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  • 1
    Publication Date: 2018-10-03
    Description: Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic treatments. In melanoma, both the BRAF/MEK/ERK and PI3-K/AKT signaling pathways are constitutively activated through multiple mechanisms, which result in cell-cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3K are of utmost importance. In this study, we found that Ashitaba ( Angelica keiskei ) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling. This led to the induction of G 1 phase cell-cycle arrest and apoptosis in melanoma cells. Importantly, 4HD or XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten -deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3K, providing hope for rapid clinical translation. Cancer Prev Res; 11(10); 607–20. ©2018 AACR .
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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  • 2
    Publication Date: 2018-05-17
    Description: Cholinesterase activity (ChA), the effective biomarker for organophosphate pesticide exposure, is possibly affected by single nucleotide polymorphisms (SNPs) in cell-cycle-related genes. One hundred and eighty workers with long-term exposure to omethoate and 115 healthy controls were recruited to explore the gene–gene and gene–environment interactions. The acetylthiocholine and dithio-bis-(nitrobenzoic acid) method was used to detect the cholinesterase activities in whole blood, erythrocytes and plasma. Genetic polymorphisms were determined by the PCR-RFLP and direct PCR electrophoresis methods. Statistical results showed that the cholinesterase activities of whole blood, erythrocytes and plasma in the exposure group were significantly lower than those in the control group ( p 〈 0.001), and erythrocyte cholinesterase activities were associated with gender, smoking and drinking in the exposure group ( p 〈 0.05). Single-locus analyses showed that there is a statistically significant difference in the ChA among the genotypes CC, CA and AA of the p21 rs1801270 locus in the control group ( p = 0.033), but not in the exposure group. A significant interaction between genes and environmental factors (i.e. p53 , p21 , mdm2, gender, smoking and drinking) affecting ChA was found through a generalized multifactor dimensionality reduction analysis. These obtained markers will be useful in further marker-assisted selection in workers with exposure to omethoate.
    Keywords: molecular biology, genetics, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Publication Date: 2018-02-09
    Description: Introduction Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients. Methods and analysis This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing. Ethics and dissemination Ethical approval has been obtained from the Peking University People’s Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. Trial registration number NCT02965391 ; Pre-results.
    Keywords: Open access, Oncology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    Publication Date: 2011-07-23
    Description: Quantum dynamical theories have progressed to the stage in which state-to-state differential cross sections can now be routinely computed with high accuracy for three-atom systems since the first such calculation was carried out more than 30 years ago for the H + H(2) system. For reactions beyond three atoms, however, highly accurate quantum dynamical calculations of differential cross sections have not been feasible. We have recently developed a quantum wave packet method to compute full-dimensional differential cross sections for four-atom reactions. Here, we report benchmark calculations carried out for the prototypical HD + OH --〉 H(2)O + D reaction on an accurate potential energy surface that yield differential cross sections in excellent agreement with those from a high-resolution, crossed-molecular beam experiment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiao, Chunlei -- Xu, Xin -- Liu, Shu -- Wang, Tao -- Dong, Wenrui -- Yang, Tiangang -- Sun, Zhigang -- Dai, Dongxu -- Zhang, Dong H -- Yang, Xueming -- New York, N.Y. -- Science. 2011 Jul 22;333(6041):440-2. doi: 10.1126/science.1205770.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, 116023, P. R. China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21778397" 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: 2013-12-21
    Description: Experimental limitations in vibrational excitation efficiency have previously hindered investigation of how vibrational energy might mediate the role of dynamical resonances in bimolecular reactions. Here, we report on a high-resolution crossed-molecular-beam experiment on the vibrationally excited HD(v = 1) + F --〉 HF + D reaction, in which two broad peaks for backward-scattered HF(v' = 2 and 3) products clearly emerge at collision energies of 0.21 kilocalories per mole (kcal/mol) and 0.62 kcal/mol from differential cross sections measured over a range of energies. We attribute these features to excited Feshbach resonances trapped in the peculiar HF(v' = 4)-D vibrationally adiabatic potential in the postbarrier region. Quantum dynamics calculations on a highly accurate potential energy surface show that these resonance states correlate to the HD(v' = 1) state in the entrance channel and therefore can only be accessed by the vibrationally excited HD reagent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Tao -- Chen, Jun -- Yang, Tiangang -- Xiao, Chunlei -- Sun, Zhigang -- Huang, Long -- Dai, Dongxu -- Yang, Xueming -- Zhang, Dong H -- New York, N.Y. -- Science. 2013 Dec 20;342(6165):1499-502. doi: 10.1126/science.1246546.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24357315" 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
    Publication Date: 2015-10-17
    Description: Large-scale genetic analysis of lethal phenotypes has elucidated the molecular underpinnings of many biological processes. Using the bacterial clustered regularly interspaced short palindromic repeats (CRISPR) system, we constructed a genome-wide single-guide RNA library to screen for genes required for proliferation and survival in a human cancer cell line. Our screen revealed the set of cell-essential genes, which was validated with an orthogonal gene-trap-based screen and comparison with yeast gene knockouts. This set is enriched for genes that encode components of fundamental pathways, are expressed at high levels, and contain few inactivating polymorphisms in the human population. We also uncovered a large group of uncharacterized genes involved in RNA processing, a number of whose products localize to the nucleolus. Last, screens in additional cell lines showed a high degree of overlap in gene essentiality but also revealed differences specific to each cell line and cancer type that reflect the developmental origin, oncogenic drivers, paralogous gene expression pattern, and chromosomal structure of each line. These results demonstrate the power of CRISPR-based screens and suggest a general strategy for identifying liabilities in cancer cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662922/" 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/PMC4662922/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Tim -- Birsoy, Kivanc -- Hughes, Nicholas W -- Krupczak, Kevin M -- Post, Yorick -- Wei, Jenny J -- Lander, Eric S -- Sabatini, David M -- 2U54HG003067-10/HG/NHGRI NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- F31 CA189437/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1096-101. doi: 10.1126/science.aac7041. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. ; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. lander@broadinstitute.org sabatini@wi.mit.edu. ; Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. lander@broadinstitute.org sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472758" target="_blank"〉PubMed〈/a〉
    Keywords: CRISPR-Cas Systems ; Cell Line, Tumor ; Cell Nucleolus/metabolism ; Gene Expression Profiling ; Gene Knockout Techniques ; *Genes, Essential ; Genetic Testing/*methods ; Genome, Human/*genetics ; Genomic Library ; Humans ; Neoplasms/genetics ; RNA Processing, Post-Transcriptional/genetics ; RNA, Guide/genetics
    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: 2016-02-26
    Description: Diamond lattices formed by atomic or colloidal elements exhibit remarkable functional properties. However, building such structures via self-assembly has proven to be challenging because of the low packing fraction, sensitivity to bond orientation, and local heterogeneity. We report a strategy for creating a diamond superlattice of nano-objects via self-assembly and demonstrate its experimental realization by assembling two variant diamond lattices, one with and one without atomic analogs. Our approach relies on the association between anisotropic particles with well-defined tetravalent binding topology and isotropic particles. The constrained packing of triangular binding footprints of truncated tetrahedra on a sphere defines a unique three-dimensional lattice. Hence, the diamond self-assembly problem is solved via its mapping onto two-dimensional triangular packing on the surface of isotropic spherical particles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wenyan -- Tagawa, Miho -- Xin, Huolin L -- Wang, Tong -- Emamy, Hamed -- Li, Huilin -- Yager, Kevin G -- Starr, Francis W -- Tkachenko, Alexei V -- Gang, Oleg -- AG029979/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 5;351(6273):582-6. doi: 10.1126/science.aad2080.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY 11973, USA. ; Department of Materials Science and Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan. ; Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA. ; Department of Physics, Wesleyan University, Middletown, CT 06459, USA. ; Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA. ; Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, NY 11973, USA. ogang@bnl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912698" 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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  • 8
    Publication Date: 2015-11-21
    Description: Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698039/" 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/PMC4698039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saxton, Robert A -- Knockenhauer, Kevin E -- Wolfson, Rachel L -- Chantranupong, Lynne -- Pacold, Michael E -- Wang, Tim -- Schwartz, Thomas U -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA189333/CA/NCI NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- F31 CA189437/CA/NCI NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01CA103866/CA/NCI NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):53-8. doi: 10.1126/science.aad2087. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586190" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Leucine/*chemistry/metabolism ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Mutation ; Nuclear Proteins/*chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; TOR Serine-Threonine Kinases/chemistry/genetics/*metabolism
    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: 2018-04-25
    Description: Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. Platelet-derived growth factor A ( PDGFA ) is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified homeobox A5 ( HOXA5 ) as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of HOXA5 in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, HOXA5 overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of HOXA5 expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates HOXA5 as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 10
    Publication Date: 2018-06-14
    Description: Microbial life inhabiting subseafloor sediments plays an important role in Earth’s carbon cycle. However, the impact of geodynamic processes on the distributions and carbon-cycling activities of subseafloor life remains poorly constrained. We explore a submarine mud volcano of the Nankai accretionary complex by drilling down to 200 m below the summit. Stable isotopic compositions of water and carbon compounds, including clumped methane isotopologues, suggest that ~90% of methane is microbially produced at 16° to 30°C and 300 to 900 m below seafloor, corresponding to the basin bottom, where fluids in the accretionary prism are supplied via megasplay faults. Radiotracer experiments showed that relatively small microbial populations in deep mud volcano sediments (10 2 to 10 3 cells cm –3 ) include highly active hydrogenotrophic methanogens and acetogens. Our findings indicate that subduction-associated fluid migration has stimulated microbial activity in the mud reservoir and that mud volcanoes may contribute more substantially to the methane budget than previously estimated.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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