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In vivo hypoxia and prostate cancer growth
No full textBackground. Solid tumors require a local vascular network that supplies O2 and nutrients for their growth. When cell proliferation exceeds angiogenesis, vasculature might become unable to sustain the O2 needs of tumors. The resulting limitation in O2 supply causes tumors to cope with an environment chronically deficient in O2 (chronic hypoxia, CH). Local over-expression of hypoxia inducible factor 1α (HIF-1α) transactivates compensatory mechanisms aimed at survival, including the angiogenic switch, which provides growth factors for the development of circulation to feed the growing tumor. However, the newly formed vessels are more twisted, tortuous, distorted and irregular than mature vessels, which leads to inefficient and irregular, perhaps pulsing oxygenation. The resulting situation resembles a paradigm whereby CH is interspersed with various reoxygenation events (CHReox). Although hypoxia is known to increase tumor aggressiveness, resistance to radiotherapy, malignant progression and enhanced metastases formation, it remains to be established if the signaling path originating from systemic hypoxia can exacerbate tumorigenesis.
Aims. Two are the aims of this thesis. First, testing the hypothesis that systemic hypoxia in vivo up-regulates prostate cancer growth. Second, to get a better insight into the role of HIF-1α, testing a condition whereby HIF-1α expression is perturbed to enable distinguishing the effects due to hypoxia from those due to HIF-1α. To this purpose, CHReox was selected as a non-pharmacological approach to alter HIF-1α expression without use of drugs and substances that may mask the results.
Methods. Male athymic nu/nu mice were xenografted with LNCaP cells and exposed for 4 weeks to either CH (10% O2) or CHReox (3 reoxygenation/week for 1 h), with normoxic mice as control.
Results. Tumors grew faster in hypoxia than in normoxia, in agreement with higher phosphorylation rate of protein kinase B (Akt), an inhibitor of apoptosis and inducer of cell proliferation. Tumor Hb content was higher in hypoxia than in normoxia, reflecting the higher blood Hb content rather than increased vascularization, in agreement with similar tissue level of VEGF, a mediator of angiogenesis. Although CH and CHReox induced similar patterns of these parameters, expression level of HIF-1α, assessed by Western blot and immunohistochemistry, was markedly higher for CHReox than CH. The inflammatory infiltrate in the tumor mass was less in hypoxia than in normoxia, in the favour of greater mass of tumor cells in hypoxia. However, although the inflammatory infiltrate displayed relevant characteristics of apoptosis, tumor cells were scarcely apoptotic.
Conclusion. Systemic hypoxia in vivo increases the rate of prostate LNCaP tumor growth in athymic nude mice, irrespectively of CH or CHReox. Such effect is influenced neither by tumor vascularization nor by VEGF. As HIF-1α expression levels are markedly different in the two hypoxic conditions, yet the tumor growth rate is essentially the same, it appears that in the tested in vivo model the HIF-1α-linked pathways are less prominent that those linked to the PI3K/Akt pathwa
Impact of hemoglobin concentration and affinity for oxygen on tissue oxygenation : the case of hemoglobin-based oxygen carriers
No full textIn patients undergoing exchange-transfusion with hemoglobin (Hb)-based oxygen (O2) carriers (HBOC), native Hb coexists with newly transfused Hb. The two Hb types share the same arterial and venous PO2, but their affinities for O2 vary. A simple spreadsheet model is described aiming at evaluating the contribution of each Hb type to the overall O2 transport characteristics as a function of the batch Hb concentration and O2 affinity in the HBOC solution, of the fraction of exchange-transfused blood/HBOC, and of the arterial PO2. This model helps to yield a quantitative estimate of how tissues with high or low O2 extraction respond to the changes cited above. The results show that the higher the exchange-transfusion ratio, the O2 transport to tissues becomes progressively impaired. However, this effect is more critical at low batch Hb concentration and high O2 affinity of the HBOC, especially for tissues/organs with high O2 extraction, whereas the arterial PO2 does not appear as critica
In vivo hyperoxia induces hypoxia-inducible factor-1α overexpression in LNCaP tumors without affecting the tumor growth rate
No full textHypoxia is a recognized cause for solid tumors malignancy and resistance, probably via hypoxia-induced overexpression of the hypoxia-inducible factor (HIF)-1α, major modulator of the cell response to oxygen deprivation. Although hyperoxia, the opposite condition, may represent a key issue to assess this paradigm, its effect on tumor growth and HIF-1α expression remains unclear. To test whether hyperoxia and hypoxia have divergent effects, and to better focus into the role of HIF-1α in vivo, athymic mice xenografted with LNCaP cells were exposed for 28 days to atmospheres containing 10, 21 or 30% O2. Whereas the xenografts grew twice faster in hypoxia, their growth rates in hyperoxia and normoxia were similar. To analyze the involved molecular mechanisms, we performed various assays in xenograft tissues. Faster xenografts growth in hypoxia was associated with higher phosphorylation of protein kinase B (Akt) and higher expression of Ki67, both related with pro-survival and cell proliferation pathways. By contrast, the expression level of HIF-1α was similar in normoxia and hypoxia, but paradoxically twice higher in hyperoxia. The protein level of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was also higher in hyperoxia, suggesting marked cell response to redox imbalance. Whereas both the vascular-endothelial growth factor (VEGF) and its receptor VEGF-R2 were overexpressed in hyperoxia, the tissue hemoglobin content was not increased, despite a slight reduction in vascularization. As a whole, this data indicates that the xenografts growth rate was independent of HIF-1α expression level, suggesting that in an in vivo setting alternative more effective proliferative paths associated with the cell response to the redox imbalance may override the paths linked to HIF-1α signaling
Chronic systemic hypoxia promotes LNCaP prostate cancer growth in vivo
No full textOBJECTIVE. Solid tumors contain underperfused regions where hypoxia-inducible factor-1α (HIF-1α) over-expression induces hypoxia adaptation and cell proliferation. We test the hypothesis that systemic hypoxia promotes prostate cancer growth in vivo and examine HIF-1α centrality in this effect. METHODS. Male athymic mice were xenografted with 3 × 10 6 LNCaP cells per each flank and exposed for 28 days to either chronic hypoxia (CH, 10% O2) or CH with reoxygenation (CHReox, 3 times/week for 1 hr), with normoxia as control (n = 17, 9, and 20, respectively). At the end of the observation, mice were euthanized and tumors harvested for analyses. RESULTS. The successful xenografts grew faster in CH and CHReox than in normoxia (first-order rate constants 0.15 ± 0.01, 0.18 ± 0.03, and 0.09 ± 0.01 day-1, P < 0.05, n = 18, 15, and 25, respectively). Furthermore, the tumor masses at the end were 4.09 ± 0.58, 3.42 ± 0.55, and 1.86 ± 0.25 mg/g bw (P < 0.05), respectively. HIF-1α, assayed by Western blot and immunofluorescence, was slightly increased in CH with respect to normoxia, but markedly overexpressed (5-10 times) in CHReox (P < 0.001). The tumor hemoglobin content, higher in CH and CHReox than in normoxia, reflected the higher blood hemoglobin concentration, not neovascularization, as supported by similar expression levels of vascular endothelial growth factor (VEGF) in the three groups. By contrast, protein kinase B (Akt) was more phosphorylated in both hypoxic groups than in normoxia (P < 0.01). CONCLUSION. In vivo systemic hypoxia promotes prostate cancer growth regardless of HIF-1α expression level and neovascularization, suggesting an important role for hypoxia-dependent pathways that do not involve HIF-1α, as the phosphatidyl inositol-3-phosphate signaling cascade
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
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