text:
- Research article
- Open access
- Published:
Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade
Arthritis Research & Therapy volume 13, Article number: R161 (2011)
Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA.
Arthritic mice were treated with RB200 alone or in combination with the TNF receptor fusion protein etanercept. We performed immunohistochemistry to assess CD31 and in vivo fluorescent imaging using anti-E-selectin antibody labelled with fluorescent dye to elucidate the effect of RB200 on the vasculature in CIA.
RB200 significantly abrogated CIA by reducing paw swelling and clinical scores. Importantly, low-dose RB200 combined with a suboptimal dose of etanercept led to complete abrogation of arthritis. Moreover, the combination of RB200 with etanercept abrogated the intensity of the E-selectin-targeted signal to the level seen in control animals not immunised to CIA.
The human pan-EGF receptor bispecific ligand trap RB200, when combined with low-dose etanercept, abrogates CIA, suggesting that inhibition of events downstream of EGF receptor activation, in combination with TNFα inhibitors, may hold promise as a future therapy for patients with RA.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by severe synovial inflammation that leads to the progressive destruction of bone and cartilage. It is a severe disabling disease that affects approximately 1% of the population worldwide [1]. Despite the introduction of biological therapies such as those that target TNFα, a significant proportion of RA patients do not demonstrate a positive response to treatment. Furthermore, biologicals such as TNFα are associated with increased risk of serious infections, including tuberculosis [2–5]. In addition, the pattern of disease in patients may change over time and alternative or additional therapy may be required.
The epidermal growth factor (EGF) ligand/receptor family has been postulated to play a role in RA pathogenesis [6]. The EGF family (ErbB and the human epidermal growth factor receptor (HER)) of cell-surface receptors belong to the receptor tyrosine kinase (RTK) superfamily and consist of extracellular domains (ECDs) and an intracellular tyrosine kinase signalling domain [7, 8]. The EGF family has four members, namely, EGF receptor (EGFR)/HER1/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4, which are activated by a large family of ligands, including EGF, as well as by transforming growth factor α (TGF-α), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), β-cellulin (BTC), epiregulin (EPR), epigen (EPG) and neuregulin (NRG) [7, 9, 10]. Within the EGFRs there are four ECDs, with domains I and III being ligand-binding domains and domains II and IV mediating binding to each other and to other members of this receptor family. Ligand binding induces the formation of homo- or heterodimers between the receptors. For example, TGF-α and EGF bind to EGFR/HER1/ErbB1, whereas NRG4 binds to HER4/ErbB4. Depending on the dimer formed, transphosphorylation of intracellular regions occurs, leading to the activation of numerous downstream signalling pathways, which results in cell proliferation, survival and differentiation [7, 9, 10]. Researchers in a number of studies have suggested that the EGF ligand/receptor family has a role in the development of inflammatory arthritis [11–14]. In addition to the presence of EGF in RA synovium [6], expression of HER2/ErbB2 has been reported [12]. Other EGFR ligands in addition to EGF have been detected, namely, TGF-α and AR [11, 15].
A number of agents targeting EGFRs have been successfully developed for the treatment of cancer. The first approved HER therapeutic drug, trastuzumab, is a monoclonal antibody that targets HER2 and has revolutionised the treatment of HER2-overexpressing, node-positive or node-negative breast cancer [16]. Cetuximab is a monoclonal antibody that targets HER1 and is prescribed for patients with metastatic colorectal cancer as well as for those with head and neck cancer. Similarly, panitumumab (mAb) is a fully human anti-HER1 antibody used for the treatment of metastatic colorectal cancer. In contrast, lapatinib is a RTK inhibitor which interrupts EGFR/HER1 and HER2/ErbB2 signalling and has been approved as a frontline therapy for triple-positive breast cancer and as an adjuvant therapy for patients who have progressed on trastuzumab. Erlotinib is used to treat non-small cell lung cancer and pancreatic cancer and is a RTK inhibitor targeting EGFR/HER1. Several other drugs targeting HER1, HER2 and HER3 are currently in development [17]. However, resistance to agents that target single HER family members can occur as a result of compensation by or upregulation of other HER family members [10]. Furthermore, the homodimerisation and heterodimerisation among members of the HER/ErbB family of receptors has implications for therapies directed against a single HER receptor [7].
The antagonist RB200 has been developed to target all four members of the EGFR family. RB200 is composed of the ECD of HER1/ErbB1 (amino acids 1 to 621) and HER3/ErbB3 (amino acids 1 to 621), fused with the Fc domain of human immunoglobulin G1 (IgG1) (HER1-HER3/Fc), and acts as a chimeric bispecific ligand trap. The HER3/Fc component of RB200 contains a 6×Histidine tag on the COOH terminal [18, 19]. RB200 has been shown to bind both HER1/ErbB1 ligands (EGF, TGF-α, HB-EGF, AR, BTC, EPR and EPG) and HER3/ErbB3 ligands (NRG1-α and NRG1-β3) with high affinity. Moreover, RB200 inhibited EGF-stimulated and NRG1-β1-stimulated tyrosine phosphorylation of HER family proteins (HER1, HER2 and HER3) in vitro and has shown potency in a variety of cell proliferation assays [18]. In addition, RB200 has been shown to inhibit tumour growth in vivo in two human xenograft (epidermoid carcinoma and non-small cell lung cancer) nude mouse models [18]. In parallel with these findings, we have shown that adenoviral delivery of a human EGFR family inhibitor, herstatin, significantly abrogated all clinical signs of collagen-induced arthritis (CIA) in mice [20]. Herstatin is an alternative splice variant of HER2/ErbB2 that retains intron 8, which results in the formation of an approximately 68 kDa protein. This protein disrupts dimerisation and serves as a natural inhibitor of native HER2/ErbB2 as well as HER1/ErbB1 and HER3/ErbB3 [21]. Thus, in addition to being well-validated targets for cancer therapy, HER-targeted treatments may have therapeutic potential across a range of autoimmune and inflammatory conditions, including RA.
In the present study, we explored the therapeutic effects of RB200 in combination with the TNFα inhibitor etanercept in murine CIA as a model of human RA. Our data demonstrate that RB200 potently reduced all measures of arthritis in CIA. Furthermore, when low-dose RB200 and etanercept were combined, there was complete abrogation of CIA. This was confirmed on the basis of in vivo E-selectin-targeted fluorescence imaging, which is a novel technique that we have shown can detect endothelial activation in CIA and delineate subclinical arthritis [22]. These data suggest that targeting EGFR-mediated responses in combination with TNFα may provide additional clinical benefit in patients with RA.
Materials and methods
Induction and assessment of arthritis
Type II collagen was extracted from bovine articular cartilage as previously described [19, 20, 23]. For induction of CIA, 12-week-old male DBA/1 (H-2q) mice (Harlan UK Ltd, Oxon, UK) received a single intradermal injection at the base of the tail of 100 μg of bovine type II collagen emulsified in complete Freund's adjuvant and Mycobacterium tuberculosis H37 Ra (Difco Becton Dickinson, Cowley, Oxford, UK). The animal work was conducted under Home Office Project Licence PPL 70/5446, 'Pathogenesis and therapy for RA', under the operatives of the Animals (Scientific Procedures) Act 1986.
The incidence of arthritis in each group of animals reached at least 80%. The earliest signs of disease were observed on day 14 after immunisation, with day 27 postimmunisation being the median day of arthritis onset. The first clinical signs of arthritis were considered to be present when oedema and/or erythema involving any one of the four paws was observed. Human TNF type II receptor fusion protein (etanercept) was obtained from Wyeth Pharmaceuticals, Taplow, UK, and RB200 was a gift from Dr Michael Shepard (Halozyme Therapeutics, San Diego, CA, USA). Control animals received equivalent volumes of PBS. The mice were treated intraperitoneally on the day of disease onset (day 1) and then on days 4 and 7 of disease with RB200 at the indicated doses. Control mice received intraperitoneal injections of either etanercept or equivalent volumes of PBS. The study involved four comparable experiments to test the efficacy of different doses of RB200. All treatments were administered in a blinded fashion.
Paw swelling was measured with 0- to 10-mm callipers (Kroeplin, Schluchern, Germany). Each limb was further assigned a clinical score as follows: 0 = normal paws and no clinical features of inflammation, 1 = slight oedema or erythema, 2 = pervading oedema or erythema involving the entire paw and 3 = pronounced oedema and erythema leading to incapacitated limb mobility.
Histological analysis
Hind paws were removed postmortem and sliced along the sagittal plane prior to fixation with 1% paraformaldehyde. Paws were decalcified for 14 days in 0.3 M ethylenediaminetetraacetic acid, and CD31 expression was examined by immunohistochemistry using anti-mouse CD31 antibody (MEC13.3 rat anti-mouse mAb; Pharmingen, San Diego, CA, USA). The sections were then incubated with biotinylated rabbit anti-rat antibody (1:400 dilution; Dako, Ely, UK), followed by avidin-biotin-peroxidase complex and diaminobenzidine-H2O2. Immunostained sections were counterstained with Harris's haematoxylin. As a negative control, rat IgG2a antibody was used (R35-95; Pharmingen). Scores were graded in a blinded fashion, and the criteria assessed were (1) proximity of CD31 staining to the joint, (2) strength of CD31 staining, (3) degree of infiltration of synovial cells into the joint and (4) overall status of joint architecture. Sections were further stained with haematoxylin and eosin as well as with toluidine blue. Each stained section was scored by a blinded observer for changes in the joint architecture using our previously described grading system [20, 24] as follows: 0 = normal, 1 = minimal synovitis and bone erosion limited to discrete foci, 2 = extensive synovial hyperplasia and some destruction of segments cartilage and bone and 3 = complete destruction of the joint architecture.
Fluorescence optical imaging in vivo
Anti-mouse E-selectin mAb (MES-1) was purified from a hybridoma cell line (a kind gift from Dr Derek Brown, UCB Celltech, Slough, UK) and conjugated to DyLight 750 near-infrared (NIR) fluorophore according to the manufacturer's instructions (Thermo Scientific, Loughborough, UK). For imaging studies, mice were anaesthetised with a mixture of isofluorane and oxygen prior to intravenous injection of 5 μg of antibody. Optical imaging was performed using a Kodak FX Pro multispectral fluorescence reflectance imaging device (Carestream Molecular Imaging, Rochester, NY, USA). Filters for excitation and emission were set to 730 nm and 770 nm, respectively. An identical imaging protocol (exposure time 60 seconds, 4× binning, F-stop 2.51, field of view 158.5, focal plane 9.4 mm) was maintained for all images as previously described [22].
Images were analysed by a blinded observer using the Kodak Molecular Imaging version 5.0 software program (Carestream Health, Rochester, NY, USA). A region of interest (ROI) created by an automated tool was determined around the inflamed or control paw. Mean ROI signal intensities are expressed as arbitrary fluorescent signal intensity units. Fluorescence greyscale images were artificially coloured for depiction purposes according a colour scale set to the highest and lowest levels of mean fluorescence intensity (MFI) (with red and purple indicating maximum and minimum light intensity, respectively). The fluorescence images were coregistered onto X-ray images taken concurrently.
Statistical analyses
The data were analysed using GraphPad Prism version 5.01 software (GraphPad Software, Inc, San Diego, CA, USA) using one-way analysis of variance (ANOVA) or two-way ANOVA as appropriate. Histological data were analysed by Χ2 test for trends.
Treatment of CIA with RB200 dose-dependently inhibited the increase in clinical score (Figure 1a) and paw swelling (Figure 1b). The mice were treated intraperitoneally on the day of disease onset (day 1) and then on days 4 and 7 of disease. RB200 at a dose of 0.1 mg/kg was ineffective, but 1 mg/kg and 10 mg/kg provided a significant benefit (P < 0.001 vs PBS for both paw swelling and change in clinical score). On day 10 of established disease, the mean increase in clinical score ± SEM from day 1 of arthritis in mice treated with either PBS or RB200 at 0.1, 1 and 10 mg/kg were 2.17 ± 0.54, 2.00 ± 0.73, 0.88 ± 0.74 and 1.14 ± 0.51, respectively (Figure 1a). There was also a reduction in hind paw swelling in RB200-treated mice (Figure 1b).
Mouse paws were taken on day 10 of arthritis, and frozen sections were cut and stained with anti-CD31 antibody. For each mouse, the metatarsal-tarsus joints of both paws were examined, and representative images from RB200- and PBS-treated mice are shown in Figures 2a through 2d. Joint sections of PBS-treated mice showed high numbers of infiltrating cells in the inflamed synovium, together with invasion and erosion of bone by the synovium, associated with marked CD31 expression. In contrast, joints from mice treated with 1 or 10 mg/kg RB200 were relatively protected, with generally normal appearance, well-preserved joint architecture and relatively few CD31-positive blood vessels. In addition, an overall subjective score between 0 and 3 was used to grade CD31-immunopositive staining. Analysis of mean scores for each treatment group showed there was a significant reduction in CD31 immunopositivity in mice treated with 10 mg/kg RB200 (P < 0.01) (Figure 2e).
Importantly, when a low dose of RB200 was combined with a suboptimal dose of the TNFα inhibitor etanercept (also given on days 1, 4 and 7 of arthritis), a marked beneficial response was observed, with the combination of 0.5 mg/kg RB200 and 1 mg/kg etanercept having a marked effect on both measures of disease activity in CIA (Figure 3). In this experiment, 0.5 mg/kg RB200 alone had no effect on paw swelling (P > 0.05 vs PBS-treated mice) and only a modest effect on clinical score (P < 0.01), whereas 10 mg/kg RB200 significantly, albeit not completely, reduced both parameters, in agreement with the experiment illustrated in Figure 1. Similarly, 1 mg/kg etanercept alone partially reduced clinical score and paw swelling (P < 0.001) (Figure 3). In contrast, the combination of low doses of RB200 and etanercept was significantly different from either low-dose etanercept alone (P < 0.001 for both clinical score and paw swelling) or low-dose RB200 alone (P < 0.001 for both clinical score and paw swelling). The effectiveness of the combination of 0.5 mg/kg RB200 and 1 mg/kg etanercept was comparable to that seen with the optimal dose of etanercept (5 mg/kg).
We further applied in vivo optical imaging to investigate the effect of RB200. Figure 4 demonstrates representative examples of fluorescence imaging with NIR dye-labelled anti-E-selectin antibody for representative mice. The images were coregistered with plain digital X-rays of arthritic paws. E-selectin-specific fluorescent signals were detected in both hind paws of animals with CIA (PBS-treated), but not in healthy (nonarthritic) mice. Fluorescent signals were also visible in the arthritic paws of mice that received low-dose etanercept alone or low-dose RB200 alone. These data further demonstrate that the combination of low-dose etanercept and RB200 has a marked effect in decreasing the E-selectin-targeted signal in animals with arthritis compared with either treatment on its own. Although both low-dose etanercept (1 mg/kg) and RB200 (0.5 mg/kg) had some overall therapeutic efficacy, it was only with combination treatment that there was complete abrogation of fluorescent signal.
Quantification of MFI over 24 hours in the different treatment groups is shown in Figure 5. For the purposes of clarity, the MFI signal returned from animals treated with either high-dose etanercept or RB200 are not included in Figure 5a but are included in Figure 5b. These data show that combination treatment returned the anti-E-selectin MFI to the levels seen in healthy animals that were not immunised against CIA (no significant difference by two-way ANOVA) (Figure 5a). Indeed the effect of combination treatment was significantly different from that seen with either low-dose etanercept alone (P < 0.01 by two-way ANOVA) or low-dose RB200 alone (P < 0.001 by two-way ANOVA). In a prior study we have demonstrated that E-selectin-targeted fluorescence imaging is able to detect subclinical levels of fluorescence in animals with a clinical score of 0 [22]. Here combination therapy involving low-dose RB200 plus low-dose etanercept abrogated fluorescent signal in all imaged paws to levels seen in healthy controls, whereas following treatment with either high-dose RB200 or etanercept, increased signal levels were evident in some of the paws (Figure 5b).
These data are supported by histological findings. Using serial sections stained with either haematoxylin and eosin or toluidine blue, we evaluated tibiotarsal joints for signs of synovitis and erosive changes to bone and cartilage. There were was a dose-dependent effect of both RB200 alone and etanercept alone on joint architecture, with progressively fewer severely destroyed joints and more joints with mild or moderate destruction (Figure 6). However, the most pronounced effect was observed when the combination treatment was used, with 64% joints appearing normal (score 0; P < 0.001 vs untreated by Chi squared test for trend) compared to 0% in mice that received low-dose RB200 alone (P > 0.05 vs untreated and P < 0.001 vs combination treatment) and 0% in mice treated with low-dose etanercept alone (P < 0.05 vs untreated and P < 0.01 vs combination treatment). Indeed the combination treatment was even more effective than high-dose etanercept alone (P < 0.05 vs combination treatment), highlighting the effectiveness of combined pan-EGFR and TNFα-targeted treatment in promoting joint protection.
Anti-HER2 antibody trastuzumab has revolutionised the treatment of patients with EGFR-positive breast cancer, and agents targeting EGFR/HER1 are in use for colorectal cancer therapy as well as for head and neck cancer. Interestingly, researchers in a number of studies have suggested that the family of EGF ligands and receptors may have a role in the development of RA. For example, expression of one of the primary ligands for EGFR/HER1, TGF-α, is increased at both the mRNA and protein levels in RA synovium [11]. High levels of another EGFR ligand, EGF, in RA synovial fluids have also been demonstrated. However, researchers in another study reported increased expression of AR, but not EGF, ERG, EPG, BTC, NRG1 or HB-EGF, at the mRNA level in RA compared to OA tissue. However, the reason for the discrepancy between this report and other studies is unclear [15]. Expression of HER2/ErbB2 in the synovium of RA patients has been described further [11, 12]. A treatment modality targeting EGFRs might therefore be an attractive option in immunotherapy for RA.
RB200 is a heterodimer of the HER1/ErbB1 and HER3/ErbB3 ECD [18, 25]. This prototypical bispecific ligand trap binds HER1/ErbB1 and HER3/ErbB3 ligands, inhibits proliferation of a broad spectrum of cultured cancer cells and suppresses growth of tumour xenografts in mouse models [18]. The efficacy of RB200 has been investigated previously in other in vivo models. RB200 inhibited EGF- and NRG1-β1-stimulated tyrosine phosphorylation of HER1, HER2 and HER3 and also showed potency in cell proliferation assays [18]. In addition, RB200 has been shown to inhibit tumour growth in vivo in two human tumour xenograft (epidermoid carcinoma and non-small cell lung cancer) nude mouse models [18]. Thus, in contrast to antibodies such as trastuzumab, RB200 has the potential to inhibit signalling by multiple EGFR ligands. In this study, we examined the effect of RB200 on established CIA, which has been widely used for in vivo testing of candidate therapeutics for RA, such as TNFα inhibitors [26, 27] and inhibitors of angiogenesis [23, 28, 29]. Moreover, we have previously reported that adenoviral delivery of the human EGFR family inhibitor herstatin significantly abrogated murine CIA [20], demonstrating that by blocking signalling downstream of HER2/ErbB2, HER3/ErbB3 was effective in CIA. In the current study, administration of RB200 produced a significant dose-dependent reduction in disease severity in CIA. Interestingly, RB200 showed effective therapeutic activity at doses as low as 1 mg/kg when administered three times in the 10-day period of arthritis. Indeed 1 mg/kg was not significantly different from 10 mg/kg (by two-way ANOVA), and higher doses of RB200 up to 15 mg/kg were no more effective (not shown). EGF has been reported to promote angiogenesis [30, 31], and there was also a significant reduction of CD31-immunopositive staining in RB200-treated mice, reflecting a reduction in synovial vessels. In comparison to controls, there was also normalisation of joint architecture in arthritic mice treated with RB200. These data suggest that inhibition of EGFR-mediated responses is of potential use for the treatment of RA.
The efficacy of combination treatment with low-dose etanercept and RB200 is of potential interest. A significant proportion of patients with RA do not respond to TNFα blockade, and therefore there is a compelling need to continue identification of alternative therapeutic strategies for chronic inflammatory diseases such as RA. Nonetheless, biological therapies, particularly those targeting TNFα, are an undoubted success in RA, and hence an approach combining TNFα inhibition with, for example, an inhibitor of angiogenesis or with an inhibitor of EGFR-induced events might be useful. Moreover, targeting such separate mechanistic pathways could be beneficial, unlike the combination of targeting IL-1 and TNFα, which has been shown to be proinfective [25]. In the present report, we demonstrate that low doses of the TNFα inhibitor etanercept plus RB200, though only modestly effective alone, completely abolished CIA to levels comparable to those observed following treatment with an optimal dose of etanercept.
We have also previously described the use of fluorescently labelled mAb against E-selectin to localise endothelial activation in inflamed tissues in vivo and have found this approach to be a sensitive, specific and quantifiable molecular imaging technique in CIA [22]. The combination of low doses of etanercept and RB200 resulted in complete abrogation of E-selectin-targeted fluorescent signal to levels seen in healthy controls and was more effective than 5 mg/kg etanercept. In fact, mice treated with 5 mg/kg etanercept displayed greater variability of MFI values, implying that disease activity may not have been completely abolished. We have previously shown a degree of fluorescent signal in mouse paws that had been given a clinical score of 0, suggesting that fluorescence imaging may be more sensitive than conventional scoring [22]. Imaging of mice treated with 5 mg/kg etanercept for 2 to 24 hours did in fact reveal that the MFI readings were significantly different (P < 0.01) from those in nonarthritic mice (not shown), whereas MFI readings for mice treated with etanercept plus RB200 were not significantly different from nonarthritic mice but lower than those treated with either low-dose etanercept alone (P < 0.01 by two-way ANOVA) or low-dose RB200 alone (P < 0.001 by two-way ANOVA). The in vivo fluorescence imaging data are supported by observations of normalised joint architecture in animals treated with etanercept plus RB200.
Our findings substantiate the hypothesis that combination treatment with low doses of etanercept and RB200 has a significant beneficial effect in CIA, although there are a number of shortcomings of this study, the most notable being the absence of mechanism of action studies to elucidate the mode of action of RB200 in CIA. In terms of a potential in vivo mechanism of action of RB200, angiogenesis is a key feature of RA [32], and indeed EGF has been reported to promote angiogenesis [30, 31, 33], in part through production of proangiogenic factors such as VEGF, IL-8 and basic fibroblast growth factor [13, 30, 34, 35]. Direct angiogenic effects have also been demonstrated in human microvascular endothelium in response to EGF or TGF-α [36–38]. Other EGFR ligands, such as NRG1-β3, have been reported to promote angiogenesis [39], and targeting EGFRs, alone or in combination with VEGF inhibition, has been shown to reduce angiogenesis in in vivo models [38, 40, 41]. Activation of EGFR signalling may also contribute to synovial hyperplasia in CIA, which is also a major pathological feature of RA that precedes clinical presentation and prevails throughout the disease [31]. This is suggested by a report that trastuzumab, which binds the HER2/ErbB2 receptor, inhibits RA synovial cell growth [12]. RB200 has the potential to inhibit responses to multiple EGFR ligands in CIA. Although inhibition of synovial angiogenesis or proliferation was not directly addressed in the present study, which is clearly a limitation in terms of understanding a possible in vivo mode of action, studies assessing whether synovial cell responses might be affected by RB200 are in progress. However, inhibition of synovial angiogenesis by RB200 could be implicated by the reduction in CD31-positive blood vessels, which we have demonstrated in CIA. Furthermore, EGF, when combined with proinflammatory mediators such as TNFα and IL-1, has been shown to increase expression by fibroblasts of matrix metalloproteinases (MMPs) such as MMP-1, MMP-3 and MMP-13 [42, 43] and to upregulate fibroblast proliferation [44]. Moreover, these responses were abrogated by a small-molecule inhibitor of HER2/ErbB2. It would be useful to examine whether RB200 modulates RA fibroblast responses in vitro, in particular by assessing MMP expression, as this would provide invaluable insight into how RB200 might affect CIA.
It is also unclear which of the many EGFR ligands RB200 inhibits in CIA. In addition to the presence of EGF in RA synovium [6], expression of TGF-α and AR has been described in RA [11, 15], and RB200 has been reported to bind to all of these ligands [18]. Interestingly, the pan-EGFR activity of RRB200 suggests that this molecule could offer additional benefit over approved treatments such as trastuzumab (a mAb that targets HER2) [45], cetuximab and panitumumab (anti-EGFR/HER1 antibodies), as well as inhibitors such erlotinib, lapatinib and gefitinib [46–48]. Resistance to these agents can occur as a result of coexpression and ligand activation of other HER family members [49–51]. Furthermore, homodimerisation and heterodimerisation among members of the ErbB receptors is known to occur [10], hence therapies directed against a single HER receptor are likely to be less effective [7], suggesting that agents such as RB200, which target multiple receptors, are desirable. Indeed the pleiotropic effects mediated by ligation of the EGFR family (for example, angiogenesis, inflammation and synovial invasion) and the expression of multiple EGFR ligands in RA suggest that pan-EGFR blockade is likely to have a broad beneficial effect in arthritis.
The studies described in this report demonstrate that the potent human EGFR HER1/HER3 ECD heterodimer RB200 has a significant abrogating effect in a mouse model of RA, namely, CIA. A recent case report described a patient with long-standing RA who had previously been treated with rituximab and adalimumab. This patient experienced a significant reduction in joint pain during treatment with anti-EGFR/HER1 antibody cetuximab for head and neck cancer [52]. Together with our data in murine CIA, these findings highlight the usefulness of targeting the EGFR family in RA.
However, cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment all likely contribute to the disease heterogeneity seen in CIA. This makes it unlikely that therapy directed at one abnormally activated signalling pathway, such as that downstream of EGFR activation, is likely to be sufficient [53]. Therefore, combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy, particularly given the increased risk of infection associated with some classes of biologicals [54–56]. Combination of RB200 with the TNFα blocker etanercept resulted in complete abrogation of arthritis, suggesting that HER-targeted therapies developed for the treatment of cancer may also be effective in RA.
analysis of variance
collagen-induced arthritis
epidermal growth factor
heparin-binding epidermal growth factor-like growth receptor
human epidermal growth factor receptor
- mAb:
monoclonal antibody
mitogen-activated protein kinase
matrix metalloproteinase
phosphate-buffered saline
rheumatoid arthritis
receptor tyrosine kinase
- TGF-α:
transforming growth factor α
tumour necrosis factor
vascular endothelial growth factor.
Feldmann M: Pathogenesis of arthritis: recent research progress. Nat Immunol. 2001, 2: 771-773. 10.1038/ni0901-771.
Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006, 295: 2275-2285. 10.1001/jama.295.19.2275.
Bongartz T, Warren FC, Mines D, Matteson EL, Abrams KR, Sutton AJ: Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials. Ann Rheum Dis. 2009, 68: 1177-1183. 10.1136/ard.2008.094904.
Furst DE: The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum. 2008, 39: 327-346.
Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X, Research Axed on Tolerance of Biotherapies Group: Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the Three-Year Prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009, 60: 1884-1894. 10.1002/art.24632.
Shiozawa S, Shiozawa K, Tanaka Y, Morimoto I, Uchihashi M, Fujita T, Hirohata K, Hirata Y, Imura S: Human epidermal growth factor for the stratification of synovial lining layer and neovascularisation in rheumatoid arthritis. Ann Rheum Dis. 1989, 48: 820-828. 10.1136/ard.48.10.820.
Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001, 2: 127-137. 10.1038/35052073.
Yarden Y: The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001, 37 (Suppl 4): S3-S8.
Shepard HM, Brdlik CM, Schreiber H: Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J Clin Invest. 2008, 118: 3574-3581. 10.1172/JCI36049.
Huang Z, Brdlik C, Jin P, Shepard HM: A pan-HER approach for cancer therapy: background, current status and future development. Expert Opin Biol Ther. 2009, 9: 97-110. 10.1517/14712590802630427.
Hallbeck AL, Walz TM, Briheim K, Wasteson A: TGF-α and ErbB2 production in synovial joint tissue: increased expression in arthritic joints. Scand J Rheumatol. 2005, 34: 204-211. 10.1080/03009740510017715.
Satoh K, Kikuchi S, Sekimata M, Kabuyama Y, Homma MK, Homma Y: Involvement of ErbB-2 in rheumatoid synovial cell growth. Arthritis Rheum. 2001, 44: 260-265. 10.1002/1529-0131(200102)44:2<260::AID-ANR42>3.0.CO;2-P.
Schreiber AB, Winkler ME, Derynck R: Transforming growth factor-α: a more potent angiogenic mediator than epidermal growth factor. Science. 1986, 232: 1250-1253. 10.1126/science.2422759.
Kameda H, Ishigami H, Suzuki M, Abe T, Takeuchi T: Imatinib mesylate inhibits proliferation of rheumatoid synovial fibroblast-like cells and phosphorylation of Gab adapter proteins activated by platelet-derived growth factor. Clin Exp Immunol. 2006, 144: 335-341. 10.1111/j.1365-2249.2006.03067.x.
Yamane S, Ishida S, Hanamoto Y, Kumagai K, Masuda R, Tanaka K, Shiobara N, Yamane N, Mori T, Juji T, Fukui N, Itoh T, Ochi T, Suzuki R: Proinflammatory role of amphiregulin, an epidermal growth factor family member whose expression is augmented in rheumatoid arthritis patients. J Inflamm (Lond). 2008, 5: 5-10.1186/1476-9255-5-5.
Di Cosimo S, Baselga J: Targeted therapies in breast cancer: where are we now?. Eur J Cancer. 2008, 44: 2781-2790. 10.1016/j.ejca.2008.09.026.
Johnston JB, Navaratnam S, Pitz MW, Maniate JM, Wiechec E, Baust H, Gingerich J, Skliris GP, Murphy LC, Los M: Targeting the EGFR pathway for cancer therapy. Curr Med Chem. 2006, 13: 3483-3492. 10.2174/092986706779026174.
Sarup J, Jin P, Turin L, Bai X, Beryt M, Brdlik C, Higaki JN, Jorgensen B, Lau FW, Lindley P, Liu J, Ni I, Rozzelle J, Kumari R, Watson SA, Zhang J, Shepard HM: Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. Mol Cancer Ther. 2008, 7: 3223-3236. 10.1158/1535-7163.MCT-07-2151.
Jin P, Zhang J, Beryt M, Turin L, Brdlik C, Feng Y, Bai X, Liu J, Jorgensen B, Shepard HM: Rational optimization of a bispecific ligand trap targeting EGF receptor family ligands. Mol Med. 2009, 15: 11-20.
Sumariwalla PF, Jin P, Zhang J, Ni I, Crawford D, Shepard HM, Paleolog EM, Feldmann M: Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen-induced arthritis. Arthritis Rheum. 2008, 58: 3071-3080. 10.1002/art.23885.
Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM: The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci USA. 1999, 96: 10869-10874. 10.1073/pnas.96.19.10869.
Gompels LL, Madden L, Lim NH, Inglis JJ, McConnell E, Vincent TL, Haskard DO, Paleolog EM: In vivo fluorescence imaging of E-selectin: quantitative detection of endothelial activation in arthritis. Arthritis Rheum. 2011, 63: 107-117. 10.1002/art.30082.
Bainbridge J, Madden L, Essex D, Binks M, Malhotra R, Paleolog EM: Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition. Arthritis Res Ther. 2007, 9: R127-10.1186/ar2340.
Sumariwalla P, Cao Y, Wu H, Feldmann M, Paleolog E: The angiogenesis inhibitor protease-activated kringles 1-5 reduces the severity of murine collagen-induced arthritis. Arthritis Res Ther. 2003, 5: R32-R39. 10.1186/ar608.
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P: Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004, 50: 1412-1419. 10.1002/art.20221.
Williams RO, Feldmann M, Maini RN: Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA. 1992, 89: 9784-9788. 10.1073/pnas.89.20.9784.
Williams RO, Mason LJ, Feldmann M, Maini RN: Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. Proc Natl Acad Sci USA. 1994, 91: 2762-2766. 10.1073/pnas.91.7.2762.
Jin P, Zhang J, Sumariwalla PF, Ni I, Jorgensen B, Crawford D, Phillips S, Feldmann M, Shepard HM, Paleolog EM: Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. Arthritis Res Ther. 2008, 10: R73-10.1186/ar2447.
Malik NM, Jin P, Raatz Y, Sumariwalla PF, Kiriakidis S, Shepard M, Feldmann M, Paleolog EM: Regulation of the angiopoietin-Tie ligand-receptor system with a novel splice variant of Tie1 reduces the severity of murine arthritis. Rheumatology (Oxford). 2010, 49: 1828-1839. 10.1093/rheumatology/keq163.
Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY: Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell. 1993, 4: 121-133.
Kumar R, Yarmand-Bagheri R: The role of HER2 in angiogenesis. Semin Oncol. 2001, 28: 27-32.
Paleolog EM: The vasculature in rheumatoid arthritis: cause or consequence?. Int J Exp Pathol. 2009, 90: 249-261. 10.1111/j.1365-2613.2009.00640.x.
Semino CE, Kamm RD, Lauffenburger DA: Autocrine EGF receptor activation mediates endothelial cell migration and vascular morphogenesis induced by VEGF under interstitial flow. Exp Cell Res. 2006, 312: 289-298.
Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997, 151: 1523-1530.
Ravindranath N, Wion D, Brachet P, Djakiew D: Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl. 2001, 22: 432-443.
Okamura K, Morimoto A, Hamanaka R, Ono M, Kohno K, Uchida Y, Kuwano M: A model system for tumor angiogenesis: involvement of transforming growth factor-α in tube formation of human microvascular endothelial cells induced by esophageal cancer cells. Biochem Biophys Res Commun. 1992, 186: 1471-1479. 10.1016/S0006-291X(05)81572-4.
Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M, Ono M: ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res. 2002, 62: 2554-2560.
Traxler P, Allegrini PR, Brandt R, Brueggen J, Cozens R, Fabbro D, Grosios K, Lane HA, McSheehy P, Mestan J, Meyer T, Tang C, Wartmann M, Wood J, Caravatti G: AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2004, 64: 4931-4941. 10.1158/0008-5472.CAN-03-3681.
Russell KS, Stern DF, Polverini PJ, Bender JR: Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol. 1999, 277: H2205-H2211.
Foy KC, Liu Z, Phillips G, Miller M, Kaumaya PT: Combination treatment with HER-2 and VEGF peptide mimics induces potent anti-tumor and anti-angiogenic responses in vitro and in vivo. J Biol Chem. 2011, 286: 13626-13637. 10.1074/jbc.M110.216820.
Wong TW, Lee FY, Emanuel SL, Fairchild CR, Fargnoli J, Fink B, Gavai A, Hammell A, Henley BJ, Hilt C, Hunt JT, Krishnan B, Kukral D, Lewin A, Malone H, Norris D, Oppenheimer S, Vite G, Yu C: Anti-tumor and anti-angiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families. Clin Cancer Res. 2011, 17: 4031-4041. 10.1158/1078-0432.CCR-10-3417.
Domeij H, Yucel-Lindberg T, Modeer T: Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. Eur J Oral Sci. 2002, 110: 302-306. 10.1034/j.1600-0722.2002.21247.x.
Huber LC, Kunzler P, Boyce SH, Michel BA, Gay RE, Ink BS, Gay S: Effects of a novel tyrosine kinase inhibitor in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 2008, 67: 389-394.
Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, Lee SH, Baik HH: Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-κB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2010, 30: 443-449. 10.1007/s00296-009-0976-6.
Shepard HM, Jin P, Slamon DJ, Pirot Z, Maneval DC: Herceptin. Handb Exp Pharmacol. 2008, 2008: 183-219.
Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM, Lackey K: The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res. 2001, 61: 7196-7203.
Diaz R, Nguewa PA, Parrondo R, Perez-Stable C, Manrique I, Redrado M, Catena R, Collantes M, Peñuelas I, Díaz-González JA, Calvo A: Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer. 2010, 10: 188-10.1186/1471-2407-10-188.
Nahta R, Yuan LX, Du Y, Esteva FJ: Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther. 2007, 6: 667-674. 10.1158/1535-7163.MCT-06-0423.
Britten CD: Targeting ErbB receptor signaling: a pan-ErbB approach to cancer. Mol Cancer Ther. 2004, 3: 1335-1342.
Sergina NV, Moasser MM: The HER family and cancer: emerging molecular mechanisms and therapeutic targets. Trends Mol Med. 2007, 13: 527-534. 10.1016/j.molmed.2007.10.002.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235: 177-182. 10.1126/science.3798106.
Sullivan T, Benjamin CG, Kempf PW, Deeken JF: Cetuximab in the treatment of rheumatoid arthritis. J Clin Rheumatol. 2010, 16: 32-33. 10.1097/RHU.0b013e3181c8e176.
Citri A, Yarden Y: EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006, 7: 505-516. 10.1038/nrm1962.
Cunnane G, Doran M, Bresnihan B: Infections and biological therapy in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2003, 17: 345-363. 10.1016/S1521-6942(02)00107-9.
Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, NIOBADASER Group: Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003, 48: 2122-2127. 10.1002/art.11137.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med. 2001, 345: 1098-1104. 10.1056/NEJMoa011110.
We are indebted to Professor Dorian O. Haskard (Imperial College, London, UK) for his support and advice regarding the in vivo imaging studies. We are grateful to the staff of the Biological Services Unit (Kennedy Institute of Rheumatology, Imperial College London, London, UK) for their help in the care and maintenance of the laboratory mice used in our studies and to Geethanjali Bahal and David Essex of the Histopathology Department, Charing Cross Hospital, London, UK, for the sectioning and staining of paw specimens. The Kennedy Institute of Rheumatology is supported by Arthritis Research UK. EMP, MF and LM were funded by a grant from Arthritis Research UK to the Kennedy Institute of Rheumatology. This work was sponsored by Receptor BioLogix Inc, Palo Alto, CA, USA (NMM). PJ and MS are former employees of Receptor BioLogix. LLG acknowledges the financial support of the Kennedy Institute of Rheumatology Trustees. The design, collection, analysis and interpretation of data were performed in collaboration by the Kennedy Institute and Receptor BioLogix.
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interests
PJ and HMS are former employees of Receptor BioLogix Inc and declare competing financial interests. MF and EMP have acted as consultants for Receptor BioLogix Inc. The other authors declare that they have no competing interests.
Authors' contributions
HMS designed the study. PJ assisted in the study design. LLG, LM and NMM performed all the experiments, data analysis and drafting of the manuscript. EMP and MF assisted in the study design and coordination and oversaw the data analysis and drafting of the manuscript. All authors read and approved the final manuscript for publication.
Authors' original submitted files for images
Below are the links to the authors' original submitted files for images.
Rights and permissions
About this article
Cite this article
Gompels, L.L., Malik, N.M., Madden, L. et al. Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade. Arthritis Res Ther 13, R161 (2011). https://doi.org/10.1186/ar3480
DOI: https://doi.org/10.1186/ar3480


text:
The White House's Fiscal Year 2019 budget proposal, released Monday, calls for work requirements for those who receive public housing subsidies and slashes funding for the Department of Housing and Urban Development by $8.8 billion.
The budget outline also zeroes out the Public Housing Capital Fund, dedicated to rehabilitating and modernizing public housing developments, and eliminates the Community Development Block Grant which local governments can use at their discretion to address a variety of community and infrastructure needs.
In a tweet, HUD Secretary Ben Carson pointed to a goal of "self-sufficiency."
The proposed budget is focused on moving more people toward self-sufficiency through reforming rental assistance programs and moving aging public housing to more sustainable platforms.
— Ben Carson (@SecretaryCarson) February 12, 2018
The budget underscores the administration's push for Congress to pass legislation to add work requirements to "require able-bodied individuals to shoulder more of their housing costs and provide an incentive to increase their earnings." It also wants "greater private sector involvement" to finance the revitalization of housing units.
The White House budget is non-binding but carries weight as a statement of the president's spending priorities. Just last week, Congress passed a two-year spending pact which Trump signed into law. In a budget addendum crafted after the bill's passage, the administration added $2 billion to its request for HUD. But even that addition would leave HUD's funding well below current spending levels.
The Trump administration's document calls for a 14.2 percent decrease from current levels, including cuts to to various rental assistance programs like the federal housing subsidy known as Section 8. The reason, according to the budget document, is "to address the increasing and unsustainable Federal costs of rental assistance."
"This is a harsh budget for housing programs that help low income families keep a roof over their head," said Will Fischer, a senior policy analyst at the Center on Budget and Policy Priorities.
HUD provides housing subsidies to about 4.7 million "very low income households," according to the the administration. Such subsidies make up about 80 percent of HUD's total budget.
The administration's changes exempt the elderly and the disabled. According to the Center on Budget and Policy Priorities, almost 90 percent of the households that "receive rental assistance through the Department of Housing and Urban Development (HUD) are elderly, disabled, working (or worked recently)."
Current rules require tenants receiving subsidies to pay at least 30 percent of their income on housing after deducting certain expenses such as medical and child care payments.
The Trump administration does away with those deductions and additionally calls to raise the floor to 35 percent "for all work-able households." The elderly and disabled would be exempted from these increases, as they are currently.
Diane Yentel, the president and chief executive officer of the , said her initial reactions to the budget were "shock and dismay." She said that rather than drastically reducing many of HUD's safety net programs, the administration should be moving to expand them
"His budget would mean more than 200,000 seniors, families, and people with disabilities could lose their rental assistance that they get today, putting them at immediate risk of evictions and potentially homelessness," Yentel said.
Copyright 2020 NPR. To see more, visit https://www.npr.org.

subset: commoncrawl


text:
Municipality puts wireless water meter-reading data to work
Town of Cary uses SAS® Analytics to analyze data from sensors, assess demand, detect problems and visually engage customers
A leaky faucet. A malfunctioning dishwasher. A cracked sprinkler head. These are more than just a headache for a homeowner or business to fix. They can be costly, unpredictable and, unfortunately, hard to pinpoint.
Through a combination of wireless water meters and an analytics-driven, customer-accessible portal, the Town of Cary, North Carolina is making it much easier to find and fix water loss issues. In the process, the town has gained a big-picture view of water usage critical to planning future water plant expansions and promoting targeted conservation efforts.
When the Town of Cary installed the wireless meters for 60,000 customers in 2010, it knew the new technology wouldn't just save money by eliminating manual monthly readings; the town also realized it would get more accurate and timely information about water consumption. The Aquastar wireless system reads meters once an hour – that's 8,760 data points per customer each year instead of 12 monthly readings. The data had tremendous potential, if it could be easily consumed.
"Monthly readings are like having a gallon of water's worth of data. Hourly meter readings are more like an Olympic-size pool of data," says Karen Mills, Finance Director for the Town of Cary. "SAS helps us manage the volume of that data nicely." In fact, the solution enables the town to analyze a half-a-billion data points on water usage and make them available, and easily consumable, to all customers.
Monthly readings are like having a gallon of water's worth of data. Hourly meter readings are more like an Olympic-size pool of data. SAS helps us manage the volume of that data nicely.
Karen Mills
Finance Director for the Town of Cary
The ability to visually look at data by household or commercial customer, by hour, has led to some very practical applications:
- The town can notify customers of potential leaks within days.
- Customers can set alerts that notify them within hours if there is a spike in water usage.
- Customers can track their water usage online, helping them to be more proactive in conserving water.
Through the online portal, one business in the Town of Cary saw a spike in water consumption on weekends, when employees are away. This seemed odd, and the unusual reading helped the company learn that a commercial dishwasher was malfunctioning, running continuously over weekends. Without the wireless water-meter data and the customer-accessible portal, this problem could have gone unnoticed, continuing to waste water and money.
The town has a much more accurate picture of daily water usage per person, critical for planning future water plant expansions. Perhaps the most interesting perk is that the town was able to verify a hunch that has far-reaching cost ramifications: Cary residents are very economical in their use of water. "We calculate that with modern high-efficiency appliances, indoor water use could be as low as 35 gallons per person per day. Cary residents average 45 gallons, which is still phenomenally low," explains Leila Goodwin, Water Resource Manager for the town. Why is this important? The town was spending money to encourage water efficiency – rebates on low-flow toilets or discounts on rain barrels. Now it can take a more targeted approach, helping specific consumers understand and manage both their indoor and outdoor water use.
SAS was critical not just for enabling residents to understand their water use, but also in working behind the scenes to link two disparate databases. "We have a billing database and the meter-reading database. We needed to bring that together and make it presentable," Mills says.
The town estimates that by just removing the need for manual readings, the Aquastar system will save more than $10 million above the cost of the project. But the analytics component could provide even bigger savings. Already, both the town and individual citizens have saved money by catching water leaks early. As the Town of Cary continues to plan its future infrastructure needs, having accurate information on water usage will help it invest in the right amount of infrastructure at the right time. Additionally, understanding water usage will help the town if it experiences something detrimental like a drought.
"We went through a drought in 2007," says Goodwin. "If we go through another, we have a plan in place to use Aquastar data to see exactly how much water we are using on a day-by-day basis and communicate with customers. We can show 'here's what's happening, and here is how much you can use because our supply is low.' Hopefully, we'll never have to use it, but we're prepared."
- Analyze a half-a-billion data points on water usage and make them available, visually, to all customers.
- Gain a big-picture view of water consumption to better plan future water plant expansions and promote targeted conservation efforts.
- Customers can know within days if they have a leak or other water-usage spike.
- Customers can set alerts to notify them immediately when their water usage exceeds a predefined amount.
- The town better understands how water is consumed.
- The town can identify when water is leaking in its network of pipes.
- The town can better prepare for future water needs and emergency events like a drought.


text:
The Final Score
(Play-by-Play #13)
by Jaci Burton
Kindle Edition, 352 pages
Published September 12th 2017 by Berkley
In the new Play-by-Play novel by the New York Times bestselling author of Rules of Contact, a star quarterback is torn between his love of the game—and the woman who may be the love of his life.
Nathan Riley is ready to follow in the footsteps of his famous football player father. He's been drafted as quarterback for his dad's former team, and his sports future is bright. When his friend Mia Cassidy moves to the same city, their years-long friendship suddenly sparks hot, reminding him of the one night they had together in college that he can never forget.
Like Nathan, Mia is from a sports dynasty family and embarking on an incredible new career—as founder of her own sports management company. Her friendship with Nathan means everything to her, and tossing sex into the mix again could jeopardize it all. But the chemistry between them has always sizzled, and it isn't long before Mia realizes she wants more with Nathan than just late-night talks and pizza.
Passion has a funny way of changing the rules, and soon Nathan and Mia realize that to win it all, they'll have to make an unexpected play for love.
A Play-by-Play Series


text:
A society not alert to signs of its own decay, because its ideology is a continuing myth of progress, separates itself from reality and envelops illusion. One yardstick by which to measure the decay in our country's political, economic, and cultural life, is the answer to this question: Do the forces of power, which have demonstrably failed, become stronger after their widely perceived damage is common knowledge?
Economic decay is all around. Poverty, unemployment, foreclosures, job export, consumer debt, pension attrition, and crumbling infrastructure are well documented. The self-destruction of the Wall Street financial giants, with their looting and draining of trillions of other people's money, have been headlines for two years. During and after their gigantic taxpayer bailouts from Washington, DC, the banks, et al, are still the most powerful force in determining the nature of proposed corrective legislation.
"The banks own this place," says Senator Richard Durbin (D-IL), evoking the opinion of many members of a supine Congress ready to pass weak consumer and investor protection legislation while leaving dominant fewer and larger banks.
Who hasn't felt the ripoffs and one-sided fine print of the credit card industry? A reform bill finally has passed after years of delay, again weak and incomplete. Shameless over their gouges, the companies have their attorneys already at work to design around the law's modest strictures.
The drug and health insurance industry, swarming with thousands of lobbyists, got pretty much what they wanted in the new health law. Insurers got millions of new customers subsidized by hundreds of billions of taxpayer dollars with very little regulation. The drug companies got their dream—no reimportation of cheaper identical drugs, no authority for Uncle Sam to bargain for discount prices, and a very profitable extension of monopoly patent protection for biologic drugs against cheaper, generic drug competition.
For all their gouges, for all their exclusions, their denial of claims and restrictions of benefits, for all their horrendous price increases, the two industries have come out stronger than ever politically and economically. Small wonder their stocks are rising even in a recession.
The junk food processing industry—on the defensive lately due to some excellent documentaries and exposes—are still the most influential of powers on Capitol Hill when it becomes to delaying for years a decent food safety bill, using tax dollars to pump fat, sugar and salt into the stomachs of our children, and fighting adequate inspections. Over seven thousand lives are lost due to contaminated food yearly in the US and many millions of illnesses.
The oil, gas, coal and nuclear power companies are fleecing consumers and taxpayers, depleting and imperiling the environment, yet they continue to block rational energy legislation in Congress to replace carbon and uranium with energy efficiency technology and renewables.
Still, even now after years of cost over-runs and lack of permanent storage for radioactive wastes, the nuclear industry has President Obama, and George W. Bush before him, pushing for many tens of billions of dollars in taxpayer loan guarantees for new nukes. Wall Street won't finance such a risky technology without you, the taxpayers, guaranteeing against any accident or default.
Both Democrats and Republicans are passing on these outrageous financial and safety risks to taxpayers.
Congress, which receives the brunt of this corporate lobbying—the carrot of money and the stick of financing incumbent challengers—is more of an obstacle to change than ever. In the past after major failures of industry and commerce, there was a higher likelihood of Congressional action. Recall, the Wall Street and banking collapse in the early 1930s. Congress and Franklin Delano Roosevelt produced legislation that saved the banks, peoples' savings and regulated the stock markets.
From the time of my book, Unsafe at Any Speed's publication in late November 1965, it took just nine months to federally regulate the powerful auto industry for safety and fuel efficiency.
Contrast the two-year delay after the Bear Stearns collapse and still no reform legislation, and what is pending is weak.
Yet the entrenched members of Congress, responsible for this astonishing gridlock, are almost impossible to dislodge even though polls have Congress at its lowest repute ever. It is a place where the majority is terrified of the corporations and the minority can block even the most anemic legislative efforts with archaic rules, especially in the Senate.
ulturally, the canaries in the coal mine are the children. Childhood has been commercialized by the giant marketers reaching them hour by hour with junk food, violent programming, video games and bad medicine. The result—record obesity, child diabetes and other ailments.
While the companies undermine parental authority, they laugh all the way to the bank, using our public airwaves, among other media, for their lucre. They can be called electronic child molesters.
We published a book in 1996 called Children First!: A Parent's Guide to Fighting Corporate Predators in the Media. This book is an understatement of the problem compared to the worsening of child manipulation today.
In a 24/7 entertained society frenetic with sound bites, Blackberries, iPods, text messages and emails, there is a deep need for reflection and introspection. We have to discuss face to face in living rooms, school auditoriums, village squares and town meetings what is happening to us and our diminishing democratic processes by the pressures and controls of the insatiable corporate state.
And what needs to be done from the home to the public arenas and marketplaces with old and new superior models, new accountabilities and new thinking.
For our history has shown that whenever the people get more engaged and more serious, they live better on all fronts.
Courtesy: Countercurrents
31 March, 2010
1 comment:
Congress has rude this country for most of the time muslims have voted for the congress most of the time. Sachcher Committee and Rang Nath Mishra Committee has concluded muslims are least developed. They have to ask each otheres for the answeres least they should ask for any reservation or special packages. My analysis is congress is a bad influance.
Subscribe to:
Post Comments (Atom)


text:
Usher Grilled in Court -- Did You Sleep with the Bridesmaid?
Usher Grilled in Court Did You Sleep with the Bridesmaid?
Screw soap operas, Usher's child custody trial has all the drama a lonely housewife needs -- 'cause his ex-wife's lawyer dropped a bombshell in court ... accusing him of sexing one of Tameka Foster's bridesmaids.
Usher was being cross-examined by Foster's lawyer yesterday in Fulton County court ... about his claim that Tameka brings nannies in and out of their children's lives.
Tameka's lawyer asked Usher if one of the nannies in question had "left Miami because you were discovered in bed with Maya Fox Davis?" Sources close to the couple tell TMZ Davis was a bridesmaid for Tameka ... and the alleged incident happened during their marriage.
Usher's attorney quickly objected, but you gotta watch the clip to see how it played out in court. There's also a contentious exchange between Usher and Tameka's lawyer regarding that whole spitting incident.
The trial is in recess, and will be back in session in July. Until then ... there's always "Revenge."


text:
When House Speaker Nancy Pelosi arrived late Tuesday night in Taiwan, its tallest building — iconic landmark Taipei 101 — lit up with words of welcome, blinking "Thank you" and "TW ♥ U.S."
While Pelosi's visit delighted people in Taiwan, it enraged Beijing and set the region on edge over what China might do in retaliation. From the Philippines to Singapore, countries are worried the status quo could turn from tension to conflict.
"What countries in this region know is that China cannot do nothing — it will look weak," says Singaporean veteran diplomat and academic Kishore Mahbubani. "China has no choice but to react," he says, adding, "at the same time, China doesn't want to start World War III."
China views Taiwan as a breakaway island that should be ruled by the mainland. The U.S. follows an intentionally vague "One China" policy, which views Taiwan as an independent entity that should eventually be integrated into China.
Pelosi has long been a critic of China and an advocate for Taiwan's democracy. She was the first House speaker to visit in 25 years, as U.S. officials generally avoid any moves that could touch off a military conflict — China versus Taiwan, and possibly, the U.S.
Southeast Asia especially feels the strain of living in the shadow of the U.S.-China rivalry. "Governments will be very cautious" talking about cross-Taiwan Strait relations, "for fear of how China will react," says Manila-based maritime expert Jay Batongbacal.
He says the region does not want to become "an arena of major power conflict," and countries would not like to be seen as taking sides.
For that reason, governments in Southeast Asia have stuck to mild statements about the importance of the U.S. and China avoiding "any miscalculation and further escalation of tensions," as the Philippines Foreign Affairs Ministry put it. Indonesia has called on "all parties to refrain from provocative actions that may worsen the situation."
China announced fresh live-fire drills in six locations near Taiwan within hours of Pelosi's arrival on the self-governed island of 23 million. Its military maneuvers have restricted air space and water routes around Taiwan, and an anxious region is watching.
Japan complained to Beijing that the area overlaps with its exclusive economic zone, while Taiwan called the move "a challenge to the international order."
The live drills — more aggressive than usual exercises — should have been anticipated, according to Dewi Fortuna Anwar, an analyst at the Indonesian Institute of Sciences, a government research agency. She calls Pelosi's trip "dangerously provocative" and says it came at a time when tensions were already high in the region.
Anwar says with Russia invading Ukraine, "We are all very nervous." The prospect of China moving on Taiwan, replicating events in Europe, looms over Asia, she says.
Anwar says the Taiwan visit by such a high-ranking U.S. official flouted the one-China policy that many countries adhere to when they conduct business with Taiwan, but refrain from sending their senior-most figures. "It's a matter of face for China," she says, and this "is spitting in their face."
Anwar questions what the endgame is for the United States: "Does it want an open war with China over Taiwan?"
Because war is so "unthinkable," says De La Salle University international studies professor Renato Cruz de Castro in Manila, regional governments don't tend to game out the geostrategic significance of Taiwan. His own government focuses instead, he says, on more manageable issues like how to evacuate the 142,000 overseas Filipino workers from Taiwan in the event of armed conflict.
Across the South China Sea, Beijing is flexing its muscle, accused of intimidating fishers, interfering with other nations' ships and occupying islands claimedby its smaller neighbors, including Vietnam and the Philippines.
Being "dragged into a U.S.-China conflict over Taiwan is pretty high on the list of anxieties for most U.S. allies and partners," says Gregory Poling with the Center for Strategic and International Studies. Pelosi's visit, he says "will be seen as, at best, unnecessarily risky to most regional governments."
That said, countries of the region "do not want the U.S. to seem a paper tiger" — which he says would only embolden further "bullying" by China.
But Batongbacal believes Pelosi's visit was neither reckless nor deserving of China's threat of military action, which he called "excessive" and "disproportional." Beijing, he says, is "hyping what should be a minor event."
Pelosi provided China "an opportunity to instigate" a confrontation, he says, and China's rhetoric sounded like "it was spoiling for a fight."
That's an outcome no one wants.
"There will be no winners in a military conflict," Anwar says. "We are much too integrated now. If you disrupt trade in the Taiwan Strait and the South China Sea, the whole economy of Southeast Asia will be destroyed."
Copyright 2022 NPR. To see more, visit https://www.npr.org.


text:
Josef von Sternberg, Merle Oberon and Charles Laughton |
The golden age of the television miniseries began in the mid-'70s - Rich Man, Poor Man was a sensation in 1976 and Roots made history in 1977. Classics like Shogun (1980), Brideshead Revisited (1981) and Winds of War (1983) soon followed. In 1976 the BBC's Masterpiece Theatre adapted Graves's historical fiction into a 12-episode landmark starring Derek Jacobi (Claudius), John Hurt (Caligula), Sian Phillips (Livia) and Patrick Stewart (Sejanus). An Emmy and BAFTA winner, I, Claudius debuted in the U.S. in 1977 and was, among other things, later acknowledged as inspiration for the blockbuster prime-time soap, Dynasty (1981 - 1989).
This year, in March, Acorn Media released a new boxed set edition celebrating the 35th anniversary of I, Claudius. Among the bonus features are extended original versions of episodes one and two, a behind-the-scenes documentary entitled I,Claudius: A Television Epic, an interview with Derek Jacobi and...a 70+ minute BBC documentary from 1965, The Epic That Never Was, about the unfinished Alexander Korda production of a Josef von Sternberg-directed film. This first version of the Graves novel starred Charles Laughton (Claudius), Merle Oberon (Messalina), Flora Robson (Livia) and Emlyn Williams (Caligula).
A sketch by Art Director/Production Designer Vincent Korda for I, Claudius |
In 1937 Korda, who would later marry Oberon, set out to produce a grand epic. In 1933 he had produced and directed The Private Life of Henry VIII, the popular film that brought Charles Laughton a Best Actor Oscar, and produced another great success in 1934 with The Scarlet Pimpernel starring Leslie Howard. Hungarian-born but based in Great Britain, Korda's dream was to make pictures in England that rivaled those coming out of Hollywood. With Henry VIII and The Scarlet Pimpernel, he'd begun to realize his dream but wanted to reach further. With Charles Laughton still under contract to him in 1937, Korda's ambition was to create a film greater than either Henry VIII or their most recent collaboration, Rembrandt (1936). Korda bought the rights from Robert Graves for the recently published I, Claudius, hired Josef von Sternberg to direct, and the project moved forward.
Charles Laughton as Claudius |
The Epic That Never Was is hosted by actor Dirk Bogarde, who recalls in his narration that as a teenager he ventured with friends to Korda's Denham Studios to watch the filming of I, Claudius. The documentary features interviews with many who worked on the film: Merle Oberon, Josef von Sternberg, Robert Graves, Emlyn Williams and Flora Robson, as well as Korda's longtime script girl and others. Only Korda and Laughton, no longer alive in 1965, are absent.
Merle Oberon as Messalina |
Flora Robson as Livia |
About 30 minutes of the 1937 production footage survives and is included in The Epic That Never Was; it is fascinating. Emlyn Williams is vile and reptilian as Caligula and Laughton's inspired Claudius foreshadows Jacobi's brilliant interpretation. As always, von Sternberg composed visually stunning, painterly scenes drenched in atmosphere.
Just a month into shooting, Oberon suffered a car accident in which she was thrown into the windshield. She was badly injured and filming was permanently halted. Emlyn Williams considered this "a godsend;" according to him, producer, director and star were not happy. Author Robert Graves, who had written an unused script for the project, assigned credit for the film's demise to Claudius himself - from beyond the grave...
John Hurt as Caligula, Derek Jacobi as Claudius, Sian Phillips as Livia |


text:
Layali White Nude Bardot Sweetheart Sequin Embellished Maxi Fishtail Dress
Next Day Delivery
Premium Elegant Luxe Detailed sequin fabric
Highly Embellished Stand-out Piece
Mermaid fishtail Maxi hourglass cut
Bardot off the shoulder sweetheart neckline
Symmetrical Stretch Fabric illusion booty hugging silhouette
Luxe Illusion sheer transparent inner fabric
Premium figure curve hugging fabric
Fitted & Stretchy Body
Inner stretch lining
Back Invisable zip
Length From Underarm Side Seam : 25"
Ideal For: Evening, Party, Cocktail Parties , events , vip , special occassion
Sku Code:Layaliwhitenude
UK & Worldwide Shipping over £75 FREE
UK 48h Tracked £4.50
UK Next Day £5.99
UK Saturday Delivery £7.99
Europe Tracked £10.99
Rest of the World Tracked £12.99
Worldwide Express (2-4 days): £30.00
We hope your shopping experience with us exceeds your expectation and that you will be delighted with your purchase.
Should you wish to return a product purchased from us, we will be happy to refund or exchange a product provided it is in fully resaleable condition. Returns should be made within a 14 day timeframe in original, undamaged packaging with all tags attached.
For more details please read our full Returns Policy.


text:
I'm pleased to announce that Supersonic Acrobatic Rocket-Powered Battle-Cars will be available today on the PLAYSTATION Network! I can say with some certainty that we are the first Unreal Engine 3 powered physics-based vehicle arena sports game available for PSN and we also might just have set the record for longest game title ever! Supersonic Acrobatic Rocket-Powered Battle-Cars lets you pick from seven cars and drops you into a high-flying, lightning-fast game of vehicle-based soccer. It also features Trophy support, custom music tracks, and YouTube support for uploading match replays.
We're really excited about getting online and playing you guys. One thing you might not have read much about is our extensive online feature set. If you're the competitive type, we have a full-fledged ranking and stats tracking system with scoreboards, and our matching system intelligently groups up players of similar skill to give you the best online experience possible. As your skill improves you can climb up the rankings and compete for the top spots on the scoreboards and maybe even win some prizes – we've got some great ideas for tournaments, but more on that in the weeks to come.
If you're more of a group player, we also have party system in which you can register a team with a unique name and then invite your PSN buddies to join it. You can then play together in ranked team matches and compete for the top spots on the Team scoreboards. We support four player split-screen both locally and online, so if you and three of your buddies want to take on the world with your own team, you can do that too!
We know how much you guys want more Trophies, so we made sure to include some good ones for you. They're split between single-player and online and I'll talk about just a few and how they fit into the game.
Champion – Beat the Tournament Mode
You can acquire this trophy by completing the tournament mode, a single player challenge that pits you against harder and harder groups of bots in Battleball matches. Sometimes you play alone, sometimes you have bots on your side, and sometimes you even have to start the match down a few points!
Hot Shot – Achieve the Most Valuable Player Award in an online ranked match.
After each match, we give out awards based on how each player did. The Most Valuable Player generally does a little bit of everything – scores goals, blocks shots, assists other players' shots, and maybe even demolishes a few of the opposing team in the process!
Showoff – Score a goal while reversing in an online ranked match
To win this trophy, you're going to have to learn how to shoot backwards! This can be a real challenge, especially in the competitive online environment, but it's a lot of fun to try and you can even save your replay and upload it to YouTube!
All Star – Earn All the Stars in Single-Player Mode
This trophy is your reward for completing all of our single-player challenges. Whether it's playing a game with a cardboard box instead of a ball, soaring high through the air to collect floating canisters, or scoring as many goals as possible in a short time, we've created a lot of fun challenges that will hone your skills for online ranked play.
Striker – Score 500 Goals in Online Ranked Matches
All I can say is this: anyone with this trophy is a Battle-Cars master.
The last thing I'll talk about is our replay system. Countless times in development we'd play a match and have something spectacular happen and wish we had an easy way to view it again and share it with friends. This inspired us to create a really powerful replay recording tool that you can use in-game to view, edit, and upload replays to share with other players.
Here's how it works: After each match you're given the option to save a replay of the entire game. From our replay manager you can view a list of your saved replays at any time. When you select one, you can choose to simply view it again, export it to YouTube, or export it to the XMB. When viewing or exporting, we give you full control of camera with the ability to focus on the ball or specific players, change angles, or go into slow-motion – just about anything you can think of, you can do it. On top of that, when you're exporting, we let you record clips however you want so you can do your editing right in-game! Of course, if you prefer, you can just export the whole thing to the XMB and edit it yourself with video editing software.
We also have a forum where you can watch for news on organized tournaments, ask us questions, post links to replays you've uploaded, or look for teammates. We'd love for you to check it out if you're interested.
The game is available today on the PLAYSTATION Network Store for $14.99 and we're making a demo available today as well, so please give it a try and we hope you enjoy it as much as we do!


text:
Wednesday, February 22, 2012
Alternative Entrepreneurs on Google Maps
Citizens in the Lab is a Google Map of interesting projects in new kinds of employment and social enterprises which embody "new values, cultural centres, galleries, projects and teams".
As an example of the kind of projects Citizens in the Lab is interested in they point to how Brixton Village in London was re-energised by young entrepreneurs and artists working together to revitalize a fading historic market. The map includes similar types of co-operative projects around the world.
If you know of any projects that are missing from the map you can add them by registering with CommunityWalk.
Subscribe to:
Post Comments (Atom)


text:
In this Part VI Tol and Green conclude that,
Table SPM.1 is wrong and misleading. It is wrong to suggest that emission reduction costs are independent of the assumed future developments. It is misleading to conclude that emissions can be substantially reduced at negative economic cost.Please have a look at their full discussion below. If you have questions or criticisms of their analysis please submit them in the comments, I am sure that Richard and Chris will be happy to engage.
Double Counting and Negative Costs
The first 5 parts of this series one of us (Tol) looked at Chapter 11 (Parts 1, 2, 3) and Chapter 3 (Part 4, 5) of the Fourth Assessment Report (AR4) of Working Group III (WGIII) of the Intergovernmental Panel on Climate Change (IPCC). Parts 4 and 5 looked at Chapter 3.
Here, we return to Chapter 11. The first and second order draft of the chapter and the review comments can be found here.
Chapters 4-10 assess the literature on emission reduction by sector (energy, transport, buildings, industry, agriculture, forestry, waste). Chapter 11 synthesizes that material, and is thus a key step towards the Summary for Policy Makers.
According to Table SPM.1, emissions can be reduced in 2030 by 5-7 GtCO2eq/yr at zero marginal costs (and thus a total benefit). This represents 7-10% of emissions in the A1B scenario (68 GtCO2eq/yr), and 10-14% of emissions in the B2 scenario (49 GtCO2eq/yr). That is, the ability to reduce emissions and make money at the same is independent of the no-policy scenario.
You can look at emission reduction in two different ways. First, you can take the present as your starting point. You would find that there are many opportunities to save energy. This is because state-of-the-art technologies are superior to the technologies that are actually in use (which were state-of-the-art when they were bought years or decades ago). Therefore, you would conclude that there are great opportunities to reduce emissions at low or negative costs.
You can also look at this from a different perspective. Energy efficiency has improved greatly in the past – without the support of climate policy – and this is likely to continue into the future. New and improved gadgets that will make people better off will be sold anyway. This is part of any reasonable projection of future emissions without climate policy. However, you would conclude that climate policy would push energy efficiency harder – and that this would cost money.
The two perspectives are equally valid, but they should be kept separate. The fuel efficiency of car engines does not improve by itself – engineers will need to make an effort. But they will make that effort because the buyer demands a bigger car with the same mileage. This does not constitute a low- or negative-cost option, let alone a success for climate policy – because it would also happen without climate policy.
Table SPM.1 mixes the two perspectives. The SRES scenarios A1B and B2 rightly assume substantial technological progress in the absence of climate policy. The results can therefore not be compared to the negative cost emission reduction potential. Table SPM.1 makes that comparison nonetheless.
Table SPM.1 even suggests that the negative cost potential is independent of such things as energy prices. The 2030 price of energy is higher in A1B than in B2. Therefore, more energy saving equipment would break even in A1B than in B2 – and the negative cost potential should be larger in A1B than in B2. It is not in Table SPM.1.
WG3 has no excuse for making a mistake like this. This issue has been known for at least 20 years, and was recently repeated in the "dangerous assumptions" paper by Pielke, Wigley and Green in Nature which rallied against the confusion between emission reduction by climate policy and by other forces.
How could this happen?
The First Order Draft of the Summary for Policy Makers does not have Table SPM.1 or anything like it. The Second Order Draft has a table which does show negative emission reduction costs – but only against a single scenario. Table SPM.1 is based on Table 11.3 in Chapter 11. Here is a comment on the Second Order Draft:Table 11.3 is sensitive to energy price developmentResponse:Table 11.3 provides alternative estimates of potentials for different carbon prices, but for specific baselines. Clearly the baselines are affected by the assumed energy prices, but it was not possible in the time available to undertake the comparison exercise using different baselines.Here's a comment on Table SPM.1:We have serious reservations about the validity and comparability of the underlying estimates from Chapters 4 to 10 […]because there is no demonstration that the estimated mitigation potentials have been evaluated properly with respect to the two baselines used for this analysis. The mitigation estimates in the SOD apparently do not take account of the technological changes already embedded in the SRES B2 and WEO 2004 reference scenarios against which the mitigation estimates were made ...Response:a fully consistent modelling framework is not available; that is why a scenario analysis was appliedSo, the authors of both the SPM and Chapter 11 were well aware that the results are problematic.
There was also this comment:The estimates of achievable mitigation (by 2030) presented in tables SPM-[1], TS-19, and 11-3, may not in fact contribute to mitigation from baseline. The estimated achievable emission reductions may be absorbed by the energy-intensity reductions and decarbonization embedded in the SRES B2/WEO (2004) baselines. If in fact estimated mitigation possibilities can truly contribute beyond that which is already embedded in the baseline scenarios, then that should be demonstrated in detail, not simply assumed.Response:Rej[ect]: mitigation potential is additional to what is included in baselineAnother comment (on Table 11.3):None of the discussion of mitigation potential […] belongs in an IPCC Assessment Report. […] Calculations of mitigation potential are only possible through application of a model that […] develops an explicit baseline […] and makes consistent assumptions about costs and performance of present and future technologies. There is an implicit model behind the original calculations presented in the chapter, but it is so simplistic and leaves out so many critical factors in estimating a marginal abatement cost curve that the results would not be accepted for publication in any reputable journal. I would be embarrassed as a chapter author to take responsibility for such flawed and naïve analysis in a report designed to be an assessment of the best research available. […] It likewise appears to assume that the same amount of mitigation be achieved at a given cost no matter what baseline emissions pathway is chosen – which clearly cannot be the case because the technologies assumed as mitigation measures may already be adopted in the baseline. Moreover, there is no demonstration that the estimated mitigation potentials have been evaluated properly with respect to either of the two baselines used for this analysis. The mitigation estimates in the draft apparently do not take account of the technological changes already embedded in the SRES B2 and WEO 2004 reference scenarios against which the mitigation estimates were made.Response:REJ[ect]: The dependence of the estimates on the baseline is recognized and allowed for.So, when the comment was gently worded, the IPCC authors admitted that the results are problematic – but no action was taken. When the same comment was raised in a less gentle voice, the IPCC authors simply denied the problem – and no action was taken.
Table SPM.1 is wrong and misleading. It is wrong to suggest that emission reduction costs are independent of the assumed future developments. It is misleading to conclude that emissions can be substantially reduced at negative economic cost.


text:
[Editor's note: After an internal review of this article, we have determined the author reached an unjustified conclusion about the Egyptian study. While the study did established an observed link between mercury exposure and autism symptoms, and while mercury-containing vaccines are one vector that can expose children to mercury (dental amalgams being another primary vector), the Egyptian study did not explicitly state or prove that mercury from vaccines caused autism, even though that explanation is a reasonable and factually-supported explanation given the fact that mercury is still found in vaccines administered to children. See this Natural News article for proof from the government of California. The Egyptian study, however, did not state that conclusion. Thus, the correct title for this article probably should have been, "Egyptian study links mercury exposure to autism symptoms; mercury in vaccines remains an exposure vector for children," which is what it has now been updated to reflect. The original title was "Egyptian study confirms autism is caused by mercury in vaccines," which is an incorrect conclusion. We are including both the original and updated title here in the interests of full transparency. We regret the error. The original story appears below, uncorrected, but should of course be read within the context of this editor's note which clarifies the issues covered by the study. Notably, the Egyptian study most certainly lends credence to the connection between mercury and autism, regardless of the exposure routes.]
Ever heard of metabolic brain disease? A team of nine scientists from top Egyptian medical schools and universities may have just confirmed that one in every 50 American children has it, and its primary cause could be mercury in vaccines.
How was this determined? Exposure to mercury can be measured by analyzing children's urinary porphyrins – excreted organic compounds that act as biomarkers for mercury toxicity. Not only does the presence of mercury in urine and blood expose the long-known link between metabolic brain disease (autism) and vaccines, but the severity of autism (and its broad array of symptoms) is directly correlated with the levels of exposure to this known neurotoxin. Yes, you read that correctly.
To put the nails in the coffin for any doubters or skeptics, of the 100 children studied, the 40 with autism spectrum disorder (ASD) had significantly higher mercury levels than their non-autistic siblings and the other healthy children in the study. In addition, the children with the most severe versions of metabolic brain disease revealed the highest levels of mercury exposure. For years and years, natural health enthusiasts have been screaming about the dangers of vaccines and mercury-loaded dental fillings, and now the truth comes out – and scientifically proven at that.
Six American studies have linked autism to mercury exposure by analyzing disordered porphyrin metabolism in autistic kids, but the mass media has been prohibited from publishing them or even discussing them at all because their sponsors are Big Pharma conglomerates. That is why you never hear anything about them on television, in newspapers or on mainstream media websites.
Another study published this past June was carried out by an international team of scientists who measured pro-inflammatory neuro peptides that indicate the presence of mercury in blood. The results showed a "positive linear relationship between mercury levels and the severity of autism symptoms."
The previously mentioned study done by the scientists from Egyptian medical schools included analyzing the mothers of autistic children who had multiple dental "silver" amalgams (mercury-loaded fillings), which the scientists said most likely contributed to the children's body levels of mercury. You could call these the "silver bullets" from the "smoking gun."
Special note: Ethyl mercury in thimerosal (used for vaccines, especially flu shots) is at least 50 times as toxic to human tissue as the methylmercury in amalgams and fish, and can prove to be twice as persistent in the brain. When mercury is injected into the blood and muscle tissue, it bypasses normal protective human filters, such as the lungs, digestive organs and the skin. This is also how mercury can cross the blood/brain barrier.
In 2015, a paper published in Behavioral Neurology by a group of researchers from the National Institute of Standards revealed results of a study of 100 autistic children with significantly high levels of mercury, lead and aluminum that may have resulted from environmental exposure. Aluminum is often also found in vaccines, and lead has been revealed to be in most U.S. tap water, sometimes at alarming levels (think of Flint, Michigan, here).
Detoxification by chelating agents could play a major role in improving the lives and mental and social capacities of children afflicted with metabolic brain disease. Remember, autism is a neurodevelopmental disorder that appears during infancy or childhood (not at birth), with a broad array of communication and learning impairments, from mild to moderate to severe. It is rarely, if ever, inherited, but rather brought on by an overload of neurotoxins either consumed, injected or ingested from environmental factors, or all of the above.
Mercury is the most toxic non-radioactive element on earth and the second most poisonous element known to mankind, second only to uranium, yet, for some reason, it's still used in vaccines as a preservative, even when there are several other options that are not toxic that would do the same job. It is scientific fact that human brain neurons permanently disintegrate in the presence of mercury within one hour of exposure. Thimerosal is a mercury containing preservative (about 50 percent mercury), and the World Health Organization warned about its use in vaccines way back in 1990.
Plus, mercury is a cumulative poison, meaning the body has difficulty removing it and it accumulates significantly over time. Some infants receive more mercury in one day than the WHO recommends as a maximum for adults for three months worth of exposure. One scientific fact most Americans do not know is that aluminum (listed as aluminum phosphate) in vaccines greatly increases the toxicity of mercury (listed as thimerosal), therefore caution about minimum mercury tolerance is severely underestimated.
Does the CDC mix vaccines with aluminum and mercury in combination? Absolutely. The Diptheria and Tetanus "toxoid" inoculations have "trace" amounts of mercury combined in the same vaccine with aluminum. What's in the whooping cough vaccine? Aluminum phosphate and formaldehyde. Mix that aluminum phosphate with a flu shot laced with mercury and measure the level (potency) of mercury and see what that does to the central nervous system and the brain. Remember, aluminum makes the vaccine more "powerful."
Since 2002, the CDC has been covering up the link between autism and the MMR vaccine. Dr. William W. Thompson, a senior scientist and epidemiologist at the US Centers for Disease Control and Prevention (Immunization Safety Branch) confessed to the vaccine-autism connection in a confession letter (an email Dr. Thompson wrote to officials at CDC via his attorneys). After being silent about the cover-up for over a decade, Dr. Thompson said he could no longer stand to look at parents whose children were suffering from autism and keep silent about the whole conspiracy, so he blew the whistle.
Sources for this article include:
Submit a correction >>


text:
Richard Rogers + Architects exhibition opens this week at the Design Museum
One of the most influential British architects of our time, Richard Rogers has established himself and his practice at the forefront of today's architectural culture through such high-profile projects as the Pompidou Centre, the Millennium Dome, the National Assembly for Wales and Terminal 5 at Heathrow Airport.
Just as his career journey launched in France and transported to the UK so too does The Richard Rogers + Architects – From the House to the City exhibition. The exhibition has been in Paris since November but comes home on Wednesday when it will open at the Design Museum.
The exhibition will present a detailed survey of Rogers' work. This spans the early years with Norman and Wendy Foster and Su Rogers at Team 4 in the 1960s and designing the Pompidou Centre with Renzo Piano in the 1970s, to the establishment and projects of the Richard Rogers Partnership – now Rogers Stirk Harbour + Partners.
Richard Rogers said: "The Design Museum is part of contemporary London's cultural revolution and one of my favourite museums. I am delighted that our work will be shown there."
The projects are arranged in colour-coded sections, with each 'urban block' evoking an architectural theme which examines a range of projects through new and archive models, photographs, drawings and films. In each thematic area – Transparent, Legible, Green, Lightweight, Public, Urban and Systems – projects that are particularly representative of that theme are explored.
Rogers' early career and influences are examined in an 'Early Work' section, and current projects by Rogers Stirk Harbour + Partners are featured in a 'Work in Progress' section. Richard Rogers + Architects – From the House to the City, curated by Nina Due and designed by Ab Rogers Design, will appear in the museum's first floor gallery, with additional installations in the Design Museum Tank, the café, and the ground floor atrium space.
Deyan Sudjic, Director of the Design Museum said: "Richard Rogers has had the most remarkable career in British architecture. Beginning with an extraordinary family house in Cornwall, then changing the shape of post-war architecture with the Pompidou Centre, and now heading up an international office that is busier than ever. The Design Museum is delighted to stage this important exhibition, the first of Richard Rogers' work in London since 1986."
architecture NOW
Tuesday, April 22, 2008
Richard Rogers + Architects exhibition, London, United Kingdom, London, United Kingdom
Subscribe to:
Post Comments (Atom)