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https://www.readbyqxmd.com/read/28453743/targeted-next-generation-sequencing-of-pediatric-neuro-oncology-patients-improves-diagnosis-identifies-pathogenic-germline-mutations-and-directs-targeted-therapy
#1
Cassie N Kline, Nancy M Joseph, James P Grenert, Jessica van Ziffle, Eric Talevich, Courtney Onodera, Mariam Aboian, Soonmee Cha, David R Raleigh, Steve Braunstein, Joseph Torkildson, David Samuel, Michelle Bloomer, Alejandra G de Alba Campomanes, Anuradha Banerjee, Nicholas Butowski, Corey Raffel, Tarik Tihan, Andrew W Bollen, Joanna J Phillips, W Michael Korn, Iwei Yeh, Boris C Bastian, Nalin Gupta, Sabine Mueller, Arie Perry, Theodore Nicolaides, David A Solomon
Background.: Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients. Methods.: We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. Results.: Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor...
May 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28442058/nuclear-transfer-alters-placental-gene-expression-and-associated-histone-modifications-of-the-placental-specific-imprinted-gene-pleckstrin-homology-like-domain-family-a-member-2-phlda2-in-cattle
#2
Daniel R Arnold, Roberta C Gaspar, Carlos V da Rocha, Juliano R Sangalli, Tiago H C de Bem, Carolina A P Corrêa, João C T Penteado, Flavio V Meirelles, Flavia L Lopes
Abnormal placental development is frequent in nuclear transfer (NT) pregnancies and is likely to be associated with altered epigenetic reprogramming. In the present study, fetal and placental measurements were taken on Day 60 of gestation in cows with pregnancies produced by AI, IVF and NT. Placentas were collected and subjected to histological evaluation, the expression of genes important in trophoblast differentiation and expression of the placental imprinted gene pleckstrin homology-like domain, family A, member 2 (PHLDA2), as well as chromatin immunoprecipitation (ChIP) for histone marks within the promoter of PHLDA2...
March 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28434146/differential-regulation-of-h3s10-phosphorylation-mitosis-progression-and-cell-fate-by-aurora-kinase-b-and-c-in-mouse-preimplantation-embryos
#3
Wenzhi Li, Peizhe Wang, Bingjie Zhang, Jing Zhang, Jia Ming, Wei Xie, Jie Na
Coordination of cell division and cell fate is crucial for the successful development of mammalian early embryos. Aurora kinases are evolutionarily conserved serine/threonine kinases and key regulators of mitosis. Aurora kinase B (AurkB) is ubiquitously expressed while Aurora kinase C (AurkC) is specifically expressed in gametes and preimplantation embryos. We found that increasing AurkC level in one blastomere of the 2-cell embryo accelerated cell division and decreasing AurkC level slowed down mitosis. Changing AurkB level had the opposite effect...
April 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#4
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28425976/prenatal-exposure-to-a-maternal-high-fat-diet-affects-histone-modification-of-cardiometabolic-genes-in-newborn-rats
#5
Bijaya Upadhyaya, Tricia Larsen, Shivon Barwari, Eli J Louwagie, Michelle L Baack, Moul Dey
Infants born to women with diabetes or obesity are exposed to excess circulating fuels during fetal heart development and are at higher risk of cardiac diseases. We have previously shown that late-gestation diabetes, especially in conjunction with a maternal high-fat (HF) diet, impairs cardiac functions in rat-offspring. This study investigated changes in genome-wide histone modifications in newborn hearts from rat-pups exposed to maternal diabetes and HF-diet. Chromatin-immunoprecipitation-sequencing revealed a differential peak distribution on gene promoters in exposed pups with respect to acetylation of lysines 9 and 14 and to trimethylation of lysines 4 and 27 in histone H3 (all, false discovery rate, FDR < 0...
April 20, 2017: Nutrients
https://www.readbyqxmd.com/read/28425177/design-and-synthesis-of-c3-substituted-%C3%AE-carboline-based-histone-deacetylase-inhibitors-with-potent-antitumor-activities
#6
Yong Ling, Jiao Feng, Lin Luo, Jing Guo, Yanfu Peng, Tingting Wang, Xiang Ge, Qibing Xu, Xinyang Wang, Hong Dai, Yanan Zhang
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low-micromolar range. In particular, the HDAC inhibition IC50 value of N-(2-(dimethylamino)ethyl)-N-(4-(hydroxylcarbamoyl)benzyl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (9 h) is five-fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat)...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28424240/the-histone-acetyltransferase-gcn5-positively-regulates-t-cell-activation
#7
Beixue Gao, Qingfei Kong, Yana Zhang, Chawon Yun, Sharon Y R Dent, Jianxun Song, Donna D Zhang, Yiming Wang, Xuemei Li, Deyu Fang
Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation...
April 19, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28421257/histone-deacetylase-inhibitors-reverse-age-related-increases-in-side-effects-of-haloperidol-in-mice
#8
Janitza L Montalvo-Ortiz, Daniel W Fisher, Guadalupe Rodríguez, Deyu Fang, John G Csernansky, Hongxin Dong
BACKGROUND: Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. METHODS: In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects...
April 18, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28418026/the-cac2-subunit-is-essential-for-productive-histone-binding-and-nucleosome-assembly-in-caf-1
#9
Francesca Mattiroli, Yajie Gu, Jeremy L Balsbaugh, Natalie G Ahn, Karolin Luger
Nucleosome assembly following DNA replication controls epigenome maintenance and genome integrity. Chromatin assembly factor 1 (CAF-1) is the histone chaperone responsible for histone (H3-H4)2 deposition following DNA synthesis. Structural and functional details for this chaperone complex and its interaction with histones are slowly emerging. Using hydrogen-deuterium exchange coupled to mass spectrometry, combined with in vitro and in vivo mutagenesis studies, we identified the regions involved in the direct interaction between the yeast CAF-1 subunits, and mapped the CAF-1 domains responsible for H3-H4 binding...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28418019/live-imaging-of-h3k9-acetylation-in-plant-cells
#10
Kazuki Kurita, Takuya Sakamoto, Noriyoshi Yagi, Yuki Sakamoto, Akihiro Ito, Norikazu Nishino, Kaori Sako, Minoru Yoshida, Hiroshi Kimura, Motoaki Seki, Sachihiro Matsunaga
Proper regulation of histone acetylation is important in development and cellular responses to environmental stimuli. However, the dynamics of histone acetylation at the single-cell level remains poorly understood. Here we established a transgenic plant cell line to track histone H3 lysine 9 acetylation (H3K9ac) with a modification-specific intracellular antibody (mintbody). The H3K9ac-specific mintbody fused to the enhanced green fluorescent protein (H3K9ac-mintbody-GFP) was introduced into tobacco BY-2 cells...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28414199/structure-of-the-prc2-complex-and-application-to-drug-discovery
#11
REVIEW
Yi Shi, Xiao-Xi Wang, You-Wen Zhuang, Yi Jiang, Karsten Melcher, H Eric Xu
The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery...
April 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28413956/structure-roles-and-inhibitors-of-a-mitotic-protein-kinase-haspin
#12
Katrin Kestav, Asko Uri, Darja Lavogina
Background Haspin (haploid germ cell-specific nuclear protein kinase) is an atypical serine/threonine-protein kinase that was for a long time considered an inactive pseudokinase due to low degree of structural homology of Haspin with the 'classical' protein kinases. However, the discovery of Haspin-catalyzed phosphorylation of histone H3 at Thr3 residue unveiled importance of Haspin in mitosis and provided yet another link between mitotic phosphorylation pathways and chromatin modifications. Results In this review of 111 publications, we have (1) briefly summarized catalytic properties and physiological roles of Haspin, (2) focussed on the architecture of Haspin and mechanisms behind its substrate recognition, (3) provided detailed insight into the advances in the development and characterization of Haspin-selective inhibitors, and (4) given overview of inhibitor scaffolds that despite targeting other protein kinases feature Haspin as a common off-target...
April 14, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28413450/fetal-testis-organ-culture-reproduces-the-dynamics-of-epigenetic-reprogramming-in-rat-gonocytes
#13
Arlette Rwigemera, Fabien Joao, Geraldine Delbes
BACKGROUND: Epigenetic reprogramming is a critical step in male germ cell development that occurs during perinatal life. It is characterized by the remodeling of different epigenetic marks such as DNA methylation (5mC) and methylation of histone H3. It has been suggested that endocrine disruptors can affect the male germline epigenome by altering epigenetic reprogramming, but the mechanisms involved are still unknown. We have previously used an organ culture system that maintains the development of the different fetal testis cell types, to evaluate the effects of various endocrine disruptors on gametogenesis and steroidogenesis in the rat...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28409880/osajin-inhibits-solar-uv-induced-cyclooxygenase-2-expression-through-direct-inhibition-of-rsk2
#14
Jong-Eun Kim, Yong-Seok Heo, Ki Won Lee
Solar ultraviolet light (sUV) has been shown to promote the development of skin disorders including inflammation, photoaging, and skin carcinogenesis. Osajin is the major bioactive isoflavone present in the fruit of Maclura pomifera, commonly referred to as the Osage orange. In this study, we observed that osajin inhibited sUV-induced cyclooxygenase (COX)-2 protein expression in both HaCaT and JB6 cells. COX-2 is a major mediator of skin inflammation. sUV activated the transcription factors nuclear factor- κB and activator protein-1 which, in turn, induces COX-2 expression...
April 14, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28407300/thrombin-induces-ccl2-expression-in-human-lung-fibroblasts-via-p300-mediated-histone-acetylation-and-nf-kappab-activation
#15
Xiaoling Deng, Xiaoqiong Zhou, Yan Deng, Fan Liu, Xiaofan Feng, Qi Yin, Yinzhen Gu, Songlin Shi, Mingyan Xu
BACKGROUND AND OBJECTIVE: Thrombin has been shown to play a key role in lung diseases such as pulmonary fibrosis via the induction of fibrotic cytokine- chemokine (CC motif) ligand-2 (CCL2) expression. We previously reported that transcription factor nuclear factor-κB (NF-κB) is responsible for thrombin-induced CCL2 expression in human lung fibroblasts (HLFs). Here we extended our study to investigate the epigenetic regulation mechanism for thrombin-induced CCL2 expression in HLF. METHODS: HLFs were cultured in F-12 medium...
April 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28401334/h3-idh-wild-type-pediatric-glioblastoma-is-comprised-of-molecularly-and-prognostically-distinct-subtypes-with-associated-oncogenic-drivers
#16
Andrey Korshunov, Daniel Schrimpf, Marina Ryzhova, Dominik Sturm, Lukas Chavez, Volker Hovestadt, Tanvi Sharma, Antje Habel, Anna Burford, Chris Jones, Olga Zheludkova, Ella Kumirova, Christof M Kramm, Andrey Golanov, David Capper, Andreas von Deimling, Stefan M Pfister, David T W Jones
Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling...
April 11, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28398002/alpha-ketoglutarate-curbs-differentiation-and-induces-cell-death-in-mesenchymal-stromal-precursors-with-mitochondrial-dysfunction
#17
Karmveer Singh, Linda Krug, Abhijit Basu, Patrick Meyer, Nicolai Treiber, Seppe Vander Beken, Meinhard Wlaschek, Stefan Kochanek, Wilhelm Bloch, Hartmut Geiger, Pallab Maity, Karin Scharffetter-Kochanek
Increased concentrations of reactive oxygen species (ROS) originating from dysfunctional mitochondria contribute to diverse aging-related degenerative disorders. But so far little is known about the impact of distinct ROS on metabolism and fate of stromal precursor cells. We here demonstrate that an increase in superoxide anion radicals due to superoxide dismutase 2 (Sod2) deficiency in stromal precursor cells suppress osteogenic and adipogenic differentiation through fundamental changes in the global metabolite landscape...
April 11, 2017: Stem Cells
https://www.readbyqxmd.com/read/28392790/hist1h1c-regulates-interferon-%C3%AE-and-inhibits-influenza-virus-replication-by-interacting-with-irf3
#18
Xiaokun Liu, Cha Yang, Yong Hu, Erming Lei, Xian Lin, Lianzhong Zhao, Zhong Zou, Anding Zhang, Hongbo Zhou, Huanchun Chen, Ping Qian, Meilin Jin
Influenza virus NS2 is well known for its role in viral ribonucleoprotein nuclear export; however, its function has not been fully understood. A recent study showed that NS2 might interact with HIST1H1C (H1C, H1.2). Histones have been found to affect influenza virus replication, such as the H2A, H2B, H3, and H4, but H1 has not been detected. Here, we found that H1C interacts with NS2 via its C-terminal in the nucleus and that H1C affects influenza virus replication. The H1N1 influenza virus replicates better in H1C knockout A549 cells compared to wild-type A549 cells, primarily because of the regulation of H1C on interferon-β (IFN-β)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28389581/tssk6-is-required-for-%C3%AE-h2ax-formation-and-the-histone-to-protamine-transition-during-spermiogenesis
#19
Kula N Jha, Swamy K Tripurani, Gibbes R Johnson
Spermiogenesis includes transcriptional silencing, chromatin condensation and extensive morphological changes as spermatids transform into sperm. Chromatin condensation involves histone hyperacetylation, transitory DNA breaks, histone H2AX Ser139 phosphorylation (γH2AX), and replacement of histones by protamines. Previously, we reported that the spermatid protein kinase TSSK6 is essential for fertility in mice, but its specific role in spermiogenesis is unknown. Here, we show that TSSK6 expression is spatiotemporally coincident with γH2AX formation in nuclei of developing mouse spermatids...
April 7, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28388576/proton-pump-inhibitor-ilaprazole-suppresses-cancer-growth-by-targeting-t-cell-originated-protein-kinase
#20
Mengzhu Zheng, Shanshan Luan, Suyu Gao, Li Cheng, Bin Hao, Jiacheng Li, Yao Chen, Xuemei Hou, Lixia Chen, Hua Li
T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole...
March 27, 2017: Oncotarget
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