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Biologics : Targets & Therapy (323)
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Safety of biologics in rheumatoid arthritis: data from randomized controlled trials and registries
Codreanu, Catalin
Damjanov, Nemanja
Biologics : Targets & Therapy
Over the past decade, the use of biologics has significantly changed the management of rheumatoid arthritis (RA). Biologics selectively target components of the immune system, resulting in better disease control. However, the growing use of biologics in RA has increased safety concerns among rheumatologists. Randomized controlled trials (RCTs) and registries are the most reliable sources of clinical safety data. Although safety data from RCTs provide certain insights into the clinical safety profile of an agent, strict constraints in study design (eg, exclusion criteria and restrictive treatment protocols) often do not accurately reflect possible safety issues in the use of the agent, either in the clinical setting or over long-term treatment. Registries, on the other hand, are not restrictive regarding patient enrollment, making them more reliable in evaluating long-term safety. A number of registries have been established globally: in Europe, the United States, and Asia. However, the availability of registry data from Eastern Europe is lacking. The notable exceptions so far are registries from the Czech Republic (ATTRA, a registry of patients treated with anti-tumor necrosis factor-alpha drugs) and Serbia (National registry of patients with rheumatoid arthritis in Serbia [NARRAS]). The current report provides an overview of safety data with biologics in RA from RCTs and registries. Availability of regional safety data from Eastern Europe is of great importance to its clinicians for making evidence-based treatment decisions in RA.
biologic therapy; biologic drugs; adverse events; infections; pregnancy; malignancies
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Multikinase inhibitors use in differentiated thyroid carcinoma
Jasim, Sina
Ozsari, Levent
Habra, Mouhammed Amir
Biologics : Targets & Therapy
Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs) that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required.
differentiated thyroid cancer; progression-free survival; adverse effects; targeted therapy; sorafenib; lenvatinib
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Inactivation of chromatin remodeling factors sensitizes cells to selective cytotoxic stress
Freeman, Miles D
Mazu, Tryphon
Miles, Jana S
Darling-Reed, Selina
Flores-Rozas, Hernan
Biologics : Targets & Therapy
The SWI/SNF chromatin-remodeling complex plays an essential role in several cellular processes including cell proliferation, differentiation, and DNA repair. Loss of normal function of the SWI/SNF complex because of mutations in its subunits correlates with tumorigenesis in humans. For many of these cancers, cytotoxic chemotherapy is the primary, and sometimes the only, therapeutic alternative. Among the antineoplastic agents, anthracyclines are a common treatment option. Although effective, resistance to these agents usually develops and serious dose-related toxicity, namely, chronic cardiotoxicity, limits its use. Previous work from our laboratory showed that a deletion of the SWI/SNF factor SNF2 resulted in hypersensitivity to doxorubicin. We further investigated the contribution of other chromatin remodeling complex components in the response to cytotoxic chemotherapy. Our results indicate that, of the eight SWI/SNF strains tested, snf2, taf14, and swi3 were the most sensitive and displayed distinct sensitivity to different cytotoxic agents, while snf5 displayed resistance. Our experimental results indicate that the SWI/SNF complex plays a critical role in protecting cells from exposure to cytotoxic chemotherapy and other cytotoxic agents. Our findings may prove useful in the development of a strategy aimed at targeting these genes to provide an alternative by hypersensitizing cancer cells to chemotherapeutic agents.
chromatin remodeling; cancer; DNA damage/repair; heat-shock response; oxidative stress
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Targeted alpha anticancer therapies: update and future prospects
Allen, Barry J
Huang, Chen-Yu
Clarke, Raymond A
Biologics : Targets & Therapy
Targeted alpha therapy (TAT) is an emerging option for local and systemic cancer treatment. Preclinical research and clinical trials show that alpha-emitting radionuclides can kill targeted cancer cells while sparing normal cells, thus reducing toxicity. 223RaCl2 (Xofigo®) is the first alpha emitting radioisotope to gain registration in the US for palliative therapy of prostate cancer bone metastases by indirect physiological targeting. The alpha emitting radioisotopes 211At, 213Bi, 225Ac and 227Th are being used to label targeting vectors such as monoclonal antibodies for specific cancer therapy indications. In this review, safety and tolerance aspects are considered with respect to microdosimetry, specific energy, Monte Carlo model calculations, biodosimetry, equivalent dose and mutagenesis. The clinical efficacy of TAT for solid tumors may also be enhanced by its capacity for tumor anti-vascular (TAVAT) effects. This review emphasizes key aspects of TAT research with respect to the PAI2-uPAR complex and the monoclonal antibodies bevacizumab, C595 and J591. Clinical trial outcomes are reviewed for neuroendocrine tumors, leukemia, glioma, melanoma, non-Hodgkins lymphoma, and prostate bone metastases. Recommendations and future directions are proposed.
biodosimetry; microdosimetry; mutagenesis; PAI2; bevacizumab; C595; J591; tumors; cancer; metastases
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Resistant mutations in CML and Ph+ALL – role of ponatinib
Miller, Geoffrey D
Bruno, Benjamin J
Lim, Carol S
Biologics : Targets & Therapy
In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013, ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of ponatinib in CML and Ph+ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of ponatinib will be highlighted, including summaries of the important clinical trials involving ponatinib as well as its current place in therapy.
BCR-ABL; T315I; Ph+ALL; PACE trial; EPIC trial; ARIAD; compound mutations
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Botulinum toxin type A products are not interchangeable: a review of the evidence
Brin, Mitchell F
James, Charmaine
Maltman, John
Biologics : Targets & Therapy
Botulinum toxin type A (BoNTA) products are injectable biologic medications derived from Clostridium botulinum bacteria. Several different BoNTA products are marketed in various countries, and they are not interchangeable. Differences between products include manufacturing processes, formulations, and the assay methods used to determine units of biological activity. These differences result in a specific set of interactions between each BoNTA product and the tissue injected. Consequently, the products show differences in their in vivo profiles, including preclinical dose response curves and clinical dosing, efficacy, duration, and safety/adverse events. Most, but not all, published studies document these differences, suggesting that individual BoNTA products act differently depending on experimental and clinical conditions, and these differences may not always be predictable. Differentiation through regulatory approvals provides a measure of confidence in safety and efficacy at the specified doses for each approved indication. Moreover, the products differ in the amount of study to which they have been subjected, as evidenced by the number of publications in the peer-reviewed literature and the quantity and quality of clinical studies. Given that BoNTAs are potent biological products that meet important clinical needs, it is critical to recognize that their dosing and product performance are not interchangeable and each product should be used according to manufacturer guidelines.
Video abstract
onabotulinumtoxinA; abobotulinumtoxinA; incobotulinumtoxinA; glabellar lines; non-interchangeability
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New product development with the innovative biomolecular sublingual immunotherapy formulations for the management of allergic rhinitis
Frati, Franco
Cecchi, Lorenzo
Scala, Enrico
Ridolo, Erminia
Dell'Albani, Ilaria
Makrì, Eleni
Pajno, Giovanni
Incorvaia, Cristoforo
Biologics : Targets & Therapy
The molecular allergy technique, currently defined as component-resolved diagnosis, significantly improved the diagnosis of allergy, allowing for differentiation between molecules actually responsible for clinical symptoms (genuine sensitizers) and those simply cross-reacting or shared by several sources (panallergens), thus influencing the appropriate management of a patient's allergy. This also concerns allergen immunotherapy (AIT), which may be prescribed more precisely based on the component-resolved diagnosis results. However, the advance in diagnosis needs to be mirrored in AIT. According to consensus documents and to expectations of specialists, therapy should be based on standardized extracts containing measured amounts of the clinically relevant molecules, ie, the major allergens. The new generation of extracts for sublingual immunotherapy fulfills these requirements and are thus defined as biomolecular (BM). BM refers to natural extracts with a defined content of major allergens in micrograms. All Staloral BM products are indicated for the treatment of allergic rhinitis with or without asthma. The effectiveness of AIT is related to its ability to modify the immunological response of allergic subjects. The 5-grass and house dust mite extracts were evaluated addressing the T helper 1, T helper 2, and T helper 3 cells by polymerase chain reaction array on mRNA extracted from Waldeyer's ring tissue (adenoids). Sublingual immunotherapy with a defined content of major allergens in micrograms induced a strong downregulation of genes involved in T helper 2 and T helper 1 activation and function, allowing the definition of the immunologic effect as "bio-homeostatic". This clinical and immunological model must be implemented with respect to other allergens, thus expanding the application of a treatment with a unique disease-modifying capacity.
allergen immunotherapy; allergy; component resolved diagnosis; major allergens; allergen molecules
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Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists
Urbano, Paulo César Martins
Soccol, Vanete Thomaz
Azevedo, Valderilio Feijó
Biologics : Targets & Therapy
Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation.
anti-TNF drugs; rheumatoid arthritis; apoptosis; NF-κB; FLIP
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Plasma membrane coenzyme Q: evidence for a role in autism
Crane, Frederick L
Löw, Hans
Sun, Iris
Navas, Placido
Gvozdjáková, Anna
Biologics : Targets & Therapy
The Voltage Dependent Anion Channel (VDAC) is involved in control of autism. Treatments, including coenzyme Q, have had some success on autism control.
Data sources
Correlation of porin redox activity and expression of autism is based on extensive literature, especially studies of antibodies, identification of cytosolic nicotinamide adenine dinucleotide reduced (NADH) dehydrogenase activity in the VDAC, and evidence for extreme sensitivity of the dehydrogenase to a mercurial. Evidence for a coenzyme Q requirement came from extraction and analog inhibition of NADH ferricyanide reductase in the erythrocyte plasma membrane, done in 1994, and reinterpreted when it was identified in VDAC in 2004. The effects of ubiquinol (the QH2 – reduced form of coenzyme Q) in children with autism were studied.
A new role for coenzyme Q in the porin channels has implications on autism. Ubiquinol, the more active form of coenzyme Q, produces favorable response in children with autism. Agents which affected electron transport in porin show parallel effects in autism.
We propose a hypothesis that autism is controlled by a coenzyme Q-dependent redox system in the porin channels; this conclusion is based on the effects of agents that positively or negatively affect electron transport and the symptoms of autism. The full understanding of the mechanism of their control needs to be established.
porin; channel; oxidation; reduction; autism
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Golimumab in unresponsive ulcerative colitis
Lippert, Elisabeth
Müller, Martina
Ott, Claudia
Biologics : Targets & Therapy
Ulcerative colitis (UC) is a chronic inflammation mainly affecting the colon mucosa. It predominantly occurs in younger patients. Until recently, the main goals in the treatment of UC were to temper the symptoms, such as diarrhea, pain, and weight loss, by using mesalazine and steroids. With newer medications, such as immunomodulators (thiopurines) and the biologics providing blockade of tumor necrosis factor (TNF), the goals of the therapy in UC have changed to long-term remission and mucosal healing. The first available anti-TNF therapy in UC included infusion therapy with infliximab every few weeks. In 2012, subcutaneously administered adalimumab gained approval for the treatment of UC in Germany. In patients with a mild disease, therapy with mesalazine, orally or topically, can be sufficient. In patients with moderate to severe disease, therapy with azathioprine or anti-TNF is often required to reach disease control; however, this is only efficient in about two-thirds of patients. Some patients either show no response or a lost response while on treatment. So, further medical options are warranted in the treatment of UC. With golimumab, a new approach in the treatment of mild to moderate UC recently became available in Germany and is a promising new option in the therapy regimen for patients with UC.
anti-TNF; biological therapy; inflammatory bowel disease
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Clinical and comparative utility of afatinib in non-small cell lung cancer
D'Arcangelo, Manolo
Hirsch, Fred R
Biologics : Targets & Therapy
The first targeted agents approved for non-small cell lung cancer (NSCLC) treatment, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, have an impressive activity in the presence of activating mutations of the EGFR gene. However, all patients develop acquired resistance principally through secondary mutations (T790M), HER2 amplification, MET amplification, and other molecular aberrations. An attempt to overcome EGFR TKI resistance has been through the development of irreversible blockers. Afatinib is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family. The pharmacologic properties of afatinib (formation of covalent bonds, inhibition of other family members, and in vitro and in vivo activity on T790M mutation positive tumors) made this drug particularly appealing to study in clinic. Therefore, an intense program of clinical research (LUX-Lung program) was started and clinical results have shown very encouraging activity profiles in patients harboring EGFR activating mutations and in those with acquired resistance to reversible TKIs.
NSCLC; EGFR; tyrosine kinase inhibitor; afatinib
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Anti-TNF therapy in Jordan: a focus on severe infections and tuberculosis
Alawneh, Khaldoon M
Ayesh, Mahmoud H
Khassawneh, Basheer Y
Saadeh, Salwa Shihadeh
Smadi, Mahmoud
Bashaireh, Khaldoun
Biologics : Targets & Therapy
A high rate of infection has been reported in patients receiving treatment with anti-tumor necrosis factor (anti-TNF). This study describes the rate of and risk factors for serious infections in patients receiving anti-TNF agents in Jordan.
This retrospective observational study was conducted at a large tertiary referral center in the north of Jordan. Between January 2006 and January 2012, 199 patients who received an anti-TNF agent (infliximab, adalimumab, or etanercept) were included. Patients received the anti-TNF treatment for rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, or other conditions. A serious infection was defined as any bacterial, viral, or fungal infection that required hospitalization, administration of appropriate intravenous antimicrobial therapy, and temporary withholding of anti-TNF treatment.
The mean duration of anti-TNF treatment was 26.2 months. Steroids were used in 29.1% of patients, while 54.8% were given additional immunosuppressant therapy (methotrexate or azathioprine). Only one anti-TNF agent was given in 70.4% of patients, while 29.6% received different anti-TNF agents for the duration of treatment. Serious infections were documented in 39 patients (19.6%), including respiratory tract infections (41%), urinary tract infections (30.8%), and skin infections (20.5%), and extrapulmonary tuberculosis in three patients (7.7%). Exposure to more than one anti-TNF agent was the only factor associated with a significant increase in the rate of infection (relative risk 1.9, 95% confidence interval 1.06–4.0, P=0.03).
Serious infections, including tuberculosis, were a common problem in patients receiving anti-TNF agents, and exposure to more than one anti-TNF agent increased the risk of serious infection.
anti-tumor necrosis factor therapy; biologics; developing world; extra-pulmonary tuberculosis; immune mediated diseases
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Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis
Kivelevitch, Dario
Mansouri, Bobbak
Menter, Alan
Biologics : Targets & Therapy
Psoriasis is a chronic, immune-mediated inflammatory disease affecting both the skin and joints. Approximately 20% of patients suffer a moderate to severe form of skin disease and up to 30% have joint involvement. Standard therapies for psoriasis include topical medications, phototherapy, and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti-inflammatory drugs followed by disease modifying antirheumatic drugs and/or tumor necrosis factor (TNF)-α inhibitors and interleukin-12/23p40 inhibitors. Treatment of both diseases is typically driven by disease severity. In the past decade, major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies, which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis. Anti-TNF-α agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis. Currently approved anti-TNF-α agents include etanercept, adalimumab, and infliximab for psoriasis and psoriatic arthritis as well as golimumab and certolizumab for psoriatic arthritis. In this article, we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis.
psoriasis; psoriatic arthritis; etanercept; biological therapy; tumor necrosis factor; safety
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Epoetin zeta in the management of anemia associated with chronic kidney disease, differential pharmacology and clinical utility
Davis-Ajami, Mary Lynn
Wu, Jun
Downton, Katherine
Ludeman, Emilie
Noxon, Virginia
Biologics : Targets & Therapy
Epoetin zeta was granted marketing authorization in October 2007 by the European Medicines Agency as a recombinant human erythropoietin erythropoiesis-stimulating agent to treat symptomatic anemia of renal origin in adult and pediatric patients on hemodialysis and adults on peritoneal dialysis, as well as for symptomatic renal anemia in adult patients with renal insufficiency not yet on dialysis. Currently, epoetin zeta can be administered either subcutaneously or intravenously to correct for hemoglobin concentrations ≤10 g/dL (6.2 mmol/L) or with dose adjustment to maintain hemoglobin levels at desired levels not in excess of 12 g/dL (7.5 mmol/L). This review article focuses on epoetin zeta indications in chronic kidney disease, its use in managing anemia of renal origin, and discusses its pharmacology and clinical utility.
biosimilar; chronic kidney disease; epoetin alfa; erythropoiesis; renal anemia; Retacrit®
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Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib
Stjepanovic, Neda
Capdevila, Jaume
Biologics : Targets & Therapy
Thyroid cancers are the most frequent neoplasms of the endocrine system and in the initial stages their prognosis is excellent. However, few therapeutic options are available for advanced or metastatic disease. In the last decade, a better understanding of the molecular events involved in the tumorigenesis of thyroid cancers has led to development of new targeted agents for the management of advanced and refractory disease. Multikinase inhibitors that are able to block pathways involved in the proliferation, invasion, and neoangiogenesis of thyroid cancer have been the most widely studied. After an international effort to identify and recruit sufficient patients, four placebo-controlled studies of multikinase inhibitors have been completed. These trials have led to the approval of the first agents with activity in advanced medullary thyroid cancers, which will probably change the landscape of treatment for iodine-refractory differentiated thyroid cancer in the near future. The purpose of this paper is to review the development of targeted agents for thyroid malignancy, with a special focus on lenvatinib, a multikinase inhibitor.
thyroid cancer; lenvatinib; tyrosine kinase inhibitors; multikinase inhibitors; targeted therapies
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Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors
Tanaka, Toshio
Hishitani, Yoshihiro
Ogata, Atsushi
Biologics : Targets & Therapy
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs) including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs). Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients.
interleukin-6; rheumatoid arthritis; adalimumab; biologic
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Advancing personalized care in hemophilia A: ten years' experience with an advanced category antihemophilic factor prepared using a plasma/albumin-free method
Berntorp, Erik
Spotts, Gerald
Patrone, Lisa
Ewenstein, Bruce M
Biologics : Targets & Therapy
Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10–65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10–65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting.
rAHF-PFM; ADVATE; FVIII; prophylaxis; pharmacokinetics; individualized
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Biologics: the role of delivery systems in improved therapy
Škalko-Basnet, Nataša
Biologics : Targets & Therapy
The beginning of the 21st century saw numerous protein and peptide therapeuticals both on the market and entering the final stages of clinical studies. They represent a new category of biologically originated drugs termed biologics or biologicals. Their main advantages over conventional drugs can be summarized by their high selectivity and potent therapeutic efficacy coupled with limited side effects. In addition, they exhibit more predictable behavior under in vivo conditions. However, up to now most of the formulations of biologics are designed and destined for the parenteral route of administration. As a consequence, many suffer from short plasma half-lives, resulting in their frequent administration and ultimately poor patient compliance. This review represents an attempt to address some of the challenges and promises in the product development of biologics both for parenteral and noninvasive administration. Some of the products currently in the pipeline of pharmaceutical development and corresponding perspectives are discussed in more detail.
biologics; drug delivery systems; medical devices
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Targeted therapy for sarcomas
Forscher, Charles
Mita, Monica
Figlin, Robert
Biologics : Targets & Therapy
Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways.
sarcoma; targeted agents; tyrosine kinase inhibitors; mTor inhibition
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Porcine dermis implants in soft-tissue reconstruction: current status
Smart, Neil J
Bryan, Nicholas
Hunt, John A
Daniels, Ian R
Biologics : Targets & Therapy
Soft-tissue reconstruction for a variety of surgical conditions, such as abdominal wall hernia or pelvic organ prolapse, remains a challenge. There are numerous meshes available that may be simply categorized as either synthetic or biologic. Within biologic meshes, porcine dermal meshes have come to dominate the market. This review examines the current evidence for their use and the limitations of knowledge. Although there is increasing evidence to support their safety, long-term follow-up studies that support their efficacy are lacking. Numerous clinical trials that remain ongoing may help elucidate their precise role in soft-tissue reconstruction.
hernia; mesh; xenograft; biologic
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A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations
Wells, Alvin F
Jodat, Nicole
Schiff, Michael
Biologics : Targets & Therapy
There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept's mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient considerations such as pain, disability, loss of function, fatigue, and quality of life.
rheumatoid arthritis; abatacept; subcutaneous; biologic DMARD; patient-reported outcomes
Related Articles
Update on the use of systemic biologic agents in the treatment of noninfectious uveitis
Pasadhika, Sirichai
Rosenbaum, James T
Biologics : Targets & Therapy
Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet's disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet's disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis.
biologics; monoclonal antibody; eye
Related Articles
Does the cis/trans configuration of peptide bonds in bioactive tripeptides play a role in ACE-1 enzyme inhibition?
Siltari, Aino
Viitanen, Riikka
Kukkurainen, Sampo
Vapaatalo, Heikki
Valjakka, Jarkko
Biologics : Targets & Therapy
The milk casein-derived bioactive tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) have been shown to prevent development of hypertension in animal models and to lower blood pressure in moderately hypertensive subjects in most but not all clinical trials. Inhibition of angiotensin-converting enzyme 1 (ACE-1) has been suggested as the explanation for these antihypertensive and beneficial vascular effects. Previously, human umbilical vein endothelial cells (HUVEC) have not been used to test ACE-1 inhibiting properties of casein derived tripeptides in vasculature.
We focused on the cis/trans configurations of the peptide bonds in proline-containing tripeptides in order to discover whether the different structural properties of these peptides influence their activity in ACE-1 inhibition. We hypothesized that the configuration of proline-containing peptides plays a significant role in enzyme inhibition.
AutoDock 4.2 docking software was used to predict suitable peptide bond configurations of the tripeptides. Besides modeling studies, we completed ACE-1 activity measurements in vitro using HUVEC cultures.
In HUVEC cells, both IPP and VPP inhibited ACE-1. Based on molecular docking studies, we propose that in ACE-1 inhibition IPP and VPP share a similar cis configuration between the first aliphatic (isoleucine or valine) and the second (proline) amino acid residues and more different configurations between two proline residues. In vivo experiments are needed to validate the significance of the present findings.
ACE inhibition; Autodock modeling; Ile-Pro-Pro; Val-Pro-Pro; vascular function
Related Articles
Therapeutic vaccines and cancer: focus on DPX-0907
Karkada, Mohan
Berinstein, Neil L
Mansour, Marc
Biologics : Targets & Therapy
In an attempt to significantly enhance immunogenicity of peptide cancer vaccines, we developed a novel non-emulsion depot-forming vaccine platform called DepoVax™ (DPX). Human leukocyte antigen (HLA)-A2 restricted peptides naturally presented by cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. In a phase I clinical study, the safety and immune-activating potential of DPX-0907 in advanced-stage breast, ovarian, and prostate cancer patients were examined, following encouraging results in HLA-A2 transgenic mice. The DPX-0907 vaccine was shown to be safe and well tolerated, with injection-site reactions being the most commonly reported adverse event. Vaccinated cancer patients exhibited a 61% immune response rate, with higher response rates in the breast and ovarian cancer patient cohorts. In keeping with the higher immune efficacy of this vaccine platform, antigen-specific responses were detected in 73% of immune responders after just one vaccination. In 83% of responders, peptide-specific T-cells were detected at two or more time points post-vaccination, with 64% of these patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T-cell memory, with the ability to secrete multiple type 1 cytokines. The novel DPX formulation promotes multifunctional effector/memory responses to peptide-based tumor-associated antigens. The data support the capacity of DPX-0907 to elicit type-1 biased immune responses, warranting further clinical development of the vaccine. In this review, we discuss the rationale for developing DPX-based therapeutic cancer vaccine(s), with a focus on DPX-0907, aimed at inducing efficient anti-tumor immunity that may eventually be shown to prolong patient survival.
immunotherapy; DepoVax™; cancer vaccine; DPX-0907
Related Articles
Anti-tumor necrosis factor (TNF) drugs for the treatment of psoriatic arthritis: an indirect comparison meta-analysis [Corrigendum]
Biologics : Targets & Therapy
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Vendor presence was fairly steady at last year's TourExpo, says Americade VP Christian Dutcher.
"We seemed to buck the trend of many other rallies, and slightly grew in '07," he says, adding, "2007 was 25th event, and there's always strong interest in an anniversary year. We also marketed the event more aggressively than prior years. We're also providing more services to our attendees, like shuttle buses to bring them to various parts of the rally."
Vendors at the Honda Hoot in Kentucky have remained steady for the last couple of years: 201 in 2006 and 200 last year. "The Honda Hoot vendor fees are among the lowest for a national rally," says Walt Miller, business manager for The Hoot.
Hoot attendance was up a bit, to 16,468 in 2007 from 15,751 in '06. Miller says the right vendor mix is key to an event's success.
"We do our best to have a good mix of vendors whose products cross most motorcycle segment lines, including non-motorcycle related vendors," Miller says. "It's heresy to say it, but many attendees do not live and breathe motorcycles 24 hours a day."
Rallies Spread As Dollars Stretch
The annual Black Hills Rally in and around Sturgis, S.D., draws about 800 to 900 vendors a year. Attendance was up slightly in 2007 (507,000) vs. 2006 (457,000).
But the downturn in the U.S. economy is forcing many rally organizers to brace for possible lower numbers this summer:
- "With the changes forecast for the industry, things are going to start to slow down a little. You may not have growth, and you may be backing away from some of the crowds you were getting in the '90s," Sturgis Rally Director Pepper Massey-Swan says.
- "We are prepared for whatever comes, and we are hoping we will get as many visitors as last year. We are seeing an improvement in the quality as well as the quantity of vendors," says Kevin Killian of the Daytona-Halifax Chamber of Commerce.
- "We are increasing our promotional activities further, but given the economic slowdown that is widely forecast, we'll be pleased if we match the 2007 numbers," says Americade's Dutcher.
Organizers expect attendees to stretch their dollars in a number of ways. "The cost of fuel is going to start having a greater impact on what people do. The mad money is drying up. You are not seeing a decline in fuel prices this winter like we have in past years," Copeland says. While Myrtle Beach Bike Week draws about 350,000 people a year, visitors seem to be shortening their visits by one day.
"The attendance was about the same, but people did not stay as long as they did before" in 2007, Copeland says. "People only have so much money to spend. You about have to drop a day somewhere to accommodate the increase in cost, or increase your budget."

subset: commoncrawl


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GRAND RAPIDS, Mich. — Following in the steps of vineyards, wine critics and specialty wine shops, D&W Fresh Market is offering virtual wine tastings. The new "Wireside Chats" are free, one-hour online forums open to all levels of wine drinkers, according to promotional materials from D&W, a Spartan Stores' banner. The chats will be hosted by D&W wine experts, wine makers and other professional guests. Participants will receive special offers. Both daytime and evening chats ...
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By David Krueger Herald Writer
STANWOOD — There's an old saying: Where there's a will, there's a way.
The Snohomish Panthers boys basketball team had the will, and, come the second half, they finally found a way.
The Panthers, ranked No. 4 in the state in the Class 4A Tacoma News Tribune boys basketball poll, got off to a slow start. But thanks to some impressive late shooting, particularly by star guard Luke Hamlin, Snohomish was able to come from behind and defeat the Stanwood Spartans 65-54 Tuesday night at Stanwood High School.
The Panthers trailed for all but five minutes in the first three quarters, and when they weren't tied their biggest lead was three, right at the end of the third quarter.
"We wanted to contest threes and make them put the ball on the floor," said Stanwood head coach Zach Ward. "We did an okay job in the first half."
But in the second half Snohomish outscored the Spartans 39-27, and began making baskets it had missed in the first half. Meanwhile, Stanwood missed baskets it had previously made.
Hamlin was a good example, scoring seven points in the first half, all in the second quarter. In the second half he had 19 points, finishing with a game-high 26.
"We don't expect that, but we like it," said Panthers head coach Len Bone.
Bone said that in the second half the Panthers were able to combat the defense of Stanwood more effectively, as the Spartans switched back and forth between a 2-3 zone and man-to-man coverage.
"We moved the ball better," said Bone, "and got some openings."
Gabe Reichenberger contributed 12 points — making a 3-pointer in each quarter – and Russell Crippen also scored 12 points for the Panthers. Mitchell Stewart (six rebounds), Crippen (five) and Hamlin (five) all helped Snohomish outrebound Stanwood 18-10 in the second half.
Stanwood got off to a 7-0 lead to start the game, and led for all but four minutes until the end of the third quarter. Cannen Roberson had eight of his 15 points in the first quarter for the Spartans. By the end of the second quarter the Panthers had cut the lead to one, 27-26, going into halftime.
Then the Panthers came out firing.
After halftime Roberson and Hamlin had the first five points for their respective teams. Snohomish took its first lead of the game two minutes into the quarter, 33-32. That lasted about four minutes before the Spartans came roaring back thanks to senior Brennan Williams, who finished the game with 14 points.
But it was only a matter of time before Hamlin, who averages nearly 24 points per game, started draining shots.
"I take what they give me," Hamlin said. "My teammates get me open."
Hamlin scored nine points in the third quarter and 10 in the fourth to seal the victory for the Panthers.
"I thought we did a good job of keeping track of him in the first half," said Ward.
Stanwood shot 39 percent (22-of-57) from the field. Drew Sears provided a spark off the bench with nine points and four rebounds. Roberson and Williams each grabbed five rebounds apiece as well.
The game was the end of the first trip through the Wesco North for both teams. The Panthers finished a perfect 5-0 in league, and are now 8-0 overall. They know that with that record — and the No. 4 ranking — teams are going to be gunning for them every night.
"We gotta play tough," Hamlin said. "We know that now that we're ranked as high as we are, teams are gonna play tough."
In the Stanwood locker room, Ward said that his team wasn't focused on Snohomish's ranking, just the fact that "they're ahead of us in the standings." With the loss, the Spartans finish their first run through the conference at 3-2 and have a 4-3 overall record.
"It's not the end of the year," Ward said. "It's three-and-two the first time through the North. The bulk of our season is in January. Our goal is to be playing our best basketball in January and we got a lot of work to do to get there."
At Stanwood H.S.
Snohomish—Yates 8, Hamlin 26, Stewart 6, Crippen 12, Baird 0, Carlson 0, Reichenberger 12, Harris 0, Caldwell 1. Stanwood—M. Garcea 0, Thayer 5, Roberson 15, Stang 4, Zipp 0, B. Garcea 1, Swenson 6, Williams 14, Sears 9. 3-point goals—Reichenberger 4, Yates 2, Hamlin 1, Crippen 1, Williams 2, Thayer 1, Roberson 1. Records—Snohomish 5-0 league, 8-0 overall. Stanwood 3-2, 4-3.


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For the second season in a row the Vikings humbled Hull - making a mockery of their visitors' title aspirations - but their night was soured by a spate of injuries.
Marquee signing Kevin Brown starred but went off 60 minutes into his debut with an ankle injury, while centre Stefan Marsh dislocated his shoulder and coach Denis Betts said: "Kevin will have a scan and we are looking at it positively and maybe it's just a twisted ankle. But Stefan could be out to 10-12 weeks."
The injuries took the shine off an impressive show with Paddy Flynn and Cameron Phelps scoring two tries each, with the other touchdowns coming from Chris Dean, Frank Winterstein and the outstanding Gareth Hock.
Betts added: "We made a dodgy start but stayed solid. We had to work hard and it's never unexciting coming here. I am happy with the way we defended and Gaz (Hock) is exciting and good for the team.
"He's going to get better but can do things other players can't do. Ben Cross also gives us a bit of punch but I am not satisfied with two wins out of four because we should have beaten St Helens too."
Last season Hull coach Peter Gentle tore into his players after an abject showing at the Stobart Stadium and tonight was no different.
"We are playing without patience and should not have conceded a try just before half time when we led 12-4," he said. "We did not give ourselves a chance with a poor completion rate and too many penalties.
"We have to do a lot better than that. We have made no progress from last year and need to make changes. The personnel out there aren't doing it."
Gentle has injuries of his own to deal with and added: "We need our two key signings Gareth Ellis and Daniel Holdsworth back, but the players out there should have done the job and didn't."
- Sports & Recreation
- American Football
- Stefan Marsh
- Denis Betts


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The Press Newspaper
The Press Newspaper
Oregon City Council on Monday, following a public hearing, approved a permanent Special Use Exception (SUE) in a non-agricultural area at 6338 Brown Road for the purpose of housing livestock.
The Planning Commission last April had recommended approval of a temporary SUE in an R-1 Low Density Residential District for the applicants and property owners Mohamed Tawil and his wife Nabil.
Brad Fields, of East Toledo, has always wanted to give back to his community.
After going and growing through some personal issues, Fields decided to give back to his community and help area youth along the way.
A permit issued by the Lake Township zoning inspector that allows a developer to deepen a detention pond in the Freedom Estates subdivision and convert it into a permanent pond is being challenged by several subdivision residents who have filed an appeal.
Dave Miesmer, zoning inspector, said Tuesday he intends to place the matter on the township zoning board of appeal's May meeting agenda.
The Fair Housing Center (FHC) is promoting a relatively new state program that helps people who are struggling to pay their mortgages.
The FHA is a HUD certified counseling agency under the Ohio Housing Finance Agency.
Dr. Mike Zalar, superintendent of Oregon City Schools District, has applied for the position of superintendent for the Gahanna-Jefferson Schools District, in Gahanna, Ohio, near Columbus.
The Gahanna-Jefferson Public Schools, according to the district's website, "is seeking an experienced administrator who embraces the challenge of leading an already excellent district to the next level while working collaboratively with the board, the community, the staff and students."
Summer Olympics
Are you watching the Summer Olympics in Rio?
No, I couldn't care less (9 Votes)
Yes, go U.S.A.! (17 Votes)
Olympics...are they on? (7 Votes)
1840544969 [{"id":"135","title":"No, I couldn't care less","votes":"9","pct":27.27,"type":"x","order":"1","resources":[]},{"id":"136","title":"Yes, go U.S.A.!","votes":"17","pct":51.52,"type":"x","order":"2","resources":[]},{"id":"137","title":"Olympics...are they on?","votes":"7","pct":21.21,"type":"x","order":"3","resources":[]}] ["#194e84","#3b6b9c","#1f242a","#37414a","#60bb22","#f2babb"] sbar 160 160 /component/communitypolls/vote/53-summer-olympics No answer selected. Please try again. Thank you for your vote. Answers Votes


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1 question, 1 venue
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I am getting a Page Not Found when clicking the view details to see the individual location.
I am getting a Page Not Found when clicking the view details to see the individual location.
Could you try going to Settings -> permalinks and click save.
let me know if that fixes your issue
thanks for trying out the plugin and your feedback
Hi Paul,
I have done everything as described but when I inserted the map onto the WordPress page - I can't see it. Won't preview.
can you share a link to that page?
Sorry Paul, did you mean the back-end?
could you try switching to the Tenty Ten or Twenty Eleven theme? Try disabling all other plugins.
Also make sure you've actually added some locations and checked the display on map for each one.
Will do. But this is the only plugin I have activated on the site at this stage. It might a theme issue though.
Yes, it is a theme conflict.
glad you were able to identify the issue.
Check for the presence of the wp_footer() function in the templates. Usually in footer.php
Many thanks!
Hi Paul,
The template we are using really meets our needs so I was wondering if you have any suggestions regarding altering the template so that the wp map marker will work with it.
Many thanks
This topic has been closed to new replies.


text:
MichaelNel... Photographer
Caryssa BeardModel Female Charlotte, North Carolina, US
My Website: FacebookMy MM URL: http://www.modelmayhem.com/caryssabeard
Mayhem # 2382482
About MeModeling and Acting are my newfound passions, and i can't get enough of them! I have been singing and dancing since before I could walk. The arts is something I will always and for the rest of my life be involved in. Growing up I was often told I would one day be a star. However, in my eyes I simply want to be successful in this industry and to give back. Fame isn't everything, mind you being noticed in that aspect would be nice, it is not my ultimate goal in life. I would rather be a role model and change lives in other ways and the best ways that i can. Some think I'm young and naive for having such thoughts, but for me it's my dream. I have that confidence and drive that many others lack, I will not give up easily.
Have you worked with Caryssa Beard? Add Credits for Caryssa Beard! >>
MichaelNel... Photographer
MFFPHOTOGR... Photographer
OkoFoto Photographer
Kelsey MModel Model
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Fast Facts About Fisher
St. John Fisher College is an independent, liberal arts institution in the Catholic tradition of American higher education. The College emphasizes liberal learning for students in traditional academic disciplines, as well as for those in more directly career-oriented fields. The College welcomes qualified students, faculty, and staff regardless of religious or cultural background.
The campus is situated on 154 park-like acres - a beautiful setting for 26 modern buildings and a warm, friendly campus community. The College offers 35 academic majors in the humanities, social sciences, sciences, business, education, and nursing, as well as 11 pre-professional programs.
Fisher offers a variety of master's and doctoral programs.
Founded in 1948 by the Congregation of St. Basil as a Catholic College for men, St. John Fisher College became independent in 1968 and coeducational in 1971 and continues to honor its Catholic and Basilian heritage.
Student-Faculty Ratio
Nearly 2,700 full-time and 200 part-time undergraduate students; 40 percent male and 60 percent female.
Typical Class Size
20 to 25 students
For 2016-2017, annual tuition for full-time students is $31,300. Housing and meal costs are $11,740 per year. View the cost breakdown.
Athletics are an important part of campus life. The College is a Division III member of the NCAA, the Eastern Collegiate Athletic Conference, Empire 8, and the Liberty League (rowing).
Men compete in baseball, basketball, cross country, football, golf, lacrosse, rowing, soccer, tennis, and track & field.
Women compete in basketball, cross country, field hockey, golf, lacrosse, rowing, soccer, softball, tennis, volleyball, and track & field.
Financial Aid
There are many forms of financial assistance available to help you afford a Fisher education. Need-based and merit-based scholarships, as well as grants, loans, and part-time employment, are available for eligible students.
Students may choose from a wide range of campus clubs and organizations, including student government, music groups, language clubs, cultural organizations, student publications, and intramural sports. Many academic departments also sponsor clubs.
Points of Pride
Several Fisher faculty members have received prestigious Fulbright Scholarships, an honor accorded to only about one thousand faculty members in the nation each year. Also, Fisher is consistently named to the President's Higher Education Community Service Honor Roll for exemplary service to America's communities.
Student & Faculty Profiles
Ray McLean '15
Ray McLean is a full-time RN at Strong Memorial Hospital, where he is the injury prevention and outreach coordinator for The Kessler Trauma Center. He also works as a part-time paramedic at Mercy Flight Central and Irondequoit Ambulance. The married father of three also volunteers as a baseball coach and is a board member for Penfield Youth Football.
Somehow, in the midst of all that, he managed to make time to further his education as a student in Fisher's RN to BSN Online program.
Ray says he chose Fisher because of the Wegmans School of Nursing's reputation and because of his initial outreach to the College, which he says was welcoming and very personal.
Also, with a schedule likes Ray's, the online coursework and flexible schedule made the whole deal work for him.
Perhaps Ray's favorite thing about the program was that he didn't feel like just a number or a statistic. Rather, he felt like a student who could better himself and, in turn, contribute to the College's reputation.
Ray hasn't slowed down since completing the program in 2015. He credits Fisher for helping him believe that he can achieve any goal he puts his heart into.


text:
'I Watch Him Like a Hawk'
By MATTHEW PURDY
Published: June 8, 1997
The pedophile was perfectly obsequious. Soft-spoken and polite, he promised his parole officer, Corey Burke, who had dropped by his Lower East Side apartment unannounced, that he was playing by the rules: home by 9 P.M., no hanging around parks, no contact with children.
When Officer Burke asked if he had heard about the recent murder of an 11-year-old girl in Chinatown, the man shook his head sadly. ''That's terrible,'' said the parolee, who had served time for molesting his two young nieces. ''I hope you catch him.''
Officer Burke, who tracks paroled sex offenders, gave his client a smile and a handshake, and was on his way. But once the door closed, Officer Burke seemed less confident. Pedophiles are cunning, he said; was the man's eagerness to please meant to deceive? What about the model airplane the man and his girlfriend were gluing together? Could that be used to lure young children?
Officer Burke punched the elevator button. ''I watch him like a hawk,'' he said.
The national debate over whether communities should be notified of the whereabouts of sex offenders after they are released from prison continues to set the fears of the public against the privacy and civil liberties concerns of ex-convicts. Each new case stokes the fear, from the conviction 10 days ago of a repeat sex offender for the murder of Megan Kanka -- the child in whose name numerous state notification laws have been passed -- to the arrest last week of a sex offender, recently released from prison, in the rape and murder of a teacher on Long Island.
In New York, hundreds of convicted sex offenders continue to live anonymously in communities, despite the state's own version of ''Megan's Law,'' because a Federal judge has ruled that it does not apply to sex offenders who were convicted before Jan. 21, 1996, when the notification law went into effect.
The levee built against the rising concern over these offenders is made of parole officers like Corey Burke. He is responsible for Manhattan south of 14th Street, where he monitors 25 rapists and child abusers whose misdeeds are the kind that stir feelings of revenge in the hearts of most people and sympathy in few.
Officer Burke has the luxury of neither. He needs to see his clients as individuals with predilections and habits, histories and, most important, futures. His job is neither to exact retribution nor to offer compassion, but to keep them from committing the same crime again.
For him to succeed, he said, ''You can't hate these people. But you can't forget who they are.''
In the view of most criminologists, sex offenders are likely to repeat their crimes. ''Predatory pedophiles represent the greatest danger to the public because they have limited control over their impulses,'' said Richard Levy, the regional director of the State Division of Parole. ''Since Megan Kanka died, the supervision of sex offenders has increased.''
In the last year, the parole division's Sex and Special Offenders Unit was expanded to take over supervision of all sex offenders in New York City and Long Island from general parole officers. There are 576 convicted sex offenders under its supervision in New York City. Parole officers like Officer Burke, who handle those cases, have been given special training in tracking them.
Parole is meant to be a supervised transition between prison and freedom. Most conventional felons released on parole have to comply with a curfew, attend counseling and visit a parole officer.
But for sex offenders, the leash is tighter. They are often prohibited from going any place where they might meet children -- playgrounds, schools or even bowling alleys. They cannot own toys, baseball cards, or anything that could be a lure for children. Computers with modems are prohibited, because parolees could download sexually explicit photographs.
If a parolee breaks a rule, he can be immediately locked up to serve the rest of his sentence. For sex offenders, parole officers have a ''zero tolerance'' policy. Parolees have been jailed for missing curfew once or having a Playboy magazine.
Parole officers who track sex offenders usually have about 30 clients, roughly half the number of other officers. But they have scheduled visits with their clients at least twice a month. Conventional felons, by contrast, make office visits as infrequently as once a month.
And officers who monitor sex offenders are expected to surprise clients with visits at odd hours and watch them surreptitiously. Officer Burke, a 6-foot-6, solidly built fellow with a loping gait, sometimes stalks one of his ''guys,'' as he calls them, for an hour or more. Then, he will gently tap him on the shoulder, ''just to let him know I'm there.''
Edward Rendelstein, who supervises the seven-person Special Offenders Unit in Manhattan, said, ''A sexual offender is more likely to keep himself under control if he feels he's being watched.''
The monitoring is so strict that civil liberties lawyers in New York have argued that those conditions make the public notification provisions of the state's sex offender notification law unnecessary, said Laura Johnson, a Legal Aid Society lawyer.
The parole officers, who often work alone, never know what they will find when they knock on a door.


text:
- Report: #211028
Report - Rebuttal - Arbitrate
Complaint Review: First Inet
First InetPO Box 689 Clearwater, Florida U.S.A.
Firstinetonlinecard.com First Inet ripoff, faudulent billing, lying, offer $100.00 gas coupon Clearwater Florida
*UPDATE EX-employee responds: How to get your money back
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This report was posted on Ripoff Report on 09/14/2006 12:53 PM and is a permanent record located here: http://www.ripoffreport.com/r/First-Inet/Clearwater-Florida/Firstinetonlinecardcom-First-Inet-ripoff-faudulent-billing-lying-offer-10000-gas-cou-211028. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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How to get your money back
AUTHOR: The - (U.S.A.)
SUBMITTED: Tuesday, April 17, 2007POSTED: Tuesday, April 17, 2007
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text:
Sometimes taxonomists create new names for groups that already have a name. They may do this because they are unaware of the original name, or they may think the organism before them belongs to a different group when in fact it does not. If two or more names are found to apply to the same group, they are considered synonyms. In most cases, the first name takes priority and is considered to be the valid or accepted name. However, there can be exceptions, and it's not always easy to determine which of a series of synonyms should be considered valid or accepted. Here we list the synonyms provided to EOL by our classification partners. We also include other versions of the name that most likely refer to the same group, for example, misspellings in the literature or different variations of the authorship associated with the name.
marks the preferred name from each source.
BioLib.cz Import
Integrated Taxonomic Information System (ITIS)
|Hyperoodontidae Gray, 1846
|Ziphiidae Gray, 1850
|Other, see comments
|Ziphiidae Gray, 1865
|Hyperoodontina Gray, 1846
World Register of Marine Species (WoRMS)
|Ziphiidae Gray, 1850
|Paikea Oliver 1922
|Dolichodon Gray, 1866
|Epiodon Burmeister, 1867
|Anarnacinae Gill 1871
|Anodon Wagler 1830
|Berardus Gray 1863
|Callidon Gray 1871
|Cetodiodon Jacob, 1825
|Chaenocetus Eschricht, 1846
|Chaenodelphinus Eschricht, 1843
|Chenocetus Gray, 1846
|Chenodelphinus Duvernoy, 1851
|Diodon Lesson 1828
|Dioplodon Gervais, 1855
|Diplodon Gray, 1866
|Frasercetus Moore 1968
|Hyperadon J. A. Allen, 1869
|Hyperdordon Gray, 1821
|Hyperodon Cope, 1865
|Hyperondon Hall & Kelson, 1959
|Hyprodon Duméril, 1806
|Lagenocetus Gray 1863
|Lagocetus Gray, 1866
|Mesiodon Gray 1866
|Mesodiodon Duvernoy 1851
|Micropteron Eschricht 1849
|Neoziphius Gray 1871
|Nodus Wagler 1830
|Oulodon von Haast 1876
|Petrorhynchus Gray 1865
|Uperoodon Gray 1843
|Uranodon Illiger 1811
|Ziphiorrhynchus Burmeister 1865
|Zyphius Moreno, 1895
|Aliama Gray 1864
|Aodon Lesson 1828
|Heterodon Blainville, in Demarest, 1817
|Micropterus Wagner, 1846
EOL content is automatically assembled from many different content providers. As a result, from time to time you may find pages on EOL that are confusing.
To request an improvement, please leave a comment on the page. Thank you!


text:
Soft and sweet describes a good cupcake. It also nicely sums up this reality competition, where chef and sous-chef teams vie for $10,000 by baking professional quality treats, playing with various themes and strange ingredients that you'd never imagine chowing down on for dessert (see: oyster cupcakes). As if that weren't soft enough, Cupcake Wars has even crowned a vegan chef! No eggs, butter, or milk? Our animal-product-loving stomachs declare war on that.
War Crimes: 10 Soft Shows That Have "Wars" In The Title
1. Cupcake Wars (Food Network, 2010-present)
Watch Now


text:
- Report: #521985
Report - Rebuttal - Arbitrate
Complaint Review: Keith Stuart - NATIONWIDE POOLS AND SPA
Keith Stuart - NATIONWIDE POOLS AND SPA1923 NW 40th Court, Pompano, Florida United States of America
Keith Stuart - NATIONWIDE POOLS AND SPA SCAM!! JOIN US REPORTING THEM TO THE FLORIDA DEPT OF BUSINESS & PROF. REGULATIONS-HAVE THEIR LICENSE REVOKED! Pompano, Florida
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NATIONWIDE POOL & SPA-- ARE SCAMMERS!! All they want is your deposit, they're all crooks!!!
They scammed us into giving them a deposit, we now have no pool and no money even after the 3 day cancellation!!! Our refund due is close to $4000.00
Please join me and file a complaint witht the FLORIDA DEPARTMENT OF BUSINESS & PROFESSIONAL REGULATIONS 850-487-1395, if they get alot of complaints they will have their license revoked!!! We should all get together and sue Keith Stuart and his company for all our deposits and close them down!!! I am considering small claims court I think all of you should too!!!
This report was posted on Ripoff Report on 11/10/2009 09:25 AM and is a permanent record located here: http://www.ripoffreport.com/r/Keith-Stuart-NATIONWIDE-POOLS-AND-SPA/Pompano-Florida-33064/Keith-Stuart-NATIONWIDE-POOLS-AND-SPA-SCAM-JOIN-US-REPORTING-THEM-TO-THE-FLORIDA-DEP-521985. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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text:
Please log in or register to manage your account
Model: 15920 Item: IVR15920
Convenient handheld calculator with protective hardcase. Impossible to lose--hard case flips away when in use. Dual solar/battery-powered for all lighting conditions. Large eight-digit display with three memory buttons. Power Source(s): Battery; Solar; Display Notation: Numeric; Number of Display Digits: 8; Memory: 4 Function/3-Key.
Printerbazaar is a one-stop destination for all your office supplies. From highly durable branded printers to a plethora of accessories, you can get your suitable product at a competitive cost.
At Printerbazaar, we are committed to make your shopping experience hassle-free by conveying the best information. We understand that office related purchasing decisions are vital and thus the right comparisons are necessary before buying.
Innovera® 83945 Remanufactured, 16194500 (Phaser 7700) Toner, 10000 Yield, Magenta
$172.66$11223 / each
Innovera® Remanufactured 10N0016 (#16) Ink, 335 Yield, Black
$20.14$1329 / each
Innovera® Remanufactured 10N0026 (#26) Ink, 275 Yield, Tri-Color
$21.65$1364 / each


text:
Displaying results 1-2 of 2 'princess bride' costumes
$24.99 from Halloween Express
Lil' Frankie's Bride Infant Costume Your little princess can now be Frankie's Bride and become the focal point of everyone's Halloween event with this cute little outfit. This costume includes a jumpsuit with attached white dress with black print for stitching and black/ white cap. Available Sizes: 6-12 months 12-24 months Shoes not included. Materials: Bunting/Gown - 90% white fabric (100% knit polyester 5% lining (100% knit polyester) 5% elastic (100% woven polyeser) ; Cap - 80% black fabric (100% knit polyester) 15% white fabric (100% knit polyeste) 5% lining (100% knit polyester). .
$54.99 from Halloween Express
Cinderella Wedding Dress Child Costume From the fabulous new Disney Cinderella movie! Be a perfect fairytale bride in this wonderful princess gown! Costume includes: Deluxe white satin-like glitter-patterned dress has a sheer sparkle stand-up collar, sheer sparkle lower sleeves and a full ankle-length skirt with sheer sparkle side drapes. Includes detachable sheer glittery wings. Available Sizes: Toddler 3-4T Child 4-6 Child 7-8 Child 10-12 Shoes are not included. This is an officially licensed Disney Cinderella product.


text:
$19.00$4.75 / ml
- Color
- Black
A natural pigmented loose mineral powder that temporarily disguises roots, covers gray hair and enhances highlights with a professional, natural looking finish.
Product blends naturally with your hair color with our exclusive applicator that delivers the perfect amount of product exactly where you want it!
|Colloidal Oatmeal, Avena Sativa Kernel Flour (Oat), Diatomaceous Earth, Calcium Silicate, Fuller's Earth/Solum Fullorum, Silica, Calcium Propionate, May Contain: Titanium Dioxide (CI 77891), Iron Oxide Brown (CI 77492), Iron Oxide Yellow (CI 77492), Iron Oxide Brown (CI 77491), Red Iron Oxide (CI 77491), Black Iron Oxide (CI 77499)
Apply to the root area using our mess-free applicator brush. Blend thoroughly with brush or fingertips. Restyle as desired. For use on dry hair only.
To close: Turn sleeves slightly to the right and pull up until bristles are covered. Slide cap over sleeve and press down.
REVIEW SNAPSHOT®by PowerReviews
Reviewed by 2 customers
Touch up between dying hair.
By Pam
from Aurora Ohio
describe yourself Minimalist
- Easy To Use
- Long-Lasting
- Makes Hair Look Thicker
- Natural Look
- Messy
Best Uses
- Between Dye Jobs
- Graying Hair
- Thicker Hair
- Touch Ups
Comments about Jonathan Product Awake Color Root Touch Up, Black, .14 oz:
I have tried several products to make my hair look thicker between dying. This product covers my gray roots. I also have thinning hair and this product fills in these areas with color. I also like that it is a powder which gives my hair a little body.
Bottom Line Yes, I would recommend this to a friend
Was this review helpful? Yes / No
- You may also flag this review
By VacayVixen
from Kailua-Kona, HI
describe yourself Beauty Conscious
- Long-Lasting
- Messy
Best Uses
Comments about Jonathan Product Awake Color Root Touch Up, Black, .14 oz:
DO NOT PURCHASE! I thought this would be perfect for travel. It's self-contained and totable. The problem begins when it comes out of the box. It gets everywhere and stains EVERYTHING. The mess and hassle to clean up off you and anything it touches (pillow, people's clothing, your clothing, etc.) is not worth it.
Bottom Line No, I would not recommend this to a friend
Was this review helpful? Yes / No
- You may also flag this review


text:
Hugh Laurie finds great depth in blues traditionJune 4, 2014 Updated: June 5, 2014 7:06pm
Photo: Valerie Macon
Actor Hugh Laurie is best known as the cane-toting, pill-popping doctor on TV's "House." But Laurie had been acting, writing and doing comedy for more than 20 years before that role.
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text:
Definition of caters in English:
A system of change-ringing using nine bells, with four pairs changing places each time.
Late 19th century: from French quatre 'four'.
For editors and proofreaders
Line breaks: ca¦ters
Definition of caters in:
What do you find interesting about this word or phrase?
Comments that don't adhere to our Community Guidelines may be moderated or removed.
= trending


text:
Metro-X Enhanced Server Set, the commercial X server from Metro Link Incorporated, satisfies all these needs. An X11R5-based server, Metro-X replaces your current XFree86 server while fitting in nicely with the rest of the XFree86 distribution, whether it is XFree-2.x or 3.x. You can successfully run an X11R5-based server on a X11R6 system with no problems at all. I tested it with Linux 1.2.x and the XFree-3.1.1 distribution.
Metro-X has accelerated support for over one hundred different graphics cards, including a variety from Diamond and Matrox, and the very high-end Imagine-128 from Number Nine. There is also touch screen support for Carroll and Elographics serial controllers and multi-headed display support, which allows you to have more than one graphics card and monitor under X.
Metro-X for Linux comes on two diskettes, together with a bound manual and a quick installation guide. The instructions in the quick installation guide are brief and to the point. After making two symbolic links, extracting the product from the disks using cpio, and then untarring it, I was ready to start the configX program which Metro-X installs in your X11 bin directory. Metro-X also installs a touch-calibration program in your X11 bin directory for users who plan to use serial controllers for touch screen support. All the other Metro-X files are installed in a /usr/lib/X11/Metro directory, which makes it easy to keep track of where everything is.
If you have ever tried configuring XFree86, you'll be very pleased with how easy it is to use configX to configure Metro-X. configX presents you with a menu from which you can select the server, graphics card, video modes, and mouse you plan to use with X. When you select the server option from the menu, you are presented with a choice of servers: one for S3 based cards, one Matrox cards, and so on.
After selecting the correct server for your video card, you get to select which extra X extensions you want your server to have. Your choices include XIE 5.0, PEX 5.1, and DEC Xtrap 3.3. I chose both XIE and PEX. configX proceeded to build the server using the shared libc and libm libraries. You can always go back and rebuild the server again should you want to add or remove extensions to or from your server.
After building the server, you select the correct video card and the video modes you wish to use. I selected my Diamond Stealth 64 from the graphics cards list and chose my video modes. configX allows you to select as many video modes as you want with different resolutions and refresh rates, as long as they all have the same number of colors. Next, you choose your mouse from the mouse menu and, finally, select the Save and Exit option, which saves the newly created Xconfig file for use with Metro-X. That is all you need to do to configure X, and I did it in under 5 minutes.
After building and configuring my server, I proceeded to fire up X using the startx command. Within seconds, X was up and running in 16.7 million colors at 1024x768 resolution, and it was fast. The installation and configuration, which took less than ten minutes combined, worked flawlessly, and I was very impressed. Switching resolution modes works just like it does with XFree86, using the CTRL ALT + and CTRL ALT - key combinations. After playing around for a bit, I decided to do some benchmarks with the xbench suite to see how my new server would compare to XFree86. On all the tests I did, at 256 - 16.7 million colors, and at different resolutions, Metro-X outperformed the XFree86-3.1.1 S3 server using my Diamond card by about 20k - 30k xstones. I was even more impressed.
If you have a graphics card which isn't supported by XFree86 (such as some Diamond cards, Matrox cards, and the Number Nine Imagine-128), if you want a simple menu-driven configuration system for X, or if you simply want more speed, I highly recommend purchasing the Metro-X Enhanced Server Set for your Linux machine. At $99, it is a real bargain. Metro-X comes with 90-day free tech support and a 30-day money back guarantee. Contact Metro Link Incorporated at (305) 938-0283, or e-mail at firstname.lastname@example.com, or check out their WWW page at www.metrolink.com.
Bogdan Urma is studying physics and computer science at Cornell University and hopes to get his B.S. by next year. He has been using Linux since 1993 and spending way too much time with it. He welcomes your comments sent by e-mail to email@example.com, or by snail mail c/o Linux Journal.
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Geek Guides
With all the industry talk about the benefits of Linux on Power and all the performance advantages offered by its open architecture, you may be considering a move in that direction. If you are thinking about analytics, big data and cloud computing, you would be right to evaluate Power. The idea of using commodity x86 hardware and replacing it every three years is an outdated cost model. It doesn't consider the total cost of ownership, and it doesn't consider the advantage of real processing power, high-availability and multithreading like a demon.
This ebook takes a look at some of the practical applications of the Linux on Power platform and ways you might bring all the performance power of this open architecture to bear for your organization. There are no smoke and mirrors here—just hard, cold, empirical evidence provided by independent sources. I also consider some innovative ways Linux on Power will be used in the future.Get the Guide


text:
- Home
- Eastwood Complete Parts Washer Kit
About Eastwood Complete Parts Washer Kit
Rugged welded steel parts washer features a large removable component shelf plus small removable parts basket. Ideal for cleaning small or large parts.Flexible nozzle lets user spray fluid on workpiece. The included flow through brush is perfect for removing tough grease and dirt off the part. Fusible link automatically closes lid in case of fire. Tank capacity is 20 gallons with solvent capacity of 12 gallons. Tank has drain hole with plug. Lower shelf can hold tools and other must have items. Includes Metal Wash and Gloves
20 Gallon Parts washer unit, Aqueous pump, Flow through brush, Large removable work shelf, Small Parts Basket, 1 pair gloves, 5 cans Metal Wash
Use appropriate gloves and eyewear protection.
1 year limited warranty. Made in China.


text:
Zodiac Sportz Wraparound Safety Glasses
Product ID: GUA_ZODIAC
Please use this reference number at any time when dealing with us so that we can identify the product you are looking at as quickly as possible.
(Please note this reference number will not be of any use to any other party except us.)
Manufacturer: Safety Source
Price: £2.95 (£3.54 inc VAT)
Zodiac Sportz Wraparound Safety Glasses
The Zodiac Sportz Wraparound Glasses have anti-scratch lens, conforms to en166ft. black frame clear lens. Modern and lightweight. The best priced clear lens protective glasses on the market. (GMISE23Z)
Brand: Safety Source
Identifier: GUA_ZODIAC
Item Details
Brand new packaged items only.
Comes with a full manufacturer warranty (not including consumable products).
Please make use of any product reviews or youtube clips we have available to learn more about the item.
This item is usually delivered within 1 working day(s).
Website Details
SSL Certified Secure website to ensure secure online ordering.
Please return the item/s if not suitable for a full refund (within 7 working days of receipt).
We guarantee security of all your personal details, we do not pass on any customer information.
Accept all payment methods including all major Credit Cards, Paypal and Amazon Payments.
Order online now using our Secure SSL Certified Secure website.
Add this product to your basket and come back at any time to complete the order.
Order by phone on 01737783101.
Order with an official purchase order by fax to 01737783102 OR by email to firstname.lastname@example.com. We will check your account status or if you do not hold an account we will credit check your organisation, confirm and process your order. Please note the first order(s) will always need to be paid upfront unless you are a government linked organisation. Goods remain the property of Sitebox Ltd until paid for in full as per our full terms and conditions.
Shopping Cart
|Comet Anti-Scratch Clear Protective Glasses
|£0.99 (ex VAT)
£1.19 (inc VAT)
|Standard Safety Goggles
|£0.99 (ex VAT)
£1.19 (inc VAT)
|Solar Sport Wraparound Safety Glasses
|£3.50 (ex VAT)
£4.20 (inc VAT)
|Zodiac Sportz Wraparound Safety Glasses
|£2.95 (ex VAT)
£3.54 (inc VAT)
|JSP Eclipse Wraparound Clear Safety Glasses
|£3.40 (ex VAT)
£4.08 (inc VAT)
good item and service...
Mrs Sandra NASH on 30. Aug
fast deliver and it was what i expected...
Andrew Dillnutt on 30. Aug
Easy ordering, quick delivery, couldn't ask for more. Would recommend this company to everyone....
Karen on 29. Aug


text:
Definition of tardiness in English:
The quality or fact of being late; lateness: forgive my tardiness, I had some very important business to attend to
More example sentences
- Luckily, the plane was delayed, so their tardiness at Heathrow went unnoticed.
- Rigidity in the labour market, wage-induced inflation and tardiness in technological adaptation were the predictable results.
- Humiliated by its tardiness in plugging into the Internet boom, Japan is determined not to suffer the same indignity in bioscience.
For editors and proofreaders
Syllabification: tar·di·ness
Definition of tardiness in:
What do you find interesting about this word or phrase?
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= trending


text:
- Report: #27057
Report - Rebuttal - Arbitrate
Complaint Review: Capital First (Ontario, Canada)
Capital First (Ontario, Canada)229 Genessee St. Buffalo, New York U.S.A.
Capital First ripoff (Ontario, Canada), World Trans Telephone These people have no heart to do this!! consumer fraud rip-off Buffalo New York
*Consumer Suggestion: CapitalFirst ripoff way too meny people
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So, I agreed and I paid him $199.00 out of savings account. The number he gave me for their customer service is disconnected and no longer in service. He also called me August 13th and offered me the same deal. I was like Sir, I already did this and I still haven't received the cards. My advice to all of you is....If they want you to pay for the credit card it is most definately a SCAM!!!!!!
Wahiawa, Hawaii
This report was posted on Ripoff Report on 08/15/2002 09:54 PM and is a permanent record located here: http://www.ripoffreport.com/r/Capital-First-Ontario-Canada/Buffalo-New-York-14201/Capital-First-ripoff-Ontario-Canada-World-Trans-Telephone-These-people-have-no-heart-t-27057. The posting time indicated is Arizona local time. Arizona does not observe daylight savings so the post time may be Mountain or Pacific depending on the time of year.
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- Only search one name at a time if Company has many AKA's.
#1 Consumer Suggestion
CapitalFirst ripoff way too meny people
AUTHOR: TrinaNicole - ()
SUBMITTED: Friday, August 16, 2002POSTED: Friday, August 16, 2002
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text:
Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
If you are reading this message, Please click this link to reload this page.(Do not use your browser's "Refresh" button). Please email us if you're running the latest version of your browser and you still see this message.
Newegg.com - Computer Parts, Laptops, Electronics, HDTVs, Digital Cameras and More!
Showing Results: Most Recent
This review is from: Bose SoundLink Mini Bluetooth Speaker
Pros: Great sound.
Plenty of volume.
Well constructed.
Cons: Little pricey but its Bose.
Wish it had come with vehicle adapter for the price.
Other Thoughts: Well kinda hard to say something that has not been said already. However I can tell you that I was very surprised with the sound quality and shear volume of this little speaker. The range is very good also. I mainly use my apple I touch.READ FULL REVIEW
This review is from: D-Link DGL-4500 Gigabit Gaming Router 802.11a/b/g/n 2.4/5GHz Selectable Dual Band Xtreme N
Pros: Works very well, speed as advertised.
Cons: nothing so far. It was a good purchase.READ FULL REVIEW
This review is from: Bose® In-Ear Headphones
Pros: -awesome Bose sound. If you are Bose owner then this is no surprise. If you are not, give these a chance, you will not be disappointed.
Cons: -price but it is Bose so you pay for what you get.
Other Thoughts: -great newegg shippingREAD FULL REVIEW


text:
Top Definition
The natural ; a hoe ; the squeeze
Basically someone who is naturally a hoe "Nat"ural thats where "NatNat comes from
dodane przez Jewelly sierpień 26, 2012
Trending Now
Can you define these popular missing words?
a female or male that fucks with the whole city basically like saying a hoe its a Atlanta slang word !!!
"Man, he the city !" , I heard she the nat nat of the school bruh go get some head from that hoe !
dodane przez LUH'baby tootie sierpień 17, 2013


text:
Bobby Dale Earnhardt wants to earn success.
There is a reputation that precedes the name Earnhardt in the world of NASCAR. The reputation is one of grit, determination, and afierce desire to finish first. Fortunately for NASCAR fans,the Earnhardt name will continue to be a fixtureon the racetrack for many years to come through thenew Earnhardt blood pursuing a racing career.
Bobby Dale Earnhardt, the 1st grandson of Dale Earnhardt, Sr.
and son of Kerry Earnhardt, is out to prove that he too deserves a chance to lineup on race day, side-by-side with todays best drivers. He is starting his racing career the same as his grandfather,Dale Earnhardt Sr.
Bobby Dale intends to earn his way onto the starting field of the biggest stages inmotorsports with determination and hard work. Bobby Dale wants to build his racingcareer on the merit of his talent and not because of the name on his driver's license
By working hard, I WIll appreciate my successes much more in the long run, he said.
Today, the Earnhardt name lives on in NASCAR through Dale Earnhardt, Jr., but Bobby DaleEarnhardt is next in line to continue the family tradition.
2012 was a great year where he gained driving experience, earn respect, and create the opportunity to drive NASCAR. His grassroots effort is something inwhich he has pride. "Im working to raise the money on my own and start in the development series like everyone else, Im no different than anyone else."
Bobby Dale Earnhardt pursued ARCA TRUCK racing because he believes the short track high action will sharpen his driving skills for his ascent to the big stage.
The 2013 ARCA Truck Series season caught the attention of many fans as he captured The Rookie of the Year title, placed 6th in overall points and recieved The Most Popular Driver Award and he intends to add his own chapter to the Earnhardt legacy one race at a time until he earns a hefty branch on the Earnhardt family tree.


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60/2 Silk is part of WEBS' Valley Yarns line. 60/2 silk runs 14,800 yards per pound and is put up on approximately 8 oz. cones. Set at 48 epi, it makes spectacular woven fabrics. For a heavier fabric with a coarser set, you can double it. Consider two or more colors together for very interesting color work.
Color Cards and Color Books for this yarn are available.
Note: Put-up of this yarn has changed to 100 grams; stock is limited on the 250g cones. Click here to go to the 100g page.


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Elliott Coues (1842-1899, author and/or artist), or Louis Agassiz Fuertes (1874-1927, artist works in 5th edition, )
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