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Strong Rationale (strong + rationale)
Selected AbstractsAltered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancersGENES, CHROMOSOMES AND CANCER, Issue 11 2006Christopher C. Benz Analysis of a collection of human breast cancers (n = 150), enriched in ERBB2-positive cases (n = 57) and involving tumor genotyping relative to population-matched blood genotyping (n = 749) for a common ERBB2 single nucleotide polymorphism Ala(G)1170Pro(C), revealed that ERBB2 amplification in breast cancer is invariably monoallelic. Analysis of paired breast cancer and blood samples from informative (G1170C heterozygotic) ERBB2-positive (n = 12) and ERBB2-negative (n = 17) cases not only confirmed monoallelic amplification and ERBB2 transcriptional overexpression but also revealed that most low ERBB2 expressing breast cancers (12/17) exhibit unbalanced allelic transcription, showing 3-fold to nearly 5,000-fold preferential expression from one of two inherited alleles. To explore cis-acting transcriptional mechanisms potentially selected during ERBB2 amplification, levels of four different ERBB2 transcript variants (5.2, 4.7, 2.1, and 1.4 kb) were correlated with total (4.6 kb) ERBB2 mRNA levels in ERBB2-positive (n = 14) versus ERBB2-negative (n = 43) primary breast cancers. Relative expression of only the 2.1 kb extracellular domain-encoding splice variant and a 4.7 kb mRNA variant that uses an alternative start site were significantly increased in association with ERBB2-positivity, implicating altered promoter usage and selective transcript regulation within the ERBB2 amplicon. Altogether, these findings provide new mechanistic insights into the development of ERBB2-positive breast cancer and strong rationale for delineating candidate cis-acting regulatory elements that may link allele-specific ERBB2 transcription in premalignant breast epithelia with subsequent development of breast cancers bearing monoallelic ERBB2 amplicons. © 2006 Wiley-Liss, Inc. [source] Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinomaJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Hung Huynh Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor , Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1R, and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10,0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10,0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10,0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC. [source] Relational aggression and victimization in gay male relationships: the role of internalized homophobiaAGGRESSIVE BEHAVIOR, Issue 5 2008Thomas M. Kelley Abstract This article presents two studies that are the first to examine relational aggression and relational victimization in gay male peer relationships. A qualitative pilot study provides a strong rationale for a subsequent empirical investigation of 100 young adult, self-identified gay males. Results of both studies demonstrate that relational aggression and relational victimization are common experiences in gay male relationships. They also reveal forms of relational aggression and victimization that appear to be unique to gay males (e.g., outing). Results of the empirical study found significant relations between engaging in relational aggression against gay males and experiencing relational victimization and between experiencing relational victimization and internalized homophobia. However, there was no significant correlation between internalized homophobia and engaging in relational aggression. A multiple regression analysis found that experiencing relational victimization was correlated more strongly with the combination of engaging in relational aggression and internalized homophobia together than with relational aggression alone. Results are discussed within the framework of Allport's "traits due to victimization" theory and Meyer's theory of "minority stress." Implications for the prevention of relational aggression/victimization in gay male relationships are offered. Aggr. Behav. 34:475,485, 2008. © 2008 Wiley-Liss, Inc. [source] Expression of intercellular adhesion molecule (ICAM)-1 or ICAM-2 is critical in determining sensitivity of pancreatic cancer cells to cytolysis by human ,,-T cells: Implications in the design of ,,-T-cell-based immunotherapies for pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2009Zhiyong Liu Abstract Background and Aims:, ,,-T cells can recognize and kill malignant cells, particularly those of epithelial origin, through mechanisms which do not require the recognition of tumor-specific antigens (innate immune response). This natural ability of ,,-T cells to kill tumor cells in a tumor antigen-independent manner provides a strong rationale for developing clinical trials designed to exploit the innate antitumor properties of ,,-T cells. Methods:,In vitro studies were carried out to asses the sensitivity of pancreatic cancer cells (MIA PaCa2, BxPC-3, PANC-1) to killing by ex vivo expanded human ,,-T cells. Results:, The capacity of ,,-T cells to bind to as well as to kill pancreatic cancer cells correlated with the degree of surface expression of key intercellular adhesion molecules (ICAM) present on pancreatic cancer cells. Moreover, pancreatic cancer cells expressing neither ICAM-1 nor ICAM-2 were bound poorly by ,,-T cells and were found to be resistant to ,,-T-cell killing. However, upon transfection of resistant cells with ICAM-1 or ICAM-2, ,,-T cells were then able to bind to and subsequently kill these cells. Conclusion:,In vitro, the expression of ICAM-1 or ICAM-2 on human pancreatic cancer cells is critically important in determining the extent to which these cells are sensitive to killing by human ,,-T cells. Accordingly, in ongoing and future clinical studies using ,,-T cells for the treatment of a variety of epithelial-derived solid tumors,including pancreatic cancer,interventions intended to modulate ICAM expression on tumor cells may become important adjuncts to ,,-T-cell-based immunotherapies. [source] Accuracy and precision of radiostereometric analysis in the measurement of three-dimensional micromotion in a fracture model of the distal radiusJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2005Rami Madanat Abstract The purpose of the current study was to verify the feasibility of radiostereometric analysis (RSA) in monitoring three-dimensional fracture micromotion in fractures of the distal radius. The experimental set-up consisted of a simulated model of an extra-articular Colles' fracture, including metallic beads inserted into the bone on either side of the fracture site. The model was rigidly fixed to high precision micrometer stages allowing controlled translation in three axes and rotation about the longitudinal and transverse axes. The whole construct was placed inside a RSA calibration cage with two perpendicular radiographic film cassettes. Accuracy was calculated as the 95% prediction intervals from the regression analyses between the micromotion measured by RSA and actual displacements measured by micrometers. Precision was determined as the standard deviation of five repeated measurements of a 200 ,m displacement or a 0.5° rotation along a specific axis. Translations from 25 ,m to 5 mm were measured with an accuracy of ±6,m and translations of 200,m were measured with a precision of 2,6 ,m. Rotations ranging from 1/6° to 2° were measured with an accuracy of ±0.073° and rotations of 1/2° were measured with a precision of 0.025°,0.096°. The number of markers and their configuration had greater impact on the accuracy and precision of rotation than on those of translation. Aside from the unknown rate of clinical marker loosening, the current results favor the use of at least four markers in each bone fragment in distal radius fractures. These results suggest a strong rationale for the use of RSA as an objective tool for comparing different treatment modalities and novel bone graft substitutes aimed at stabilization of fractures of the distal radius. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Epigenetics and the embodiment of race: Developmental origins of US racial disparities in cardiovascular healthAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 1 2009Christopher W. Kuzawa The relative contribution of genetic and environmental influences to the US black-white disparity in cardiovascular disease (CVD) is hotly debated within the public health, anthropology, and medical communities. In this article, we review evidence for developmental and epigenetic pathways linking early life environments with CVD, and critically evaluate their possible role in the origins of these racial health disparities. African Americans not only suffer from a disproportionate burden of CVD relative to whites, but also have higher rates of the perinatal health disparities now known to be the antecedents of these conditions. There is extensive evidence for a social origin to prematurity and low birth weight in African Americans, reflecting pathways such as the effects of discrimination on maternal stress physiology. In light of the inverse relationship between birth weight and adult CVD, there is now a strong rationale to consider developmental and epigenetic mechanisms as links between early life environmental factors like maternal stress during pregnancy and adult race-based health disparities in diseases like hypertension, diabetes, stroke, and coronary heart disease. The model outlined here builds upon social constructivist perspectives to highlight an important set of mechanisms by which social influences can become embodied, having durable and even transgenerational influences on the most pressing US health disparities. We conclude that environmentally responsive phenotypic plasticity, in combination with the better-studied acute and chronic effects of social-environmental exposures, provides a more parsimonious explanation than genetics for the persistence of CVD disparities between members of socially imposed racial categories. Am. J. Hum. Biol., 2009. © 2008 Wiley-Liss, Inc. [source] PROSPECT lost: when a pilot project does not look to learnPUBLIC ADMINISTRATION & DEVELOPMENT, Issue 2 2008Michael Mattingly Abstract If a development project is destined to reach only a selection of its intended beneficiaries or to give them only momentary or uncertain benefits, there is a strong rationale for making it instead a project of trials from which lessons can be taken for obtaining the impact that it may not otherwise have. Because the fundamental problems and opportunities of development are very complex by their nature, interventions that seek to test practice knowledge and to learn above all else may have the greatest potential for benefit in the long term. A project that wishes to create experience from which others can learn will engage in research, so it must be conceived, led and conducted as such. This means it must be designed with knowledge of research. It must be led with an appreciation and understanding of research method. Specific research activities must be conducted that produce knowledge and promote its up-take, so that learning is a principle project outcome. The large urban anti-poverty project, PROSPECT, conducted in Lusaka, Zambia, illustrates this argument. Copyright © 2008 John Wiley & Sons, Ltd. [source] Quantifying the duration of pre-diabetesAUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH, Issue 3 2010Melanie Y. Bertram Abstract Objective: Interventions for individuals with pre-diabetes are efficacious, however, identification of people with pre-diabetes does not occur in Australia. This study aims to calculate the duration of pre-diabetes, in order to provide supporting evidence for a screening program. Methods: We carried out a systematic review and random effects meta-analysis to identify if an increased risk of mortality is present in people with pre-diabetes. The result of this meta-analysis as well as information on prevalence, remission of pre-diabetes and transition to diabetes from an Australian cohort study, were used in the software program DisMod to calculate duration. Results: From 2,578 articles identified, 11 studies met the inclusion criteria. The pooled relative risk of all-cause mortality was 1.26 (1.17-1.34) with no sign of heterogeneity between the studies. The average duration of pre-diabetes was 8.5 years in males aged 30+ and 10.3 years in females aged 30+. Conclusions: The duration of pre-diabetes in Australia is long enough to warrant a screening program. The finding is robust to sensitivity testing of very large variations in the epidemiological parameters. Implications: If the interventions following screening are shown to be cost-effective, a strong rationale for the implementation of a screening program exists. [source] 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growthCANCER, Issue 12 2005Noriyuki Takai M.D. Abstract BACKGROUND Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25,30% of ovarian carcinoma cases and a correlation between increased HER2 expression and decreased survival has been demonstrated. HER2 is a ligand-less member of the HER family that functions as the preferred coreceptor for epidermal growth factor receptor (EGFR), HER3, and HER4. METHODS An approach was developed to target HER2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders HER2's recruitment into a functional HER complex. RESULTS HER2 was robustly expressed in all eight ovarian carcinoma cell lines; expression of EGFR and HER3 was variable. Even though four of the eight cell lines responded to EGF, 2C4 antibody moderately inhibited in vitro proliferation of only two cell lines (OVCA433 and SK-OV-3). Furthermore, ligand-stimulated p-MAPK expression was inhibited by 2C4 only in these two cell lines after exposure to EGF. Immunoprecipitation and eTag analysis revealed that OVCA433 expressed heterodimers of EGFR/HER2, and these heterodimers were disrupted after treatment with 2C4, whereas OVCA432 cells did not have these heterodimers. In murine xenograft experiments, the in vivo growth of OVCA433, but not of OVCA432, ovarian carcinoma cells was significantly inhibited by 2C4 treatment of the mice. CONCLUSION 2C4 is able to disrupt the HER signaling pathway and inhibit the in vitro and in vivo growth of ovarian carcinoma cell lines. The response appears limited to lines in which HER2 heterodimers were able to transduce proliferative signals. Our findings suggest a strong rationale to conduct clinical trials of 2C4 in a subset of patients with ovarian tumors. Cancer 2005. © 2005 American Cancer Society. [source] Endowments: Stable Largesse or Distortion of the Polity?PUBLIC ADMINISTRATION REVIEW, Issue 3 2007Renée A. Irvin As ever more private resources are held in foundations and nonprofit organizations' endowment funds, more scholars and practitioners are demanding that these assets be put to good use immediately. Those favoring the preservation of capital,primarily representing private foundations,sound unnecessarily cautious. This article examines endowment conservation from a variety of critical angles, finding strong rationales for both conserving and liquidating endowments. Policy responses to the buildup of endowment assets include requiring a faster payout or regulating the amount and type of administrative expenses included in annual payout. This article reviews the relationship of the business cycle and wealth distribution to annual giving. The most prudent course, in view of the cyclical nature of giving as well as the substantial generational wealth currently held by elders, appears to be to conserve significant assets now in order to establish a stable flow of future social benefits. [source] | |||||||||||||