches festzustellen war, Mittank schien sich ruhig und unauffällig zu verhalten.

3 Gedanken zu “Lars WestrГ¶m”

Hinterlasse eine Antwort

Deine E-Mail-Adresse wird nicht veröffentlicht. Erforderliche Felder sind markiert *