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https://www.readbyqxmd.com/read/29467326/loss-of-epigenetic-regulator-tet2-and-oncogenic-kit-regulate-myeloid-cell-transformation-via-pi3k-pathway
#1
Lakshmi Reddy Palam, Raghuveer Singh Mali, Baskar Ramdas, Sridhar Nonavinkere Srivatsan, Valeria Visconte, Ramon V Tiu, Bart Vanhaesebroeck, Axel Roers, Alexander Gerbaulet, Mingjiang Xu, Sarath Chandra Janga, Clifford M Takemoto, Sophie Paczesny, Reuben Kapur
Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition...
February 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29467020/insulin-like-growth-factor-1-mediated-regulation-of-mir-193a-expression-promotes-the-migration-and-proliferation-of-c-kit-positive-mouse-cardiac-stem-cells
#2
Yuning Sun, Rongfeng Xu, Jia Huang, Yuyu Yao, Xiaodong Pan, Zhongpu Chen, Genshan Ma
BACKGROUND: C-kit-positive cardiac stem cells (CSCs) have been shown to be a promising candidate treatment for myocardial infarction and heart failure. Insulin-like growth factor (IGF)-1 is an anabolic growth hormone that regulates cellular proliferation, differentiation, senescence, and death in various tissues. Although IGF-1 promotes the migration and proliferation of c-kit-positive mouse CSCs, the underlying mechanism remains unclear. METHODS: Cells were isolated from adult mouse hearts, and c-kit-positive CSCs were separated using magnetic beads...
February 21, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29452350/extra-virgin-olive-oil-contains-a-metabolo-epigenetic-inhibitor-of-cancer-stem-cells
#3
Bruna Corominas-Faja, Elisabet Cuyàs, Jesús Lozano-Sánchez, Sílvia Cufí, Sara Verdura, Salvador Fernández-Arroyo, Isabel Borrás-Linares, Begoña Martin-Castillo, Ángel G Martin, Ruth Lupu, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Vicente Micol, Jorge Joven, Antonio Segura-Carretero, Javier A Menendez
Targeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO) capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid decarboxymethyl oleuropein aglycone (DOA) could selectively target sub-populations of epithelial-like, aldehyde dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24-/low CSC...
February 14, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29435168/low-fat4-expression-is-associated-with-a-poor-prognosis-in-gastric-cancer-patients
#4
Xiaoting Jiang, Zhengchuang Liu, Yingjie Xia, Jungang Luo, Ji Xu, Xujun He, Houquan Tao
In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29432154/5-azacytidine-prevents-relapse-and-produces-long-term-complete-remissions-in-leukemia-xenografts-treated-with-moxetumomab-pasudotox
#5
Fabian Müller, Tyler Cunningham, Stephanie Stookey, Chin-Hsien Tai, Sandra Burkett, Parthav Jailwala, Maryalice Stetler Stevenson, Margaret C Cam, Alan S Wayne, Ira Pastan
Moxetumomab pasudotox (Moxe) is a chimeric protein composed of an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A and kills CD22-expressing leukemia cells. It is very active in hairy-cell leukemia, but many children with relapsed/refractory acute lymphoblastic leukemia (ALL) either respond transiently or are initially resistant. Resistance to Moxe in cultured cells is due to low expression of diphthamide genes (DPH), but only two of six ALL blast samples from resistant patients had low DPH expression...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29340103/anti-neoplastic-drugs-increase-caveolin-1-dependent-migration-invasion-and-metastasis-of-cancer-cells
#6
Natalia I Díaz-Valdivia, Claudia C Calderón, Jorge E Díaz, Lorena Lobos-González, Hugo Sepulveda, Rina J Ortíz, Samuel Martinez, Veronica Silva, Horacio J Maldonado, Patricio Silva, Sergio Wehinger, Verónica A Burzio, Vicente A Torres, Martín Montecino, Lisette Leyton, Andrew F G Quest
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29302025/aprdx1-mutant-allele-causes-a-mmachc-secondary-epimutation-in-cblc-patients
#7
Jean-Louis Guéant, Céline Chéry, Abderrahim Oussalah, Javad Nadaf, David Coelho, Thomas Josse, Justine Flayac, Aurélie Robert, Isabelle Koscinski, Isabelle Gastin, Pierre Filhine-Tresarrieu, Mihaela Pupavac, Alison Brebner, David Watkins, Tomi Pastinen, Alexandre Montpetit, Fadi Hariri, David Tregouët, Benjamin A Raby, Wendy K Chung, Pierre-Emmanuel Morange, D Sean Froese, Matthias R Baumgartner, Jean-François Benoist, Can Ficicioglu, Virginie Marchand, Yuri Motorin, Chrystèle Bonnemains, François Feillet, Jacek Majewski, David S Rosenblatt
To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name "epi-cblC". The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation...
January 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29299950/interleukin-17-promotes-the-production-of-underglycosylated-iga1-in-dakiki-cells
#8
Jia-Ru Lin, Ji Wen, Hui Zhang, Li Wang, Fang-Fang Gou, Man Yang, Jun-Ming Fan
BACKGROUND: Interleukin 17 (IL-17) plays an important role in the pathogenesis of autoimmune diseases and might be associated with IgA nephropathy (IgAN). This study aimed to investigate the effect of IL-17 on autoimmune pathogenesis in IgA nephropathy. METHODS: DAKIKI cells were cultured and stimulated with IL-17 to perform dose-dependent and time-dependent experiments. Cell proliferation was examined by cell counting and the Cell Counting Kit-8 (CCK-8) assay. The IgA concentration and the degree of galactosylation in the supernatant were tested using ELISA and a helix aspersa (HAA) lectin binding assay, respectively...
November 2018: Renal Failure
https://www.readbyqxmd.com/read/29285667/epigenetic-erasing-and-pancreatic-differentiation-of-dermal-fibroblasts-into-insulin-producing-cells-are-boosted-by-the-use-of-low-stiffness-substrate
#9
Georgia Pennarossa, Rosaria Santoro, Elena F M Manzoni, Maurizio Pesce, Fulvio Gandolfi, Tiziana A L Brevini
Several studies have demonstrated the possibility to revert differentiation process, reactivating hypermethylated genes and facilitating cell transition to a different lineage. Beside the epigenetic mechanisms driving cell conversion processes, growing evidences highlight the importance of mechanical forces in supporting cell plasticity and boosting differentiation. Here, we describe epigenetic erasing and conversion of dermal fibroblasts into insulin-producing cells (EpiCC), and demonstrate that the use of a low-stiffness substrate positively influences these processes...
December 28, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/29279013/novel-approaches-to-diagnosis-and-treatment-of-juvenile-myelomonocytic-leukemia
#10
Franco Locatelli, Mattia Algeri, Pietro Merli, Luisa Strocchio
Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies...
January 3, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29249821/aza-ms-a-novel-multiparameter-mass-spectrometry-method-to-determine-the-intracellular-dynamics-of-azacitidine-therapy-in-vivo
#11
A Unnikrishnan, A N Q Vo, R Pickford, M J Raftery, A C Nunez, A Verma, L B Hesson, J E Pimanda
The cytidine analogue, 5-azacytidine (AZA; 5-AZA-cR), is the primary treatment for myelodysplastic syndrome and chronic myelomonocytic leukaemia. However, only ~50% of treated patients will respond to AZA and the drivers of AZA resistance in vivo are poorly understood. To better understand the intracellular dynamics of AZA upon therapy and decipher the molecular basis for AZA resistance, we have developed a novel, multiparameter, quantitative mass spectrometry method (AZA-MS). Using AZA-MS, we have accurately quantified the abundance of the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA and the cytoplasm within the same sample using nanogram quantities of input material...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29246089/expression-and-regulation-of-retinoic-acid-receptor-responders-in-the-human-placenta
#12
Hanna Huebner, Andrea Hartner, Wolfgang Rascher, Reiner Strick R, Sven Kehl, Felix Heindl, David L Wachter, Matthias W Beckmann, Fabian B Fahlbusch, Matthias Ruebner
INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/29227276/alteration-in-the-cytokine-secretion-pattern-in-t-cells-of-patients-with-cystic-fibrosis-caused-by-dna-methyltransferase-inhibitor-5-azacitidine
#13
E Kvaratskhelia, N Dabrundashvili, M Gagua, E Maisuradze, M Kamkamidze, E Abzianidze
Cystic fibrosis (CF) is the autosomal-recessive disorder caused by mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The Airway inflammation plays a central role in the progression of CF disease. Cystic fibrosis characterized by the overproduction of the pro-inflammatory cytokines and reduced expression of anti-inflammatory cytokines. Although the mechanisms of abnormal cytokine expression is still poorly understood, altered epigenetic regulations in T cells might contribute. In the present study we examined the expression of IFN-γ and IL-10 by CF T cells prior to and following 5-azaC treatment...
November 2017: Georgian Medical News
https://www.readbyqxmd.com/read/29225771/methylation-mediated-gadd45%C3%AE-enhanced-the-chemosensitivity-of-hepatocellular-carcinoma-by-inhibiting-the-stemness-of-liver-cancer-cells
#14
Xiao-Juan Hou, Qiu-Dong Zhao, Ying-Ying Jing, Zhi-Peng Han, Xue Yang, Li-Xin Wei, Yu-Ting Zheng, Feng Xie, Bai-He Zhang
Background: Defects of the growth arrest DNA damage-inducible gene 45β (Gadd45β) play an important role in the progression of tumor and confer resistance to chemotherapy. However, the role of Gadd45β in the apoptosis of hepatocellular carcinoma is still not clear. Purpose of this study was to explore the effect of Gadd45β on the apoptosis of liver cancer cells, and the possible mechanism was examined. Result: In this study, we first confirmed the decreased expression of Gadd45β in human liver cancer tissues and human liver cancer cell lines, when compared to the peri-tumor liver tissue and normal liver cells...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/29222813/reln-signaling-modulates-glioblastoma-growth-and-substrate-dependent-migration
#15
Markus Schulze, Christ Violonchi, Stefan Swoboda, Tobias Welz, Eugen Kerkhoff, Sabine Hoja, Susanne Brüggemann, Johann Simbürger, Jörg Reinders, Markus J Riemenschneider
Glioblastoma (GBM) represents the most common and most malignant type of primary brain tumor and significantly contributes to cancer morbidity and mortality. Invasion into the healthy brain parenchyma is a major feature of glioblastoma aggressiveness. Reelin (RELN) is a large secreted extracellular matrix glycoprotein that regulates neuronal migration and positioning in the developing brain and sustains functionality in the adult brain. We here show that both RELN and its main downstream effector DAB1 are silenced in glioblastoma as compared to non-neoplastic tissue and mRNA expression is inversely correlated with malignancy grade...
December 8, 2017: Brain Pathology
https://www.readbyqxmd.com/read/29214328/5-azacytidine-treatment-and-tapbf-d-over-expression-increases-glutenin-accumulation-within-the-wheat-grain-by-hypomethylating-the-glu-1-promoters
#16
Jiantang Zhu, Linlin Fang, Jiaqi Yu, Ying Zhao, Fanguo Chen, Guangmin Xia
5-azaC treatment and TaPBF - D over-expression decrease C-methylation status of three Glu - 1 gene promoters, and aid in enhancing the expression of the Glu - 1 genes. The wheat glutenins exert a strong influence over dough elasticity, but the regulation of their encoding genes has not been firmly established. Following treatment with 5-azacytidine (5-azaC), both the weight and glutenin content of the developing and mature grains were significantly increased. The abundance of transcript produced by the Glu-1 genes (encoding high-molecular-weight glutenin subunits), as well as those encoding demethylases and transcriptional factors associated with prolamin synthesis was higher than in grain of non-treated plants...
December 6, 2017: TAG. Theoretical and Applied Genetics. Theoretische und Angewandte Genetik
https://www.readbyqxmd.com/read/29208426/5-azacytidine-engages-an-ire1%C3%AE-egfr-erk1-2-signaling-pathway-that-stabilizes-the-ldl-receptor-mrna
#17
Nourhen Mnasri, Maya Mamarbachi, Bruce G Allen, Gaétan Mayer
Hepatic low-density lipoprotein receptor (LDLR) is the primary conduit for the clearance of plasma LDL-cholesterol and increasing its expression represents a central goal for treating cardiovascular disease. However, LDLR mRNA is unstable and undergoes rapid turnover mainly due to the three AU-rich elements (ARE) in its proximal 3'-untranslated region (3'-UTR). Herein, our data revealed that 5-azacytidine (5-AzaC), an antimetabolite used in the treatment of myelodysplastic syndrome, stabilizes the LDLR mRNA through a previously unrecognized signaling pathway resulting in a strong increase of its protein level in human hepatocytes in culture...
December 2, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29203668/epigenetic-therapy-activates-type-i-interferon-signaling-in-murine-ovarian-cancer-to-reduce-immunosuppression-and-tumor-burden
#18
Meredith L Stone, Katherine B Chiappinelli, Huili Li, Lauren M Murphy, Meghan E Travers, Michael J Topper, Dimitrios Mathios, Michael Lim, Ie-Ming Shih, Tian-Li Wang, Chien-Fu Hung, Vipul Bhargava, Karla R Wiehagen, Glenn S Cowley, Kurtis E Bachman, Reiner Strick, Pamela L Strissel, Stephen B Baylin, Cynthia A Zahnow
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy...
December 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29190771/synergistic-role-of-5-azacytidine-and-ascorbic-acid-in-directing-cardiosphere-derived-cells-to-cardiomyocytes-in-vitro-by-downregulating-wnt-signaling-pathway-via-phosphorylation-of-%C3%AE-catenin
#19
Reddy Sailaja Mundre, Pavani Koka, Prakash Dhanaraj, Nitin Khatri, Sanjana Vig, Yamini Chandramohan, Anuradha Dhanasekaran
BACKGROUND: Cardiosphere derived cells (CDCs) represent a valuable source in stem cell based therapy for cardiovascular diseases, yet poor differentiation rate hinders the transplantation efficiency. The aim of this study is to check the ability of 5-Azacytidine (Aza) alone and in combination with ascorbic acid (Aza+AA) in delineating CDCs to cardiomyogenesis and the underlying Wnt signaling mechanism in induced differentiation. METHODS: CDCs were treated with Aza and Aza+AA for a period of 14 days to examine the expression of cardiac specific markers and Wnt downstream regulators by immunofluorescence, real time PCR and western blot...
2017: PloS One
https://www.readbyqxmd.com/read/29181164/recent-findings-on-epigenetic-gene-abnormalities-involved-in-uterine-cancer
#20
Megumi Yanokura, Kouji Banno, Yusuke Kobayashi, Hiroyuki Nomura, Shigenori Hayashi, Eiichiro Tominaga, Daisuke Aoki
Selective aberrant genetic effects that do not depend on abnormal DNA sequences are referred to as epigenetic abnormalities and are involved in carcinogenesis. In uterine cancer, various genes involved in apoptosis, cell cycle, DNA repair, cell proliferation and cell adhesion are abnormally methylated, resulting in gene silencing. Reversal of such epigenetic abnormalities in cancer cells is a potential strategy for cancer therapy, and studies on epigenetic abnormalities and treatment methods in uterine cancer are in progress...
November 2017: Molecular and Clinical Oncology
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