Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression
Cathrin J. Czupalla
Makoto M. Taketo
Karl H. Plate
- Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.
Context-induced creativity and the figurative use of taste terms
- For reasons of space, we only discussed one text in which the metaphors used seem to take their root in the context in which it has been written. One text is definitely not enough to make any definite claims on how widespread this phenomenon is. Given what we know about the two domains - FOOD and TASTE - one has reasons to believe that when speakers/conceptualisers(e.g. journalists) describe something which stands in some relation to both, they may intuitively be reaching for taste metaphors of the kind described above on the premise that this kind of ‘ornamentation’ will add some spice to what the addressee might otherwise consider a trivial (and boring) topic. At the same time, taste is only one among many properties a particular item of food or a substance (e.g. sugar) has. In consequence, one may well imagine contexts in which it is not its taste, but other properties (e.g. what Harbottle [1997:183] refers to as its 'pure white and deadly ’ image) that will make the conceptualiser reach for a particular linguistic or conceptual metaphor.
Credit in the Body of Christ (Northern France, 1300-1600)
- This project began when I encountered an accusation made in 1496 in a jurisdictional dispute between the duke of Orléans and the bishop of Orléans. The king’s attorney told the Parlement of Paris how “a sergeant found a certain person in the environs of Orléans with a full basket of blank citations with which to vex and trouble a bunch of poor winegrowers. When he seized the citations, he was cited and then excommunicated,” joining what the duke’s attorney believed were “twelve or fourteen thousand” excommunicates from whom the bishop sought to profit through the fees for sealing their absolutions. I later encountered further accusations that bishops had made a “business” or marchandise of ecclesiastical justice, notably against the bishop of Angers in the mid-1520s and against the archbishop of Besançon in the 1570s.
All of these episodes point to a practice that is nearly imperceptible to historians because the bulk of evidence for it is to be found in the interstices of the beaten paths of legal and social history and because it mixes economic and religious matters in a strikingly unfamiliar manner. From the thirteenth to the sixteenth century, excommunication for debt offered ordinary people an economical, efficacious enforcement mechanism for small-scale, daily, unwritten credit. At the same time, the practice offered holders of ecclesiastical jurisdiction an important opportunity to round out their incomes, particularly in the difficult fifteenth century. My sources come mostly from Northern France, though the practice appears to have existed across the continent. From one perspective, the practice was a grave abuse by which the Church sold its salvific magic to creditors. From another, the practice encouraged charitable, ostensibly interest-free lending within the Body of Christ and provided a mechanism of enforcement for credit that lacked any written proof or that was too minor to be worth pursuing in royal courts. This transitional practice reveals a level of credit below that of the letters of change, annuities secured on real property, or written obligations beloved of economic historians and historians of banking. Though the excellent works of Craig Muldrew and Laurence Fontaine, among others, have illuminated credit in the early modern world, the type of credit that most often gave rise to excommunications for debt is often only visible through this practice – a practice that illuminates the religious, social, and economic transformations of the sixteenth century. Studying the practice casts light on the transition from the face-to-face, local economies of the high Middle Ages to the regional economies of the early modern period, on how the Reformation shaped early modern regimes of credit, and on how the disappearance of ecclesiastical civil justice facilitated the emergence of early modern juridically sovereign territories.
The Inhibition of Stat5 by a Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target Gene Transactivation and the Growth of Breast and Prostate Tumor Cells
- The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.
Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers
Catherine M. Kelly
Gianluca Del Conte
W. Fraser Symmans
- INTRODUCTION: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.
METHODS: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years.
RESULTS: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.
CONCLUSIONS: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.
Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease
Hans Theodor Eich
- INTRODUCTION: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as "Histiocytosis X", "Type II Histiocytosis" or "Langerhans Cell Granulomatosis". Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis.
METHODS AND MATERIAL: Eight closely cooperating centres collected patients' data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined.
RESULTS: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9-134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3-50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed.
CONCLUSION: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.
Yellow fever disease: density equalizing mapping and gender analysis of international research output
Jan David Alexander Groneberg
- Background: A number of scientific papers on yellow fever have been published but no broad scientometric analysis on the published research of yellow fever has been reported. The aim of the article based study was to provide an in-depth evaluation of the yellow fever field using large-scale data analysis and employment of bibliometric indicators of production and quantity.
Methods: Data were retrieved from the Web of Science database (WoS) and analyzed as part of the NewQis platform. Then data were extracted from each file, transferred to databases and visualized as diagrams. Partially by means of density-equalizing mapping makes the findings clear and emphasizes the output of the analysis.
Results: In the study period from 1900 to 2012 a total of 5,053 yellow fever-associated items were published by 79 countries. The United States (USA) having the highest publication rate at 42% (n = 751) followed by far from Brazil (n = 203), France (n = 149) and the United Kingdom (n = 113). The most productive journals are the "Public Health Reports", the "American Journal of Tropical Medicine and Hygiene" and the "Journal of Virology". The gender analysis showed an overall steady increase of female authorship from 1950 to 2011. Brazil is the only country of the five most productive countries with a higher proportion of female scientists.
Conclusions: The present data shows an increase in research productivity over the entire study period, in particular an increase of female scientists. Brazil shows a majority of female authors, a fact that is confirmed by other studies.
G-CSC Report 2010
- The present report gives a short summary of the research of the Goethe Center for Scientific Computing (G-CSC) of the Goethe University Frankfurt. G-CSC aims at developing and applying methods and tools for modelling and numerical simulation of problems from empirical science and technology. In particular, fast solvers for partial differential equations (i.e. pde) such as robust, parallel, and adaptive multigrid methods and numerical methods for stochastic differential equations are developed. These methods are highly adanvced and allow to solve complex problems..
The G-CSC is organised in departments and interdisciplinary research groups. Departments are localised directly at the G-CSC, while the task of interdisciplinary research groups is to bridge disciplines and to bring scientists form different departments together. Currently, G-CSC consists of the department Simulation and Modelling and the interdisciplinary research group Computational Finance.
World robotics 2013 : industrial robots
- Unique publication on the worldwide distribution of industrial robots based on company reports: about 40 country reports 2007 - 2012; by application areas; by industrial branches; by types of robots; and by other technical and economic variables. Data on production, exports and imports; Trends in robot densities, i.e. number of robots; per 10,000 persons employed in relevant sectors; Forecast 2013 - 2016; Special Features: Case Studies on Profitability of Robot Investments
The easy-to-please construction in Middle English
- The aim of this article is to follow the changes that took place in the history of easy-to-please constructions. To fully apprehend that, we will begin by looking at Middle English infinitives and the change which affected them. Our attempt here is to prove that Early Middle English to was at its intermediate stage of development, i.e. it was neither a preposition nor inflection. In Late Middle English, to reached its final stage of a gradual evolution heading TR On account of the analysis of to and infinitives in Middle English, new constructions in which easv-to-please appear will be explained.