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A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma
No full textAngiogenesis and vasculogenesis are regulated in large
part by several different growth factors and their
associated receptor tyrosine kinases (RTKs). Foremost
among these is the vascular endothelial growth factor
(VEGF) family including VEGF receptor (VEGFR)-2
and -1. VEGFR ligand binding and biological activity are
regulated at many levels, one of which is by a soluble,
circulating form of VEGFR-1 (sVEGFR-1). This sVEGFR-1
can act as a competitive inhibitor of its ligand, serve
as a possible biomarker, and play important roles in
cancer and other diseases such as preeclampsia.
Recombinant forms of sVEGFR-2 have been shown to
have antiangiogenic activity, but a naturally occurring
sVEGFR-2 has not been described previously. Here,
we report such an entity. Having a molecular weight
of f160 kDa, sVEGFR-2 can be detected in mouse and
human plasma with several different monoclonal and
polyclonal anti-VEGFR-2 antibodies using both ELISA
and immunoprecipitation techniques. In vitro studies
have determined that the sVEGFR-2 fragment can
be found in the conditioned media of mouse and
human endothelial cells, thus suggesting that it may
be secreted, similar to sVEGFR-1, or proteolytically
cleaved from the cell. Potential biological activity of this
protein was inferred from experiments in which mouse
sVEGFR-2 could bind to VEGF-coated plates. Similar
to sVEGFR-1 and other soluble circulating RTKs,
sVEGFR-2 may have regulatory consequences with
respect to VEGF-mediated angiogenesis as well
as potential to serve as a quantitative biomarker of
angiogenesis and antiangiogenic drug activity,
particularly for drugs that target VEGF or VEGFR-2
Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water
No full textA number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs
Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose
No full textPerhaps the most significant recent advance in oncology therapeutics has been the approval of
various “molecularly targeted” anti-cancer drugs. Currently, there are a large number of similar drugs in early or
late stage development, including antiangiogenic agents. Clinical development of such drugs suffers from
several handicaps including determining whether a patient’s cancer expresses the target and is functionally
contributing to cancer growth, monitoring biologic activity, and determining optimal biologic dose. The last
problem is related to the low frequency of objective tumor responses (tumor shrinkage) caused by such drugs,
or the lack of dose limiting toxicities necessary to define a maximum tolerated dose (MTD), or expression of
optimal therapeutic activity at doses below the MTD, when one can be defined. These problems necessitate the
development of alternative pharmacodynamic surrogate markers.
Here we summarize several such promising markers for monitoring targeted antiangiogenic activity, and
establishing optimal therapeutic/biologic dosing. The first is molecular - plasma VEGF – levels of which are
rapidly and significantly increased in a dose dependent manner after injection of normal or tumor bearing mice
with anti-VEGFR-2 antibodies. The second is a cellular marker, and more generic in nature - circulating VEGF
receptor-2 positive cells found in peripheral blood, some of which may be circulating endothelial progenitor
cells. Levels of such cells are suppressed in a dose dependent manner which correlate with previously
determined optimal biologic/therapeutic anti-tumor activity of various antiangiogenic drugs or treatments.
Finally, another promising marker we discuss is soluble VEGFR-2
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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