Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Quantitative trait loci conferring grain mineral nutrient concentrations in durum wheat 3 wild emmer wheat RIL population

Mineral nutrient malnutrition, and particularly deficiency in zinc and iron, afflicts over 3 billion people worldwide. Wild emmer wheat, Triticum turgidum ssp. dicoccoides, genepool harbors a rich allelic repertoire for mineral nutrients in the grain. The genetic and physiological basis of grain protein, micronutrients (zinc, iron, copper and manganese) and macronutrients (calcium, magnesium, potassium, phosphorus and sulfur) concentration was studied in tetraploid wheat population of 152 recombinant inbred lines (RILs), derived from a cross between durum wheat (cv. Langdon) and wild emmer (accession G18-16). Wide genetic variation was found among the RILs for all grain minerals, with considerable transgressive effect. A total of 82 QTLs were mapped for 10 minerals with LOD score range of 3.2–16.7. Most QTLs were in favor of the wild allele (50 QTLs). Fourteen pairs of QTLs for the same trait were mapped to seemingly homoeologous positions, reflecting synteny between the A and B genomes. Significant positive correlation was found between grain protein concentration (GPC), Zn, Fe and Cu, which was supported by significant overlap between the respective QTLs, suggesting common physiological and/or genetic factors controlling the concentrations of these mineral nutrients. Few genomic regions (chromosomes 2A, 5A, 6B and 7A) were found to harbor clusters of QTLs for GPC and other nutrients. These identified QTLs may facilitate the use of wild alleles for improving grain nutritional quality of elite wheat cultivars, especially in terms of protein, Zn and Fe

Polyp measurement based on CT colonography and colonoscopy: variability and systematic differences

To assess the variability and systematic differences in polyp measurements on optical colonoscopy and CT colonography. Gastroenterologists measured 51 polyps by visual estimation, forceps comparison and linear probe. CT colonography observers randomly assessed polyp size two-dimensionally (abdominal and intermediate window) and three-dimensionally (manually and semi-automatically). Linear mixed models were used to assess the variability and systematic differences between CT colonography and optical colonoscopy techniques. The variability of forceps and linear probe measurements was comparable and both showed less variability than measurement by visual assessment. Measurements by linear probe were 0.7 mm smaller than measurements by visual assessment or by forceps. The variability of all CT colonography techniques was lower than for measurements by forceps or visual assessment and sometimes lower (only 2D intermediate window and manual 3D) compared with measurements by linear probe. All CT colonography measurements judged polyps to be larger than optical colonoscopy, with differences ranging from 0.7 to 2.3 mm. A linear probe does not reduce the measurement variability of endoscopists compared with the forceps. Measurement differences between observers on CT colonography were usually smaller than at optical colonoscopy. Polyps appeared larger when using various CT colonography techniques than when measured during optical colonoscop

Macrophage-Specific ApoE Gene Repair Reduces Diet-Induced Hyperlipidemia and Atherosclerosis in Hypomorphic Apoe Mice

Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account for up to 10% of plasma apoE levels. This study examined the contribution of macrophage-derived apoE expression levels in diet-induced hyperlipidemia and atherosclerosis.Hypomorphic apoE (Apoe(h/h)) mice expressing wildtype mouse apoE at ∼2-5% of physiological levels in all tissues were derived by gene targeting in embryonic stem cells. Cre-mediated gene repair of the Apoe(h/h) allele in Apoe(h/h)LysM-Cre mice raised apoE expression levels by 26 fold in freshly isolated peritoneal macrophages, restoring it to 37% of levels seen in wildtype mice. Chow-fed Apoe(h/h)LysM-Cre and Apoe(h/h) mice displayed similar plasma apoE and cholesterol levels (55.53±2.90 mg/dl versus 62.70±2.77 mg/dl, n = 12). When fed a high-cholesterol diet (HCD) for 16 weeks, Apoe(h/h)LysM-Cre mice displayed a 3-fold increase in plasma apoE and a concomitant 32% decrease in plasma cholesterol when compared to Apoe(h/h) mice (602.20±22.30 mg/dl versus 888.80±24.99 mg/dl, n = 7). On HCD, Apoe(h/h)LysM-Cre mice showed increased apoE immunoreactivity in lesional macrophages and liver-associated Kupffer cells but not hepatocytes. In addition, Apoe(h/h)LysM-Cre mice developed 35% less atherosclerotic lesions in the aortic root than Apoe(h/h) mice (167×10(3)±16×10(3) µm(2) versus 259×10(3)±56×10(3) µm(2), n = 7). This difference in atherosclerosis lesions size was proportional to the observed reduction in plasma cholesterol.Macrophage-derived apoE raises plasma apoE levels in response to diet-induced hyperlipidemia and by such reduces atherosclerosis proportionally to the extent to which it lowers plasma cholesterol levels

Disease acceptance and adherence to imatinib in Taiwanese chronic myeloid leukaemia outpatients

Background The launch of imatinib has turned chronic myeloid leukaemia (CML) into a chronic illness due to the dramatic improvement in survival. Several recent studies have demonstrated that poor adherence to imatinib may hamper the therapeutic outcomes and result in increased medical expenditures, whilst research on exploring the reasons for non-adherence to imatinib is still limited. Objective This study aimed to explore the experience of patients as they journey through their CML treatments and associated imatinib utilisation in order to understand the perceptions, attitudes and concerns that may influence adherence to imatinib treatment. Setting This study was conducted at oncology outpatient clinics in a medical centre in southern Taiwan. Methods CML patients who regularly attended the oncology outpatient clinics to receive imatinib treatment from October 2011 to March 2012 were invited to participate in the study. Semi-structured face-to-face interviews were used to explore patients’ experiences and views of their treatment, their current CML status and CML-related health conditions, their concerns about imatinib treatment and imatinib-taking behaviours. Patient interviews were recorded, transcribed verbatim and thematically analysed using the constant comparison approach. Main outcome measure Themes related to patients’ views of the disease and health conditions, worries and concerns influencing imatinib utilisation behaviours are reported. Results Forty-two CML patients participated in the interviews. The emerging themes included: acceptance of current disease and health status, misconceptions about disease progression, factors associated with adherence to imatinib, concerns and management of adverse drug effects. Participants regarded CML as a chronic disease but had misconceptions about disease progression, therapeutic monitoring, resistance to imatinib and symptoms of side effects. Participants were generally adherent to imatinib and favoured long-term prescriptions to avoid regular outpatient visits for medication refills. Experiencing adverse effect was the main reason influencing adherence and led to polypharmacy. Most participants altered medicine-taking behaviours to maintain long-term use of imatinib. Conclusion Taiwanese CML patients are adherent to imatinib but report changing their medication-taking behaviour due to adverse drug effects and associated polypharmacy. Patients’ misconceptions of the disease and medication suggests that it is necessary to improve communication between patients and healthcare professionals. Routinely providing updated information as part of the patient counselling process should be considered as a means of improving this communication

Transformation, adaptation and development: relating concepts to practice

In recent years there has been a growing number of academic reviews discussing the theme of transformation and its association with adaptation to climate change. On the one hand this has stimulated exchange of ideas and perspectives on the parameters of transformation, but it has also given rise to confusion in terms of identifying what constitutes a non-incremental form of adaptation on the ground. What this article aims to do instead is help researchers and practitioners relate different interpretations of transformation to practice by proposing a typological framework for categorising forms of change that focuses on mechanisms and objectives. It then discusses how these categorisations link to the broader conceptions and critiques noted above, with the idea that this will enable those who seek to analyse or plan adaptation to better analyse what types of action are potentially constitutive of transformation. In doing so, it should equally assist in the identification and specification of critical questions that need to be asked of such activity in relation to issues of sustainability and equity. As the term transformation gains ground in discussions of climate change adaptation, it is necessary to take a step back, review quite what commentators mean when they use the word, and consider the implications on people, especially the most vulnerable and marginalised, of “doing” or promoting transformation in its different forms

Home Range Use and Movement Patterns of Non-Native Feral Goats in a Tropical Island Montane Dry Landscape

Advances in wildlife telemetry and remote sensing technology facilitate studies of broad-scale movements of ungulates in relation to phenological shifts in vegetation. In tropical island dry landscapes, home range use and movements of non-native feral goats (Capra hircus) are largely unknown, yet this information is important to help guide the conservation and restoration of some of the world’s most critically endangered ecosystems. We hypothesized that feral goats would respond to resource pulses in vegetation by traveling to areas of recent green-up. To address this hypothesis, we fitted six male and seven female feral goats with Global Positioning System (GPS) collars equipped with an Argos satellite upload link to examine goat movements in relation to the plant phenology using the Normalized Difference Vegetation Index (NDVI). Movement patterns of 50% of males and 40% of females suggested conditional movement between non-overlapping home ranges throughout the year. A shift in NDVI values corresponded with movement between primary and secondary ranges of goats that exhibited long-distance movement, suggesting that vegetation phenology as captured by NDVI is a good indicator of the habitat and movement patterns of feral goats in tropical island dry landscapes. In the context of conservation and restoration of tropical island landscapes, the results of our study identify how non-native feral goats use resources across a broad landscape to sustain their populations and facilitate invasion of native plant communities

Glucocorticoid Receptor and Sequential P53 Activation by Dexamethasone Mediates Apoptosis and Cell Cycle Arrest of Osteoblastic MC3T3-E1 Cells

Glucocorticoids play a pivotal role in the proliferation of osteoblasts, but the underlying mechanism has not been successfully elucidated. In this report, we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3-E1 cells. It was found that the inhibitory effects were largely attributed to apoptosis and G1 phase arrest. Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor (GR), as they were abolished by GR blocker RU486 pre-treatment and GR interference. G1 phase arrest and apoptosis were accompanied with a p53-dependent up-regulation of p21 and pro-apoptotic genes NOXA and PUMA. We also proved that dexamethasone can’t induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference. These data demonstrate that proliferation of MC3T3-E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P53 activation

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO