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  • 1
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    HIV DNA is heavily uracilated, which protects it from autointegration [Microbiology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-06-01
    Description: Human immune cells infected by HIV naturally contain high uracil content, and HIV reverse transcriptase (RT) does not distinguish between dUTP and dTTP. Many DNA viruses and retroviruses encode a dUTPase or uracil-DNA glycosylase (UNG) to counteract uracil incorporation. However, although HIV virions are thought to contain cellular UNG2, replication of HIV produced in cells lacking UNG activity does not appear to be impaired. Here we show that HIV reverse transcripts generated in primary human immune cells are heavily uracilated (〉500 uracils per 10 kb HIV genome). We find that HIV DNA uracilation, rather than being dangerous, may promote the early phase of the viral life cycle. Shortly after reverse transcription, the ends of the HIV DNA are activated by the viral integrase (IN) in preparation for chromosomal insertion. However, the activated ends can attack the viral DNA itself in a suicidal side pathway, called autointegration. We find here that uracilation of target DNA inhibits the strand transfer of HIV DNA ends by IN, thereby inhibiting autointegration and facilitating chromosomal integration and viral replication. When uracilation is increased by incubating uracil-poor cells in the presence of increasing concentrations of dUTP or by infecting with virus that contains the cytosine deaminase APOBEC3G (A3G), the proportion of reverse transcripts that undergo suicidal autointegration decreases. Thus, HIV tolerates, or even benefits from, nonmutagenic uracil incorporation during reverse transcription in human immune cells.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Crystal structures of Transportin 3 [Microbiology] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-02-19
    Description: Transportin 3 (Tnpo3, Transportin-SR2) is implicated in nuclear import of splicing factors and HIV-1 replication. Herein, we show that the majority of cellular Tnpo3 binding partners contain arginine-serine (RS) repeat domains and present crystal structures of human Tnpo3 in its free as well as GTPase Ran- and alternative splicing factor/splicing...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    pHLIP Var3 as a marker of acidic malignant lesions [Medical Sciences] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-08-05
    Description: Current strategies for early detection of breast and other cancers are limited in part because some lesions identified as potentially malignant do not develop into aggressive tumors. Acid pH has been suggested as a key characteristic of aggressive tumors that might distinguish aggressive lesions from more indolent pathology. We therefore...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Cell surface pH measurements [Applied Biological Sciences] (2016)
    National Academy of Sciences
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    Publication Date: 2016-07-21
    Description: We have developed a way to measure cell surface pH by positioning a pH-sensitive fluorescent dye, seminaphtharhodafluor (SNARF), conjugated to the pH low insertion peptide (pHLIP). It has been observed that many diseased tissues are acidic and that tumors are especially so. A combination of effects acidifies tumor cell interiors,...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    A combinatorial strategy for treating KRAS-mutant lung cancer (2016)
    Springer Nature
    In: Nature
    Details
    Publication Date: 2016-06-30
    Description: A combinatorial strategy for treating KRAS-mutant lung cancer Nature 534, 7609 (2016). doi:10.1038/nature18600 Authors: Eusebio Manchado, Susann Weissmueller, John P. Morris, Chi-Chao Chen, Ramona Wullenkord, Amaia Lujambio, Elisa de Stanchina, John T. Poirier, Justin F. Gainor, Ryan B. Corcoran, Jeffrey A. Engelman, Charles M. Rudin, Neal Rosen & Scott W. Lowe Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 6
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    Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints (2016)
    Springer Nature
    Details
    Publication Date: 2016-02-19
    Description: Article Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer. Nature Communications doi: 10.1038/ncomms10501 Authors: Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Grit S. Herter-Sprie, Kevin A. Buczkowski, William G. Richards, Leena Gandhi, Amanda J. Redig, Scott J. Rodig, Hajime Asahina, Robert E. Jones, Meghana M. Kulkarni, Mari Kuraguchi, Sangeetha Palakurthi, Peter E. Fecci, Bruce E. Johnson, Pasi A. Janne, Jeffrey A. Engelman, Sidharta P. Gangadharan, Daniel B. Costa, Gordon J. Freeman, Raphael Bueno, F. Stephen Hodi, Glenn Dranoff, Kwok-Kin Wong, Peter S. Hammerman
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 7
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    RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015)
    Springer Nature
    Details
    Publication Date: 2015-03-13
    Description: Article Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process. Nature Communications doi: 10.1038/ncomms7377 Authors: Matthew J. Niederst, Lecia V. Sequist, John T. Poirier, Craig H. Mermel, Elizabeth L. Lockerman, Angel R. Garcia, Ryohei Katayama, Carlotta Costa, Kenneth N. Ross, Teresa Moran, Emily Howe, Linnea E. Fulton, Hillary E. Mulvey, Lindsay A. Bernardo, Farhiya Mohamoud, Norikatsu Miyoshi, Paul A. VanderLaan, Daniel B. Costa, Pasi A. Jänne, Darrell R. Borger, Sridhar Ramaswamy, Toshi Shioda, Anthony J. Iafrate, Gad Getz, Charles M. Rudin, Mari Mino-Kenudson, Jeffrey A. Engelman
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 8
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    AIDS/HIV. A reversal of fortune in HIV-1 integration (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-06-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Engelman, Alan -- New York, N.Y. -- Science. 2007 Jun 29;316(5833):1855-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. alan_engelman@dfci.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17600205" target="_blank"〉PubMed〈/a〉
    Keywords: CD4-Positive T-Lymphocytes/immunology/virology ; Cell Line, Tumor ; DNA Shuffling ; *Directed Molecular Evolution ; HIV Infections/drug therapy ; HIV Long Terminal Repeat ; HIV-1/genetics/*metabolism/physiology ; Humans ; Integrases/*genetics/*metabolism ; Lymphocyte Activation ; Proviruses/metabolism/physiology ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; *Virus Integration
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
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    A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-20
    Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" 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/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Combined Chemotherapy Protocols ; Benzimidazoles/*pharmacology/therapeutic use ; Biomarkers, Tumor/genetics/metabolism ; *Clinical Trials, Phase II as Topic ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluorodeoxyglucose F18 ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mutation/genetics ; Pharmacogenetics/*methods ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Randomized Controlled Trials as Topic ; Reproducibility of Results ; Taxoids/*therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; ras Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 10
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    Systematic identification of genomic markers of drug sensitivity in cancer cells (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-31
    Description: Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349233/" 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/PMC3349233/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garnett, Mathew J -- Edelman, Elena J -- Heidorn, Sonja J -- Greenman, Chris D -- Dastur, Anahita -- Lau, King Wai -- Greninger, Patricia -- Thompson, I Richard -- Luo, Xi -- Soares, Jorge -- Liu, Qingsong -- Iorio, Francesco -- Surdez, Didier -- Chen, Li -- Milano, Randy J -- Bignell, Graham R -- Tam, Ah T -- Davies, Helen -- Stevenson, Jesse A -- Barthorpe, Syd -- Lutz, Stephen R -- Kogera, Fiona -- Lawrence, Karl -- McLaren-Douglas, Anne -- Mitropoulos, Xeni -- Mironenko, Tatiana -- Thi, Helen -- Richardson, Laura -- Zhou, Wenjun -- Jewitt, Frances -- Zhang, Tinghu -- O'Brien, Patrick -- Boisvert, Jessica L -- Price, Stacey -- Hur, Wooyoung -- Yang, Wanjuan -- Deng, Xianming -- Butler, Adam -- Choi, Hwan Geun -- Chang, Jae Won -- Baselga, Jose -- Stamenkovic, Ivan -- Engelman, Jeffrey A -- Sharma, Sreenath V -- Delattre, Olivier -- Saez-Rodriguez, Julio -- Gray, Nathanael S -- Settleman, Jeffrey -- Futreal, P Andrew -- Haber, Daniel A -- Stratton, Michael R -- Ramaswamy, Sridhar -- McDermott, Ultan -- Benes, Cyril H -- 086357/Wellcome Trust/United Kingdom -- 1U54HG006097-01/HG/NHGRI NIH HHS/ -- P41GM079575-02/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 28;483(7391):570-5. doi: 10.1038/nature11005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460902" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects/*genetics ; *Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Neoplasm/*genetics ; Genetic Markers/*genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Indoles/pharmacology ; Neoplasms/*drug therapy/*genetics/pathology ; Oncogene Proteins, Fusion/genetics ; Pharmacogenetics ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Protein c-fli-1/genetics ; RNA-Binding Protein EWS/genetics ; Sarcoma, Ewing/drug therapy/genetics/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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