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      Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue

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          Abstract

          In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called ‘master modulators’ of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning ‘communication’ in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control—in contrast to an immediate, ‘poisoning’ with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

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          Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer

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            Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

            This systematic review and meta-analysis is the first to evaluate the evidence for an association between metformin use and cancer outcomes in patients undergoing treatment with curative intent for individual cancer types. Our findings suggest that adjuvant metformin could have beneficial effects, particularly on cancer outcomes in colorectal and prostate cancer. Randomised trials are warranted.
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              Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.

              Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear in solid tumors, but the underlying mechanism remains elusive. By establishing a cellular model that mimics the relative frequency of authentic translocation events without proliferation selection, we report mechanisms of nuclear receptor-dependent tumor translocations. Intronic binding of liganded androgen receptor (AR) first juxtaposes translocation loci by triggering intra- and interchromosomal interactions. AR then promotes site-specific DNA double-stranded breaks (DSBs) at translocation loci by recruiting two types of enzymatic activities induced by genotoxic stress and liganded AR, including activation-induced cytidine deaminase and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymes synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by nonhomologous end joining pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded nuclear receptor and genotoxic stress underlies nonrandom tumor translocations, which may function in many types of tumors and pathological processes.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                09 November 2018
                November 2018
                : 19
                : 11
                : 3540
                Affiliations
                [1 ]Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93042 Regensburg, Germany; daniel.heudobler@ 123456ukr.de (D.H.); michael.rechenmacher@ 123456kr.de (M.R.); florian.lueke@ 123456ukr.de (F.L.); martin.vogelhuber@ 123456ukr.de (M.V.); tobias.pukrop@ 123456ukr.de (T.P.); wolfgang.herr@ 123456ukr.de (W.H.)
                [2 ]Department Biology, Universita’ di Roma Tor Vergata, 00173 Rome, Italy; ghibelli@ 123456uniroma2.it
                [3 ]Institut for Analytical Chemistry, Faculty Chemistry, University Vienna, A-1090 Vienna, Austria; christopher.gerner@ 123456univie.ac.at
                Author notes
                Author information
                https://orcid.org/0000-0003-4964-0642
                https://orcid.org/0000-0002-1821-7887
                Article
                ijms-19-03540
                10.3390/ijms19113540
                6274845
                30424016
                25740844-4905-45d7-bf45-3d61a3f44b45
                © 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
                : 28 September 2018
                : 06 November 2018
                Categories
                Review

                Molecular biology
                anakoinosis,communicative reprogramming,nuclear transcription factors,metronomic low-dose chemotherapy,glitazones,all-trans retinoic acid,cox-2 inhibitor,master modulators,undruggable targets,therapy pillar,peroxisome proliferator-activated receptors (ppars),energy homeostasis,metabolic regulations,organ cross-talk,cancer and reprogramming of energy metabolism,systems biology

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