334 research outputs found

    LNK (SH2B3): paradoxical effects in ovarian cancer.

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    LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers

    The vertical distribution of ozone instantaneous radiative forcing from satellite and chemistry climate models

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    We evaluate the instantaneous radiative forcing (IRF) of tropospheric ozone predicted by four state-of-the-art global chemistry climate models (AM2-Chem, CAM-Chem, ECHAM5-MOZ, and GISS-PUCCINI) against ozone distribution observed from the NASA Tropospheric Emission Spectrometer (TES) during August 2006. The IRF is computed through the application of an observationally constrained instantaneous radiative forcing kernels (IRFK) to the difference between TES and model-predicted ozone. The IRFK represent the sensitivity of outgoing longwave radiation to the vertical and spatial distribution of ozone under all-sky condition. Through this technique, we find total tropospheric IRF biases from -0.4 to + 0.7 W/m(2) over large regions within the tropics and midlatitudes, due to ozone differences over the region in the lower and middle troposphere, enhanced by persistent bias in the upper troposphere-lower stratospheric region. The zonal mean biases also range from -30 to + 50 mW/m(2) for the models. However, the ensemble mean total tropospheric IRF bias is less than 0.2 W/m(2) within the entire troposphere

    Study Protocol for the COVID-19 Pandemic Adjustment Survey (CPAS): A Longitudinal Study of Australian Parents of a Child 0–18 Years

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    Background: The COVID-19 pandemic presents significant risks to the mental health and wellbeing of Australian families. Employment and economic uncertainty, chronic stress, anxiety, and social isolation are likely to have negative impacts on parent mental health, couple and family relationships, as well as child health and development. Objective: This study aims to: (1) provide timely information on the mental health impacts of the emerging COVID-19 crisis in a close to representative sample of Australian parents and children (0–18 years), (2) identify adults and families most at risk of poor mental health outcomes, and (3) identify factors to target through clinical and public health intervention to reduce risk. Specifically, this study will investigate the extent to which the COVID-19 pandemic is associated with increased risk for parents’ mental health, lower well-being, loneliness, and alcohol use; parent-parent and parent-child relationships (both verbal and physical); and child and adolescent mental health problems. Methods: The study aims to recruit a close to representative sample of at least 2,000 adults aged 18 years and over living in Australia who are parents of a child 0–4 years (early childhood, N = 400), 5–12 years (primary school N = 800), and 13–18 years (secondary school, N = 800). The design will be a longitudinal cohort study using an online recruitment methodology. Participants will be invited to complete an online baseline self-report survey (20 min) followed by a series of shorter online surveys (10 min) scheduled every 2 weeks for the duration of the COVID-19 pandemic (i.e., estimated to be 14 surveys over 6 months). Results: The study will employ post stratification weights to address differences between the final sample and the national population in geographic communities across Australia. Associations will be analyzed using multilevel modeling with time-variant and time-invariant predictors of change in trajectory over the testing period. Conclusions: This study will provide timely information on the mental health impacts of the COVID-19 crisis on parents and children in Australia; identify communities, parents, families, and children most at risk of poor outcomes; and identify potential factors to address in clinical and public health interventions to reduce risk

    Metropolitan New York in the Greenhouse: Air Quality and Health Effects

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    A variety of potential effects on human health resulting from climate change have been identified in several assessments. According to an international panel{sup 1} they include direct effects of extreme temperatures on cardiovascular deaths, secondary effects due to vector-borne diseases or crop yields, and tertiary effects such as those that might arise from conflicts over freshwater supplies. To this fist we add the secondary effects of increased air pollution, which may result either directly from climate change or indirectly from increased air conditioning loads and the corresponding pollutant emissions from electric utilities. Higher ozone concentrations have been linked to increased ambient temperatures by both theory and observations of monitoring data. A similar association with particulate matter has been limited to observations, thus far. The pollution-heat linkage has been recognized before` but health effects have not been evaluated in terms of predictions of the joint effects of both agents. This paper has been prepared in two sections. First, we discuss the ozone situation with special reference to the Northeast Corridor and New York. In the second section, we present estimates of the health effects of climate change on New York and discuss some mitigation options

    DNA methylation-associated inactivation of TGFΞ²-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers

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    The transforming growth factor Ξ² (TGFΞ²)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFΞ² signalling, and RUNX3, which facilitates TGFΞ²-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0–83% in adult tumours and 0–50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFΞ²-related genes are frequently deregulated through aberrant methylation in many human malignancies

    Disrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice

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    and why disruption of circadian rhythm may lead to tumorigenesis. oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor
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