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https://www.readbyqxmd.com/read/28157711/the-repurposed-anthelmintic-mebendazole-in-combination-with-trametinib-suppresses-refractory-nrasq61k-melanoma
#1
Cynthia M Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F Petricoin, Michael B Atkins, Stephen W Byers, Dean S Rosenthal
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28150056/myc-inhibits-jnk-mediated-cell-death-in-vivo
#2
Jiuhong Huang, Yu Feng, Xinhong Chen, Wenzhe Li, Lei Xue
The proto-oncogene Myc is well known for its roles in promoting cell growth, proliferation and apoptosis. However, in this study, we found from a genetic screen that Myc inhibits, rather than promotes, cell death triggered by c-Jun N-terminal kinase (JNK) signaling in Drosophila. Firstly, expression of Drosophila Myc (dMyc) suppresses, whereas loss of dMyc enhances, ectopically activated JNK signaling-induced cell death. Secondly, dMyc impedes physiologically activated JNK pathway-mediated cell death. Thirdly, loss of dMyc triggers JNK pathway activation and JNK-dependent cell death...
February 1, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28111071/cooperative-binding-of-transcription-factors-orchestrates-reprogramming
#3
Constantinos Chronis, Petko Fiziev, Bernadett Papp, Stefan Butz, Giancarlo Bonora, Shan Sabri, Jason Ernst, Kathrin Plath
Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1...
January 26, 2017: Cell
https://www.readbyqxmd.com/read/28095325/peroxisome-proliferator-activated-receptor-%C3%AE-activation-inhibits-liver-growth-through-mir-122-mediated-downregulation-of-cmyc
#4
Andrei A Yarushkin, Yuliya A Kazantseva, Vyacheslav S Kobelev, Yuliya A Pustylnyak, Vladimir O Pustylnyak
Although NR1C3 agonists inhibit cell growth, the molecular mechanism of their action has not been thoroughly characterized to date. A recent study demonstrated that NR1C3 can regulate miR-122 by binding to its promoter. Given that miR-122 can indirectly regulate cMyc-mediated promitogenic signaling by targeting E2f1, we hypothesized that NR1C3 activation inhibits hepatocyte proliferation through miR-122-mediated cMyc downregulation. In the present study, we examined if liver hyperplasia induced by a strong chemical mitogen for the liver, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of NR1I3, can be repressed by NR1C3 activation through miR-122 upregulation...
January 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28092744/quercetin-induces-apoptosis-and-autophagy-in-primary-effusion-lymphoma-cells-by-inhibiting-pi3k-akt-mtor-and-stat3-signaling-pathways
#5
Marisa Granato, Celeste Rizzello, Maria Saveria Gilardini Montani, Laura Cuomo, Marina Vitillo, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone
Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/β-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited PI3K/AKT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc...
January 5, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28077463/novel-method-for-detection-of-glycogen-in-cells
#6
Alexander V Skurat, Dyann Segvich, Anna A DePaoli-Roach, Peter J Roach
Glycogen, a branched polymer of glucose, functions as an energy reserve in many living organisms. Abnormalities in glycogen metabolism, usually excessive accumulation, can be caused genetically, most often through mutation of the enzymes directly involved in synthesis and degradation of the polymer leading to a variety of glycogen storage diseases (GSDs). Microscopic visualization of glycogen deposits in cells and tissues is important for the study of normal glycogen metabolism as well as diagnosis of GSDs...
January 10, 2017: Glycobiology
https://www.readbyqxmd.com/read/28068320/myc-suppresses-tumor-invasion-and-cell-migration-by-inhibiting-jnk-signaling
#7
X Ma, J Huang, Y Tian, Y Chen, Y Yang, X Zhang, F Zhang, L Xue
Tumor metastasis, but not primary overgrowth, is the leading cause of mortality for cancer patients. During the past decade, Drosophila melanogaster has been well-accepted as an excellent model to address the intrinsic mechanism of different aspects of cancer progression, ranging from tumor initiation to metastasis. In a genetic screen performed in Drosophila, aiming to find novel modulators of tumor invasion, we identified the oncoprotein Myc as a negative regulator. While expression of Myc dramatically blocks tumor invasion and cell migration, loss of Myc promotes cell migration in vivo...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28056299/-application-of-rabbit-monoclonal-antibody-gcet2-in-diagnosis-of-diffuse-large-b-cell-lymphoma
#8
H Y Pan, X X Zhang, Y Y Weng, R Zhou
Objective: To prepare a rabbit monoclonal antibody GCET2 and to investigate its diagnostic value in the workup of diffuse large B-cell lymphoma (DLBCL). Methods: GCET2 rabbit monoclonal antibody was developed by using RabMAb(®) technology, and its specificity was confirmed by ELISA, Western blot, immunohistochemistry (IHC) and flow cytometry. A panel of immunomarkers including GCET2, CD10, bcl-6, MUM1, GCET1, FOXP1, Ki-67 and CMYC was evaluated in 81 cases of DLBCLs, 5 cases of follicular lymphomas (FL) and 2 cases of Burkitt's lymphomas...
December 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28056296/-expression-of-pdgfra-and-cmyc-in-extranodal-nk-t-cell-lymphoma-and-their-prognostic-implications
#9
Y P Chen, W F Zhu, J Y Lin, T M He, H M Ma, J P Lu, X A Ye, C W Xu, G Chen
Objective: To investigate the relationship between expression of PDGFRA/CMYC and clinicopathologic features of extranodal NK/T-cell lymphoma. Methods: Fifty-four cases of extranodal NK/T-cell lymphoma were included in the study.Immunohistochemistry was used to detect the expression of CD20, CD2, CD3, CD56, TIA1, GrB, Ki-67, PDGFRA and CMYC.In situ hybridization was performed to detect the presence of EBV encoded small RNA (EBER). Fifty cases of nasopharyngeal mucosal lymphoid tissue hyperplasia were used as normal control...
December 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28045943/arginine-and-lysine-transporters-are-essential-for-trypanosoma-brucei
#10
Christoph Mathieu, Juan P Macêdo, Daniel Hürlimann, Corina Wirdnam, Alexander C Haindrich, Marianne Suter Grotemeyer, Amaia González-Salgado, Remo S Schmidt, Ehud Inbar, Pascal Mäser, Peter Bütikofer, Dan Zilberstein, Doris Rentsch
For Trypanosoma brucei arginine and lysine are essential amino acids and therefore have to be imported from the host. Heterologous expression in Saccharomyces cerevisiae mutants identified cationic amino acid transporters among members of the T. brucei AAAP (amino acid/auxin permease) family. TbAAT5-3 showed high affinity arginine uptake (Km 3.6 ± 0.4 μM) and high selectivity for L-arginine. L-arginine transport was reduced by a 10-times excess of L-arginine, homo-arginine, canavanine or arginine-β-naphthylamide, while lysine was inhibitory only at 100-times excess, and histidine or ornithine did not reduce arginine uptake rates significantly...
2017: PloS One
https://www.readbyqxmd.com/read/28029649/mir-200c-is-a-cmyc-activated-mirna-that-promotes-nasopharyngeal-carcinoma-by-downregulating-pten
#11
Pan Chen, Xiaofang Guo, Liming Zhang, Wenling Zhang, Qingyu Zhou, Zhi Tian, Ying Zheng, Qianjin Liao, Heran Wang, Guiyuan Li, Jin Huang, Xiayu Li
The c-Myc transcription factor regulates a complex transcriptional program that leads to cellular transformation by targeting a large number of protein-encoding genes and non-coding RNAs. In this study, we show that a microRNA, miR-200c, is a novel c-Myc target that promotes cellular transformation and metastasis in nasopharyngeal carcinoma. MiR-200c achieves this oncogenic effect, at least in part, by targeting and inhibiting the tumor suppressor gene PTEN (phosphatase and tensin homolog), which is a key inhibitor of the AKT kinase signaling that promotes tumorigenesis in nasopharyngeal carcinoma...
December 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27986451/involvement-of-an-rna-binding-protein-containing-alba-domain-in-the-stage-specific-regulation-of-beta-amastin-expression-in-trypanosoma-cruzi
#12
Leticia Pérez-Díaz, Tais Caroline Silva, Santuza M R Teixeira
Amastins are surface glycoproteins, first identified in amastigotes of T. cruzi but later found to be expressed in several Leishmania species, as well as in T. cruzi epimastigotes. Amastins are encoded by a diverse gene family that can be grouped into four subfamilies named α, β, γ, and δ amastins. Differential expression of amastin genes results from regulatory mechanisms involving changes in mRNA stability and/or translational control. Although distinct regulatory elements were identified in the 3' UTR of T...
January 2017: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/27966782/impact-of-cryopreservation-on-caprine-fetal-adnexa-derived-stem-cells-and-its-evaluation-for-growth-kinetics-phenotypic-characterization-and-wound-healing-potential-in-xenogenic-rat-model
#13
Anjali Somal, Irfan A Bhat, Indu Baiju, Anuj Pratap Singh, Bibhudatta S K Panda, Perumal Arumugam Desingu, Sriti Pandey, Mukesh Kumar Bharti, Amar Pal, G Saikumar, Vikash Chandra, G Taru Sharma
This study was conducted to know the impact of cryopreservation on caprine fetal adnexa derived mesenchymal stem cells (MSCs) on the basic stem cell characteristics. Gravid caprine uteri (2-3 months) were collected from local abattoir to derive {amniotic fluid (cAF), amniotic sac (cAS), Wharton's jelly (cWJ) and cord blood (cCB)} MSCs and expanded in vitro. Cells were vitrified at 3(rd) passage (P3) using 10% DMSO. Post thaw viability and cellular properties were assessed. Cells were expanded to determine growth kinetics, tri-lineage differentiation, localization and molecular expression of MSCs and pluripotency markers; thereafter, these cells were transplanted in the full-thickness (2 × 2cm(2) ) rat skin wound to determine their wound healing potential...
December 14, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27966264/pd1-and-pdl1-expression-in-primary-central-nervous-system-diffuse-large-b-cell-lymphoma-are-frequent-and-expression-of-pd1-predicts-poor-survival
#14
Marion Four, Valère Cacheux, Ariane Tempier, Dolorès Platero, Michel Fabbro, Grégory Marin, Nicolas Leventoux, Valérie Rigau, Valérie Costes-Martineau, Vanessa Szablewski
Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare and aggressive type of diffuse large B-cell lymphoma (DLBCL) whit poorly understood pathogenesis. Finding biomarkers associated with patient survival may be important for understanding its physiopathology and to develop new therapeutic approaches. We investigated 32 PCNS-DLBCL from immunocompetent patients for BCL2, CMYC, LMO2, and P53 expression and for cytogenetic aberrations of BCL2, BCL6, and MYC genes, all known for their prognostic value in systemic DLBCL (s-DLBCL)...
December 13, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27934592/generation-of-merrf-patient-derived-induced-pluripotent-stem-cell-line-imerrf-c7
#15
Dong Liang, Huanran Hu, Tianhui Xu, Yan Wang, Ping Hu, Zhengfeng Xu
Human iPSC line iMERRF-C7 was generated from PBMCs of a patient with mitochondrial disorder MERRF. Using Sendai virus, the reprogramming factors Oct3/4, Sox2, Klf4, and cMyc were delivered non-integratively. The resulting iPSCs expressed pluripotency markers, could differentiate into the three germ layers in vivo, had normal genomic structure, and retained the disease-causing m.8344 mutation with similar heteroplasmic level.
November 5, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27926868/cmyc-regulates-the-size-of-the-premigratory-neural-crest-stem-cell-pool
#16
Laura Kerosuo, Marianne E Bronner
The neural crest is a transient embryonic population that originates within the central nervous system (CNS) and then migrates into the periphery and differentiates into multiple cell types. The mechanisms that govern neural crest stem-like characteristics and self-renewal ability are poorly understood. Here, we show that the proto-oncogene cMyc is a critical factor in the chick dorsal neural tube, where it regulates the size of the premigratory neural crest stem cell pool. Loss of cMyc dramatically decreases the number of emigrating neural crest cells due to reduced self-renewal capacity, increased cell death, and shorter duration of the emigration process...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#17
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27884981/tissue-damage-and-senescence-provide-critical-signals-for-cellular-reprogramming-in-vivo
#18
Lluc Mosteiro, Cristina Pantoja, Noelia Alcazar, Rosa M Marión, Dafni Chondronasiou, Miguel Rovira, Pablo J Fernandez-Marcos, Maribel Muñoz-Martin, Carmen Blanco-Aparicio, Joaquin Pastor, Gonzalo Gómez-López, Alba De Martino, Maria A Blasco, María Abad, Manuel Serrano
Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity...
November 25, 2016: Science
https://www.readbyqxmd.com/read/27875298/benzyl-isothiocyanate-bitc-induces-reactive-oxygen-species-dependent-repression-of-stat3-protein-by-down-regulation-of-specificity-proteins-in-pancreatic-cancer
#19
Ravi Kasiappan, Indira Jutooru, Keshav Karki, Erik Hedrick, Stephen Safe
The antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH)...
December 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27875275/histone-chaperone-aplf-regulates-induction-of-pluripotency-in-murine-fibroblasts
#20
Khaja Mohieddin Syed, Sunu Joseph, Ananda Mukherjee, Aditi Majumder, Jose M Teixeira, Debasree Dutta, Madhavan Radhakrishna Pillai
Induction of pluripotency in differentiated cells through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and cellular Myc involves reprogramming at the epigenetic level. Histones and their metabolism governed by histone chaperones constitute an important regulator of epigenetic control. We hypothesized that histone chaperones facilitate or inhibit the course of reprogramming. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs)...
December 15, 2016: Journal of Cell Science
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