Showing papers by "Ludwig Maximilian University of Munich published in 2005"

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

Abstract: background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)

NF-kappaB: linking inflammation and immunity to cancer development and progression.

Abstract: There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.

Suicide prevention strategies: a systematic review.

Abstract: ContextIn 2002, an estimated 877 000 lives were lost worldwide through suicide. Some developed nations have implemented national suicide prevention plans. Although these plans generally propose multiple interventions, their effectiveness is rarely evaluated.ObjectivesTo examine evidence for the effectiveness of specific suicide-preventive interventions and to make recommendations for future prevention programs and research.Data Sources and Study SelectionRelevant publications were identified via electronic searches of MEDLINE, the Cochrane Library, and PsychINFO databases using multiple search terms related to suicide prevention. Studies, published between 1966 and June 2005, included those that evaluated preventative interventions in major domains; education and awareness for the general public and for professionals; screening tools for at-risk individuals; treatment of psychiatric disorders; restricting access to lethal means; and responsible media reporting of suicide.Data ExtractionData were extracted on primary outcomes of interest: suicidal behavior (completion, attempt, ideation), intermediary or secondary outcomes (treatment seeking, identification of at-risk individuals, antidepressant prescription/use rates, referrals), or both. Experts from 15 countries reviewed all studies. Included articles were those that reported on completed and attempted suicide and suicidal ideation; or, where applicable, intermediate outcomes, including help-seeking behavior, identification of at-risk individuals, entry into treatment, and antidepressant prescription rates. We included 3 major types of studies for which the research question was clearly defined: systematic reviews and meta-analyses (n = 10); quantitative studies, either randomized controlled trials (n = 18) or cohort studies (n = 24); and ecological, or population- based studies (n = 41). Heterogeneity of study populations and methodology did not permit formal meta-analysis; thus, a narrative synthesis is presented.Data SynthesisEducation of physicians and restricting access to lethal means were found to prevent suicide. Other methods including public education, screening programs, and media education need more testing.ConclusionsPhysician education in depression recognition and treatment and restricting access to lethal methods reduce suicide rates. Other interventions need more evidence of efficacy. Ascertaining which components of suicide prevention programs are effective in reducing rates of suicide and suicide attempt is essential in order to optimize use of limited resources.

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

Abstract: CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.

Physical Foundations of Cosmology

Abstract: Inflationary cosmology has been developed over the last twenty years to remedy serious shortcomings in the standard hot big bang model of the universe. This textbook, first published in 2005, explains the basis of modern cosmology and shows where the theoretical results come from. The book is divided into two parts; the first deals with the homogeneous and isotropic model of the Universe, the second part discusses how inhomogeneities can explain its structure. Established material such as the inflation and quantum cosmological perturbation are presented in great detail, however the reader is brought to the frontiers of current cosmological research by the discussion of more speculative ideas. An ideal textbook for both advanced students of physics and astrophysics, all of the necessary background material is included in every chapter and no prior knowledge of general relativity and quantum field theory is assumed.

A Shrinkage Approach to Large-Scale Covariance Matrix Estimation and Implications for Functional Genomics

Abstract: Inferring large-scale covariance matrices from sparse genomic data is an ubiquitous problem in bioinformatics. Clearly, the widely used standard covariance and correlation estimators are ill-suited for this purpose. As statistically efficient and computationally fast alternative we propose a novel shrinkage covariance estimator that exploits the Ledoit-Wolf (2003) lemma for analytic calculation of the optimal shrinkage intensity. Subsequently, we apply this improved covariance estimator (which has guaranteed minimum mean squared error, is well-conditioned, and is always positive definite even for small sample sizes) to the problem of inferring large-scale gene association networks. We show that it performs very favorably compared to competing approaches both in simulations as well as in application to real expression data.

Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles.

Abstract: Cytotoxicity of CdSe and CdSe/ZnS nanoparticles has been investigated for different surface modifications such as coating with mercaptopropionic acid, silanization, and polymer coating. For all cases, quantitative values for the onset of cytotoxic effects in serum-free culture media are given. These values are correlated with microscope images in which the uptake of the particles by the cells has been investigated. Our data suggest that in addition to the release of toxic Cd 2+ ions from the particles also their surface chemistry, in particular their stability toward aggregation, plays an important role for cytotoxic effects. Additional patch clamp experiments investigate effects of the particles on currents through ion channels.

Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.

Abstract: Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).

The genome of the social amoeba Dictyostelium discoideum

Abstract: The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.

1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR).

Abstract: BACKGROUNDThese Guidelines for Paediatric Parenteral Nutrition have been developed as a mutual project of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN; www.espghan.org) and the European Society for Clinical Nutrition and Metabolism (ESPEN; www.espen.org). T

A pooled analysis of bone marrow micrometastasis in breast cancer

Abstract: BACKGROUND We assessed the prognostic significance of the presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer by means of a pooled analysis. METHODS We combined individual patient data from nine studies involving 4703 patients with stage I, II, or III breast cancer. We evaluated patient outcomes over a 10-year follow-up period (median, 5.2 years), using a multivariable piecewise Cox regression model. RESULTS Micrometastasis was detected in 30.6 percent of the patients. As compared with women without bone marrow micrometastasis, patients with bone marrow micrometastasis had larger tumors and tumors with a higher histologic grade and more often had lymph-node metastases and hormone receptor-negative tumors (P<0.001 for all variables). The presence of micrometastasis was a significant prognostic factor with respect to poor overall survival and breast-cancer-specific survival (univariate mortality ratios, 2.15 and 2.44, respectively; P<0.001 for both outcomes) and poor disease-free survival and distant-disease-free survival during the 10-year observation period (incidence-rate ratios, 2.13 and 2.33, respectively; P<0.001 for both outcomes). In the multivariable analysis, micrometastasis was an independent predictor of a poor outcome. In the univariate subgroup analysis, breast-cancer-specific survival among patients with micrometastasis was significantly shortened (P<0.001 for all comparisons) among those receiving adjuvant endocrine treatment (mortality ratio, 3.22) or cytotoxic therapy (mortality ratio, 2.32) and among patients who had tumors no larger than 2 cm in diameter without lymph-node metastasis and who did not receive systemic adjuvant therapy (mortality ratio, 3.65). CONCLUSIONS The presence of micrometastasis in the bone marrow at the time of diagnosis of breast cancer is associated with a poor prognosis.

ICF linking rules: an update based on lessons learned.

Abstract: Objective Outcome research seeks to understand the end results of health services. Researchers use a wide variety of outcome measures including technical, clinical and patient-oriented measures. The International Classification of Functioning, Disability and Health (ICF) as a common reference framework for functioning may contribute to improved outcome research. The objective of this paper is to provide an updated version of the linking rules published in 2002 and illustrate how these rules are applied to link technical and clinical measures, health-status measures and interventions to the ICF. Results Three specific linking rules have been established to link health-status measures to the ICF and one specific linking rule has been created to link technical and clinical measures and interventions. A total of 8 linking rules have been established for use with all different outcome measures and with interventions. Conclusion The newly updated linking rules will allow researchers systematically to link and compare meaningful concepts contained in them. This should prove extremely useful in selecting the most appropriate outcome measures among a number of candidate measures for the applied interventions. Further possible applications are the operationalization of concrete ICF categories using specific measures or the creation of ICF category-based item bankings.

The DNA sequence of the human X chromosome

Abstract: The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Soft Sweeps: Molecular Population Genetics of Adaptation From Standing Genetic Variation

Abstract: A population can adapt to a rapid environmental change or habitat expansion in two ways. It may adapt either through new beneficial mutations that subsequently sweep through the population or by using alleles from the standing genetic variation. We use diffusion theory to calculate the probabilities for selective adaptations and find a large increase in the fixation probability for weak substitutions, if alleles originate from the standing genetic variation. We then determine the parameter regions where each scenario—standing variation vs . new mutations—is more likely. Adaptations from the standing genetic variation are favored if either the selective advantage is weak or the selection coefficient and the mutation rate are both high. Finally, we analyze the probability of “soft sweeps,” where multiple copies of the selected allele contribute to a substitution, and discuss the consequences for the footprint of selection on linked neutral variation. We find that soft sweeps with weaker selective footprints are likely under both scenarios if the mutation rate and/or the selection coefficient is high.

Protein function prediction via graph kernels

Abstract: Motivation: Computational approaches to protein function prediction infer protein function by finding proteins with similar sequence, structure, surface clefts, chemical properties, amino acid motifs, interaction partners or phylogenetic profiles. We present a new approach that combines sequential, structural and chemical information into one graph model of proteins. We predict functional class membership of enzymes and non-enzymes using graph kernels and support vector machine classification on these protein graphs. Results: Our graph model, derivable from protein sequence and structure only, is competitive with vector models that require additional protein information, such as the size of surface pockets. If we include this extra information into our graph model, our classifier yields significantly higher accuracy levels than the vector models. Hyperkernels allow us to select and to optimally combine the most relevant node attributes in our protein graphs. We have laid the foundation for a protein function prediction system that integrates protein information from various sources efficiently and effectively. Availability: More information available via www.dbs.ifi.lmu.de/Mitarbeiter/borgwardt.html. Contact: borgwardt@dbs.ifi.lmu.de

Shortest-path kernels on graphs

Abstract: Data mining algorithms are facing the challenge to deal with an increasing number of complex objects. For graph data, a whole toolbox of data mining algorithms becomes available by defining a kernel function on instances of graphs. Graph kernels based on walks, subtrees and cycles in graphs have been proposed so far. As a general problem, these kernels are either computationally expensive or limited in their expressiveness. We try to overcome this problem by defining expressive graph kernels which are based on paths. As the computation of all paths and longest paths in a graph is NP-hard, we propose graph kernels based on shortest paths. These kernels are computable in polynomial time, retain expressivity and are still positive definite. In experiments on classification of graph models of proteins, our shortest-path kernels show significantly higher classification accuracy than walk-based kernels.

The Economics of Fairness, Reciprocity and Altruism--Experimental Evidence and New Theories.

Abstract: Most economic models are based on the self-interest hypothesis that assumes that material self-interest exclusively motivates all people. Experimental economists have gathered overwhelming evidence in recent years, however, that systematically refutes the self-interest hypothesis, suggesting that concerns for altruism, fairness, and reciprocity strongly motivate many people. Moreover, several theoretical papers demonstrate that the observed phenomena can be explained in a rigorous and tractable manner. These theories then induced a first wave of experimental research which offered exciting insights into both the nature of preferences and the relative performance of competing fairness theories. The purpose of this chapter is to review these developments, to point out open questions, and to suggest avenues for future research. We also discuss recent neuroeconomic evidence that is consistent with the view that many people have a taste for mutual cooperation and the punishment of norm violators. We further illustrate the powerful impact of fairness concerns on cooperation, competition, incentives, and contract design.

An empirical Bayes approach to inferring large-scale gene association networks

Abstract: Motivation: Genetic networks are often described statistically using graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standard algorithms for graphical models inapplicable, and inferring genetic networks an 'ill-posed' inverse problem. Methods: We introduce a novel framework for small-sample inference of graphical models from gene expression data. Specifically, we focus on the so-called graphical Gaussian models (GGMs) that are now frequently used to describe gene association networks and to detect conditionally dependent genes. Our new approach is based on (1) improved (regularized) small-sample point estimates of partial correlation, (2) an exact test of edge inclusion with adaptive estimation of the degree of freedom and (3) a heuristic network search based on false discovery rate multiple testing. Steps (2) and (3) correspond to an empirical Bayes estimate of the network topology. Results: Using computer simulations, we investigate the sensitivity (power) and specificity (true negative rate) of the proposed framework to estimate GGMs from microarray data. This shows that it is possible to recover the true network topology with high accuracy even for small-sample datasets. Subsequently, we analyze gene expression data from a breast cancer tumor study and illustrate our approach by inferring a corresponding large-scale gene association network for 3883 genes. Availability: The authors have implemented the approach in the R package 'GeneTS' that is freely available from http://www.stat.uni-muenchen.de/~strimmer/genets/, from the R archive (CRAN) and from the Bioconductor website. Contact: korbinian.strimmer@lmu.de

Individual Risk Attitudes: New Evidence from a Large, Representative, Experimentally-Validated Survey

Abstract: This paper presents new evidence on the distribution of risk attitudes in the population, using a novel set of survey questions and a representative sample of roughly 22,000 individuals living in Germany. Using a question that asks about willingness to take risks in general, on an 11-point scale, we find evidence of heterogeneity across individuals, and show that willingness to take risks is negatively related to age and being female, and positively related to height and parental education. We test the behavioral relevance of this survey measure by conducting a complementary field experiment, based on a representative sample of 450 subjects, and find that the general risk question is a good predictor of actual risk-taking behavior. We then use a more standard lottery question to measure risk preferences in our sample of 22,000, and find similar results regarding heterogeneity and determinants of risk preferences, compared to the general risk question. The lottery question also makes it possible to estimate the coefficient of relative risk aversion for each individual in the sample. Using five questions about willingness to take risks in specific domains - car driving, financial matters, sports and leisure, career, and health - the paper also studies the impact of context on risk attitudes, finding a strong but imperfect correlation across contexts. Using data on a collection of risky behaviors from different contexts, including traffic offences, portfolio choice, smoking, occupational choice, participation in sports, and migration, the paper compares the predictive power of all of the risk measures. Strikingly, the general risk question predicts all behaviors whereas the standard lottery measure does not. The best predictor for any specific behavior is typically the corresponding context-specific measure.

Recommendations for competitive sports participation in athletes with cardiovascular disease : a consensus document from the study group of sports cardiology of the working group of cardiac rehabilitation and exercise physiology and the working group of myocardial and pericardial diseases of the european society of cardiology

Abstract: A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology.

Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes

Abstract: Studies of higher-order chromatin arrangements are an essential part of ongoing attempts to explore changes in epigenome structure and their functional implications during development and cell differentiation. However, the extent and cell-type-specificity of three-dimensional (3D) chromosome arrangements has remained controversial. In order to overcome technical limitations of previous studies, we have developed tools that allow the quantitative 3D positional mapping of all chromosomes simultaneously. We present unequivocal evidence for a probabilistic 3D order of prometaphase chromosomes, as well as of chromosome territories (CTs) in nuclei of quiescent (G0) and cycling (early S-phase) human diploid fibroblasts (46, XY). Radial distance measurements showed a probabilistic, highly nonrandom correlation with chromosome size: small chromosomes-independently of their gene density-were distributed significantly closer to the center of the nucleus or prometaphase rosette, while large chromosomes were located closer to the nuclear or rosette rim. This arrangement was independently confirmed in both human fibroblast and amniotic fluid cell nuclei. Notably, these cell types exhibit flat-ellipsoidal cell nuclei, in contrast to the spherical nuclei of lymphocytes and several other human cell types, for which we and others previously demonstrated gene-density-correlated radial 3D CT arrangements. Modeling of 3D CT arrangements suggests that cell-type-specific differences in radial CT arrangements are not solely due to geometrical constraints that result from nuclear shape differences. We also found gene-density-correlated arrangements of higher-order chromatin shared by all human cell types studied so far. Chromatin domains, which are gene-poor, form a layer beneath the nuclear envelope, while gene-dense chromatin is enriched in the nuclear interior. We discuss the possible functional implications of this finding.

Linear transmit processing in MIMO communications systems

Abstract: We examine and compare the different types of linear transmit processing for multiple input, multiple output systems, where we assume that the receive filter is independent of the transmit filter contrary to the joint optimization of transmit and receive filters. We can identify three filter types similar to receive processing: the transmit matched filter, the transmit zero-forcing filter, and the transmit Wiener filter. We show that the transmit filters are based on similar optimizations as the respective receive filters with an additional constraint for the transmit power. Moreover, the transmit Wiener filter has similar convergence properties as the receive Wiener filter, i.e., it converges to the matched filter and the zero-forcing filter for low and high signal-to-noise ratio, respectively. We give closed-form solutions for all transmit filters and present the fundamental result that their mean-square errors are equal to the errors of the respective receive filters, if the information symbols and the additive noise are uncorrelated. However, our simulations reveal that the bit-error ratio results of the transmit filters differ from the results for the respective receive filters.

Resistance to Insulin Therapy Among Patients and Providers Results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study

Abstract: OBJECTIVE - To examine the correlates of patient and provider attitudes toward insulin therapy. RESEARCH DESIGN AND METHODS - Data are from surveys of patients with type 2 diabetes not taking insulin (n = 2,061) and diabetes care providers (nurses = 1,109; physicians = 2,681) in 13 countries in Asia, Australia, Europe, and North America. Multiple regression analysis is used to identify correlates of attitudes toward insulin therapy among patients, physicians, and nurses. RESULTS - Patient and provider attitudes differ significantly across countries, controlling for individual characteristics. Patients rate the clinical efficacy of insulin as low and would blame themselves if they had to start insulin therapy. Self-blame is significantly lower among those who have better diet and exercise adherence and less diabetes-related distress. Patients who are not managing their diabetes well (poor perceived control, more complications, and diabetes-related distress) are significantly more likely to see insulin therapy as potentially beneficial. Most nurses and general practitioners (50-55%) delay insulin therapy until absolutely necessary, but specialists and opinion leaders are less likely to do so. Delay of insulin therapy is significantly less likely when physicians and nurses see their patients as more adherent to medication or appointment regimens, view insulin as more efficacious, and when they are less likely to delay oral diabetes medications. CONCLUSIONS - Patient and provider resistance to insulin therapy is substantial, and for providers it is part of a larger pattern of reluctance to prescribe blood glucose-lowering medication. Interventions to facilitate timely initiation of insulin therapy will need to address factors associated with this resistance.