TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2-Expressing Monocytes in Human Breast Tumors.

PURPOSE: Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs. EXPERIMENTAL DESIGN: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas. RESULTS: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells. CONCLUSIONS: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response. Clin Cancer Res; 19(13); 3439-49. ©2013 AACR.

Tie Strength and Family Formation : which Personal Relationships are Influential ?

Based on the analysis of qualitative interviews in western Germany, we argue that personal relationships have a strong impact on individuals' family formation processes and fertility intentions. We identify persons who influence individuals' fertility choices. Strong ties, such as those among core family members (i.e., parents and siblings), are an important contributing factor, but we are also able to show that weak ties, such as those among colleagues, and acquaintances need to be considered when examining social influence on family formation processes. Apart from single network partners, we have identified influential groups of persons. Such groups serve as a comparative standard regarding the timing of having one's first child and subsequent children.

National character does not reflect mean personality trait levels in 49 cultures

Most people hold beliefs about personality characteristics typical members of their own and others' cultures. These perceptions of national character may be generalizations from personal experience, stereotypes with a "kernel of truth", or inaccurate stereotypes. We obtained national character ratings of 3989 people from 49 cultures and compared them with the average personality scores of culture members assessed by observer ratings and self-reports. National character ratings were reliable but did not converge with assessed traits. Perceptions of national character thus appear to be unfounded stereotypes that may serve the function of maintaining a national identity.

Embryonic vascular endothelial cells are malleable to reprogramming via Prox1 to a lymphatic gene signature.

BACKGROUND: In vivo studies demonstrate that the Prox1 transcription factor plays a critical role in the development of the early lymphatic system. Upon Prox1 expression, early lymphatic endothelial cells differentiate from the cardinal vein and begin to express lymphatic markers such as VEGFR-3, LYVE-1 and Podoplanin. Subsequent in vitro studies have found that differentiated vascular endothelial cells can be reprogrammed by Prox1 to express a lymphatic gene profile, suggesting that Prox1 can initiate the expression of a unique gene signature during lymphangiogenesis. While the in vitro data suggest that gene reprogramming occurs upon Prox1 expression, it is not clear if this is a direct result of Prox1 in vascular endothelial cells in vivo. RESULTS: Overexpression of Prox1 in vascular endothelial cells during embryonic development results in the reprogramming of genes to that of a more lymphatic signature. Consequent to this overexpression, embryos suffer from gross edema that results in embryonic lethality at E13.5. Furthermore, hemorrhaging and anemia is apparent along with clear defects in lymph sac development. Alterations in junctional proteins resulting in an increase in vascular permeability upon Prox1 overexpression may contribute to the complications found during embryonic development. CONCLUSION: We present a novel mouse model that addresses the importance of Prox1 in early embryonic lymphangiogenesis. It is clear that there needs to be a measured pattern of expression of Prox1 during embryonic development. Furthermore, Prox1 reprograms vascular endothelial cells in vivo by creating a molecular signature to that of a lymphatic endothelial cell.

Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy.

Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+ -fibronectin, sVEGFR-2, sVEGFR-1, salphaVbeta3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. salphaVbeta3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and salphaVbeta3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value.

Thermodynamic investigations in the Si-Ge-rich part of the ruthenium-silicon-germanium system

This paper reports molar heat capacities of Ru50SixGe(50-x) and Ru40SiyGe(60-y) ternary solid solutions determined by differential scanning calorimetry. A second order transition has been characterised for alloys ranging from Ru40Ge60 to Ru40Si10Ge50 at temperatures ranging from 850 to 1040 K, respectively. Tie lines have been established at 1000-900-800-700-600 degrees C by electron microprobe measurements on annealed alloys of the two phase domains: Ru50SixGe(50-x)-Ru40SiyGe(60-y) and Ru40SiyGe(60-y)-SizGe(100-z).

The Same, but Different: Central Banks, Regulatory Agencies, and the Politics of Delegation to Independent Authorities

Independent regulatory agencies are the institutional foundations of the regulatory state that, during the past 15 years, has gained prominence throughout Europe. This article studies the rise of independent authorities in European countries by comparing regulatory agencies and central banks. Delegation to independent central banks and to independent regulatory agencies is similar in many respects. In both cases, agents are deliberately made independent from political principals through a specific institutional design. Moreover, it has been argued that delegation to both central banks and regulatory agencies is linked to the need for policy-makers to improve the credibility of policy commitments, to the wish of incumbent politicians to tie the hands of future majorities, and to the extent to which the institutional contexts safeguard policy stability. Through an analysis of the formal independence of central banks and regulatory agencies in Western Europe, this article identifies an empirical puzzle that casts doubts on the accuracy of current explanations. Veto players and the uncertainty of incumbent policy-makers in respect to their re-election prospects matter for delegation to both central banks and regulatory agencies, but in opposite ways. Making sense of these anomalies is necessary to achieve a better understanding of delegation to independent authorities.

Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.

Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.

Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study.

BACKGROUND: Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. METHODS: We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. RESULTS: Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5-98.8), 80.8% specificity (72.6-87.1), positive likelihood ratio 4.9 (3.4-7.1), negative likelihood ratio 0.083 (0.022-0.32), and misclassification rate 0.20 (standard error 0.038). CONCLUSIONS: In Tanzanian children with WHO-defined clinical pneumonia, combinations of host biomarkers distinguished between end-point pneumonia, other infiltrates, and normal chest x-ray, whereas clinical variables did not. These findings generate pathophysiological hypotheses and may have potential research and clinical utility.

Laparoscopic technique to perform a true Stamm gastrostomy in children.

PURPOSE: A surgical gastrostomy is mandatory in cases where a PEG is not feasible. Various minimally invasive techniques have been described, but many involve unusable materials in small children and/or have risk of disunion. We describe a technique for true Stamm gastrostomy performed by laparoscopy (LSG) with a purse string suture and four points of attachment onto the wall. METHOD: We reviewed 20 children who underwent an LSG from 2010 to 2013. After incision of the skin at the location planned for the gastrostomy, using three 3-5mm ports the stomach is fixed to the wall by three suspension stitches, which are entered and then emerged subcutaneously. A fourth stitch of attachment is used to make an award on the stomach and tie around the gastrostomy tube. RESULTS: Mean age was 4.2years, with 70% aged <2years. All children were malnourished, most often severely. All but two underwent a concomitant fundoplication. Feeding through the gastrostomy started on D0 or D1. Total feeding by gastrostomy was achieved in a mean duration of 2.9day. Mean hospital stay was 4.5days. There was no perioperative complication. Mean follow-up was 14months. Once, the balloon was accidently deflated and reinflated in the wall leading to its necrosis. Five peristomial granulomas were noticed. It was always possible to replace the tube by a gastrostomy device at least 6weeks after surgery. CONCLUSION: This new technique for true Stamm gastrostomy by laparoscopy reproduces exactly the one done by laparotomy, without special equipment. It can be made since the neonatal period, in all the circumstances when a laparoscopy is possible.

Management Control for Corporate Sustainability Execution: The Role of Employee Compensation

The research described in this thesis examines the characteristics, the benefits and the challenges associated with the implementation of management accounting systems in the field of Corporate Social Responsibility (CSR). Applied to the CSR context, management accounting relates to the identification, elaboration and communication of information about an organization's interactions with the society and the environment. Based on this information, firms are able to make decisions to achieve social and environmental objectives and provide evidence justifying the benefits and the costs of such actions. The study begins by focusing on green management and exploring the characteristics of Environmental Management Accounting (EMA) systems within firms. The first chapter informs the reader about the growing body of EMA research and reveals unexplored relevant aspects that need to be further investigated. The work also emphasizes the importance of developing new theoretical hypotheses and appropriate research designs to empirically tackle new aspects of EMA and gain understanding on the use of these practices. Subsequently, given the acknowledged importance of control systems in influencing the behaviour of individuals within organizations, the remaining two chapters of the dissertation focus on the functioning of CSR-linked incentives assigned to employees in the form of compensation plans. The second chapter examines the determinants influencing corporate provision of incentives for the attainment of environmental targets. Empirical analysis of a sample of international firms reveals that companies are likely to use green incentives as mechanisms to increase the efficacy in contracting with their employees as well as to respond to social influences. Finally, the third chapter investigates the effectiveness of contracting associated with the use of CSR-linked executive compensation. Empirical analysis of a sample of US-based companies shows that corporate choice to tie senior executives' pay to CSR targets promotes the firm's CSR performance. Cette thèse examine les caractéristiques, avantages et défis associés à l'utilisation des systèmes de contrôle de gestion dans le domaine de la Responsabilité Sociale des Entreprises (RSE). Dans le contexte de la RSE, les activités du contrôle de gestion impliquent l'identification, l'élaboration et la communication d'informations qui concernent les interactions des organisations avec la société et l'environnement. Avec ces informations les entreprises sont en mesure de prendre des décisions visant à atteindre les objectifs sociaux et environnementaux de l'organisation et de documenter les bénéfices et coûts de ces actions. Dès le début, la thèse se concentre sur les caractéristiques des systèmes de contrôle de gestion environnementale au sein des entreprises. Le premier chapitre passe en revue la littérature existante et révèle des aspects inexplorés. Pour ce faire, le travail suggère le développement de nouvelles théories ainsi que l'utilisation de méthodes appropriées. Ces dernières doivent permettre d'aborder empiriquement de nouveaux aspects des systèmes de contrôle environnemental et faciliter la compréhension sur l'utilisation de ces pratiques. Considérant l'importance des systèmes de contrôle pour influencer le comportement des individus au sein des organisations, la suite du travail se concentre sur le fonctionnement des contrats de rémunération des employées liées aux résultats de la RSE. Plus particulièrement, le deuxième chapitre examine les facteurs qui influencent la décision des entreprises d'assigner des objectifs environnementaux aux employées. L'analyse empirique d'un échantillon d'entreprises internationales montre que les entreprises sont susceptibles d'utiliser des mécanismes incitatifs écologiques pour augmenter l'efficacité des contrats ainsi que pour répondre aux influences sociales. Finalement, le troisième chapitre analyse l'efficacité des contrats de rémunération des dirigeants liés aux résultats de la RSE. L'analyse empirique d'un échantillon de sociétés américaines indique que le choix de l'entreprise de lier la rémunération des dirigeants à des objectifs de la RSE favorise la performance RSE de l'organisation.