1,721,073 research outputs found
Neurotensin-derived branched peptides and uses thereof
No full text0001] The instant invention refers to in vivo stable branched peptides derived from the sequence of Neurotensin (NT). The peptides may be conjugated to functional units for specific targeting of cancer cells. Thus they can be used for diagnosis and/or therapy of tumors.
BACKGROUND ART
[0002] One of the major problems in classic chemotherapy is the non-specific toxicity of most anticancer agents even for normal cells. Then, specific targeting of tumors is the main challenge in the research on cancer therapy and diagnosis.
[0003] Presently, innovative tumor-specific therapies follow the strategy of targeting tumor associated proteins, specifically expressed or over expressed on tumor cells.
[0004] The observation that receptors for different endogenous regulatory peptides are expressed in a number of primary human cancers, opened new perspectives on the use of synthetic peptides for tumor-selective targeting.
[0005] Neurotensin (NT) is a 13 amino acid peptide that has the dual function of neurotransmitter or neuromodulator in the central nervous system and local hormone in the periphery. NT receptors are overexpressed in severe malignancies such as small cell lung cancer, colon, pancreatic and prostate carcinomas. NT stabilized analogues have been proposed for tumor therapy several years agoand NT is still considered the best possible candidate for a peptide-based therapy of exocrine pancreatic carcinomasin consideration of the high incidence and density of NT receptors in these tumors. Over 75% of all ductal pancreatic carcinomas over-express NT receptors, whereas normal pancreas tissue, pancreatitis and endocrine pancreas do not.
[0006] Tumor receptor-targeting is fundamental in approaching the problem of non-specific toxicity of cancer chemotherapies and it is a precious tool for tumor localization by radioisotopes. Nonetheless, the in vivo use of peptides has largely been limited by their short half-life.
[0007] The inventors of the present invention previously demonstrated that synthesis of peptides in branched dendrimeric form results in molecules that can retain peptide biological activity and are very resistant to proteolytic activity of biological fluids, thus having a markedly higher half-life with respect to monomeric peptides.
[0008] The instant invention refers to in vivo stable dendrimeric peptides derived from NT. Such peptides are also conjugated to functional units to be used to target cancer cells. In particular, conjugation of NT4(8-13) with either the photosensitizer Che6 or the chemotherapic molecule MTX has shown to be specific for tumor cells and non-toxic to healthy ones, then overcoming the secondary effects of the classic chemotherapeutics when given systemically to mice.
[0009] In the present invention, in addition to the specificity of the molecules, an increased activity of the conjugated molecules compared to free uncoupled drug was observed. The molecules of the present invention were selected among a pool of numerous analogues that the inventors synthesized. The 'carrier' peptide (neurotensin) is the best carrier among a number of others. For example, luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin-releasing hormone (GnRH) (QHWSYGLRPG, SEQ ID No. 3), presented in vitro binding profiles lower than NT. In addition, the linkers used in the present invention were selected for each new molecule because of their large influence on the activity of the molecule. For example NT(8-13)4-beta-Ala-Biotin was shown to loose binding activity to NT receptor compared to NT(8-13)4; whereas NT4-peg-Biotin maintained IC50 values comparable to that of NT4. NT(1-13)4-Fluorescein and NT(8-13)4-Fluorescein are able to stain cancer cells and tissue more efficiently than NT(8-13)4-beta-Ala-K(PEG-Fluorescein) and the fluorophore is also more stable. Finally, the chemotherapeutic moiety was chosen on the basis of its functional groups such as to be selectively and univocally used for the coupling. The strength of the bond was modulated depending on the site and mode of action of the drug itself, the best conjugation was selected. As an example 6-mercaptopurine conjugated to neurotensin through an 'uncleavable' linker was completely non cytotoxic, the same drug conjugated through a 'cleavable' linker was active, but the activity resulted insufficient to be considered for further development. Similarly, monastrol derivative is not the first choice of compound in the present invention. Taken together, these specific features render the objects of the present invention unique and preferable over any possible analogue
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
Use of the Conduit Flow Process for the simulation of passive mitigation measures against the piezometric damming effect at the new underground High Speed railway station of Florence
No full textThe new High Speed railway station of the city of Florence will be located below ground level inside a huge excavation, 25 m b.g.s deep, 450 m long and 50 m wide; the pit, already built, is surrounded by concrete cutoff walls causing a piezometric damming effect against the main aquifer of the Arno River. As permanent mitigation measure against the piezometric mounding, the design of the station considers a series of drain pipes drilled horizontally on up and down gradient sides of the pit and connected by blind wall tubes. A numerical finite differences model has been implemented with the Modflow code, in order to quantify the expected damming effect and to properly design the drain-based mitigation measures (i.e. frequency and length of the drains). One of the major challenges of the numeric approach was the coupling between the groundwater flow in the porous medium and the water flow towards and through the drains and the blind wall tubes connecting the sides of the excavation. Thus, the drains were simulated using a recently published Modflow Process originally developed for karst conduits (Conduit Flow Process - CFP), which allows combining the groundwater flow in the porous medium with laminar or turbulent flow into pipes. In order to guarantee an acceptable head differential between both sides of the excavation, the results showed that the system should permit a discharge flow rate of about 0.026 m3/s, considering a hydraulic gradient equal to 0.5% (i.e. hydraulic gradient from the averaged piezometric distribution before pit excavation). Conductance turned out to be the most influent parameter towards the effectiveness of the drainage system
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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