text:
Molecular imaging of rheumatoid arthritis: emerging markers, tools, and techniques
DOI: 10.1186/ar4542
© Put et al.; licensee BioMed Central Ltd. 2014
Received: 16 October 2013
Accepted: 8 April 2014
Published: 15 April 2014
Early diagnosis and effective monitoring of rheumatoid arthritis (RA) are important for a positive outcome. Instant treatment often results in faster reduction of inflammation and, as a consequence, less structural damage. Anatomical imaging techniques have been in use for a long time, facilitating diagnosis and monitoring of RA. However, mere imaging of anatomical structures provides little information on the processes preceding changes in synovial tissue, cartilage, and bone. Molecular imaging might facilitate more effective diagnosis and monitoring in addition to providing new information on the disease pathogenesis. A limiting factor in the development of new molecular imaging techniques is the availability of suitable probes. Here, we review which cells and molecules can be targeted in the RA joint and discuss the advances that have been made in imaging of arthritis with a focus on such molecular targets as folate receptor, F4/80, macrophage mannose receptor, E-selectin, intercellular adhesion molecule-1, phosphatidylserine, and matrix metalloproteinases. In addition, we discuss a new tool that is being introduced in the field, namely the use of nanobodies as tracers. Finally, we describe additional molecules displaying specific features in joint inflammation and propose these as potential new molecular imaging targets, more specifically receptor activator of nuclear factor κB and its ligand, chemokine receptors, vascular cell adhesion molecule-1, αVβ3 integrin, P2X7 receptor, suppression of tumorigenicity 2, dendritic cell-specific transmembrane protein, and osteoclast-stimulatory transmembrane protein.
Anatomical imaging techniques have long been used to diagnose and monitor rheumatoid arthritis (RA). Over the past decade, these techniques have dramatically improved. For example, it is now possible to detect bone erosions within 6 to 8 weeks after arthritis onset. Nevertheless, pure anatomical imaging of even the earliest structural damage misses the preceding molecular, cellular, and physiological changes in the very early stages of RA pathogenesis. Molecular imaging, currently being developed in many domains of medical research and diagnostic practice, offers the possibility to visualize the early functional changes in RA [1]. This non-invasive technique allows early diagnosis, disease monitoring, guidance of treatment strategy, and possibly prediction of the outcome following the selected treatment. For example, patients can be selected for receiving a certain drug on the basis of the presence of the corresponding drug target, as was suggested for treatment of refractory monoarthritis patients with TNF-α antagonists after imaging with 99mtechnetium (Tc)-infliximab [2]. Some RA drugs are relatively expensive; hence, it is important to determine which patients may respond to a proposed therapy and which ones will not. Additionally, patients who are likely to develop a more severe disease can be identified and selected for more intensive treatment or more frequent monitoring. Molecular imaging of joint pathology both in human and in animal models of arthritis will improve our knowledge of the pathogenesis of the disease. In animals, imaging can be performed before and at different time points after the clinical onset of arthritis in the same animal with minimal perturbation of the experiment, and therefore more information can be obtained with fewer animals. Questions such as 'which are the earliest processes taking place in the pathogenesis of arthritis?' and 'which cells are most important in the disease process at which stage?' might become answered by live-animal imaging with specific probes. In addition, imaging of early-onset inflammation requires sensitive techniques characterized by limited background and non-specific signals.
The pathogenesis of arthritis – which cells can we target?
Macrophages are central effectors of synovial inflammation in RA and their abundance and degree of activation are correlated with disease severity [6]. Macrophages act through release of inflammatory factors, phagocytosis, and antigen presentation [4]. In RA, precursors from the monocyte/macrophage lineage are attracted from the blood to the inflamed joint and fuse to become active multinucleated osteoclasts, causing bone destruction.
T cells represent approximately 40% of immune cells in the synovial infiltrate of RA joints and have been implicated in different steps of RA pathology; they promote development of an autoimmune response and production of autoantibodies. Another role of T cells is the production of cytokines and induction of cytokine production by other cells [7]. B cells contribute to RA by the production of autoantibodies, antigen presentation, and T-cell activation [8]. They are indispensable for the development of arthritis as evident from the observation that the depletion of B cells abrogates the development of collagen-induced arthritis (CIA), an animal model for RA [9], and by the effectiveness of the B cell-depleting antibody, rituximab, that binds the CD20 surface molecule on B cells and inhibits the disease [10].
Synovial fibroblasts contribute to RA pathology by releasing matrix-degrading enzymes, including matrix metalloproteinases (MMPs) and cathepsins, which cause cartilage destruction [11]. Osteoblasts differentiate from mesenchymal stem cells and produce bone matrix. At their surface, these cells express receptor activator of nuclear factor-kappa-B ligand (RANKL), which is essential for osteoclast formation [12]. Blood vessel formation is elevated in RA joints and is associated with increased numbers of endothelial progenitor cells. Endothelial cells express cell adhesion molecules that facilitate rolling, binding, and transendothelial migration of leukocytes [13].
The evolution of arthritis imaging
Anatomical imaging techniques
Conventional radiography is readily available, inexpensive, and reproducible. It allows the visualization of anatomical changes in established RA, such as erosions, joint space narrowing, and juxta-articular bone loss [14]. Ultrasonography (grey-scale imaging, power Doppler) has been in use for over 30 years. It can be routinely used in the clinic and was found to be more sensitive and accurate than clinical examination or conventional radiography [15]. This technique provides information on bone degradation, synovitis, and inflammation of tendons and entheses. Since ultrasound cannot penetrate bone, osteitis cannot be detected [16]. Practical impediments are the lack of standard protocols for evaluation of RA and, therefore, strict dependence on the physician's skills. Hence, implementation studies in daily practice are still needed. When magnetic resonance imaging (MRI) was introduced, it soon became evident that this technique outperforms radiography in detecting early bone erosions [17, 18]. MRI images are two- and three-dimensional and have a higher contrast resolution, consequently soft tissues can be distinguished more efficiently. With MRI it is possible to detect synovial hyperplasia, bone changes, and cartilage degradation but also signs of RA in the pre-erosive phase [14]. It has now become the gold-standard modality for imaging synovitis in patients with early arthritis. Interestingly, several publications report accurate prediction of radiographic damage by MRI assessment of erosions or inflammation [19, 20]. In a study of 42 patients with early RA, baseline MRI erosion scores could predict the development of erosions that became visible by radiography after 1 year. Absence of MRI-detectable erosions predicted the absence of erosions after this time period [21].
Molecular imaging – state of the art
Structural imaging techniques, though very useful, fail to provide information on the underlying biochemical processes. Therefore, novel imaging modalities using molecular probes such as optical imaging (bioluminescence, fluorescence, and near-infrared, or NIR; 600 to 750 nm) or nuclear imaging (scintigraphy; positron emission tomography, or PET; and single-photon emission computed tomography, or SPECT) are currently being improved for arthritis imaging.
The term optical imaging encompasses techniques, such as bioluminescence and fluorescence, that use light as the primary imaging method. Bioluminescence enables visualization of biological processes in vivo. It is a powerful tool for preclinical imaging but less applicable in a clinical setting as it requires administration of foreign enzymes. Fluorescence imaging holds more promise for clinical applications, especially since the development of NIR probes that allow deeper penetration into tissues and less background interference. Nuclear imaging techniques, such as scintigraphy, PET, and SPECT, use markers that are labeled with radioisotopes. Radioactive tracers provide the advantage of deep tissue penetration and low background compared with optical imaging techniques. PET and SPECT produce three-dimensional images and are more sensitive than structural imaging. SPECT is less expensive than PET and uses radiotracers with a longer half-life but has a lower resolution. Additionally, linkage of SPECT tracers requires modifications that might interfere with binding of the marker to the target.
Use of molecular imaging methods might facilitate early diagnosis, disease monitoring, and guidance of treatment strategy, but studies unequivocally demonstrating their value in daily practice are needed. Molecular imaging could be very useful for the selection of patients in phase II clinical trials that evaluate new drugs in a small patient group. The imaging allows measurement of the expression of a given therapeutic target in each individual patient. The level of this expression may be used to select those patients who are most likely to respond to the new therapy. Such an analysis may limit the number of patients who are required in a phase II proof-of-concept trial and may improve the chances of success, but will depend on factors such as the inter-individual variability and the response stratification prediction of the imaging. Imaging is also a powerful tool for animal experimentation; it enables researchers to gather data over a period of time in the same animal. Since the 1990s, molecular imaging has been applied to study arthritis in preclinical imaging of experimental animal models and has evolved from the use of simpler methods, such as autoradiography and planar gamma camera imaging, to more advanced techniques, including fluorescence, PET, and SPECT imaging, that show higher sensitivity and provide more detailed information. The development of the necessary equipment allowing small animal imaging has led to important progress in the field. Fluorescence imaging has greatly advanced as a whole-animal imaging technique and this is due mostly to the development of NIR fluorophores. The background signal in lower wavelengths strongly decreases sensitivity of fluorescence imaging but is significantly less in the NIR range. Nuclear imaging has become more accessible for preclinical research as well; PET and SPECT scanners have been adapted for imaging of small animals.
Emerging techniques and markers to facilitate molecular imaging of arthritis
Probes for molecular imaging
Development of new molecular imaging probes for introduction into the clinic is challenging. The regulatory pathway for diagnostics shares features with that for new therapeutics, but the potential revenue from commercialization is lower.
The use of molecular imaging in the clinic
General tracers
Available imaging agents for rheumatoid or experimental arthritis
Developmental phase
General tracers
18 F-fluoro-2-deoxy-D-glucose
Glucose metabolism, inflammation
Clinical use for detection of inflammation and cancer
Alterations in bone metabolism, osteoblastic activity
Clinical use for bone scanning
Cell membrane synthesis, inflammation
Clinical use for detection of prostate cancer
Trial in 10 patients with inflammatory joint disease
Circulating blood plasma proteins and leukocytes, inflammation
Clinical use for detection of inflammation
99mTc-polyclonal human immunoglobulin G
Increase in vascular permeability, hyperemia, inflammation
Multiple trials in patients with rheumatic disorders
99mTc-/111In-labeled leukocytes
Influx of leukocytes into inflamed tissue
Clinical use for infectious and inflammatory disorders
Multiple trials in patients with RA
Leukocytes (binds to receptors on neutrophils and mononuclear phagocytes)
Trial with 10 patients with RA
Radiolabeled biologicals
99mTc-anti-CD4 mAb
T cells
Case study in 1 patient with RA, trial in 6 patients with RA
99mTc-anti-CD3 mAb
T cells
Trials in 7 patients with RA, 2 psoriatic arthritis patients, and 38 patients with RA
Trial in 4 patients with active RA
Multiple trials with patients with RA
Phase 3 study (NCT01590966)
99mTc-/124I-anti-CD20 mAb
B cells
Trials in 6 patients with RA and 20 patients with chronic inflammatory autoimmune disease
Specific molecular markers
99mTc-acetylated poly-(1,3)-D-galactoside
Mononuclear phagocyte trafficking (binds CD14 and CD11b)
Trials for tumoral, inflammatory and infectious diseases
Preclinical, rabbit antigen-induced arthritis
Endothelium activation and macrophage recruitment (binds to somatostatin receptor)
Clinical use for detection of tumors
Trial in 14 patients with RA
Monocytes and macrophages (binds to peripheral benzodiazepine receptors)
Trials in 11 patients with RA, 6 patients with RA, and 29 patients with arthralgia
111In-E-selectin-binding peptide
Activated vascular endothelium
Preclinical, rat adjuvant arthritis
99mTc-anti-E-selectin Fab/(Fab′)2 fragment
Activated vascular endothelium
Trial in 26 patients with RA
NIR-anti-E-selectin Ab
Activated vascular endothelium
Preclinical, CIA, and TNF-α-induced paw edema
99mTc-annexin V
Apoptosis (binds to phosphatidylserine)
Multiple trials in cancer patients
Preclinical, CIA
Preclinical, AIA
Preclinical, murine arthritis model
99mTc-folic acid (EC20)
Activated macrophages, folate receptor
Phase 2 study in patients with autoimmune disease (NCT00588393)
Activated macrophages, folate receptor
Mouse arthritis models
18 F-PEG-folate
Activated macrophages, folate receptor
Preclinical, methylated bovine serum albumin-induced arthritis
64Cu-/18 F-galacto-arginine-glycine-aspartic acid
Activated macrophages, osteoclasts, endothelial cells
Clinical use, tumor angiogenesis
Preclinical, osteopetrosis, and osteoporosis mouse models
NIR-matrix metalloproteinase-specific probe
Sites of matrix degradation and inflammation
Preclinical, CIA, rat OA
99mTc-anti-macrophage mannose receptor
Subset of macrophages
Preclinical, CIA
Radiolabeled biologicals
Several biologicals approved for the treatment of RA have been radiolabeled and evaluated for imaging, and this provides a number of advantages. These drugs are already being developed commercially, and their safety has been assessed. Radiolabeled therapeutics might provide an earlier, more specific diagnosis and facilitate monitoring of treatment efficacy. Importantly, confirmation of the presence of the target in the patient before treatment initiation provides the possibility of personalized therapy, which can significantly reduce treatment costs. In this context, anti-CD3 [46–48], anti-CD4 [42–45], anti-CD20 [53, 54], and anti-TNF-α (infliximab [2, 50] and adalimumab [51, 52]) have been evaluated for imaging of RA, and most perform relatively well. An exception is IL-1 receptor antagonist (anakinra), which failed to show any specific localization in synovia of RA patients as compared with healthy synovia [49]. As evident from clinical trials, uptake of radiolabeled monoclonal anti-CD3 antibodies (OKT-3), which target all T cells, was detectable in inflamed joints of patients with RA and levels correlated with inflammation scores from physical examination [46–48]. Anti-CD4 antibodies (MAX.16H5) target a more specific subset of T lymphocytes. These antibodies were also evaluated for visualization of inflammatory foci in patients with RA [42–45]. Early studies on the specificity of the antibody signal yielded conflicting results [73], but this specificity was later confirmed in a study using Fab fragments. A higher accumulation of anti-CD4 Fab′ fragments compared with control Fab′ fragments was clearly shown in adjuvant-induced arthritis [74]. Rituximab, a chimeric monoclonal anti-CD20 antibody, is licensed for treatment of RA and has demonstrated good efficacy in a subset of patients [75]. 99mTc-rituximab was shown to localize in inflamed joints of patients with RA [53, 54]. Here, an interesting intra-articular and inter-individual variability was exposed, providing an explanation for the failure of anti-CD20 therapy in certain patients [54]. Finally, with respect to anti-TNF-α, imaging of patients with active RA by using 99mTc-anti-TNF-α showed a high correlation with inflammation detected by MRI and proved to be more sensitive than clinical examination [52]. In addition, Conti and colleagues [2] reported that imaging with anti-TNF-α in patients with active arthritis just before treatment with infliximab could predict the efficacy of the anti-TNF-α therapy.
As evident from Table 1, these radiopharmaceuticals have been evaluated in trials dating back several years; for some of them, no real implementation in imaging has been reported in recent years. Further development of radiolabeled drugs for imaging purposes is subjected to important limitations: (a) the safety issues of murine and chimeric monoclonal antibodies; problems with immunogenicity are now being handled by humanization of the antibodies. (b) The safety profile of the pharmaceutical. Administration of anti-CD3 antibodies, for example, may cause serious adverse effects in some patients, such as the cytokine release syndrome. (c) The inefficacy of certain drugs in patients with RA. As mentioned, anti-CD4 antibody was demonstrated to have potential for location of inflammatory regions, but the lack of therapeutic results in RA has halted further development for imaging. (d) The high costs associated with development and production of these therapies.
In our opinion, radiolabeled anti-CD20 and anti-TNF-α antibodies show the most potential for clinical use. Their effectiveness as treatment for RA has been established, and the first results on identification of patients who will respond to therapy look promising. Further implementation studies demonstrating their value in selecting patients for specific therapies are needed. Currently, conflicting results are found in the literature - coming mostly from registries - about switching to another mode of action or to another TNF blocker in patients failing their first anti-TNF treatment [76, 77]. In the future, the use of radiolabeled antibodies in appropriate randomized studies could help to produce more solid data that might give guidance to clinicians.
Specific tracers for imaging of arthritis in preclinical models
Molecular imaging in animal models is necessary for the development of new tracers but can also be used as an additional objective parameter to assess arthritis in an experimental context, thereby providing detailed information on the disease process. Tracers have evolved to target molecules more specifically than 18 F-FDG or 99mTc-MDP, which visualize general processes (glucose metabolism and bone turnover), and we can see an evolution in the use of more sophisticated techniques for preclinical research. An example of the technical evolution can be seen in the development of tracers that target the folate receptor, a 38-kDa glycosyl-phosphatidylinositol-anchored protein that binds folic acid [65]. The folate receptor is expressed at very low levels in most tissues in homeostatic conditions, except for the kidneys and placenta. Under these circumstances, folic acid is taken up by carriers [78]. Expression of the folate receptor in pathogenic conditions seems to be restricted to several cancer cells and activated macrophages. Interestingly, high-level expression of this receptor was found in activated synovial macrophages from patients with RA [79], a feature that has been exploited in imaging. In 2002, Turk and colleagues [66] published a study in which the folate receptor was targeted in rats with adjuvant-induced arthritis by using 99mTc-labeled folic acid. Gamma scintigraphy was applied to produce images of the inflamed paws, and uptake could be detected in arthritic joints [66]. However, the resolution of this technique is very low. Chen and colleagues [68] developed a fluorescence-labeled folate probe (NIR2-folate) that allowed improved resolution in two mouse models of arthritis and the possibility of detecting arthritis at an early time point. So far, however, fluorescent imaging is being hindered by limited tissue penetration and is not yet optimized for use in patients with RA. Recently, an improved PET tracer (18 F-polyethylene glycol-folate) targeting the folate receptor was shown to hold promise for imaging RA in patients, as it was successfully used in an antigen-induced arthritis model [69]. A folate receptor-targeting agent, 99mTc-EC20 (FolateScan), has been produced and evaluated in the clinic for the assessment of inflammation in joints of patients with RA or other diseases [67, 80]. In a study including 40 RA patients with active and inactive disease, joint involvement was assessed by screening with FolateScan. The number of actively involved joints identified by FolateScan correlated with erythrocyte sedimentation rates and C-reactive protein levels. Larger numbers of actively involved joints were detected with FolateScan than were identified by clinical examination. It was concluded that imaging with FolateScan may be a more sensitive method than physical examination for assessing disease activity [67]. Upregulation of the folate receptor in activated macrophages is also being exploited for targeting of folate-linked drugs to these macrophages in RA [81, 82]. Imaging with FolateScan might help to predict the success rate of this technique.
Vascular endothelium, activated in inflammatory processes, transiently expresses the surface glycoprotein E-selectin in response to cytokines such as IL-1β and TNF-α. Selectins facilitate tethering and rolling of leukocytes on endothelium. These mechanisms commence early in the pathogenesis of arthritis. Fluorescently labeled anti-E-selectin antibodies were successfully used for imaging in a mouse model for RA, enabling detection of subclinical manifestations, monitoring effects of therapy, and quantification of disease [61]. In patients with RA, 99mTc-anti-E-selectin-Fab appeared to be suitable for scintigraphic imaging of synovitis and showed a higher specificity than 99mTc- hydroxymethylene diphosphonate bone imaging [60].
Intercellular adhesion molecule-1 (ICAM-1) is another potential target for imaging of arthritis as it was demonstrated to be expressed on synovial endothelial cells and mice deficient in ICAM-1 showed a reduction in arthritis incidence and severity [84]. In CIA, antibodies targeting ICAM-1 were conjugated to gadolinium diethylenetriamine pentaacetic acid and were able to detect early inflammatory symptoms before the onset of the chronic destructive phase [85].
In arthritic joints, increased apoptotic cells are detected in the synovial membrane [86]. These cells can be imaged by the use of radiolabeled annexin V that binds to phosphatidylserine, which is associated with the inner leaflet of the plasma membrane. It was found that 99mTc-annexin could visualize arthritic joints before the onset of bone destruction [62].
Inflammatory cytokines, such as IL-1β and TNF-α, stimulate the production of MMPs that degrade the extracellular matrix. Levels of MMPs increase in the serum and the synovial fluid of patients with RA. MMP-1, −2, −3, −9, and −13 appear to be most important in RA. Recently, Ryu and colleagues [71] demonstrated the use of an MMP-3-specific polymeric probe for visualization of arthritis by NIR fluorescence imaging. The probe was developed by the conjugation of a NIR dye, an MMP substrate peptide, and a quencher to chitosan nanoparticles. Imaging with this probe allowed early diagnosis of arthritis in mice with CIA. More specifically, at 2 weeks after immunization, before any signs of structural or anatomical changes, a signal from the MMP-3 probe could be detected [71].
Development of these molecular markers is still in its infancy; many have only recently been evaluated for imaging of arthritis in preclinical models. Some show potential for further development, such as MMP-specific probes, which are being commercialized and are entering research labs. Others are less promising for the future and this is due mostly to lower specificity. The targeted cell type might not be exclusively expressed in the inflamed joint or the probe might bind to irrelevant targets, resulting in non-specific signals and low target-to-background ratios.
Potential new targets to be considered for in vivo imaging of arthritis
Molecules in the following section were chosen for discussion because they have been shown, or suggested, to be involved in the pathogenesis of arthritis through functional preclinical studies and expression studies in animal models or patients.
RANK and RANKL
RANKL is a type I-membrane protein of the TNF receptor superfamily, expressed on osteoblasts and T cells. RANKL knockout mice exhibit severe osteopetrosis because of a complete absence of osteoclasts. Furthermore, the importance of RANK-RANKL signaling for bone destruction in arthritis has been demonstrated in several studies [87, 88]. Inhibition of RANKL by denosumab, a human monoclonal antibody, has been effective for the treatment of RA-associated bone loss [89] and bone metastasis in cancer [90]. The receptor for RANKL, RANK, can be detected on pre-osteoclasts in the blood as well as on mature osteoclasts [91]. Importantly, RANK has already proven to be a potential marker for the detection of bone metastasis [92–94]. RANK and RANKL can thus be considered valuable molecular targets for the treatment of bone loss and have great value as markers for RA-associated bone pathology.
Chemokine receptors
Chemokines and their receptors are involved in the recruitment of leukocytes to the site of inflammation; they are key molecules in the pathogenesis of RA and present possible targets for imaging. CCR1 and CCR5 are the ones most implicated in RA. CCR1 is abundantly expressed by macrophages in the inflamed synovium and peripheral blood monocytes of patients with RA, suggesting an important role in recruitment of leukocytes from the circulation. A trial involving 160 patients with RA showed evidence of a beneficial effect of treatment with the small-molecule CCR1 antagonist CCX354-C [95]. CCR5 is highly expressed in the rheumatoid synovium, particularly by T helper (Th)1 lymphocytes [96]. Antagonists of CCR5 have proven to be capable of inhibiting the development of collagen- and adjuvant-induced arthritis [97, 98].
Surface molecules involved in cell adhesion and cell signaling
VCAM-1 is thought to be responsible for recruitment and retention of leukocytes in the inflamed synovium. It is found on fibroblast-like synoviocytes in the synovial lining layer and is upregulated upon stimulation with various cytokines [99]. As mentioned, nanobodies targeting VCAM-1 have proven their worth in imaging of atherosclerotic lesions. The expression of VCAM-1 in arthritis suggests that these nanobodies might also be useful in imaging of arthritic joints.
Integrins, a large family of heterodimeric transmembrane glycoproteins, mediate cell-cell and cell-matrix interactions. Their expression is upregulated in the pro-inflammatory environment of the rheumatoid synovium and leads to production of matrix-degrading enzymes and cytokines [100]. Vitaxin, a humanized monoclonal antibody that blocks the interactions of αvβ3 with its ligands, was tested as treatment for RA in clinical trials [101]. Mature and active osteoclasts express αvβ3; consequently, inhibition or deficiency of the β3 integrin was shown to cause impaired differentiation and function of osteoclasts [102]. Imaging studies were performed with the tripeptide Arg-Gly-Asp (RGD), which binds with high affinity to αvβ3. PET imaging with 64Cu-labeled RGD allowed detection of changes in osteoclast numbers in mouse models for osteopetrosis or osteoporosis [70], suggesting that 64Cu-RGD may be suitable for imaging of osteoclast changes in RA.
Another cell surface molecule implicated in the pathogenesis of RA is the purinoreceptor P2X7, which was shown to be expressed by synoviocytes from RA joints. P2X7 is expressed by various cells, including osteoblasts and osteoclasts, and has been implicated in the formation of multinuclear cells. Triggering of this receptor results in enhanced IL-6 secretion and its absence was shown to result in a loss of ATP-dependent leukocyte function, including IL-1β production and L-selectin shedding [103]. In animal models of arthritis, deficiency of the P2X7 receptor is associated with lower incidence and severity of arthritis [104].
Suppression of tumorigenicity 2 (ST2) is a member of the Toll-like/IL-1 receptor superfamily that participates in inflammatory processes, such as production of Th2 cytokines. The ST2/IL-33 pathway has been implicated in RA pathogenesis, and treatment of CIA with ST2-Fc fusion protein ameliorated the disease and downregulated production of IL-6, IL-12, and TNF-α [105].
Dendritic cell-specific transmembrane protein (DC-STAMP) and osteoclast-stimulatory transmembrane protein (OC-STAMP) are highly expressed by osteoclasts and essential for the fusion of macrophages to multinuclear cells and bone degradation [106]. DC-STAMP was suggested to be a marker for circulating osteoclast precursors in inflammatory arthritis as it was found to be increased on peripheral blood mononuclear cells of patients with psoriatic arthritis [107]. DC-STAMP and OC-STAMP could be valuable for therapy development and imaging of osteoclasts in arthritis.
Challenges for development of new molecular probes
High selectivity of molecular imaging probes is mandatory and represents the most important aspect to consider when developing new candidates for imaging. A second challenge to consider is resolution; theoretically, molecular imaging could also help in showing specific localizations of inflammation, distinguishing enthesitis from arthritis in spondyloarthritis versus RA, but this would require techniques with better resolution. To qualify the cost-effectiveness of a new marker, the molecular imaging method should have an impact on patient management. As stated above, molecular imaging methods might be of help in designing and evaluating proof-of-concept phase I and II trials assessing specific targets. The use of these tools, however, will become established only if they facilitate daily treatment practice in making an appropriate choice for the best treatment option or are able to guide the physician in tapering expensive treatment if a specific state of prolonged remission has been reached. Ultimately, as stated in a recent editorial by Smolen and Aletaha [108], better markers will be needed to make a transition toward real personalized medicine.
The field of molecular imaging has grown substantially in the past two decades; tools and techniques have evolved, and new molecular markers are being identified. Molecular imaging will be of help in a preclinical context by offering a reliable and subjective manner to assess the disease severity and by providing more detailed knowledge of the disease process. Some of the markers will enter the clinic to facilitate diagnosis, monitoring of disease progression, and determination of treatment strategy in a subset of patients. Finally, an important role for molecular imaging may be situated in the assessment of efficacy of new drugs and in the design and evaluation of clinical trials.
- 99mTc-MDP:
99mtechnetium-methylene diphosphonate
Collagen-induced arthritis
Computed tomography
Dendritic cell-specific transmembrane protein
Intercellular adhesion molecule-1
Matrix metalloproteinase
Macrophage mannose receptor
Magnetic resonance imaging
Osteoclast-stimulatory transmembrane protein
Positron emission tomography
Rheumatoid arthritis
Receptor activator of nuclear factor-kappa-B
Receptor activator of nuclear factor-kappa-B ligand
Single-photon emission computed tomography
Suppression of tumorigenicity 2
- Tc:
- Th:
T helper
- TNF-α:
Tumor necrosis factor-alpha
Vascular cell adhesion molecule-1.
We are grateful to Prof. Alfons Billiau for critical revision of the manuscript. Our work was supported by grants from the Regional Government of Flanders (GOA program), the Belgian Federal Government (Interuniversitary Attraction Poles program), and the Government Agency for Innovation by Science and Technology (IWT, Strategisch Basisch Onderzoek project coordinated by Patrick De Baetselier, Laboratory of Cellular and Molecular Immunology, VIB Laboratory of Myeloid Cell Immunology, Brussels, Belgium).
Authors' Affiliations
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Compare Kia Garages and Specialists in Fareham with Who Can Fix My Car.
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subset: commoncrawl


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'World's fastest man' inspires Nos Galan races in Cynon Valley
20 December 2012 Last updated at 08:36 GMT
BBC Radio Wales has been looking at Welsh traditions throughout the festive period.
The Nos Galan races have been taking place in south Wales in the Cynon Valley every New Years Eve for more than 50 years.
Their inspiration goes back to the legend surrounding an 18th Century runner who was said to be the fastest man in the world, as Stephen Fairclough reports.


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06-03-2013 06:01 PM - edited 06-03-2013 06:21 PM
Hello. Read the title for my problem. Earlier today, I played a round or two of MP with my friends on my Xbox. I left to do some things and came back around 2 hours later. Now when I start the game it tells me it's checking my DLC, then my save data, and then my DLC again.
Problem is, it stays on the Checking DLC screen forever. It doesn't freeze, but it just sits there loading. I let it run for about 45 minutes and it was still loading.
It has the little press Y to connect to EA button in the background, and when I hit it it tells me the server is unavaliable and to try again later. I know the servers are up and fine; my friends are all playing right now.
I've tried deleting all the DLC, clearing my cache, disconnecting from the internet and trying then to change my settings only to find that it gets stuck on the Checking DLC pop up even offline, changing discs, and playing it on a different xbox on the same account. Nothing worked. It's driving me crazy right now, for the love of god someone help.
Also, nice live chat, EA. I've been waiting over an hour. ETA 10 minutes, pffffft.
We'll make sure it's you by sending you a code for your trusted devices.Learn more about Login Verification on EA Help
We want to make finding the help you need better, faster, and easier.So, we've had some work done at help.ea.com


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Rates in SGD (taxes & fees included), shown as:
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S$98 Avg. price/night
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Located in Lijiang , this popular property offers an ideal place of rest and relaxation. Hotel was constructed in 2013. The property is made up of one main floor. There are a total of 56 rooms on the premises. The property consists of 16 single rooms and 40 double rooms. Set in the city centre, the Hotel offers easy access to the city and all it has to offer. The Hotel is located a few minutes away from the airport.
Lashi Lake International Wetland Park Lijiang City, Lijiang 674100, China


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Video of the UFC 145 press conference with UFC president Dana White, UFC lightweight champion Jon Jones, and his former teammate-turned-rival, former light heavyweight champion Rashad Evans. watch video >>
http://www.mmaweekly.com/ -- On Wednesday, UFC light heavyweight champion Jon Jones and challenger Rashad Evans came face to face one more time ahead of their highly anticipated UFC 145 showdown. watch video >>
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The time for talking is almost over - light-heavyweight champion Jon Jones and rival Rashad Evans will finally meet to settle the score! Watch UFC 145 Saturday, April 21 live on Pay-Per-View and UFC. watch video >>
The Highlights and the staredown from todays press conference. What was special with the press conference, was that only Champ Jones and Evans were present. Focus was entirely shifted to the main eve watch video >>
The Post fight press conference for UFC 145 went underway directly after the main event between Jon Jones and Rashad Evans was finished. Dana White answered questions as to what he thought of the fig watch video >>
MMA H.E.A.T was on the scene for the UFC 145 post-fight press conference in Atlanta, Georgia. In attendance were UFC President Dana White, UFC light heavyweight champion Jon "Bones" Jones, "Suga" Ra watch video >>
Highlights from the post-fight press conference for UFC 145: Jones vs. Evans on Saturday, April 21, at Philips Arena in Atlanta. watch video >>


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HELP! 7.7 Non Responsive
I have had my tab 7.7 through Verizon for about a year and a few months. Not Rooted, Not modified, nothing. All updates through VZ done. I basically use it when travelling or a few times gaming (not sure why I even bought it... other than watching movies on the plane and in hotel rooms when flying for work).
Anyhow... I have been using it recently to play poker (WSOP) at home at night. I usually keep it plugged in and I have never seen it get low on battery (maybe that was a mistake).
Tonight... with 0 problems ever... I go to start playing my game (WSOP). It is NON RESPONSIVE. No matter what I do... it appears to be dead.
It was plugged in when I reached for it. I have unplugged and replugged it in numerous times. I have held down the power button, let it go, etc numerous times and for numerous lengths. I pulled out the SIM card, the SD card, put them back in. I have done everything I can think of... it appears to be DEAD.
SO... a few questions with this. First and foremost... WTF??? Is there any way to force the back cover off and pull the battery (main reason why I don't by phones without a removable battery). Any way to recover? I don't care about the cache.. or saving any data.. just want it to work.
If any answer to above is "your screwed).. my next question would be... any way to get out of the contract? I bought this pretty close to when it first came out... I paid close to $600... on 2 year contract. I think I have until next March or April. They are now selling for something like $250. I got screwed... I know. But I don't want to pay MORE than the price they are asking now to end my contract on it. Since I now have the S4.. I could just share data IF it was even workin.
Somebody please help. THis tablet has never been abused... and has been used lightly (mainly for games and movies.. never dropped.. and just seems way to strange to just stop working out of the blue).
Thanks in advance!!!
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Re: HELP! 7.7 Non Responsive
Try leaving it plugged in for a good 24 hours without touching it. Then see if it comes back to life.
If that doesn't work, I suppose one possibility would be a power surge that fried something in the tablet. Do you notice any singe marks on the charging cable or plug? If so, see if a different charger works.
Do you have insurance? If not, then call Verizon and ask them what your options are. 2nd option is to call Samsung.
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Re: HELP! 7.7 Non Responsive
I had mine become nonresponsive one time where it would not power up holding the power button about five seconds. I found out from Samsung to hold that power button for 20 seconds, so I did and my 7.7 came alive. Not sure what caused my tablet to hang up and I felt a little sheepish because the information about holding the power button for 20 seconds is in the users manual. Try it. It might work.
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Lent begins tomorrow! Sign up for one of our Easter devotions.
8:22 While the earth remains. This qualifies "neither will I ever again" in v. 21. God will preserve the earth until the final judgment (2 Pet. 3:7,13); the earthly order will not end prematurely.
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Decisions by pharmaceutical companies to seek to develop new therapeutic approaches to any disease are a strategic matter for them alone. No external body advises companies not to carry out research.
The pharmaceutical industry and the Medical Research Council took the lead earlier this year to meet and discuss how therapeutic advances made by the industry in other related fields, such as Alzheimer's disease, could be adopted.
Dr Jeff Kipling
Director of Science and Technology
The Association of the British Pharmaceutical Industry
London SW1Reuse content


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SBJ: Forty Under 40 Class of 2017 revealed SBJ: NBA's RSN ratings down 15 percent SBJ: Sports Media: Ratings math SBD: Redskins Analyst: Is McCloughan Drinking Again? SBG: Spurs Plan To Drop 'White Hart Lane' SBD: MLBAM Hires Michael Paull To Be BAMTech CEO SBD: Audi Signs Naming-Rights Deal With DC United SBD: Monster Easing Into NASCAR Title Sponsorship SBD: Former Player Says WNBA Has "Harmful Culture" SBD: NBC Criticized For Airing Avalanche-Sabres
SMS 2014: One-on-one with Vice Sports publisher Will KierskyOctober 15, 2014 12:23 PM
Even in a crowded sports media marketplace, Vice Sports still sees a clear lane of opportunity ahead. Will Kiersky, publisher of the fledging Vice Sports, was featured in a one-on-one interview to start the second day of the 2014 CSE Sports Marketing Symposium.
"On one end of the sports media spectrum, there's a lot of live event coverage and highlights of that, and on the other side, especially in the digital space, there's a lot of opinion," he said. "We saw a lane where we could focus on the athletes and storytelling."
Launched in June 2014, Vice Sports has already drawn the interest of some of the biggest names in sports, such as New York Knicks player Carmelo Anthony, which has come as a surprise to Kiersky. "We try to give athletes a platform to be as honest as they'd like to be, and give them a comfortable place to speak," he said. "Carmelo's people actually hit us up and told us he'd like to get involved, and it led to a different conversation about free agency than having a camera in his face in the locker room."
The new venture has attracted another audience that surprised Kiersky, as well: female readers. As with most Vice Media brands, the typical reader has fallen into the 18-35 demographic, but numbers that Vice Sports' viewers are roughly 55 percent male and 45 percent female, which Kiersky said speaks to the strength of its female writing staff.While the site is still new, Kiersky said that Vice is already discussing what is the next big step While some plans include new initiatives, such as a short film series and an international look at the world of sports, he said Vice wouldn't forget the one key that will continue to make it successful. "The best way to grow is by telling really great stories and sharing good content and videos that people will want to share," he said.
Other quick takes from Kiersky:
On Derek Jeter's new website, The Players' Tribune: "I think it's fantastic that there are new ways for athletes to tell their story. Often we forget they're regular people thrust into extraordinary situations."
On his biggest concern about the launch: "Vice has a great reputation, but we don't have a lot of currency in the mainstream sports world. We weren't sure what reaction we were going to get from athletes, but it's been great so far."
On bringing an established personality to the brand: "We like to develop young talent, so I don't know if right now if that sort of thing would work."
SMS 2014: SAP Spotlight: Using data to maximize performanceOctober 15, 2014 11:46 AM
In a presentation on Day 2 of the 2014 CSE Sports Marketing Symposium, Frank Wheeler of SAP Media and Sports Entertainment outlined how his company uses data technologies to help clients maximize performance. Wheeler pointed to three main areas of focus: The fan, the player and the business.
On the fan: Wheeler highlighted his company's engagement tools, such as the NFL Player Comparison Tool and the NBA Stats website, as well as fan databases to help target individual interests. "It starts with a transaction history. They go into surveys. They go into web. They're collecting more and more mobile information… How can they leverage that data to gain more insight on the fan and engage with him on more of a one-to-one basis?"
On the player: "Wearable technology is big. I know the NFL is looking at sensor data for the players. The NBA is currently using the SportVU camera system in every arena across the league. Capturing that information and sharing that information with the team, with the coaches, with the players, with the fans, working with those types of organizations on how they can better visualize that data and get the best out of that data."
On the business: Wheeler highlighted the tools that SAP has running in SAP Arena in Mannheim, Germany, as an example of the how analytics can help a sports franchise. "The manager of the arena can be sitting in a suite tied into a management dashboard where it's changing real time on revenue he has for tickets, what type of tickets – season tickets or individual tickets. He can look at how many beers he's sold, how many schnitzels he's sold. All of that data is available through the systems that they're using through POS and the backend solutions. It's all tied to financials, all tied to P&L reporting, all in real time."
2014 SMS: Faces in the CrowdOctober 15, 2014 09:16 AM
SMS 2014: Ideas that move us forward: Cross-Cultural MarketingOctober 15, 2014 08:28 AM
Cross-Cultural Marketing
Tony Harris, Al Jazeera English, moderator
Jennifer Jones, AT&T Mobility
Kenny Mithell, NASCAR
Roberto Ruiz, Univision Communications
Marc Strachan, Diageo
"Multicultural marketing or diverse marketing or cross marketing, whatever you want to call it, is just Marketing 101, ladies and gentlemen," said Marc Strachan, vice president of multicultural marketing for Diageo. "Let's get rid of the titles. Let's get rid of the silos. If you are a marketer, there's money in them there hills and you'd better go after it."
Kenny Mitchell, managing director of brand and consumer marketing for NASCAR, cited the change in broad demographics as reason to reject marketing specifically to individual ethnicities. Mitchell: "If you look at a world where one out of two babies that are born are [people] of color. If you look at marketing to millennials, 40 percent of them are of color. If you are doing that in a silo you are doing yourself a disservice. We are marketing to the sports world. We are marketing to fans. We are marketing to the U.S., and the U.S. is diverse."
"What is important is that you are inclusive and that you think about multicultural consumers from the get-go," said Roberto Ruiz, senior vice president of strategy and insights for Univision Communications. "You do this holistically. You think about this as a comprehensive package, not as an afterthought."Jennifer Jones, AT&T vice president of diverse markets, said that a diverse audience will inevitably be included when marketers tap into the things consumers care about. "Everyone has passions, and sports is a passion," she said.
"Look at millennials now, in particular," said Mitchell. "If something doesn't look the way that they're used to the world being shown, they're going to feel uncomfortable. You're actually disinviting them by showing a world that doesn't reflect who they are, who their friends are and what their world looks like."
While there is progress in this area, said Jones, it is still a challenge to create top-down, companywide support. "It remains a journey," she said. "It's a journey against the inertia of how we've always done things."
SMS 2014: Ideas that move us forward: LGBT CommunityOctober 15, 2014 07:56 AM
Reaching the LGBT Community
Kate Fagan, ESPN, moderator
Robert Boland, NYU
Patrick Burke, You Can Play
Layshia Clarendon, Indiana Fever
Kristine Friend, Marriott International
Hilary Shaev, WNBA
The panel, which focused on the LGBT community as one of "Ideas That Move Us Forward" discussions at the conference, was moderated by ESPN writer Kate Fagan and included Robert Boland, professor of sports management at New York University; Patrick Burke, the co-founder of You Can Play; Indiana Fever guard Layshia Clarendon; Kristine Friend, senior director of segment marketing for Marriott International; and WNBA Vice President of Marketing Hilary Shaev.
"I think there's three ways brands can [interact with the LGBT community]," said Shaev. "One is do nothing, two is market to, and the third and the best would be to engage with."
Friend said she takes this point of view when forming Marriott's Love Travels campaign. "When you can kind of get at the core of what the sense of belonging means to somebody, regardless of who they are, I think you can really engage," she said, "and that person just aspires to be a part of your brand, be part of what you're doing."The panelists cited the Love Travels campaign, the WNBA's pride initiative and Nike's social media success with its Be True campaign as successful examples what can be accomplished by properly engaging with the community.
"The only reason left why you would not be diving in head-first is because you don't get it and you're not paying attention to what's going on," said Burke. "There's no risk involved. Any metric will show you that. There's billions of dollars being left on the table by [the marketing] industry."
Added Boland: "There will be people who will be left on the sideline because they don't think they need to be there. It never hurts to push the envelope."
The panel also discussed a change in the way that women, both straight and gay, are portrayed as representatives of brands and organizations. The traditional notion of selling the sex appeal of an attractive female athlete is in decline, according to Shaev.
"Sex sells sex," she said. "It doesn't sell tickets to sporting events. What becomes sexy is authenticity. It's about athletes portraying themselves on the court as exactly who they are."
When asked about the broad attention given to gay male athletes like Michael Sam and Jason Collins, Clarendon spoke of how the lack of coverage for lesbian athletes hurts the community. "It speaks to the assumption that if you're an athlete and you're a woman, you're a lesbian, because you would never play sports because you like them," she said. "We have to give [gay women] the same publicity. We have to make it just as big of a deal."
2014 SMS: Faces in the CrowdOctober 15, 2014 07:31 AM
SMS 2014: Panelists say there's no question the college sports business model will changeOctober 14, 2014 07:05 PM
Changes in College Sports
Ed Desser, Desser Sports Media
David Greenspan, Winston & Strawn
Ramogi Huma, Nat'l College Players Assoc.
Michael McCann, Univ. of New Hampshire
SMS 2014 Podcast:
College writer Michael Smith and Executive Editor Abraham Madkour discuss the hot-button college panel from Day 1 of the 2014 CSE Sports Marketing Symposium in New York.
Desser, who was called as an expert witness during the O'Bannon case, said a review of court documents showed how the NCAA is operating as a professional sports league. Desser: "There's no pretense at the NCAA that the revenue side of college athletics is anything but a professional operation." Ramogi Huma, president of the National College Players Association, said college football and basketball "are not amateur sports. They are pro sports… Amateurism [in college athletics] is not a moral issue...it's a financial issue."
Huma said NCAA rules need to be reformed, pointing to Louisville player Kevin Ware, who broke his leg during a Final Four game in 2013. Huma said Louisville had the option to not pay for the player's medical expenses and could have stripped his scholarship. "We've been fighting for basic protections for [college athletes] for over a decade." Huma said colleges could find money to pay athletes by putting a portion of media revenue in a trust fund until athletes complete their degree. He dismissed criticism that paying college basketball and football players would hurt women's sports and non-revenue sports. He predicted women's sports would wind up with more funding. "Title IX is the law of the land," he said. Huma also suggested that college athletic departments have plenty of areas where they can cut costs, from paring travel for non-revenue sports to pulling back on construction plans. "Don't build facilities with waterfalls, trap doors and slides," he said.
David Greenspan, partner with Winston & Strawn, said players should be compensated in some way. "Revenues are being generated," he said. "Games on TV are being watched largely because of the kids playing the games." Desser suggested that relaxing some NCAA rules, like allowing players to do local endorsements, would boost interest in the game.
SMS 2014: How cause marketing helps corporations win beyond the playing fieldOctober 14, 2014 06:39 PM
Winning beyond the playing field
Tom Brasuell, MLB
Flo Bryan, CSE
Michael Robichaud, MasterCard
Chad Royale-Pascoe, Boys and Girls Clubs of America
"You can't just take a check and say, 'Fine, use my logo,'" said Flo Bryan, senior vice president of cause and diversity marketing at CSE. "It has to be authentic, and it needs to be a story that is integrated well. It's all about being able to hit multiple passion points for the consumer."
There also has been a shift in thinking among the causes in the industry, as well, said Michael Robichaud, senior vice president of global sponsorships at MasterCard. "It used to be the case that when the one person who cared about the cause left a corporation, that's when the check stopped coming," he said. "Cause-based organizations now understand that the partnership has to be mutually beneficial over time."
Chad Royale-Pascoe, national vice president of corporate and cause partnerships at
the Boys and Girls Clubs of America, said that one of the most important steps on the road to that beneficial relationship is to be very clear on the goals of each party. "Each partner we work with has different goals and results in mind regarding our relationship, and it's much better when we're up front and honest about what sort of goals we have in mind," he said. Royale-Pascoe highlighted his organization's relationship with Buffalo Wild Wings, in which the restaurant chain is measuring the success of its partnership by the number of kids who sign up for team sports.
Quick takes from the panel:
On interest in partnering:
Tom Brasuell, vice president of community affairs at MLB, said that while the league has even more interest from sponsors in being aligned with the league for a cause, as well as from the causes themselves, it's now choosing those relationships carefully. "We actually have a lot fewer than we used to have, as we have decided that we wanted to go with partners that are really interested in the specific causes," he said.
On the extended reach of cause marketing:
Robichaud noted that MasterCard's sports cause marketing partnerships have resonated with the female audience, a result that wasn't necessarily intended but proved to be something the company is proud of.
On shared success between company and cause:
"You can do good by doing good, and there's nothing wrong with that," said Bryan.
SMS 2014 Podcast: Analyzing the college panelOctober 14, 2014 06:02 PM
Among the comments:
■ "The bottom line is that the model is going to change. Is it going to change somewhat, is it going to change drastically, that's what's to be determined."
■ "That's frightening. If you're a commissioner or if you're an athletic director and you've done business one way for the last 20 to 30 years, and now what's being proposed is an open-market system — free agency, players with agents — that's a completely different model. And I think that's what frightens the administrators now and has them so much on the defensive. That takes them in a direction where they're not sure how to operate."
■ "I think it's probably naive to think that Olympic sports and women's sports will not be impacted somewhat. … It's going to have an impact."
2014 SMS: Faces in the CrowdOctober 14, 2014 04:11 PM


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Open Mission
Summary: The fall of Yavin IV has brought about the capture of 5 military soldiers of the Republic who have high level access to sensitive intelligence. This elite Special Forces division was last heard defending freighters during the evacuation. Information gathered from The Shield organization's top agents have uncovered vivid details of a ship on the outskirts of the planet which has the highest probability of containing these Special Operations personnel. Recovering them is our top priority.
Mission: Breach the medium-class star ship and secure military personnel. Attempt to commandeer the vessel.
Risk Assessment: The starship has been reviewed by intellegence SATS, and is concluded to be a heavily equipped warship. Moderate star fighter loadout is suspected, as well as a substantial crew population. Intelligence reports that the possibility of the Sith being onboard is high. This is a high-risk operation that requires a prestine level of tact.
Jedi Objective: Infiltrate the ship and locate Sergeant First Class Malesyn and the 4 Republic Soldiers under his lead. Operatives of the Shield are granting clearance to find and take down the Captain of the ship, preferably alive.
Sith Objective: Defend against the intruding rebels. Evidence of their attack confirms Malesyn has important information vital to the location of the Republic's most recent base of operations. Protect the hostages at all costs. And eliminate or escape from the wave of Republic forces.
SIDE NOTES: The ship in question operates at the behest of the Emperor's Imperial fleet. Granting access to any Sith who is tasked to be onboard. (concluding that it should not be hard to have your OC on board ).
The RP will begin on June 6th, 2011 at approximately 2200 U.S. EastCoast Time.
Anyone wishing to participate can simply show at the time specified. Note that this is a Side plot based on progression of my own accord, and does not necessarily effect the main plot established by the room. This is an opportunity for me to expand on some things I've wanted to expand on as well as test the idea of having members set up open missions. I hope to see those who are interested Saturday!
Any questions you can note me.


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Giant Bloody SyringeItem #: 12333
Giant Bloody Syringe
This giant syringe slowly fills up with fake blood when drawn up. Looks as if the evil doctor would take all of the patient's blood! Gross! The syringe hasn't got any kind of needle so there's no risk of injury. The perfect accessory for Nutty Professor Mask, Fetish Nurse Costume and sadistic shrinks. The syringe is 23cm long!


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NYC Pilgrim Pedal Thanksgiving Day Bicycle Ride
Various locations
Until Thu Nov 27 2014
- $
Photograph: Ed Haas
Not yet rated
Time Out says
Wed Nov 9 2011
Get active on Turkey Day with a bike ride event where everyone can feel like a champion. Certified instructors take care that no rider gets left behind, and prizes will be awarded for the best costume and best themed bike. The 10- to 12-mile tour starts at 23rd Street and the East River in Manhattan and takes cyclists through Brooklyn and Queens, with a sit-down coffee-and-breakfast social at a Brooklyn diner midway through the trip. Children must be accompanied by a parent or guardian. Ages 1 and up.
CommentsAdd +
Venue details
Various locations Greenpoint and Williamsburg
New York
Various locations
- Greenpoint and Williamsburg
New York
- Greenpoint and Williamsburg
- Various locations
- Event phone:
(917) 536-6120
- Event website:
- Categories:
Walks & tours. Bike tours. Sports. Cycling. Things to Do
- Good for:
Mood. Energetic and active. Off the beaten path. Outdoor activities. Kids. Hands-on for kids
- Event type:
- Date Time Price information
Thu Nov 22 20128:00am$20; coffee mugs $10


text:
Friday Challenge: Sweet Amazing Beautiful
Uploaded by TheresaK, May 15 2011 05:04 PM
- Owner:
- Uploaded: May 15 2011 05:04 PM
- Views: 490
- Category: Scraplift Challenge
A simple page that has instantly become one of my favorites. I'm glad I could sneak a few moments to put this together. Aiden (left) and Michaela at 9 months.
Theresa, Alden and Michaela are darling, precious little ones! I'm so happy you're scrapping again and back on the mb! It's good to see you. LOVE your layout.
I'm glad you found time to put this layout together, Theresa! It's great!! I like the blended photo, and the simplicity of this layout. They are darling babies! Thanks for joining the challenge.
Such a gorgeous little photo of two gorgeous little babies. Love the word art and your layout is just perfect.
Beautiful layout starring those precious bablies. I love your word art, and the way you used the flowers.
What cuties! I love the tiny flowers you added and your lovely WA!
Image META information
|MRE SSPaper Crafty; ASO SSEmb Reawakening Photo Mask; ABR Sweet Words; ABR Tender Moments Flowers


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