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  • 1
    Publication Date: 2018-05-16
    Description: Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer to allow optimal surgery and aim for pathologic response. However, many breast cancers are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem–like cell (CSC) phenotype and contributing to tumor relapse. Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of breast cancer cells. Using cell lines, patient-derived xenograft models, and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors. Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte–macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT. Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370–82. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2012-05-25
    Description: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berger, Michael F -- Hodis, Eran -- Heffernan, Timothy P -- Deribe, Yonathan Lissanu -- Lawrence, Michael S -- Protopopov, Alexei -- Ivanova, Elena -- Watson, Ian R -- Nickerson, Elizabeth -- Ghosh, Papia -- Zhang, Hailei -- Zeid, Rhamy -- Ren, Xiaojia -- Cibulskis, Kristian -- Sivachenko, Andrey Y -- Wagle, Nikhil -- Sucker, Antje -- Sougnez, Carrie -- Onofrio, Robert -- Ambrogio, Lauren -- Auclair, Daniel -- Fennell, Timothy -- Carter, Scott L -- Drier, Yotam -- Stojanov, Petar -- Singer, Meredith A -- Voet, Douglas -- Jing, Rui -- Saksena, Gordon -- Barretina, Jordi -- Ramos, Alex H -- Pugh, Trevor J -- Stransky, Nicolas -- Parkin, Melissa -- Winckler, Wendy -- Mahan, Scott -- Ardlie, Kristin -- Baldwin, Jennifer -- Wargo, Jennifer -- Schadendorf, Dirk -- Meyerson, Matthew -- Gabriel, Stacey B -- Golub, Todd R -- Wagner, Stephan N -- Lander, Eric S -- Getz, Gad -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-03/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-01/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 9;485(7399):502-6. doi: 10.1038/nature11071.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622578" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosome Breakpoints/radiation effects ; DNA Damage ; DNA Mutational Analysis ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Guanine Nucleotide Exchange Factors/*genetics/metabolism ; Humans ; Melanocytes/metabolism/pathology ; Melanoma/*genetics/pathology ; Mutagenesis/radiation effects ; Mutation/*genetics/radiation effects ; Oncogenes/genetics ; Sunlight/*adverse effects ; Ultraviolet Rays/adverse effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-05-24
    Description: The formation mechanism of pentazolate anion (PZA) is not yet clear. In order to present the possible formation pathways of PZA, the potential energy surfaces of phenylpentazole (PPZ), phenylpentazole radical (PPZ-R), phenylpentazole radical anion (PPZ-RA), PPZ and m -chloroperbenzoic acid ( m -CPBA), p -pentazolylphenolate anion ( p -PZPolA) and m -CPBA, and p -pentazolylphenol ( p -PZPol) and m -CPBA were calculated by the computational electronic structure methods including the hybrid density functional, the double hybrid density functional and the coupled-cluster theories. At the thermodynamic point of view, the cleavages of C–N bonds of PPZ and PPZ-R need to absorb large amounts of heat. Thus, they are not feasible entrance for PZA formation at ambient condition. But excitation of PPZ and deprotonation of PPZ-RA probably happen before cleavage of C–N bond of PPZ at high-energy condition. As to the radical anion mechanism, the high accuracy calculations surveyed that the barrier of PZA formation is probably lower than that of dinitrogen evolution, but the small ionization potential of PPZ-RA gives rise to the unstable ionic pair of sodium PPZ at high temperature. In respect of oxidation mechanism, except for PPZ, the reactions of p -PZPolA and p -PZPol with m -CPBA can form PZA and quinone. The PZA formations have the barriers of about 20 kcal mol –1 which compete with the dinitrogen evolutions. The stabilities of PZA in both solid and gas phases were also studied herein. The proton prefers to transfer to pentazolyl group in the (N 5 ) 6 (H 3 O) 3 (NH 4 ) 4 Cl system which leads to the dissociation of pentazole ring. The ground states of M(N 5 ) 2 (H 2 O) 4 (M = Co, Fe and Mn) are high-spin states. The pentazolyl groups confined by the crystal waters in the coordinate compounds can improve the kinetic stability. As to the reactivity of PZA, it can be persistently oxidized by m -CPBA to oxo-PZA and 1,3-oxo-PZA with the barriers of about 20 kcal mol –1 .
    Keywords: inorganic chemistry, physical chemistry, computational chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 4
    Publication Date: 2018-07-05
    Description: Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis, Published online: 04 July 2018; doi:10.1038/s41388-018-0322-0 Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis
    Print ISSN: 0950-9232
    Topics: Medicine
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  • 5
    Publication Date: 2014-08-01
    Description: DNA methylation is a crucial element in the epigenetic regulation of mammalian embryonic development. However, its dynamic patterns have not been analysed at the genome scale in human pre-implantation embryos due to technical difficulties and the scarcity of required materials. Here we systematically profile the methylome of human early embryos from the zygotic stage through to post-implantation by reduced representation bisulphite sequencing and whole-genome bisulphite sequencing. We show that the major wave of genome-wide demethylation is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethylation of the paternal genome is much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in male pronuclei is already lower than that in female pronuclei. The inverse correlation between promoter methylation and gene expression gradually strengthens during early embryonic development, reaching its peak at the post-implantation stage. Furthermore, we show that active genes, with the trimethylation of histone H3 at lysine 4 (H3K4me3) mark at the promoter regions in pluripotent human embryonic stem cells, are essentially devoid of DNA methylation in both mature gametes and throughout pre-implantation development. Finally, we also show that long interspersed nuclear elements or short interspersed nuclear elements that are evolutionarily young are demethylated to a milder extent compared to older elements in the same family and have higher abundance of transcripts, indicating that early embryos tend to retain higher residual methylation at the evolutionarily younger and more active transposable elements. Our work provides insights into the critical features of the methylome of human early embryos, as well as its functional relation to the regulation of gene expression and the repression of transposable elements.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Hongshan -- Zhu, Ping -- Yan, Liying -- Li, Rong -- Hu, Boqiang -- Lian, Ying -- Yan, Jie -- Ren, Xiulian -- Lin, Shengli -- Li, Junsheng -- Jin, Xiaohu -- Shi, Xiaodan -- Liu, Ping -- Wang, Xiaoye -- Wang, Wei -- Wei, Yuan -- Li, Xianlong -- Guo, Fan -- Wu, Xinglong -- Fan, Xiaoying -- Yong, Jun -- Wen, Lu -- Xie, Sunney X -- Tang, Fuchou -- Qiao, Jie -- England -- Nature. 2014 Jul 31;511(7511):606-10. doi: 10.1038/nature13544. Epub 2014 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2]. ; 1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2] Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China [3]. ; 1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2] Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China [3]. ; Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China. ; 1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2] Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China. ; Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. ; 1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Biodynamic Optical Imaging Center &Center for Reproductive Medicine, College of Life Sciences, Third Hospital, Peking University, Beijing 100871, China [2] Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079557" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *DNA Methylation ; DNA Transposable Elements/genetics ; Embryo, Mammalian ; Embryonic Stem Cells/physiology ; *Epigenesis, Genetic ; Female ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Germ Cells/metabolism ; Histones/metabolism ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Male ; Mice ; Promoter Regions, Genetic/genetics ; Short Interspersed Nucleotide Elements/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-10-15
    Description: Periodic stripe patterns are ubiquitous in living organisms, yet the underlying developmental processes are complex and difficult to disentangle. We describe a synthetic genetic circuit that couples cell density and motility. This system enabled programmed Escherichia coli cells to form periodic stripes of high and low cell densities sequentially and autonomously. Theoretical and experimental analyses reveal that the spatial structure arises from a recurrent aggregation process at the front of the continuously expanding cell population. The number of stripes formed could be tuned by modulating the basal expression of a single gene. The results establish motility control as a simple route to establishing recurrent structures without requiring an extrinsic pacemaker.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Chenli -- Fu, Xiongfei -- Liu, Lizhong -- Ren, Xiaojing -- Chau, Carlos K L -- Li, Sihong -- Xiang, Lu -- Zeng, Hualing -- Chen, Guanhua -- Tang, Lei-Han -- Lenz, Peter -- Cui, Xiaodong -- Huang, Wei -- Hwa, Terence -- Huang, Jian-Dong -- New York, N.Y. -- Science. 2011 Oct 14;334(6053):238-41. doi: 10.1126/science.1209042.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21998392" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl-Butyrolactones/metabolism ; Bacterial Load ; Cell Proliferation ; Culture Media ; Diffusion ; Escherichia coli K12/cytology/genetics/*growth & development/*physiology ; Gene Expression Regulation, Bacterial ; Gene Regulatory Networks ; Kinetics ; Models, Biological ; Movement ; Quorum Sensing ; Synthetic Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-08-21
    Description: Excessive intake of dietary fats leads to diminished brain dopaminergic function. It has been proposed that dopamine deficiency exacerbates obesity by provoking compensatory overfeeding as one way to restore reward sensitivity. However, the physiological mechanisms linking prolonged high-fat intake to dopamine deficiency remain elusive. We show that administering oleoylethanolamine, a gastrointestinal lipid messenger whose synthesis is suppressed after prolonged high-fat exposure, is sufficient to restore gut-stimulated dopamine release in high-fat-fed mice. Administering oleoylethanolamine to high-fat-fed mice also eliminated motivation deficits during flavorless intragastric feeding and increased oral intake of low-fat emulsions. Our findings suggest that high-fat-induced gastrointestinal dysfunctions play a key role in dopamine deficiency and that restoring gut-generated lipid signaling may increase the reward value of less palatable, yet healthier, foods.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tellez, Luis A -- Medina, Sara -- Han, Wenfei -- Ferreira, Jozelia G -- Licona-Limon, Paula -- Ren, Xueying -- Lam, Tukiet T -- Schwartz, Gary J -- de Araujo, Ivan E -- DC009997/DC/NIDCD NIH HHS/ -- DK020541/DK/NIDDK NIH HHS/ -- DK026687/DK/NIDDK NIH HHS/ -- DK085579/DK/NIDDK NIH HHS/ -- P30 DK026687/DK/NIDDK NIH HHS/ -- UL1RR024139/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 16;341(6147):800-2. doi: 10.1126/science.1239275.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The John B. Pierce Laboratory, New Haven, CT 06519, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23950538" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Appetite ; Corpus Striatum/*metabolism ; Dietary Fats/*administration & dosage ; Dopamine/deficiency/*metabolism ; Endocannabinoids/*administration & dosage/biosynthesis/*physiology ; Energy Intake ; Ethanolamines/*administration & dosage ; Feeding Behavior ; Gastrointestinal Tract/*metabolism ; Homeostasis ; Intestine, Small/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oleic Acids/*administration & dosage/biosynthesis/*physiology ; PPAR alpha/genetics/metabolism ; Reward ; Signal Transduction ; Vagus Nerve/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2013-03-09
    Description: Freestanding nanowires have ultrahigh elastic strain limits (4 to 7%) and yield strengths, but exploiting their intrinsic mechanical properties in bulk composites has proven to be difficult. We exploited the intrinsic mechanical properties of nanowires in a phase-transforming matrix based on the concept of elastic and transformation strain matching. By engineering the microstructure and residual stress to couple the true elasticity of Nb nanowires with the pseudoelasticity of a NiTi shape-memory alloy, we developed an in situ composite that possesses a large quasi-linear elastic strain of over 6%, a low Young's modulus of ~28 gigapascals, and a high yield strength of ~1.65 gigapascals. Our elastic strain-matching approach allows the exceptional mechanical properties of nanowires to be exploited in bulk materials.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hao, Shijie -- Cui, Lishan -- Jiang, Daqiang -- Han, Xiaodong -- Ren, Yang -- Jiang, Jiang -- Liu, Yinong -- Liu, Zhenyang -- Mao, Shengcheng -- Wang, Yandong -- Li, Yan -- Ren, Xiaobing -- Ding, Xiangdong -- Wang, Shan -- Yu, Cun -- Shi, Xiaobin -- Du, Minshu -- Yang, Feng -- Zheng, Yanjun -- Zhang, Ze -- Li, Xiaodong -- Brown, Dennis E -- Li, Ju -- New York, N.Y. -- Science. 2013 Mar 8;339(6124):1191-4. doi: 10.1126/science.1228602.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Beijing 102249, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23471404" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-10-24
    Description: The lentiviruses HIV and simian immunodeficiency virus (SIV) subvert intracellular membrane traffic as part of their replication cycle. The lentiviral Nef protein helps viruses evade innate and adaptive immune defenses by hijacking the adaptor protein 1 (AP-1) and AP-2 clathrin adaptors. We found that HIV-1 Nef and the guanosine triphosphatase Arf1 induced trimerization and activation of AP-1. Here we report the cryo-electron microscopy structures of the Nef- and Arf1-bound AP-1 trimer in the active and inactive states. A central nucleus of three Arf1 molecules organizes the trimers. We combined the open trimer with a known dimer structure and thus predicted a hexagonal assembly with inner and outer faces that bind the membranes and clathrin, respectively. Hexagons were directly visualized and the model validated by reconstituting clathrin cage assembly. Arf1 and Nef thus play interconnected roles in allosteric activation, cargo recruitment, and coat assembly, revealing an unexpectedly intricate organization of the inner AP-1 layer of the clathrin coat.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638387/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638387/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Qing-Tao -- Ren, Xuefeng -- Zhang, Rui -- Lee, Il-Hyung -- Hurley, James H -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50GM082250/GM/NIGMS NIH HHS/ -- R01 AI120691/AI/NIAID NIH HHS/ -- R01AI120691/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Oct 23;350(6259):aac5137. doi: 10.1126/science.aac5137.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA. ; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. jimhurley@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26494761" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Keywords: EXPRESSION ; proliferation ; MUTATIONS ; CENTRAL-NERVOUS-SYSTEM ; FACTOR-I ; medulloblastoma ; 3T3-L1 ADIPOCYTES ; INSULIN-RESISTANCE ; MITOCHONDRIAL DYSFUNCTION ; RHABDOID TUMORS
    Abstract: PURPOSE: We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was first identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. EXPERIMENTAL DESIGN: Quantitative RT-PCR, microarrays and cell culture RESULTS: Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (Groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets PID1 mRNA was lower in glioblastomas (GBMs), the most malignant gliomas, compared to other astrocytomas, oligodendrogliomas and non-tumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared to classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients with higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in glioma and GBM patients. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT) and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolarization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. CONCLUSIONS: These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors.
    Type of Publication: Journal article published
    PubMed ID: 24300787
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