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  • However irrespective of the data implicating

    2018-11-07

    However, irrespective of the data implicating EBV-infected B cells, the data presented here suggests memory nfps are of central importance in for the development of MS. Developing agents that are more specific for these CD19+, CD27+ B memory cells may improve the risk-benefit ratio compared to current therapies, which target multiple subsets of cells.
    Contributions
    Source of Funding
    Declaration of Interests None considered to be relevant. However, DB is a founder and consultant to Canbex therapeutics and has received nfps research funds from Canbex therapeutics, Sanofi-Genzyme and Takeda in the past 3years. MM has received honoraria or meeting support from Novartis, Genzyme and AbbVie; GP is a shareholder of Canbex therapeutics. GG has received fees for participation in advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis and Teva. Research support from Biogen, Genzyme, Ironwood, Merck, Merck Serono and Novartis; KS has been a PI of trials sponsored by Novartis, Roche and Teva and involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex and has received honoraria and meeting support from Biogen, Merck, Novartis, Teva, Merck.
    Search Strategy and Selection Criteria The review was based on initial analysis of leukocyte phenotyping data from clinical trials and was used to formulate the hypothesis for the content of the review. References were then identified by searches of Pubmed and Google.co.uk. These used the search terms relating to the “non-proprietary drug name” and/or “class of drug type” and “memory B cell” or “CD27” with or without “multiple sclerosis”. Preference was given to work conducted in multiple sclerosis versus other autoimmune diseases. The final reference list was generated on the basis of relevance to the topic covered in the review.
    Outstanding Questions
    Acknowledgements
    Introduction Palmitate, the enzymatic product of fatty acid synthase (FASN), serves multiple essential and diverse functions within tumor cells to maintain cellular conditions that promote survival, growth, and proliferation. It provides a substrate for the anabolic synthesis of long-chain and complex cellular lipids and post-translational protein modification. Palmitate and palmitate-derived lipids function in cell metabolism, membrane architecture, protein localization, and intracellular signaling; cellular processes that are altered during oncogenic transformation and cancer progression (Gonzalez-Guerrico et al., 2016; Menendez and Lupu, 2007; Daniels et al., 2014; Flavin et al., 2010). Tumor cells have increased demand for ATP and metabolic macromolecules and must sustain survival and mitogenic signal transduction (Ward and Thompson, 2012; Vander Heiden et al., 2009), which requires lipid raft membrane microdomains densely packed with lipid-modified signaling proteins (e.g. H/N/K-Ras, EGFR, Akt) and lipid-based signaling molecules such as diacylglycerol and phosphatidylinositol (Simons and Sampaio, 2011; Lingwood and Simons, 2010; Levental et al., 2010). Whether a cause or consequence, FASN expression increases with tumor progression in many tumor types, including lung, breast, pancreatic, ovarian, colorectal, and prostate cancer (Ueda et al., 2010; Shah et al., 2006; Zaytseva et al., 2012; Witkiewicz et al., 2008; Sebastiani et al., 2006; Puig et al., 2008), and increased FASN expression associates with diminished survival and response to classical chemotherapeutic agents (Ueda et al., 2010; Tao et al., 2013; Nguyen et al., 2010; Notarnicola et al., 2012; Witkiewicz et al., 2008; Zaytseva et al., 2012). Thus, FASN presents an attractive target for the development of selective inhibitors for the treatment of cancer. Strong rationale exists for developing selective, highly active FASN inhibitors as both a single agent cancer therapy and also in combination with targeted and standard chemotherapy agents.