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The matrix metalloproteinase (MMP) family of enzymes is comprised of critically important extracellular matrix remodeling proteases whose activity has been implicated in a number of key normal and pathologic processes. The latter include tumor growth, progression, and metastasis as well as the dysregulated angiogenesis that is associated with these events. As a result, these proteases have come to represent important therapeutic and diagnostic targets for the treatment and detection of human cancers. In this review, we summarize the literature that establishes these enzymes as important clinical targets, discuss the complexity surrounding their choice as such, and chronicle the development strategies and outcomes of their clinical testing to date. The status of the MMP inhibitors currently in US Food and Drug Administration approved clinical trials is presented and reviewed. We also discuss the more recent and successful targeting of this enzyme family as diagnostic and prognostic predictors of human cancer, its status, and its stage. This analysis includes a wide variety of human cancers and a number of human sample types including tissue, plasma, serum, and urine.
Matrix metalloproteases (MMPs) are a multigene family of zinc-dependent endopeptidases that share a similar structure and which collectively, have the capacity to degrade virtually every component of the extracellular matrix (ECM). The basic domain structure of MMP family members is provided in Figure 1. MMP activity is inhibited specifically and reversibly by a group of structurally related, endogenous inhibitors known as tissue inhibitors of metalloproteases (TIMPs). To date, four TIMPs have been identified: TIMP-1, -2, -3, and -4.1–3 The role of MMPs and TIMPs in tumor growth, metastasis, and angiogenesis has been widely investigated. We refer the reader to a number of comprehensive reviews on this topic4–7 as well as for a review of the general biochemistry of the MMP family.2,8,9 Based on their substrate specificity, MMPs have been divided into distinct subclasses: collagenases, gelatinases, stromelysins, and matrilysins. However, MMPs exhibit considerable promiscuity with respect to their substrates, leading to considerable redundancy in biologic functions as discussed below.
A related family of enzymes, the a disintegrin and metalloprotease (ADAMs), include integral membrane and secreted glycoproteins comprised of two subgroups: the membrane-anchored ADAMs10–12 and the secreted ADAMTSs (Fig 1).13 Like MMPs, some ADAM family members have a zinc binding consensus sequence at their catalytic site and display proteolytic activity. ADAMs are multifunctional enzymes involved in ectodomain shedding, regulation of growth factor availability, and in cell-cell/matrix interactions in both normal and pathologic states.10–12 Unlike the MMPs, a role for ADAMs in tumorigenesis has only now begun to be explored.
In most organs, the principle components of the ECM are collagens and numerous other proteins including laminin, entactin, and proteoglycans that make up the basement membrane. Tumor cells overexpress proteases and/or induce expression of these enzymes in neighboring stromal cells in order to degrade the basement membrane and invade the surrounding tissue. Several MMPs have been implicated in the ECM degradation associated with tumor growth and angiogenesis. This proteolytic activity is also required for a cancer cell to invade a nearby blood vessel (intravasation) and then extravasate at a distant location and invade the distant tissue in order to seed a new metastatic site (Fig 2).
ECM degradation products display unique biologic properties that can trigger a variety of cellular signals. For example, cleavage of collagen IV and laminin-5 generates cryptic peptides that can in turn promote migration of tumor cells.14,15 MMP substrates include non-ECM molecules, ranging from growth factor precursors and cell surface adhesion molecules to angiogenic inhibitor precursors (Fig 2). E-cadherin is cleaved by MMP-3, MMP-7, and ADAM10,16,17 leading to the release of soluble E-cadherin and the disruption of cell-cell interactions leading to disruption of cell adhesion and increase in migration. In addition, several integrins can serve as substrates for MMPs (Fig 2). For example, MT1-MMP can process pro-αv, -α5, -α3,18 a process that can contribute to αvβ5-mediated signaling and migration in breast tumor cells.19
MMPs have also been implicated in the epithelial to mesenchymal transition (EMT), a hallmark of cancer progression to metastasis.20 During EMT, tumor cells acquire migratory characteristics and more readily invade into surrounding tissues and metastasize to secondary sites. Activation of growth factors and cleavage of adhesion molecules are some of the proposed mechanisms underlying MMP-induced EMT. Proteolytic activation of latent transforming growth factor–β has been shown to be essential during MMP-28–induced EMT.21 MMP-3–induced EMT has been shown to be the result of E-cadherin cleavage22 and increased expression of an alternatively spliced form of Rac1b.23
Recent studies point to an emerging role for MMPs in modulating aspects of immunity and inflammation during tumorigenesis.24 Cytokine signaling is an integral aspect of inflammation. A variety of cytokines, cytokine receptors, and chemokines have been found to undergo MMP-mediated cleavage. For example, MMP-7 and/or ADAM17 activity is required for release of the proangiogenic inflammatory cytokine tumor necrosis factor (TNF) -α from its membrane-bound form. 25–27 In breast cancer, MMP-9 expression is upregulated in tumor-associated stromal cells including neutrophils, macrophages, and lymphocytes28 and may play a role in tumor-associated inflammation.
Several members of the MMP and ADAM family can regulate cellular proliferation by modulating the bioavailability of growth factors or cell-surface receptors (Fig 2). For example, the bioavailability of insulin-like growth factors (IGFs) is mainly regulated by IGF binding proteins (IGFBP). MMP-1, -2, -3, and ADAM12 cleave IGFBP-3,29–31 while IGFBP-1 is a substrate for MMP-11.32 Ligands for several growth factor receptors are processed by MMP/ADAM family members as well. Chief among them are the epidermal growth factor (EGF) receptor ligands: heparin-binding EGF (HB-EGF), amphiregulin, betacellulin, heregulin, and epiregulin. Normally, signaling via the EGF receptor (EGFR) pathway is tightly controlled. In cancer, as a consequence of increased shedding of active EGFR ligands and induction of constitutively active EGFR kinases, signaling through these pathways is upregulated, resulting in uncontrolled proliferation, migration, and survival of cancer cells. MMP-3, -7, ADAM17, and ADAM12 can proteolytically release HB-EGF allowing it to transactivate the EGFR33–35 and in turn promote tumor growth and angiogenesis.36 ADAM17 overexpression in breast cancer cells can lead to increased proliferation, migratory, and invasive capacity of cancer cells,37 properties that can be attributed in part, to the increased shedding of basement membrane transforming growth factor–α and amphiregulin in these cells.38,39
MMPs have been shown to promote angiogenesis through their release of angiogenic factors stored in the ECM such as vascular endothelial growth factor (VEGF)40,41 and basic fibroblast growth factor (bFGF; Fig 2).42 Stroma-derived MMP-9 can facilitate the liberation of ECM-sequestered VEGF during tumor angiogenesis.41 Similarly, cleavage of perlecan by MMP-1 and MMP-3 releases active bFGF.42
Angiogenesis is the formation of new blood vessels from a preexisting one. It is widely believed that a tightly controlled balance of pro- and antiangiogenic molecules regulates angiogenesis in tumors. MMPs play complex and sometimes conflicting roles in regulating angiogenesis. Remodeling of the ECM during angiogenesis is accomplished largely through the activity of MMPs.4,8,43 Angiogenic mitogens, such as bFGF and VEGF, can stimulate the production of MMPs by capillary endothelial cells.44,45 Studies have also demonstrated that MMPs are involved in the angiogenic switch, one of the earliest stages of tumor growth and progression. In a model of tumor progression which reliably recapitulates this switch, MMP-2 was shown to play an important role in the development of the angiogenic phenotype.46 It has also been shown that MMP-9 can be a regulator of the angiogenic switch in a pancreatic tumor model,41 further confirming the pro-angiogenic role of MMPs. These findings strongly suggest that MMP activity is critical, not only to the initiation of angiogenesis, but to the maintenance of the growing vascular bed, which in turn supports tumor growth and metastasis. MMP activity can, however, result in the production of negative regulators of angiogenesis as well. For example, MMPs have now been shown to cleave the parent molecules plaminogen and collagen XVIII into the cryptic, endogenous angiogenesis inhibitors, angiostatin47,48 and endostatin,49 respectively. These data underline the importance of MMPs as both positive and negative regulators of angiogenesis and cancer.
One of the more promising and exciting applications of MMPs in human cancers is as potential cancer biomarkers, both diagnostic and prognostic. Below we review their exploitation as tools for early detection, disease progression, and metastasis. We have specifically included those biomarkers for which validation studies have accompanied the preliminary discovery analyses (Table 1).50–96
Evidence is emerging that members of the MMP and/or ADAM family can serve not only as potential markers for diagnosis and prognosis, early detection, and risk assessment, but also as indicators of tumor recurrence, metastatic spread, and response to primary and adjuvant therapy for breast cancer. MMP-9 levels in tumor tissue as well as serum, plasma, and urine are significantly elevated in patients with breast cancer.51–53,71
We have previously reported that the detection of urinary ADAM12 in patients with breast cancer is predictive of disease status and stage and that ADAM12 protein levels in urine increase with progression of disease.55 Expression of a related enzyme, ADAM17, is significantly elevated in high-grade breast tumor tissue and correlates with shorter overall patient survival.56 Immunohistochemical (IHC) analysis of human breast biopsy materials have indicated that MMP-13 may be a useful prognostic indicator for invasive breast cancer. In this study, tumor-derived MMP-13, correlated with expression of Her2/neu and TIMP-1 and with aggressive tumor phenotypes and inversely correlated with overall patient survival.50
Recently, efforts have focused on the use of MMPs and ADAMs as potential biomarkers of early breast cancer. Studies from our laboratory indicate that urinary MMP-9 and ADAM12, in addition to being predictive markers for breast cancer, may also prove useful as noninvasive breast cancer risk assessment tools.97 Differential global gene expression analysis of tissue samples from patients with atypical ductal hyperplasia and a history of cancer versus patients with no history or who did not subsequently develop breast cancer indicated that MMP-1 mRNA and protein levels were upregulated in precancerous lesions.57 MMP-1 mRNA could also be detected in cells collected from nipple aspirates suggesting that MMP-1 might be useful as a diagnostic marker for screening atypical ductal hyperplasia to identify women with lesions that may eventually develop into cancer.57
Metastatic breast cancer involves the regional lymph nodes (LN) and liver or bone resulting in significant morbidity. Several independent studies have used circulating MMP-9 activity to predict metastatic spread of disease as well as to monitor patient response to primary and adjuvant therapy and to evaluate outcome.54,98 High levels of serum MMP-9 and TIMP-1 are associated with increased incidence of LN metastasis and decreased relapse-free and overall survival rates.51 MMPs may also be useful in predicting therapeutic efficacy. Plasma MMP-9 levels decrease after the surgical removal of primary breast tumors and a progressive decrease in plasma MMP-9 was observed in patients who responded well to adjuvant therapy.54 Importantly, in all patients who suffered a relapse of disease there was a gradual increase of plasma MMP-9 activity 1 to 8 months before the clinical diagnosis of recurrence.54 High MMP-14 mRNA expression (> 10% cells) in primary breast tumor tissue can also predict shorter overall survival.99
Nowhere is the need more urgent for sensitive and specific biomarkers for early diagnosis and to screen high-risk patients than in pancreatic cancer. This disease is extremely difficult to diagnose in its early stages due to a lack of specific symptoms and the limitations of current diagnostic methods. Several studies have evaluated differentially expressed biomarkers for pancreatic cancer using tissue, blood, or pancreatic juice. Serum and tissue levels of MMP-9 are significantly higher in patients with pancreatic ductal adenocarcinoma than in patients with chronic pancreatitis and healthy controls.58 Active MMP-2 levels are upregulated in the pancreatic juice of patients with cancer (100%) as compared with patients with chronic pancreatitis (2%) or normal controls (0%).59 Similarly, plasma as well as tumor tissues from patients with pancreatic ductal adenocarcinoma have significantly elevated MMP-7 levels60 which may predict shortened survival of patients.61
Of the ADAMs studied to date, only ADAM9 has been analyzed in relation to pancreatic cancer. IHC analysis of ADAM9 in tumor tissue samples indicated that an increased expression of this protease correlates with poor tumor differentiation and shortened overall survival.62
Several studies have reported that plasma and/or serum levels of MMP-9 and TIMP-1 are elevated in patient with stage III or IV lung cancer when compared with those in patients with nonmalignant lung diseases.63,64 Retrospective studies of non–small-cell lung cancer (NSCLC) tissue found that MMP-7 expression was higher in squamous cell carcinomas than in adenocarcinomas and correlated with significantly lower overall survival in patients.65 In a similar study that included 159 patients with stage III and IV NSCLC, MMP-7 status correlated inversely with overall response to chemotherapy. These findings suggest that MMP-7 expression in NSCLC may be a significant prognostic factor and could be predictive of response to chemotherapy and outcome. MMP-1 overexpression has been reported in lung cancer cells100 and DNA variants of MMP-1 have been linked to lung cancer risk and susceptibility.66 Several single nucleotide polymorphisms within the MMP-1 gene have been shown to be significantly associated with the risk of early-onset lung cancer in particular for subgroups with high smoking intensity.67
Studies of ADAM-type proteases as biomarkers for lung cancer are rare. One exception is ADAM28, whose levels were found to be higher in lung carcinoma tissue compared with healthy lung tissue and correlated significantly with tumor size and LN metastasis.101
As is expected, a majority of the biomarker studies in patients with bladder cancer have focused on urine. Studies from our group and others have shown that urinary MMP-2 and MMP-9 levels correlate with presence of bladder cancer as well as stage and grade of disease.69–73 We have recently reported the identification of several MMP species in urine from patients with primary tumors in the bladder and prostate including MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin complex and MMP-9 dimer.70 Each urinary MMP species was detected at significantly higher rates in urine from patients with cancer as compared with controls. The difference in detection of MMP species in the urine of the two types of cancers studied may serve as a tumor-specific fingerprint that can indicate both the presence of a tumor as well as its location.70 Increased levels of MMP-9 and MMP-2 in urine correlate with increased expression of these proteases in bladder tumor tissue as well.68 Urinary MMP-9 levels when combined with telomerase analysis of exfoliated cells from voided urine could also increase the sensitivity of cytology, a commonly used method for bladder cancer detection and monitoring.73 ADAM12 mRNA and protein were found to be upregulated in bladder cancer tissue and urinary ADAM12 levels were higher in patients with bladder cancer.102
MMP-2 and MMP-9 have been studied as potential prognostic biomarkers of colorectal cancer. A study of patients with Dukes' stages A to D colorectal cancer found that high levels of MMP-2, but not MMP-1, -7, and -13, in the malignant epithelium and stroma were associated with decreased survival.74 Elevated plasma MMP-2 levels have also been shown to correlate with lymph node metastasis.75 Enhanced MMP-9 staining in primary tumors was found to be an independent marker of poor prognosis in a study with T3-T4 node-negative patients.76 Plasma MMP-2 and MMP-9 levels were significantly elevated in patients with colorectal cancer and those with adenomatous polyps, and significant reduction in both were observed after tumor resections, suggesting their potential as markers for therapeutic efficacy.77 These MMPs may not be prognostic markers for tumor recurrence, however, since plasma proMMP-2 and -9 activities did not correlate with disease relapse after surgery.103
In addition to the gelatinases, serum MMP-7 levels were reported to predict decreased survival in patients with advanced colorectal cancer.78 A study of paired colorectal tumor and normal mucosal tissues revealed the significant correlation between MMP-1 levels and pathology (ie, Dukes' stage, tumor depth, and lymphatic invasion).79 MMP-13 activity was significantly elevated in tumor samples and the tumor to normal tissue ratio of MMP-13 activity significantly correlated with poor survival.80
MMP-2, -9, and -14 are among the most studied MMPs as biomarkers for ovarian cancer. MMP-9 activity in tissue extracts was significantly increased in advanced ovarian cancers (International Federation of Gynecology and Obstetrics stage III) compared with benign tumors and was found to be an independent prognosticator of poor survival.81 In another study of invasive epithelial ovarian cancer, high stromal expressions of MMP-9 and -14 were significantly correlated with cancer progression and were independent prognostic markers.82 Correlation with ovarian cancer progression has also been reported for MMP-282,104 and elevated levels of MMP-2 in cancer cells of peritoneal implants were associated with a significant risk of death in stage III ovarian carcinomas.83
Tissue MMPs have also been shown to distinguish different histotypes of ovarian cancer, which is a significant finding given that different histotypes have different prognoses.105 A recent study showed that more than 90% of clear-cell carcinomas expressed moderate to high levels of MMP-2 or MMP-14, compared with 30% to 55% of the other ovarian cancer histotypes (serous, endometroid, and mucinous), whereas MMP-9 was expressed more widely in other histotypes.84 Importantly, the cellular source of MMPs must be considered when evaluating MMPs as ovarian cancer biomarkers. For example, strong MMP-9 levels in cancer cells were associated with longer survival whereas strong stromal MMP-9 was associated with shorter survival, suggesting a dual role for MMP-9 during ovarian cancer progression.106
Among the ADAM family members, ADAM17 expression was significantly increased in both early and advanced ovarian cancer tissues and correlated with the expression of HB-EGF.85
MMP-2, -9, -15, and -26 expression in tissue or serum have been positively correlated with Gleason score in prostate cancer.107–109 Among these MMPs, the activities of plasma MMP-2 and -9 increased significantly in metastatic prostate cancer.86 Furthermore, overexpression of MMP-2 in cancer tissue was associated with shorter disease-free survival in a study with T3N0-2M0 patients.88 Analysis of MMP-2 and -9 levels in radical prostatectomy specimens revealed these two as significant predictors of cancer recurrence.87 These two enzymes may also be markers of therapeutic efficacy, since both the levels and activities of plasma MMP-2 and -9 decreased significantly in metastatic patients after therapy.86 In addition, increased urinary MMP-9 activity has been shown to distinguish between prostate and other types of cancer (eg, bladder cancer).70 MMPs can also be combined with other markers to increase their predictive capability. For example, the mRNA ratio of gelatinases (MMP-2 and MMP-9) to E-cadherin in biopsy samples independently predicted prostate cancer stage.110
ADAM8 levels in prostate cancer tissue have been significantly correlated with higher tumor status, positive nodal status, and higher Gleason scores.89 Higher ADAM9 levels were associated with shortened prostate-specific antigen relapse-free survival.90
Elevated tissue levels of MMP-2 and MMP-9 have been reported in aggressive brain tumors.91–94 Positive MMP-2 expression in tissue was also associated with shorter survival in patients with malignant brain tumors.92 Both latent and activated forms of MMP-2 and MMP-9 have been detected in the cerebrospinal fluid of patients with brain tumors.95 In studies of primary glial tumors and other CNS tumors, we have recently shown that detection of MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin complex, and/or VEGF in the urine predicted disease status and therapeutic efficiency of patients with brain cancer.96,111 Importantly, these studies showed that the upregulation of MMP-2 and -9 in the source tumor tissue was also reflected in CSF as well as in urine of these patients.
It is important to note that the measurement of MMPs in body fluids, in particular serum or plasma, can be influenced by the type of fluid and method of collection and storage. For example, basal MMP-9 levels in serum/plasma can be influenced by the use of EDTA or heparin,112 a problem that can be alleviated by using sodium citrate instead.113 Another issue to be considered is that of sample storage. For example, it has been reported that plasma MMP-9 is unstable and degrades rapidly even when stored at −80°C.114,115 This problem can be alleviated by storing samples in liquid nitrogen and analyzing them shortly after collection.
The context in which these or any other biomarkers are utilized in the clinic is a critical consideration. It has been suggested that, rather than being used as screening tools, MMPs might best be used to provide useful clinical information as part of a longitudinal assessment of a patient's disease progression and therapeutic efficacy with the patient himself/herself serving as an internal control.
Given the important roles that MMPs play in tumor growth, metastasis, and the dysregulated angiogenesis that drives them, there has been significant attention paid to the development of clinically useful antagonists of this enzyme family. There are a number of matrix metalloproteinase inhibitors (MMPIs) that are currently being tested in all three phases of clinical trials against a variety of human cancers (Table 2).116–119 The promise of this therapeutic approach has yet to be realized and the academic, pharmaceutical, and biotechnology arenas continue to debate the potential issues underlying the lack of therapeutic success in cancer treatment. Although certainly not in the majority, there have been some promising results from some clinical trials. For example, Neovastat administration resulted in a significantly longer median survival time in patients with refractory renal cell carcinoma in a phase II trial.120 However, in many cases, when there appeared to be positive results, the reports indicated that although biomarker levels decreased in the course of the treatment, positive clinical correlates were not necessarily observed.
Peptidomimetic MMPIs are pseudopeptide derivatives that mimic the structure of collagen at the MMP cleavage site.121 These substrate-based MMPIs are usually broad spectrum and block MMP activity by occupying the substrate-binding site and chelating the zinc with, in most cases, a hydroxamic acid functional group. The earliest generation of these inhibitors, including batimastat (BB-94), had low water solubility and was therefore not orally available. The next generation of hydroxamate-based inhibitors, such as marimastat (BB-2516), was designed to be orally available, however, they were commonly associated with musculoskeletal syndrome, probably due to their off-target effects on non-MMP metalloproteinases.122
To improve specificity, the current knowledge of the three-dimentional conformation of the enzyme active site has been incorporated into the design of MMPIs. These structure-based inhibitors include tanomastat (BAY 12-9566; Bayer Corporation, West Haven, CT), prinomastat (AG3340; Agouron Pharmaceuticals, La Jolla, CA), and BMS-275291 Bristol-Myers-Squibb, New York, NY. Some of these inhibitors also contain hydroxamic acid group to chelate zinc, such as prinomastat. Musculoskeletal toxicity has also been reported in clinical trials with prinomastat and BMS-275291.123,124 These MMPIs, while not as broad spectrum as the substrate-based MMPIs, still target several enzymes with similar potency. New structure-based inhibitors targeting a single MMP have been described for MMP-12 and -13.125,126
Another group of MMPIs are the chemically modified tetracyclines (CMTs), which do not possess antibiotic activities.127,128 CMTs may inhibit MMPs by binding to the key metal ions, such as zinc and calcium, or by regulating MMP transcription.129 CMTs used as MMPIs include metastat (COL-3), minocycline, and doxycycline.
Novel mechanism-based MMPIs have also been reported.130 One of the first of such inhibitors, SB-3CT, was designed to be highly selective for gelatinases. It covalently binds to the active site of MMP-2 and restructures the enzyme back to its proenzyme state.131 It reduced liver metastasis and increased survival in an aggressive mouse model of T-cell lymphoma.132 A new variant of this inhibitor class further improves the specificity by exclusively targeting MMP-2.133
Several small molecule inhibitors targeted specifically to the ADAM family of enzymes have also been recently evaluated.134–136 Of these, INCB7839 (Incyte Corporation, Wilmington, DE), a sheddase inhibitor, is currently in phase II clinical trials against breast carcinoma and several other solid tumors. Such inhibitors could prove to be particularly useful in targeting tumors dependant on EGFR signaling either as single agents or in a synergistic manner with currently approved tyrosine kinase inhibitors. Notably, unlike the first generation MMPIs, INCB7839 did not induce musculoskeletal adverse effects in initial animal studies.136
Far less attention has been given to the issues limiting the use of the TIMPs in the clinical setting, with the key limitations being the difficulty in the large scale production of biologically active protein and optimization of drug delivery. Just as is the case with their cognate enzymes, the TIMPs have also now been shown to be multifunctional proteins with activities independent of their MMP inhibitory ones.4,137,138 Interestingly, there may be significant clinical potential in exploiting these non-MMP activities in that this strategy might permit circumvention of the limitations associated with the targeting of MMP inhibition alone.
The road to clinical use of MMPIs has not been straightforward. The reader is referred to a number of recent reviews for an extensive analysis of the design, development, and complexities that have slowed and limited the creation and mobilization of MMPIs into the clinic.139,140 Several reasons might explain the unfavorable clinical outcomes in some of the MMPI clinical trials in various cancer types. Firstly, adverse effects, including musculoskeletal syndrome, have limited the maximum-tolerated dose of the early generation of MMPIs, thereby limiting drug efficacy. Secondly, the best window for MMPI treatment may have been missed in patients recruited in the trials who are often at the most advanced, metastatic stage of cancer. In addition, the nonspecific nature of the inhibitors has negatively impacted the therapeutic efficacy of these inhibitors due, at least in part, to the wide range of MMPs and physiological events affected.
As is the case for many anticancer drugs, MMPIs may actually be more effective when administered at earlier stages of cancer progression rather than when a patient is suffering from end stage disease having experienced failure with all other conventional therapies. Therapy at an earlier stage in disease progression might also afford the opportunity to use lower doses of drug thereby perhaps limiting the toxicity that has so hampered these trials. Interestingly, Hanahan et al141 demonstrated that MMPIs (in this case the broad spectrum, hydroxamate-based BB-94) would be most useful when tested in the very early stages of tumor progression, in the RIP1-Tag2 model of pancreatic carcinogenesis, such as at the time of the angiogenic switch.
As discussed earlier, MMPs can be multifaceted during cancer progression. Several MMPs have been shown to be protective against cancer. Tumor progression in various animal models has been inversely correlated with the expression status of MMP-3, -8, and -12.142–144 In human studies, MMP-12 overexpression in the tumor has also been associated with more positive prognosis.145 Importantly, the same MMP may play an opposite role at different stages of cancer progression. For example, a study with a transgenic mouse model of invasive squamous cell carcinoma suggested that MMP-9 stimulates proliferation during the early stages of cancer but restricts further malignant progression at later stages.146 For many of these MMPs, it remains unclear exactly which effect, positive or negative, they are exerting and these effects can vary as a function of different cancer types and different stages of disease.147
The mechanisms underlying the putative protective activities of MMPs are not fully understood. One potential mechanism may be the processing of antiangiogenic factors (cryptic angiogenic inhibitors) from inactive parental proteins.47–49,148,149 Another possible mechanism is the participation of MMPs in the host defense against a tumor143,150 by modulating the activities of chemokines and cytokines.151
Another major challenge in developing MMP-targeted therapy is the accurate evaluation of MMPI efficacy in vivo. To overcome this hurdle, a MMP-2-sensitive imaging probe has been studied which contains a MMP-2 peptide substrate and quenched near-infrared fluorochromes.152 Fluorescence is detected when the peptide is cleaved by active MMP-2. A significant reduction in probe fluorescence in implanted tumors was detected in live mice treated with MMPI prinomastat. These noninvasive imaging techniques make it possible to evaluate the therapeutic efficacy of MMPIs in patients and may also be used to monitor MMP activity at different stages of cancer progression. Taken together, such techniques provide insight into the functions of MMPs in cancer and may lead to effective MMP-targeting therapeutics.
The authors gratefully acknowledge Kristin Johnson for graphics assistance and Susan Connors for her contributions. Due to space constraints, we have in some cases been forced to cite review articles as opposed to the original articles.
Supported by Grants No. R01 CA118764 and P01 CA45548 from the National Institutes of Health, and by the Ellison Foundation.
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Roopali Roy, Predictive Biosciences, Inc. (C); Marsha A. Moses, Predictive Biosciences, Inc. (C) Stock Ownership: Marsha A. Moses, Predictive Biosciences, Inc. Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Roopali Roy, Jiang Yang, Marsha A. Moses
Financial support: Marsha A. Moses
Manuscript writing: Roopali Roy, Jiang Yang, Marsha A. Moses
Final approval of manuscript: Roopali Roy, Jiang Yang, Marsha A. Moses
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Discussion in 'Virtual Console, WiiWare and DSIWare' started by cif, Apr 3, 2007.
Why not?
Wow, didn't even think about that. Why not? Ninty could do it, im sure, but seeing ho much trouble they are having with the current vc (or their marketing strategys) they could take a while to get out. But it should be feasable. Great idea! :thumbsup:
I would vote for GB and GBC but GBA games yet, aren't people still making GBA games that could hurt sales for the actual system. Once the GBA model is retired I would love to see this though.
good point
Yeah Nintendo always have seemed to support playing hand-held games on their console so I'd say the chances are pretty good.
That'd be great. I'd love to play Pokemon Red and Blue on the Wii.
I tould be nice, at least GBC-GBA, I had a GBC myself, I didn't like the fact that it wasn't backlit, but having a color portable gaming system was amazing, for that time, now I expect it, but I always loved playing GEX enter the geko, that was such a sweet game
i was just thinking that Nintendo should make Game Boy games on the VC. It would be really awsome!
Yeah, remember the Super Gameboy that let you play GB games on your SNES? I can see them doing a similar format for offering GB/GBC games. Though i doubt they'll start bringing over GBA games until that market is completely eclipsed by the DS.
But i wonder what the pricing scheme would be given the games currently offered... 500 points for GB/GBC? or would it be less given the black/white or limited color range of those games and smaller graphics/resolution.
Have you guys ever seen GB/GB color games on a normal TV
They dont work to well
There designed for the small screen
It be better if you can download them onto the wii then transfer them across to the DS and store them on a official gba flash cart
Now thats a superb idea.
Actually that would be horrible..too much work.. what would be good is a VC for DS.. but then again dosent DS already play all the old cartriges???
If the games looked ok on wii from the hand helds then it would be OK but apparently the they dont translate too well to th big screen
I'd race to buy the Zelda games for any of the GBs. I lost interest having to play on the mini screen.
I like handhelds the way they are. I dont think id buy them on the vc if they were in it.
You cant play GB/gbc games on the ds (I have tryed)
Besides the cart sticks out
Also if they where about 200 wii ponits each id be interseted
What does it say? I mean it has to do something, does it say there is no game inserted or that the media is not compatible? I do not know this being I have not gotten my DS, I should be recieving it in about 2 hours
Not to mention, my brother's GBA played classic games even though the cart stuck out (used to be my GBA, I gave him my GBA when I got my PSP)
Cartridges sticking out shouldn't be a problem. You can play old gameboy games on the gameboy player for the gamecube and they stick out a lot. Kinda wish Nintendo would have a gameboy player for the wii though.
They dont fit and nothing comes up on the main screen
Edit :
Heres a method of playing GBA games on the wii WITH OUT down loading
It useies the carts (the links for the divice are dead but you might be able to find them on ebay)
I found it on a HB site that I know of
I say just Gameboy and Gameboy Color. Reason is, they don't work on DS and pretty much history. GBA is a no, people still buy them.
With this method you could possibly play GB/gbc games as well

subset: commoncrawl


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Bespoke Real Estate Solution?s management embraces challenges and view obstacles as opportunities to think differently towards a common goal. They evaluate each individual real estate project with the knowledge that they are affecting the lives of people and families along the way.
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Bespoke Real Estate Solutions LLC purchases distressed properties and helps homeowners to successfully overcome real estate related problems. They buy properties in the areas of Broward, Palm Beach, and Martin County in any condition.
Types of properties include:
- Vacant Homes
- Fire Damage
- Bad Tenant(s)
- Repairs Needed
- Divorce
- Estate Sale(s)
- Behind on Payments
- Absentee Owner Properties
- Wholesale Properties to Investors
Julie Ann Probst and Michelle Rey Lutein close quickly and handle all of the necessary paperwork with local title companies. Headquartered in Jupiter, FL, Bespoke Real Estate Solutions is becoming one of Florida?s leading firms specializing in real estate solution services.
Media Links:
Facebook Company Page: https://www.facebook.com/Bespoke-Real-Estate-Solutions-1672418086304960/timeline/
To learn more about Bespoke Real Estate Solutions please contact:
Rockwell Global Media
For the original version on PRWeb visit: http://www.prweb.com/releases/JulieAnn/Probst/prweb13013801.htm


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Drunk without drinking?
HEALTH It seems whenever someone with celiac disease restricts himself from gluten, he becomes an excited advocate, inferring that no one should eat gluten. This is transferrence of a personal disease. The Paleo diet is a recent fad that restricts carbohydrates. But here's a new reason why some might need to cut the carbs.
If you find yourself falling down drunk after a beer and pretzels or perhaps after having a turkey sandwich with chips, your gut might be secretly sneaking a drink. A rare medical condition is called auto-brewery syndrome or intoxicating gut syndrome. It causes a gastrointestinal organism called Saccharomyces cerevisiae to convert carbohydrates to fermented yeast. It's like having your own internal brewery. If you're not ready to eliminate all pasta, burgers and fries from your diet, the antifungal drug fluconazole is capable of killing Saccharomyces cerevisiae in the gastrointestinal tract.
- Drunk without alcohol: Auto-brewery syndrome ferments food in gut. Gwen Gowen, et al. via 20/20, thedenverchannel.com
- Rare Condition Causes People to Brew Beer in Their Own Belly. gawker.com
- Auto-brewery syndrome. wikipedia.org


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Manipal: Two riders from Kunjalu were injured when a Mahindra Bolero pick-up vehicle collided with the bike they were riding at the Press Corner here.
Sachin and his elder brother Gururaj were riding their Honda Activa scooter were injured in the mishap.
It has been blamed on the rash and negligent driving on the part of the pick-up driver. A case has been registered at the Manipal police station.


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How one visual artist had to fall out of love with his work to find his own style.
By Dave Benton
Behance members weigh in on why carving out your own artistic voice is the most important thing you can do as a creative. It's defensible, something you can lean back on regardless of trends and something you can sell that others can't. The ultimate goal is artistic expression, and not necessarily artistic perfection.
By Matt McCue
How 3D artist Nick Campbell (aka Greyscalegorilla) built his career (and a small business) on teaching.
A design original speaks out on the importance of being surprising, shocking, and outrageous.
Side projects aren't a waste of time, as long as you undertake the right ones.
Pick up another creative habit and see your main hustle in a whole new way.
By Srinivas Rao
Because nobody likes cold calling.
By Monika Kanokova
Reinventing yourself isn't just a stunt, it's required to survive.
By Elizabeth Grace Saunders
Our survivor's guide on how to navigate your first project with a large brand. How big? Apple big.


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Georgian restaurant Tamada is conveniently located in London's north west area of St. John's Wood. We are on Boundary road, which is just off Abbey road. There are various parking bays in front of the restaurant for guest's disposals. Alternatively you can park for free on numerous residence bays after 18.30.
Georgian restaurant Tamada is only a short walk away from Kilburn High Road, Swiss Cottage or St. John's Wood tube stations.
Restaurant Tamada is also very close to bus stops, which are served by busses 139 and 189. Plan your route with Google maps or use the map provided underneath to see where the restaurant is.
Georgian Restaurant "Tamada" serving authentic Caucasus cuisine in London
and offers wines from the Cradle of wine making.


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A successful method for deterring rainwater intrusion into walls is the rain screen approach. You have probably seen them before-even a rain fly over a tent is a simple example of rain screen. Rain screens shed most of the rain and manage the rest, preventing moisture intrusion and the resulting ...Download Now
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This document discusses about Electrochromic windows, which can block the glare of the sun or provide instant privacy with the flip of a switch. Electrochromic windows are part of a new generation of technologies called switchable glazing-or "smart" windows-which change the light transmittance, transparency, or shading of windows in response ...Download Now
Energy-Efficient Interior Storm Windows
Homeowners are usually interested in lowering their energy expenses. However, they are not willing to pay large costs or sacrifice the appearance of their home to do so. Interior storm windows provide a compromise by effectively increasing the energy performance of a home by updating single-pane windows at significant cost ...Download Now
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Windows are no longer simple panes of glass, but have evolved into complex engineered systems. Recent innovations such as double-glazed, gas-filled windows provide greater insulating value and improved energy efficiency, a benefit for windows used in any climate. New and widely used low-emissivity (low-e) coatings may be applied to glass ...Download Now
In areas prone to earthquakes and high winds, codes for shear wall design now require builders to use let-in bracing or costly plywood site-built assemblies. Two manufacturers are now helping to streamline construction of shear walls by providing pre-manufactured modular products that are cost effective and easy to design, specify, ...Download Now
Energy Efficiency in Remodeling: Windows
This fact sheet is intended to provide you with information about windows -- the factors that affect their energy performance, available options, and potential savings and other benefits associated with better windows. In older homes, windows are often one of the largest sources of heat loss in winter due to ...Download Now
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Convenient and effective artificial lighting is one of the important advances of the 20th century. Artificial lighting allows us to work and play inside and outside our homes independent of the time of day, and also often serves aesthetic purposes. Artificial lighting is generally employed for three types of uses: ...Download Now
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If you've ever admired an old, unpainted barn that has survived 100 years or more of weather, it's easy to wonder why you should use a finish on your home. However, the cracks, fissures, and air spaces that give weathered barn siding its character wouldn't be acceptable on most houses. ...Download Now


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NEW YORK YANKEES Men's Solid Sweep Sleep Pants
Style# 2010830
$34.99 $27.99
Style# 2010830
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Fandom's a day and night thing for you, and for watching the game at home in the evening, be ready for a comfortable few hours. As you cheer the team from the couch, wear these sleep pants, designed in team colors and featuring the Yankees logo printed on the left side. Soft cotton jersey makes these a must for lounging now and catching a few Zs later.
- Made out of 60% cotton/40% polyester jersey knit
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- Country of Origin: Imported
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Here is a list of Frequently Asked Questions.
Should you not find the answer to your question here, do not hesitate to contact us at firstname.lastname@example.com
Q: Why do I have to sign an employment contract?
According to the various social security schemes, an employment contract shall guarantee a "package" of pension contributions plus social security coverage made of several items, such as sickness and maternity benefits, invalidity benefits, old age benefits, survivor's benefits, benefits in respect of accidents at work and occupational diseases, unemployment benefits, family benefits, etc.
Q: Is my salary to be considered before or after tax?
A: Before. Your salary will be subject to any applicable employers and employee's national insurance and income tax. A monthly "mobility allowance" flat rate will be allocated to you to cover expenses linked to your personal household, relocation and travel expenses.
Q: How long is this scholarship for?
A: 3 years. Regardless of whether you manage to complete your PhD degree or not.
Q: What do all these acronyms mean?
A: ESR: Early Stage Researcher. A researcher who, at the time of recruitment by the beneficiary, has not yet been awarded the doctorate degree and is in the first 4 years (full-time equivalent) of his/her research career.
ER: Experienced Researcher. A researcher who, at the time of recruitment by the beneficiary, is: 1) in possession of a doctoral degree, independently of the time taken to aquire it, or has at least four years of full-time equivalent research experience and 2) has less than five years of full-time equivalent research experience.
WP: Work Package
Q: When will I start my PhD?
A. After April 1st. The exact starting date of your PhD depends on two factors:
– Your host University rules. Most institutions allow students to start on specific dates, usually October and/or January.
– Your supervisor's preference. Get in touch with them to find out when they would like you to start.
Q: How can I get tips and advice on relocating to a new country?
A: Visit our forum. Alternatively you can find some information on the Euraxess website.
Q: During my PhD will I be offered the possibility to attend courses?
A: Yes. Marie Curie ITNs are all about forming a new generation of prepared, multidisciplinary and competitive scientists. Visit the Training session of our website to find out more about the INsecTIME training programme.
Q: Where can I find more information about Marie Curie ITNs in general?
A: Visit their website!
Q: Can I get in touch with ERSs belonging to different Marie Curie ITNs?
A: Sure. Visit the Marie Curie Alumni web portal, where past, present and future Marie Curie researchers that have benefited or are still benefiting from the European Commission's Marie Curie programme for researchers' mobility can register and enjoy the benefits of membership.


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Download EBOOK Two Little Girls in Blue PDF for free
Category: Fiction
The author of the book: Mary Higgins Clark
Format files: PDF, EPUB, TXT, DOCX
The size of the: 711 KB
Language: English
Edition: SIMON & SCHUSTER
Date of issue: 20 March 2007
Description of the book "Two Little Girls in Blue":In this riveting thriller from Queen of Suspense and #1 "New York Times" bestselling writer Mary Higgins Clark brilliantly weaves the mystery of twin telepathy into a mother's search for a kidnapped child, presumed dead. When Margaret and Steve Frawley come home to Connecticut from a black-tie dinner in New York, their three-year-old twins, Kathy and Kelly, are gone. The police found the babysitter unconscious, and a ransom note from the "Pied Piper" demands eight million dollars. Steve's global investment firm puts up the money, but when they go to retrieve the twins, only Kelly is in PDF the car. The dead driver's suicide note says he inadvertently killed Kathy. At the memorial, Kelly tugs Margaret's arm and says: "Mommy, Kathy is very scared of that lady. She wants to come home right now." At first, only Margaret believes that the twins are communicating and that Kathy is still alive. But as Kelly's warnings become increasingly specific and alarming, FBI agents set out on a desperate search.
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Recently, I've been inspired by some of my favourite bloggers who started posting weekly photos (mostly of their gorgeous kids) from the beginning of the year. I missed the boat on that particular project as my own little guy was fighting a fever, and if I do anything I like to do it right. It wasn't until I thought about really capturing a certain age that I thought I'd start The 18 to 30 Project. Weekly images of my son Hugo from 1.5 to 2.5 years (or 18 months to 30 months). Hugo turned 18 months on the 12th, but since my trip to Paris last week, I have been playing catch up ever since. So here I will be posting the first two installments of the project. The black and white images are of the day he turned 18 months, and the colour images were taken just a week after. It is such an exciting age as so many things are changing all the time. I think Hugo still as enough puppy fat to look like a baby, but truth be told my little boy is growing so fast it makes me want to hold tight to him now, and maybe if I hold him tight enough he will stay just as he is.
The 18 to 30 Project is about more than just photographing my son. I have been wanting to improve my photography and learn more about the process for a long time. I hope to take a course when I return home to Australia. I can barely even get my head around the technical terms in English so, I figure it's best not to venture in to it in French. Not yet.
I hope I will be able to keep up with this project. My subject is someone who rather dislikes staying in one place for more than a second, and chasing this guy around the park, camera in hand, is challenging to say the least.
Also check out 18 to 30 Project • Life • Photography •


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LOS ANGELES - The wishes Michael Jackson expressed in his will began to come into reality Monday during a lengthy court hearing, with his mother, Katherine, placed firmly in charge of rearing his children and the two men he designated still at the reins of his financial empire.
As a media frenzy buzzed outside, a surprise motion from Jackson's longtime dermatologist injected some drama inside the courtroom: An attorney for the doctor, Arnold Klein, tried to enter objections to the parenting of Jackson's children.
Klein has had a lengthy part in Jackson's story line. He not only served as Jackson's doctor, but one of his employees, Deborah Rowe, married Jackson in 1996 and gave birth to two of the singer's children. Most recently, Klein's medical records have been subpoenaed as part of the police investigation of Jackson's death.
Kaplan's objections created a few tense moments in the courtroom, but Los Angeles Superior Court Judge Mitchell Beckloff quickly dispatched him, saying Klein didn't have legal standing.
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Why I Think PLANET HULK And WORLD WAR HULK Movies Can Work
Planet Hulk and World War Hulk offer natural progressions for the character and present the best avenues to portray the Hulk on the big screen. Read on for my take on why this is something that could work very well, and why we should be looking forward to it.
Filed Under: "
After the alleged scoop that Latino Review's El Mayimbe dropped yesterday, many comic fan sites have been in an uproar over the potential ramification that Planet Hulk and World War Hulk movies have on Phase 3 of the MCU. Specifically, many fans are perturbed by this as they feel a Planet Hulk film sounds silly if not unlikely. At the same time, they feel portraying Hulk as a villain in Avengers 3 would be taking a step backwards from what they believe made the Hulk so popular in the first Avengers film. I, however, disagree with those two lines of thought and feel that they are in part influenced by a misconception of what exactly made Hulk popular in The Avengers and how a World War Hulk storyline would be handled in The Avengers 3. In this piece I will be breaking down the argument for why Planet Hulk and World War Hulk can work in Phase 3 of the MCU by addressing the criticisms of going in such a route.
Argument 1: The reason Hulk was so popular in the Avengers was because Marvel portrayed him as a hero
This is a misconception. The reason Hulk was a crowd pleaser and fan favorite in the Avengers is not particularly because he was played up as a hero but because we finally got to see the Hulk we've all wanted; one that smashes puny aliens and gods and looks cool while doing it. One that grins at the prospect of smashing something and has hilariously timed quips. Part of the problem with the first two Hulk movies was that the Hulk was only portrayed as a rampaging green monster and they didn't even attempt to touch on the comedic aspect of the character or, dare I say, his adorable side. The Avengers finally offered us a chance to see that and, wouldn't you know it, Marvel struck gold with it. So, from that Marvel realized that one of the ingredients necessary for a successful Hulk movie is depicting not only the giant green monster aspect of the character but the more comedic side of the Huk.
Argument 2: A Planet Hulk movie would be too silly for the general audience to buy into
A movie focused on a giant green monster is already silly in the first place. If there's anything that Marvel learned from Phase 1 about Hulk it's that audiences are willing to buy into the character, just not in the way they were portraying him in the first Hulk movie. Audiences don't want to see the Hulk being chased around by United States military for an entire movie nor do they want to see him fighting against regular people who he can't smash for obvious reasons. Planet Hulk offers Marvel the chance to capitalize on what I explained made him popular in the Avengers by giving him real threats that he can physically smash without horrifying families and their kids. It also presents the opportunity to show what the Hulk can be like without being chased around and on the run; what he can be like when he has an agenda.
Argument 3: Having the Hulk shot into space would be a step backward from what Marvel finally established in the Avengers
You could look at it that, or you could look at it as a natural progression of the character that works with what Joss Whedon said about digging a knife into the team. The Hulk is only going to be able to work with the Avengers for so long before the fact that he is a rage based monster rears its head again. No matter what, it's inevitable that Banner is going to lose control somehow. If not lose control, framed and used by someone. The Hulk character is, at its core, a tragic hero and ultimately must always be played up that way after a certain point. However, what Planet Hulk does is explore that tragic hero aspect of the character in a much more interesting light than traditional Hulk stories do. As I mentioned earlier, rather than play up the Hulk as a monster on the run, Planet Hulk shows us a much more contemporary tragic hero who has been betrayed by his allies and sent into exile. The Hulk, rather than run, must fight his way through an unknown planet to survive and conquer and eventually extract his revenge on the people who betrayed him. When I think about the type of character Hulk is played up as in Planet Hulk I think of a funnier version of Kratos. It has the potential to be gold on the big screen.
Argument 4: Having Hulk portrayed as a villain in Avengers 3 would hurt toy sales and wouldn't give the audience anyone to root for
This would be a valid argument if Hulk were to be the main villain of Avengers 3, which he in all likelihood will not be. In the MCU, Marvel Studios takes multiple storylines from the comics and combines them all into one film, an amalgamation if you will. The World War Hulk storyline would be just one element of a much bigger plot going on in the film. It's possible that Hulk returns to Earth with the true villain of the film and plans to extract revenge on the people who (he thinks at least) betrayed him, but ends up rejoining the Avengers through the course of the film and helps them take down the main antagonist. This would offer a great feel-good moment in the film and bring the Hulk's journey which began in The Avengers 2 to a satisfying conclusion and further vindicate the Hulk as a true hero. If anything, this plotline could help boost Hulk toy sales, not hurt them.
Argument 5: Bruce Banner would not be in the film enough, which is a problem because Mark Ruffalo's performance was a highlight of the Avengers
One of the faults in the first two films (see a pattern here?) is that they focused far too much on Bruce Banner when audiences came to see the Hulk. Banner has already proven he can't carry a movie, the Hulk probably can. Banner can work in spurts, especially with the wry sense of humor Ruffalo brings to the role, but too much of him just gets stale. A 70% Hulk, 30% Banner split is probably the best option.
Argument 6: Planet Hulk would be too expensive
If Marvel can make a Guardians of the Galaxy movie, they can make a Planet Hulk movie. 'Nuff said.
Argument 7: There is not enough time nor characters to introduce the Illuminati into the MCU
The MCU already has an Illuminati...they're called the World Security Council, who we saw in The Avengers.
Argument 8: Why would they shoot Hulk into space anyway?
As I said earlier, these movies are amalgamations of many comic book storylines. The Avengers combined several elements of the 616 Avengers line of comics with the Ultimate universe's equivalent, the Ultimates. In the 616 universe, the set up for Planet Hulk is that the Illuminati are fed up with the Hulk's actions and vote to ship him out to space. Now, the reasoning for this in the MCU could be pulled from the Ultimates 2 comics, which shows that public opinion has turned against the Hulk when it is discovered he has murdered hundreds of people. Now, obviously the Hulk won't be murdering people in the Avengers 2, but the basic concept could be the same.
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Showing Suppliers 1 - 20 of 72
Define Instruments (1 Products)
Address: 5711 Preston Oaks Road, Suite 142, Dallas, TX
Business Type: Manufacturer
Description: Manufacturer of industrial instrumentation for process measurement, indication and control Define Instruments manufactures innovative products for industrial automation, measurement, indication and process control. We develop robust industrial instruments for a variety of applications in... (more)
PHOENIX CONTACT USA (1 Products)
Address: Customer Technology Center 3993 W. Sam Houston Parkway North Suite 500, Houston, TX
Business Type: Manufacturer
Description: Phoenix Contact develops and manufactures industrial electrical and electronic technology products that power, protect, connect and automate systems and equipment. Our products are used in many industries, including: Automotive Water/wastewater Transportation Power... (more)
R. STAHL, Inc. (2 Products)
Business Type: Manufacturer
Description: Superior Engineering for Worldwide Explosion Proof and Explosion Protection Products For more than 80 years, R. STAHL has fulfilled a unique role in protecting lives and property in harsh and hazardous (classified) locations. R. STAHL is acknowledged as the world's foremost... (more)
View Catalog
Address: R. STAHL Inc. 13259 N. Promenade Blvd, Stafford, TX
Address: 13259 N. Promenade Blvd., Stafford, TX
Radwell International (18 Products)
Address: 3401 Ave. E East, Arlington, TX
Business Type: Distributor, Service
Description: The Story of Radwell Brian Radwell, President and CEO explains it like this: "Radwell International sells and repairs industrial electrical and electronic control devices. We sell and repair timers, counters, photoelectric sensors, circuit breakers, pushbuttons, PLC's,... (more)
Rotronic Instrument Corp. (4 Products)
Address: 508 Spicewood Court, Keller, TX
Business Type: Manufacturer
Description: Precision Humidity measurement for industrial, scientific, and HVAC applications. For over three decades ROTRONIC has been developing and manufacturing state of the art humidity measurement instrumentation. ROTRONIC's products are used around the world in diverse industries ranging... (more)
TT Electronics (8 Products)
Address: 1645 Wallace Drive, Carrollton, TX
Business Type: Manufacturer
Description: TT Electronics has years of experience and expertise in engineering and delivering electronics for applications in the harshest environments across industrial, transportation, aerospace, defence and medical markets. We work hard to develop strong long-term relationships with our customers, many... (more)
Delta Controls Ltd.
Address: 11490 Westheimer, Suite 850, Houston, TX
Business Type: Manufacturer
Description: Your Trusted Partner in Process Instrumentation Delta Controls designs and manufactures high quality, reliable and accurate temperature and pressure measurement instruments for process monitoring and control applications worldwide. Delta Controls... (more)
SAMSON Controls, Inc.
Address: 4111 Cedar Boulevard, Baytown, TX
Business Type: Manufacturer
Description: SAMSON - A name recognized worldwide as a synonym for high-quality work, entrepreneurial spirit and innovative strength. The company is not only known for a complete product line in instrumentation and controls, but also offers the most modern integrated automation systems. The field of expertise... (more)
Stellar Technology, Inc.
Address: 4001 W. Sam Houston Parkway N. Ste. 140, Houston, TX
Business Type: Manufacturer, Service
Description: Since 1991, Stellar Technology has been engineering and manufacturing transducers, transmitters, and related instrumentation. Initially serving only the Aerospace industry, STI now provides a complete line of pressure, load, LVDT, temperature and specialty products, each manufactured with the same... (more)
Ultra Electronics, manufacturer of Weed Instrument products
Address: 707 Jeffrey Way PO Box 300, Round Rock, TX
Business Type: Manufacturer
Description: Ultra Electronics is a leading manufacturer of temperature sensors and transmitters, nuclear qualified instrumentation and industrial fiber optic networking equipment. The company is ISO 9001:2000 registered and operates from a modern 50,000 sq. ft (4,600 sq. m) facility located on the outskirts of... (more)
Winters Instruments
Address: 10757 Cutten Road, Building 7, Houston, TX
Business Type: Manufacturer
Description: Since 1953, Winters Instruments has been providing quality built instrumentation to all markets that require pressure and temperature measurement. Through the years, the company has grown in size and reputation and is now a leading, global manufacturer of industrial instrumentation. Their... (more)
AccuTru Sensor Technologies
Address: 817 Russell Palmer Road, Kingwood, TX
Business Type: Manufacturer
Cameron's Measurement Systems Division
Address: (Formerly NuFlo Measurement Systems) 14450 JFK Boulevard, Houston, TX
Business Type: Manufacturer, Distributor
Description: Cameron's Measurement Systems Division (Formerly NuFlo Measurement Systems) Cameron's Measurement Systems Division designs, manufactures and distributes measurement and control instrumentation for the global oil and gas and process control industries. The Division was... (more)
CAMERON Valves & Measurement
Address: 3250 Briarpark Drive, Suite 300, Houston, TX
Business Type: Manufacturer
Description: CAMERON Valves & Measurement is a leading provider of valves and measurement systems to the Oil and Gas industry. The group's products are primarily used to control, direct and measure the flow of oil and gas as it is moved from individual wellheads through flow lines, gathering... (more)
Daily Thermetrics Corporation
Address: 5700 Hartsdale Drive, Houston, TX
Business Type: Manufacturer, Distributor
Description: Since 1973, Daily Thermetrics has provided the process industries with precise temperature measurement instrumentation. We are known for quality, engineering and delivering to the demanding needs of our customers. We have patents on multipoints and provide temperature instrumentation all over the... (more)
Detection & Measurement Systems, Inc.
Address: 9920 W. Sam Houston Parkway S., Suite 430, Houston, TX
Business Type: Distributor, Service
Eads Company (The)
Address: 13843 N. Promenade Blvd., Ste. 100, Stafford, TX
Business Type: Distributor
Egar, Inc.
Address: 602 Ninth Street North, Texas City, TX
Business Type: Distributor
Fieldbus Foundation
Address: 9005 Mountain Ridge Drive, Bowie Building, Suite 200, Austin, TX
Business Type: Distributor


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Thirty people have died and over 50 were injured as two coaches trains derailed.
Thirty people have died and over 50 were injured as two coaches of the Dehradun-Varanasi Janta Express derailed in Uttar Pradesh's Rae Bareli district.
The accident took place around 9.30 on Friday morning as the train was coming to a stop at the Bachhrawan railway station - 30 km from Rae Bareli.
It was likely that there was a brake failure, news agency ANI quoted railway sources as saying. The engine overshot the signal, two compartments were derailed.
One of the coaches, which was a general compartment, has been crushed by the impact -- the rescue work took around 6 hours. The other was a guard compartment which is likely to have been vacant. If not for the vacant coach, the number of casualties would have been higher, officials told NDTV.
In a series of tweets, Railway Minister Suresh Parbhu said Railways has been prioritising safety as a "thrust area". An inquiry has been ordered into the incident, he also said.
Source: ndtv


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While you knelt down in front of my pussy, I put on a show for you! I teased you with my freshly shaven butt hole and sweet smelling pussy. I fucked my peach right in front of your face and it drove you wild!! Before I fucked my ass so good until shit poured out the sides, I opened and closed my butt hole giving you a glimpse of what's inside!
This felt amazing! The consistency is what I call perfect for fucking. It is so thick and holds onto my toy so tight when I pull it in and out of my asshole!
Length: 15:00s Resolution: 1920x1080Download Format: mp4File Size: 1 GB


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Halloween Flashbacks and A Tease…
You all know that we have a tradition of creative Halloween costumes in our family, with the most famous being the "Fruit of the Womb" and "The Monkeys Jumping on the Bed float" or perhaps the "Halloweiners" from our first Halloween. I'll let you be the judge.
As the boys get older, the more say they have in their costumes, and it's become a little less of a riot. However, we still get into the creativity side. Last year, Brad did some magic with duct tape, and this year we have at least one more group costume up our sleeve.
But Just for Fun, Let's Look Back at Our Last 6 Years of Quadruplet Halloween Costumes:
"Our Little Halloweiners" in 2007
"The Adorable Giraffe Herd" in 2008
"The Monkeys Jumping on the Bed" in 2009
"Our Little Heart Attacks" in 2010
"Fruit of the Womb" in 2011
And Our Duct Tape "Knight and Shining Armors" of 2012
And the clue for this year's costume…


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TERI University in the News
Latest NewsRecipe to cut car pollution - Bus corridors, diesel curbs to 10-fold parking fee hike
The Telegraph (Online), 13 November 2017
New Delhi: Suresh Jain has generated graphs and numbers on his desktop that outline what it will take for the National Capital Region, plagued by dangerous air pollution levels that peak each winter, to dramatically clean its air.
His calculations predict a possible 66 per cent drop in inhalable particulate matter (PM) from passenger vehicles and a 90 per cent fall in PM emissions from goods vehicles --- but only if the government pushes through policies that disruptively change transportation habits.
Such cuts in PM emissions could lead to vast improvements in air quality because multiple studies have suggested that vehicle tailpipe emissions make up over 30 per cent of PM over India's most polluted cities.
"The policies and the technologies needed for cleaner air are clear," said Jain, professor of air pollution and health at TERI University in New Delhi, who has spent over a decade trying to determine how government policies might help curb air pollution.
"But are we willing to pay the price to breathe cleaner air?"
Jain and other environmental experts are happy that one key policy measure is in the pipeline: the Centre last year announced new emission standards and fuel quality for all vehicles from 2020.
The Bharat Stage VI standards are expected to lower PM by 82 per cent from diesel cars and 67 per cent from heavy duty vehicles.
But experts caution about the hurdles facing other critically important policies, meant to encourage the use of public transport, nudge people away from personal diesel cars, phase out old vehicles and enforce on-road emission checks. Diesel vehicles have traditionally been more polluting than petrol vehicles. But the automobile industry and consumers across India have piggybacked on diesel's low cost, although the subsidy is intended to benefit the farmers who use it for tractors and water pumps.
The New Delhi-based non-government Centre for Science and Environment (CSE) says the proportion of diesel cars among the new cars sold nationwide rose from 4 per cent in 1998-99 to 16 per cent in 2003-04 and to 54 per cent in 2011-12. Activists campaigning against diesel vehicles have highlighted that the World Health Organisation has classified diesel exhaust as carcinogenic. A typical diesel car emits about 10 times the levels of oxides of nitrogen spouted by a petrol car. These compounds can trigger exacerbations of asthma and other health disorders.
"We're now seeing a backlash against diesel in many countries. Beijing has already banned diesel, and London and Paris are phasing out diesel cars," said Anumita Roychowdhury, CSE executive director.
Several expert panels have since the year 2000 advised the government to introduce high additional excise or an emission tax to offset the fuel price advantage and discourage private diesel cars.
"But we haven't seen willingness to do this, possibly because of automobile industry pressure and lack of understanding of the health risks of diesel," Roychowdhury said.
But some engineers argue that the problem with diesel vehicles comes from old engines and not new ones.
"Diesel has been unfairly demonised," said Avinash Aggarwal, professor of mechanical engineering at the Indian Institute of Technology, Kanpur.
"If we instantly eliminate all diesel vehicles older than 15 years from India's roads, we'd cut emissions by over one-third. The real issue is effective enforcement of such bans."
But Roychowdhury and others cite tests that suggest that even modern diesel cars have failed to achieve their prescribed Euro VI emission standards when tested on road conditions.
The emissions study by Jain and his colleagues at TERI University predicts dramatic cuts in PM emissions if all vehicles meet the prescribed emission standards and goods vehicles are also fitted with diesel particulate filters.
The study predicts large PM emission cuts from passenger cars if local authorities augment public transport networks, increase parking fees by up to 10 times (from the current Rs 20 to Rs 200) and create dedicated bus corridors that allow buses to maintain speeds up to 25kmph.
"Our main finding (is that) we need multiple policy measures to significantly reduce vehicular emissions," Jain said.
Some environmental scientists assert that achieving cleaner air demands actions beyond vehicular emissions.
"Industrial stack emissions, waste burning in our cities, and natural sources -- they all need to be addressed," said Tirthankar Banerjee, assistant professor at the Banaras Hindu University, who earlier this year published a paper that quantified how much each of these sources contributes to air pollution.
Read More...
LG encourages youths to travel, pursue dreams
Indian Express (Online), 10 November 2017
New Delhi, Nov 10 (PTI) Delhi Lt Governor (LG) Anil Baijal today at a convocation ceremony advised the youth to travel to understand global issues and gain new experiences and encouraged them to pursue their dreams.
The LG was speaking at the TERI University's Convocation here. Baijal asked students to pursue their dreams and also to travel to understand the global issues of sustainable development.
"You may even decide to take a break and consider all options. I would urge you to travel and and take on new experiences and drop on those when it comes to a decision that can shape your future," he said.
Eighteen students were conferred with doctoral degrees and 195 received master degrees from the TERI University.
Read More...
TERI University hosts its 10th convocation
ANI News (Online), 10 November 2017
New Delhi [India], November 10 (ANI-NewsVoir): With the growing need for developing alternative methods through specialized education to create a sustainable living, TERI University graduates on Friday, at their convocation ceremony, dedicated themselves to the importance of environmental protection and the need to maintain equity, ecological security, and the wealth of natural resources.
TERI University held its 10th Convocation ceremony today in which 18 students were conferred with doctoral degrees and 195 received master's degree from the university.
Present on the occasion were Anil Baijal, Hon'able Lt. Governor, Delhi as the Chief Guest for the convocation and Monique Barbut, the Executive Secretary of the United Nations Convention to Combat Desertification (UNCCD) as the Guest of Honour, along with Ashok Chawla">Ashok Chawla the Chancellor, TERI University, Dr. Leena Srivastava, Vice Chancellor TERI University and Dr. Rajiv Seth, Pro-VC TERI University.
Advising the passing students to pursue their dreams in addition to travelling to understand the global issues of sustainable development, Anil Baijal, Lt. Governor, Delhi said, "The education pedagogy at TERI University has been a win-win model to create knowledge and capacity in various areas of sustainable development, a laudable at a time when the world is facing serious challenges of sustainability and climate change. It is gratifying to know that TERI University has partnerships with various state governments and global university's to develop an informed cadre of professionals well-equipped to tackle, beyond cultural boundries and sectoral divisions, the interwoven challenges of extreme poverty, disease, climate change and ecosystem vulnerability."
Commencing the convocation ceremony, Ashok Chawla">Ashok Chawla, Chancellor, TERI University, spoke about the growth of the TERI University, and brought out the importance of the unique programs offered by the University.
He said, "That issues of environment management and climate change cannot be handled solely by the government but has to be handled by all stakeholders including the younger generations such as the students. He urged the students to carry the mantle of environment protection and become active citizens in improving the environment as decision makers and leaders of the future."
Vice-Chancellor Dr. Leena Srivastava stressed on the role that TERI University can play to advance towards a sustainable living in a mega city like Delhi, which has its unique environmental and ecological challenges.
"TERI University and its students can play a significant role, in collaboration with the Government of Delhi-NCT, to find such climate friendly solutions to identified problems and also act as change agents to help with the implementation. Beyond air pollution, are a range of other sustainability challenges that would help with both mitigation and adaptation to climate change - water, waste and energy management, biodiversity conservation, mobility etc. - and lead to more sustainable development."
The Guest of Honour Barbut, UN Under Secretary General and the Executive Secretary of the United Nations Convention to Combat Desertification, called on the new graduatesto be innovators, and challenged them to "Imagine what your villages of the future will look like."
She stressed that whereas knowledge is important, it is a tool to help us to imagine how to change the challenges we face. "In each new challenge, I apply what I have learned, but I also try to imagine an entirely different way to get things done. Because it takes at least one person, with imagination, to think something is possible before it can ever come to pass," she added.
Academicians, researchers and students at TERI University are already involved in the following areas with various Government departments of India:
• Water Resources, waste management and sanitation: Various projects such as Urban water metabolism, Landscape approach for water management in Gangetic planes, Water-energy nexus, and Urban water and sanitation, strengthens various flagship missions loudly promulgated by the Government of India viz. Skill Development, Smart cities and Swachh Bharat Mission. Our approach includes (i) basic research to guide policy with evidence, and (ii) strengthening the capacity of Institutions and Stakeholders.
• Energy and Emission Management: University has carried out projects on integrated energy-environment systems modelling and their implications on global and local environment and health. We worked on impact of various urban infrastructure schemes on mitigation of greenhouse gas emissions for COP-21 (for Ministry of Urban Development), sustainable mobility and strategic energy and environmental analysis for multi-modal transport system.
• School awareness programmes: School University Network (SUN) of TERI University is an initiative to trigger curiosity and creative thought processes in sustainability science amongst school children and to build communities for bringing positive change in local areas.
•Urban Development and Sustainable Buildings Management: Cities are engines of economic growth and can lead investments required for sustainable infrastructure. The urban approaches chosen, and the infrastructure decisions made will have severe consequences in climate change adaptation and mitigation; and Responsible Consumption and Production. TERI University has structured first-of-its-kind masters courses on 'Sustainable Consumption and Production' for mid-career policy makers and professionals.
TERI University is the only institution of advanced learning in the country established with the mission of contributing globally by serving society through formal education and research in fields like environment, sustainability, energy conservation, policy and management. At the Convocation, MA degrees were awarded in Public Policy & Sustainable Development (PPSD) and Sustainable Development Practices (SDP); MSc degrees in Environmental Studies and Resource Management (ESRM), Geoinformatics, Plant Biotechnology (PBT), Climate Science and Policy (CSP), Water Science and Governance (WSG), and Environmental and Resources Economics; MTech in Renewable Energy Engineering and Management (REEM) and Urban Development and Management (UDM), Water Science and Governance (WSG); and MBA in Business Sustainability and Master of Laws in Environment and Natural Resources Law, Infrastructure and Business Law.
In its more than decade old existence, the University has become a centre of research excellence in its field, producing over 1200 post graduates with high-level cross-specialisation skills in environment and sustainability fields as well as nearly 80 PhDs, who have gone on to contribute to society through engagements with corporate-driven CSR initiatives, leading NGOs, government agencies and statutory bodies working in the field and have even become social entrepreneurs. TERI University has partnerships with various universities and institutes across the world.
To walk-the-talk, the TERI University campus provides a setting which enhances learning and showcases the concept of modern green buildings. The campus is aesthetically designed with several features of passive solar design, energy-efficiency and water and waste management systems. TERI University students undergo training and internships with government, multilateral and multinational agencies during as a part of academic curriculum. The university has a placement cell, as employment is considered as an integral part of the system. The cell taps government agencies like Dept. of Environment (Govt. of NCT, Delhi), FAO, multinational companies like ACC, Tata Power, Reliance Energy Ltd. and multilateral organisations like WWF, Action Aid International etc. for internships and employment programmes.(ANI-NewsVoir)
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|Applied knowledge
|The Times of India (Education Times), 20 March 2017


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Hi there,
I would like to buy my aunt and uncle a gift certificate to a restaurant in the city for Christmas. They are big fans of Italian food, steakhouses, etc. and are big wine drinkers - a good wine list is key! Some places I know they have been and liked are:
Cite (the former)
Osteria al Doge
Maloney and Porcelli
Last year I sent them to Eleven Madison Park and then loved it - I am planning on spending about $100 this year because I am now in grad school, and, well, poor :), but the place can cost more than that.
A bit more about the recipients:
They are in their 50s but are somewhat "hip" (both work in the music industry) and eat in the city quite often. That being said, I'm looking for something a that is more about the food than being super trendy.
If possible I'd like to do something outside of the theater district (we go there quite a bit!). Any suggestions are welcome!
Thanks for your help in advance and Happy Holidays!


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Myanmar Rising: Five-part series. Radio France Internationale. May 2013.
Myanmar has undergone a series of rapid changes in the last few years, as the country emerges from decades of military rule.
After more than five decades of censorship, Myanmar's artists now have greater freedom and the contemporary art scene is thriving, though some artists still struggle to avoid government scrutiny.
A generation is growing up that looks likely to live very different lives from their parents. No longer isolated, young people in Myanmar are embracing the internet, cellphones, and a new-found freedom of expression.
Myanmar's tourism industry is enjoying an unprecedented boom, as the country opens up to foreigners after decades of isolation and international sanctions. But the boom means hotel prices are skyrocketing, and there is a shortage of accommodation in some areas amid concerns that Myanmar might not be ready for the tourist influx.
Recent changes to media law means that there are more newspapers going to print and censorship has for the most part been lifted.
International aid and finance are once again flowing into Myanmar, whose military government launched reforms two years ago. But can the south-east Asian country absorb the sudden influx of money?
This five-part series, recorded for Radio France Internationale, looks at Myanmar reemergence on to the world stage.


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Scania 12 Tonne Bogie Axle Tipper Truck Hire
- Title
- Scania 12 Tonne Bogie Axle Tipper Truck
- Make
- Scania
- Condition
- Excellent
- Weight Capacity
- 12 Tonne
- Number in Fleet
- 1
We have a team of expert arborists who are committed to providing the very best in tree maintenance and removal. With a wealth of experience, they can recommend which branches are best removed and which can safely remain. Our tree removal service is all encompassing from the tips of the uppermost branches right down to the base of the stump. Our grinding is so efficient, you can landscape over top of where the stump used to be. And when it comes to total tree removal? You will never even know there was a tree there!
North Brisbane Trees - Samford, QLD
- Address
PO Box 619, SAMFORD QLD 4520
- Website
- http://www.northbrisbanetrees.com.au/


text:
You can contact us in by phone at (603) 427-6800 or email us at the address below. We will get back to you as soon as we can.
If the matter requires immediate attention, please call us.
North Coast Family Health
875 Greenland Road, Unit A-1
Portsmouth, NH 03801
Phone: (603) 427-6800
Fax: (603) 427-2801
Email: info [at] naturopathic-doctors [dot] com (subject: Website%20Inquiry)
NOTE: Email is not secure. While we make every effort to ensure your confidentiality, the insecure nature of email means we cannot guarantee it. If a matter is urgent or sensitive, please call us at (603) 427-6800 instead. By sending an email, you acknowledge this.


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Fookes Software Support Information - Suggested Reading
Expand Messages
- Hi All,
I'm on a "working" vacation. If you write me, mail may be slow in
getting back to you until I get caught up and off vacation. I'm
sorry for any inconvenience this may have caused you. Please type
"ASAP" in the Subject line if your situation requires a fast
answer and I'll try to do what I can. I do handle lost
registration keys and the like immediately each time I connect. I
try to daily, but cannot always get to a local access and haven't
found the time to figure out how to use my wireless. At times, if
I cannot find a local access number I use the 1-800 for 10 cents
a minute, like now sending this off. :)
Did Unto These Hills; Trail of Tears in Cherokee, NC first. Most
excellent out door play of the historical Trail of Tears when the
Cherokee Indians were forced off their land. Road through Smokey
Mountain National Park and up to York Beach, ME to visit friends
and did Attitash while there. An awesome dry sled ride 1.25 miles
long on board in track - people getting broken ribs burnt skin
from wiping out on fiber glass track. I was tucked down deep full
speed with very little braking to prevent me from going off
track. Had part of sled off track at times. <bg> Totally wicked
I'm staying in the hotel today. Superman, The Predator, The Mind
Eraser, and The Viper (roller coasters) at Six Flags at Darien
Lake took their toll on me day before yesterday, this 55 year old
man, so I need a break. My son is with me, and my wife and girls
went to some falls today. We were at Niagara Falls yesterday. Off
to Six Flags Glen Falls tomorrow - yippie!!! tomorrow - more
wicked roller coasters! Superman was the best at Darien Lake. Son
and I gave it a 9.5. Got first seat and did whole ride with hands
in air -totally awesome dude! Still have 3 more Six Flags to do
including the last one with Kingda Ka: 128 MPH - long drop, total
ride lasts only 50 seconds. Stomach must have to be left at
almost top of the fall down. <bg> We are saving the 10+ (1 out of
10 for it. :) This 55 year young woke up yesterday singing in my
head: You shake my nerves and rattle my brain, too much lovin
drives a man in sane! :) It elt like my brain was bouncing around
in my skull (severe pain, but mouth still watering and sweaty
hands yelling more, more, more!!! Dreamed about Rock n Roller
Coaster at Disney/MGM that son and I went on - he too had the
same dream. LOL Later...
Happy Camper,
A merry heart doeth good like a medicine:
but a broken spirit drieth the bones.
See ya in the funnies! ;)
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