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  • 1
    Publication Date: 2018-02-16
    Description: Purpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small-cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. Experimental Design: We determined correlation of Etk with autophagy in SCLC. And direct inhibition of autophagy was performed to validate its effect on chemoresistance. Coimmunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify the interaction of Etk and PFKFB4, after a microarray analysis. In vitro and in vivo gain or loss-of-function analyses and evaluation of PFKFB4 expression in SCLC specimens, were done to validate its role in chemoresistance. Ibrutinib was administrated in SCLC cells to verify its synergistic anti-tumor effect with chemotherapy using preclinical models including a PDX model. Results: Downregulation of Etk suppressed autophagy in chemoresistant SCLC cells, and direct inhibition of autophagy sensitized cells to chemotherapy. PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) was identified as a downstream target of Etk and an Etk-interacting protein, which promoted chemoresistance in SCLC and was associated with poor therapeutic response and prognosis. Furthermore, ibrutinib was found to exhibit a synergistic anti-tumor effect with chemotherapy in targeting Etk. Conclusions: Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC. Clin Cancer Res; 24(4); 950–62. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    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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  • 3
    Publication Date: 2013-01-26
    Description: Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423787/" 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/PMC4423787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Franklin W -- Hodis, Eran -- Xu, Mary Jue -- Kryukov, Gregory V -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2OD002750/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33CA126674/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM07753/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 22;339(6122):957-9. doi: 10.1126/science.1229259. Epub 2013 Jan 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23348506" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; *Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/genetics ; Melanoma/*genetics ; *Mutation ; *Promoter Regions, Genetic ; Proto-Oncogene Proteins c-ets/metabolism ; Telomerase/chemistry/*genetics/metabolism ; Transcription, Genetic
    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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  • 4
    Publication Date: 2014-03-08
    Description: Multiferroics have attracted strong interest for potential applications where electric fields control magnetic order. The ultimate speed of control via magnetoelectric coupling, however, remains largely unexplored. Here, we report an experiment in which we drove spin dynamics in multiferroic TbMnO3 with an intense few-cycle terahertz (THz) light pulse tuned to resonance with an electromagnon, an electric-dipole active spin excitation. We observed the resulting spin motion using time-resolved resonant soft x-ray diffraction. Our results show that it is possible to directly manipulate atomic-scale magnetic structures with the electric field of light on a sub-picosecond time scale.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kubacka, T -- Johnson, J A -- Hoffmann, M C -- Vicario, C -- de Jong, S -- Beaud, P -- Grubel, S -- Huang, S-W -- Huber, L -- Patthey, L -- Chuang, Y-D -- Turner, J J -- Dakovski, G L -- Lee, W-S -- Minitti, M P -- Schlotter, W -- Moore, R G -- Hauri, C P -- Koohpayeh, S M -- Scagnoli, V -- Ingold, G -- Johnson, S L -- Staub, U -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1333-6. doi: 10.1126/science.1242862. Epub 2014 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Quantum Electronics, Eidgenossische Technische Hochschule (ETH) Zurich, Wolfgang-Pauli-Strasse 16, 8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24603154" 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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  • 5
    Publication Date: 2014-03-01
    Description: Control of structure at the atomic level can precisely and effectively tune catalytic properties of materials, enabling enhancement in both activity and durability. We synthesized a highly active and durable class of electrocatalysts by exploiting the structural evolution of platinum-nickel (Pt-Ni) bimetallic nanocrystals. The starting material, crystalline PtNi3 polyhedra, transforms in solution by interior erosion into Pt3Ni nanoframes with surfaces that offer three-dimensional molecular accessibility. The edges of the Pt-rich PtNi3 polyhedra are maintained in the final Pt3Ni nanoframes. Both the interior and exterior catalytic surfaces of this open-framework structure are composed of the nanosegregated Pt-skin structure, which exhibits enhanced oxygen reduction reaction (ORR) activity. The Pt3Ni nanoframe catalysts achieved a factor of 36 enhancement in mass activity and a factor of 22 enhancement in specific activity, respectively, for this reaction (relative to state-of-the-art platinum-carbon catalysts) during prolonged exposure to reaction conditions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Chen -- Kang, Yijin -- Huo, Ziyang -- Zhu, Zhongwei -- Huang, Wenyu -- Xin, Huolin L -- Snyder, Joshua D -- Li, Dongguo -- Herron, Jeffrey A -- Mavrikakis, Manos -- Chi, Miaofang -- More, Karren L -- Li, Yadong -- Markovic, Nenad M -- Somorjai, Gabor A -- Yang, Peidong -- Stamenkovic, Vojislav R -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1339-43. doi: 10.1126/science.1249061. Epub 2014 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578531" 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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  • 6
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-03-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Xiong-Wei -- Wang, Wei -- Dong, Yun-Wei -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1079. doi: 10.1126/science.347.6226.1079-b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, China. ; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, China. dongyw@xmu.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745154" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biodiversity ; *Conservation of Natural Resources ; *Wetlands
    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: 2015-11-07
    Description: The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic beta cell function, we examined pancreatic islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that beta cell clock ablation in adult mice caused severe glucose intolerance. Thus, cell type-specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669216/" 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/PMC4669216/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perelis, Mark -- Marcheva, Biliana -- Ramsey, Kathryn Moynihan -- Schipma, Matthew J -- Hutchison, Alan L -- Taguchi, Akihiko -- Peek, Clara Bien -- Hong, Heekyung -- Huang, Wenyu -- Omura, Chiaki -- Allred, Amanda L -- Bradfield, Christopher A -- Dinner, Aaron R -- Barish, Grant D -- Bass, Joseph -- ES05703/ES/NIEHS NIH HHS/ -- K01 DK105137/DK/NIDDK NIH HHS/ -- P01 AG011412/AG/NIA NIH HHS/ -- P01AG011412/AG/NIA NIH HHS/ -- P60 DK020595/DK/NIDDK NIH HHS/ -- P60DK020595/DK/NIDDK NIH HHS/ -- R01 DK090625/DK/NIDDK NIH HHS/ -- R01 ES005703/ES/NIEHS NIH HHS/ -- R01DK090625/DK/NIDDK NIH HHS/ -- T32 DK007169/DK/NIDDK NIH HHS/ -- T32 GM007281/GM/NIGMS NIH HHS/ -- T32 HL007909/HL/NHLBI NIH HHS/ -- T32GM07281/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):aac4250. doi: 10.1126/science.aac4250.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ; Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA. ; Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA. Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA. ; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 52705, USA. ; Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA. Department of Chemistry, University of Chicago, Chicago, IL 60637, USA. ; Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. j-bass@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542580" target="_blank"〉PubMed〈/a〉
    Keywords: ARNTL Transcription Factors/genetics/metabolism ; Animals ; CLOCK Proteins/metabolism ; Circadian Rhythm/*genetics ; Diabetes Mellitus, Type 2/genetics/metabolism ; Enhancer Elements, Genetic/*physiology ; Exocytosis/genetics ; *Gene Expression Regulation ; Glucose Intolerance ; Homeodomain Proteins/metabolism ; Humans ; Insulin/*secretion ; Insulin-Secreting Cells/*secretion ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Trans-Activators/metabolism ; Transcription, Genetic
    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: 2018-03-20
    Description: Hepatic APCs play a critical role in promoting immune tolerance in the liver. Recently, we have demonstrated that TLR2 stimulation on liver sinusoidal endothelial cells reverted their suppressive properties to induce T cell immunity. However, there is a paucity of information about how TLR2 stimulation modulates the immunological function of other hepatic APCs. In the current study, we investigated whether TLR2 stimulation influences the function of intrahepatic myeloid-derived cells (iMDCs) and elucidated the mechanisms involved in iMDC-induced T cell immunity. We could show that iMDCs from C57BL/6 mice can potently suppress T cell activation in a cell contact–independent manner. Ag presentation by iMDCs leads to naive CD8 T cell tolerance. To our surprise, instead of inducing cell functional maturation, TLR2 ligand palmitoyl-3-cysteine-serine-lysine-4 (P3C) stimulation further strengthens the suppressive and tolerogenic properties of iMDCs. After P3C administration, the population of Kupffer cells (KCs) of iMDCs dramatically increased. Mechanism analysis shows that KCs are essential for the enhanced inhibition of T cell activation by P3C-stimulated iMDCs. The iMDC-mediated CD8 T cell inhibition was mediated by soluble mediators, one of which was IL-10 secreted by KCs after P3C stimulation. IL-10 blockade could partially abolish iMDC-mediated T cell inhibition. Moreover, hepatitis B virus particle stimulation on iMDCs could also induce IL-10 production by the cells in a TLR2-dependent way. Our results have implications for our understanding of liver-specific tolerance and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 9
    Publication Date: 2018-04-14
    Description: WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA-associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target. IMPORTANCE Human cytomegalovirus (HCMV) has a large (~235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 10
    Publication Date: 2018-04-27
    Description: We identified 20 to 22 resistance genes, carried in four incompatibility groups of plasmids, in each of five genetically closely related Salmonella enterica serovar Typhimurium strains recovered from humans, pigs, and chickens. The genes conferred resistance to aminoglycosides, chloramphenicol, sulfonamides, trimethoprim, tetracycline, fluoroquinolones, extended-spectrum cephalosporins and cefoxitin, and azithromycin. This study demonstrates the transmission of multidrug-resistant Salmonella strains among humans and food animals and may be the first identification of mphA in azithromycin-resistant Salmonella strains in Taiwan.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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