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      Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

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          Abstract

          Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is responsible for the regulation of a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. At the same time, this transcription factor can control the expression of a plethora of genes that promote tumor cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis. The aberrant activation of this transcription factor has been observed in several types of cancer and is known to contribute to aggressive tumor growth and resistance to therapeutic treatment. Although NF-κB has been identified to be a major contributor to cancer initiation and development, there is evidence revealing its role in tumor suppression. This review briefly highlights the major mechanisms of NF-κB activation, the role of NF-κB in tumor promotion and suppression, as well as a few important pharmacological strategies that have been developed to modulate NF-κB function.

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          Epithelial-mesenchymal transitions: twist in development and metastasis.

          Epithelial-mesenchymal transitions (EMT) are vital for morphogenesis during embryonic development and are also implicated in the conversion of early stage tumors into invasive malignancies. Several key inducers of EMT are transcription factors that repress E-cadherin expression. A recent report in Cell (Yang et al., 2004) adds Twist to this list and links EMT to the ability of breast cancer cells to enter the circulation and seed metastases.
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            Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

            Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.
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              TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future.

              Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF - now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
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                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                27 July 2018
                September 2018
                : 6
                : 3
                : 82
                Affiliations
                [1 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; yu.rou.puar@ 123456gmail.com (Y.R.P.); phcsmk@ 123456nus.edu.sg (M.K.S.); phcfanl@ 123456nus.edu.sg (L.F.)
                [2 ]Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6009, Australia; frank.arfuso@ 123456curtin.edu.au
                [3 ]Institute of Molecular and Cellular Biology (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore
                [4 ]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
                [5 ]Centre for Cancer Biology (University of South Australia and SA Pathology), Adelaide, SA 5000, Australia
                Author notes
                [* ]Correspondence: phcgs@ 123456nus.edu.sg (G.S.); vinayt@ 123456imcb.a-star.edu.sg (V.T.); Tel.: +65-6516-3267 (G.S.)
                Article
                biomedicines-06-00082
                10.3390/biomedicines6030082
                6163404
                30060453
                020507b4-befe-4400-a12b-1a0811441b1a
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 June 2018
                : 24 July 2018
                Categories
                Review

                nf-κb,cancer,apoptosis,metastasis,pharmacological inhibition

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