42,083 research outputs found
Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets
No full textChronic lymphocytic leukaemia (CLL) is the commonest haematological malignancy in the western world and is incurable by cytotoxic therapy. Considerable research effort has identified the signal transduction pathways in CLL cells that contribute to anti-apoptotic signalling. Some pathways are constitutively activated in CLL cells but upregulated in normal cells only when protein tyrosine kinases (PTKs) are activated by ligands. This review describes which PTKs are aberrantly activated in CLL cells and are potential targets for inhibition. Additional potential targets within pathways downstream of these PTKs include Mek/Erk, mTorc1, protein kinase C, PI-3 kinase/Akt, nuclear factor-?B and cyclin-dependent protein kinase. Numerous studies have identified chemical agents and antibodies that selectively kill CLL cells, irrespective of their genetic resistance to conventional chemotherapeutic agents, and which can overcome cytoprotective microenvironmental signalling. These studies have resulted in identification of novel therapies, some of which are currently undergoing clinical trials. In vitro and animal model studies and clinical trials could determine which inhibitors of which targets are the likely to be most effective and least toxic either singly or in combination
p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies
No full textThe p53 tumor suppressor protein has a key role in the induction of apoptosis of chronic lymphocytic leukemia (CLL) cells. Abnormalities within the p53 pathway identify a subset of patients with a poor prognosis. This review describes recent advances in understanding the mechanisms that regulate p53 levels and the role of p53 in the control of the cell cycle and of apoptosis. The classical model of p53-mediated apoptosis emphasizes the transcriptional activation of proapoptotic genes. In contrast, a novel model emphasizes p53's non-transcriptional actions as the major route of apoptosis induction, whereas its transcriptional arm predominantly upregulates antiapoptotic genes, thus providing a negative feedback mechanism that limits apoptosis. Further studies have identified the Notch pathway as a candidate p53-induced antiapoptotic mechanism. In contrast to the classical model, the novel model predicts that pharmacological inhibition of p53's transcriptional function or of the Notch signaling pathway will augment apoptosis induction by cytotoxic agents. Therapeutic strategies based on the novel model, which we review here for the first time, may significantly augment the antitumor actions of cytotoxic agents in CLL and in other malignancie
The dialogue between the author and the hero in the “Notes” of G. R. Derzhavin
No full textВ центре внимания автора статьи «Записки» Г. Р. Державина, представляющие по своей сути его автобиографию. Труд этот был создан на закате жизни, он включает все важнейшие события жизни Г. Р. Державина, поэта и государственного деятеля. Рассказ ведется от третьего лица, что придает особую атмосферу повествованию, выстраивается своеобразный диалог между автором и героем, все это и является предметом исследования автора статьи.The focus of the author of the article “Notes” G. R. Derzhavin, representing in essence his autobiography. This work was created at the end of his life; it includes all the most important events in the life of G. R. Derzhavin, poet and statesman. The story is told in a third person, which gives a special atmosphere to the story, a certain dialogue emerges between the author and the hero, all this is the subject of the author's research
Gravastars in f(R, G) gravity
No full textThis paper is focused on the study of gravitational vacuum stars or, briefly, gravastars in f(R, G) gravity, where R and G stand for the Ricci scalar and Gauss–Bonnet invariant term, respectively. Due to the involvement of highly non-linear differential equations, solutions are found by using some appropriate numerical techniques. The main structure of gravastars has been discussed according to core, shell, and exterior regions for a well-known f(R, G) gravity cosmological model. Mass–radius evolution is described graphically for the considered gravastar, and it is shown that the mass is directly proportional to the radius.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Introduction: Starring the Author
No full textLiterary celebrity is by now a familiar feat of contemporary literary culture, but it continues to raise complex questions about the history and development of fame, the interplay between the cultural marketplace and the official culture of critics and the canon, and the relation between authorial agency and public appropriation. This introduction addresses these questions by approaching literary celebrity as a merging of two discursive constructions: the celebrity-function and the author-function. By combining insights from celebrity studies, literary history and cultural memory studies, the introduction conceptualizes literary celebrity as a discursive construction with several variables, such as the author’s self-presentation, the circulation of his public identity, changing opinions on literature and writership, and the public afterlife of the author’s image
Spherically symmetric solution of f(R,G) gravity at low energy
No full textThe weak-field and slow-motion limit of f(R,G) gravity is developed up to (v/c)(4) order in a spherically symmetric background. Considering the Taylor expansion of a general function f around vanishing values of R and G, we present general vacuum solutions up to (v/c)(4) order for the gravitational field generated by a ball-like source. The spatial behaviors at (v/c)(2) order are the same for f(R,G) gravity and f(R) gravity, and their corresponding real valued static behaviors are presented and compared with the one in general relativity. The static Yukawa-like behavior is proved to be compatible with the previous result of the most general fourth-order theory. At (v/c)(4) order, the static corrections to the Yukawa-like behavior for f(R,G) gravity, f(R) gravity, and the Starobinsky gravity are presented and compared with the one in general relativity.National Natural Science Foundation of China [11120101004, 11475006]SCI(E)[email protected]; [email protected]
Real Estate Development: An overview
No full textGreen Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Urban Development Managemen
Letter from J. R. Eakin to Arthur G. Ringland
No full textLetter (copy) from J. R. Eakin to Arthur C. Ringland about the alignment of 40 acres near the Buggeln ranch
R v G and R [2003] UKHL 50, House of Lords
No full textEssential Cases: Criminal Law provides a bridge between course textbooks and key case judgments. This case document summarizes the facts and decision in R v G and R [2003] UKHL 50, House of Lords. The document also included supporting commentary from author Jonathan Herring.</p
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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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