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  • 1
    Publication Date: 2018-12-01
    Description: Background/Aim: This study aimed to determine the effect of different BRCA1 exonal mutations on the clinical course of epithelial ovarian cancer (EOC). Patients and Methods: Clinicopathological variables and survival outcomes were compared among 53 primary EOC patients with pathogenic BRCA1 mutations in exons 1-11 (5’ mutations) and in exons 12-24 (3’ mutations). Results: BRCA1 5’ exonal mutations were found in 35 (66.0%) patients. The median follow-up period was 40 months. Clinicopathological variables remained unchanged between the two groups. Patients with 5’ mutations had a significantly longer progression-free survival than those with C-terminal mutations (p=0.034), better predicting progression-free survival [2.923 (1.402-6.093), p=0.004], but not overall survival in cases of multiple relapses (p=0.497). Conclusion: N-terminal BRCA1 mutations in EOC patients are associated with favourable primary progression-free survival, a trend observed only in primary progression-free survival, not in overall survival.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 2
    Publication Date: 2018-10-05
    Description: The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.
    Keywords: Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-04-05
    Description: Thin, soft, skin-like sensors capable of precise, continuous measurements of physiological health have broad potential relevance to clinical health care. Use of sensors distributed over a wide area for full-body, spatiotemporal mapping of physiological processes would be a considerable advance for this field. We introduce materials, device designs, wireless power delivery and communication strategies, and overall system architectures for skin-like, battery-free sensors of temperature and pressure that can be used across the entire body. Combined experimental and theoretical investigations of the sensor operation and the modes for wireless addressing define the key features of these systems. Studies with human subjects in clinical sleep laboratories and in adjustable hospital beds demonstrate functionality of the sensors, with potential implications for monitoring of circadian cycles and mitigating risks for pressure-induced skin ulcers.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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  • 4
    Publication Date: 2018-03-06
    Description: KRAS is the most frequently mutated oncogene in human tumors, and its activating mutations represent important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here, we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA. The survival, proliferation, and tumorigenicity of cancer cells in vitro and the growth of tumors in vivo were determined after delivery of Cas9 and guide RNA. We identified guide RNAs that efficiently target mutant KRAS without significant alterations of the wild-type allele. Doxycycline-inducible expression of this guide RNA in KRAS -mutant cancer cells transduced with a lentiviral vector encoding Cas9 disrupted the mutant KRAS gene, leading to inhibition of cancer cell proliferation both in vitro and in vivo. Intra-tumoral injection of lentivirus and adeno-associated virus expressing Cas9 and sgRNA suppressed tumor growth in vivo, albeit incompletely, in immunodeficient mice. Expression of Cas9 and the guide RNA in cells containing wild-type KRAS did not alter cell survival or proliferation either in vitro and in vivo. Our study provides a proof-of-concept that CRISPR can be utilized to target driver mutations of cancers in vitro and in vivo.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2018-01-28
    Description: Introduction Thread embedding acupuncture (TEA) is a special type of acupuncture that inserts certain medical threads (eg, catgut or polydioxanone) into subcutaneous tissue or muscles at specific points. Although TEA has been widely used for the treatment of musculoskeletal pain in Korea, China and Taiwan, evidence regarding its efficacy is lacking. The aim of this protocol is to evaluate the effectiveness and safety of TEA in the treatment of musculoskeletal pain, by conducting a systematic review and meta-analysis. Methods and analysis The following 16 databases will be searched from their inception to 14 May 2017: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, three Chinese database (China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database and the Wanfang database) and eight Korean databases (Korean Medical Database, Korean Association of Medical Journal Editors, Korean Studies Information Service System, Korean National Assembly Digital Library, National Digital Science Library, Oriental Medicine Advanced Searching Integrated System, ’Database Periodical Information Academic and Korean Traditional Knowledge Portal'). The WHO International Clinical Trials Registry Platform will also be searched to retrieve the recently completed studies. All randomised controlled studies in which TEA was used on specific points for the treatment of musculoskeletal pain will be included and no restrictions on language will be applied. The risk of bias of each study will be evaluated by the Cochrane risk of bias tool. Mean difference or standardised mean difference for continuous data and risk ratio for dichotomous data will be calculated with 95% CIs using a random effects model or a fixed effects model. Additional subgroup and sensitivity analyses will be conducted according to a predefined protocol. Ethics and dissemination No ethical issues are predicted. The systematic review will be published in a peer-reviewed journal or conference presentation. These findings will summarise the current evidence of TEA for the treatment of musculoskeletal pain and may provide guidance for clinicians and patients to select TEA for musculoskeletal pain. PROSPERO registration number CRD42015019046.
    Keywords: Open access, Anaesthesia
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 6
    Publication Date: 2015-03-25
    Description: B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In approximately 25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441554/" 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/PMC4441554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhengshan -- Shojaee, Seyedmehdi -- Buchner, Maike -- Geng, Huimin -- Lee, Jae Woong -- Klemm, Lars -- Titz, Bjorn -- Graeber, Thomas G -- Park, Eugene -- Tan, Ying Xim -- Satterthwaite, Anne -- Paietta, Elisabeth -- Hunger, Stephen P -- Willman, Cheryl L -- Melnick, Ari -- Loh, Mignon L -- Jung, Jae U -- Coligan, John E -- Bolland, Silvia -- Mak, Tak W -- Limnander, Andre -- Jumaa, Hassan -- Reth, Michael -- Weiss, Arthur -- Lowell, Clifford A -- Muschen, Markus -- 101880/Wellcome Trust/United Kingdom -- CA180794/CA/NCI NIH HHS/ -- CA180820/CA/NCI NIH HHS/ -- R01 AI068150/AI/NIAID NIH HHS/ -- R01 AI113272/AI/NIAID NIH HHS/ -- R01 CA137060/CA/NCI NIH HHS/ -- R01 CA139032/CA/NCI NIH HHS/ -- R01 CA157644/CA/NCI NIH HHS/ -- R01 CA169458/CA/NCI NIH HHS/ -- R01 CA172558/CA/NCI NIH HHS/ -- R01CA137060/CA/NCI NIH HHS/ -- R01CA139032/CA/NCI NIH HHS/ -- R01CA157644/CA/NCI NIH HHS/ -- R01CA169458/CA/NCI NIH HHS/ -- R01CA172558/CA/NCI NIH HHS/ -- U01 CA157937/CA/NCI NIH HHS/ -- U10 CA180794/CA/NCI NIH HHS/ -- U10 CA180820/CA/NCI NIH HHS/ -- U10 CA180827/CA/NCI NIH HHS/ -- U10 CA180886/CA/NCI NIH HHS/ -- U24 CA114737/CA/NCI NIH HHS/ -- U24 CA196172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 May 21;521(7552):357-61. doi: 10.1038/nature14231. Epub 2015 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Laboratory Medicine, University of California, San Francisco, California 94143, USA. ; Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA. ; Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA. ; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10466, USA. ; Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Philadelphia 19104, USA. ; University of New Mexico Cancer Center, Albuquerque, New Mexico 87102, USA. ; Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA. ; Pediatric Hematology-Oncology, University of California, San Francisco, California 94143, USA. ; Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033, USA. ; Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA. ; Autoimmunity and Functional Genomics Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA. ; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2M9, Canada. ; Department of Anatomy, University of California, San Francisco, California 94143, USA. ; Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany. ; BIOSS Centre for Biological Signalling Studies and Faculty of Biology, Albert-Ludwigs-Universitat Freiburg, and MPI of Immunbiologie and Epigenetics, 79104 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799995" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics ; Animals ; Antigens, CD/metabolism ; Antigens, CD31/metabolism ; B-Lymphocytes/drug effects/*metabolism/*pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Drug Resistance, Neoplasm/drug effects ; Enzyme Activation/drug effects ; Female ; Fusion Proteins, bcr-abl/genetics ; Gene Deletion ; Humans ; Intracellular Signaling Peptides and Proteins/agonists/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Phosphoric Monoester Hydrolases/antagonists & inhibitors/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug ; therapy/genetics/*metabolism/*pathology ; Precursor Cells, B-Lymphoid/drug effects/metabolism/pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/deficiency/genetics/metabolism ; Protein-Tyrosine Kinases/metabolism ; Receptors, Antigen, B-Cell/deficiency/genetics/metabolism ; Receptors, Immunologic/genetics/metabolism ; *Signal Transduction/drug effects ; Tyrosine/metabolism ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2016-03-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhengshan -- Shojaee, Seyedmehdi -- Buchner, Maike -- Geng, Huimin -- Lee, Jae Woong -- Klemm, Lars -- Titz, Bjorn -- Graeber, Thomas G -- Park, Eugene -- Tan, Ying Xim -- Satterthwaite, Anne -- Paietta, Elisabeth -- Hunger, Stephen P -- Willman, Cheryl L -- Melnick, Ari -- Loh, Mignon L -- Jung, Jae U -- Coligan, John E -- Bolland, Silvia -- Mak, Tak W -- Limnander, Andre -- Jumaa, Hassan -- Reth, Michael -- Weiss, Arthur -- Lowell, Clifford A -- Muschen, Markus -- Nature. 2016 Mar 9. doi: 10.1038/nature16997.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958840" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-07-17
    Description: Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compounds have been identified that selectively target core clock proteins. From an unbiased cell-based circadian phenotypic screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, our studies using KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589997/" 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/PMC3589997/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirota, Tsuyoshi -- Lee, Jae Wook -- St John, Peter C -- Sawa, Mariko -- Iwaisako, Keiko -- Noguchi, Takako -- Pongsawakul, Pagkapol Y -- Sonntag, Tim -- Welsh, David K -- Brenner, David A -- Doyle, Francis J 3rd -- Schultz, Peter G -- Kay, Steve A -- GM074868/GM/NIGMS NIH HHS/ -- GM085764/GM/NIGMS NIH HHS/ -- GM096873/GM/NIGMS NIH HHS/ -- MH051573/MH/NIMH NIH HHS/ -- MH082945/MH/NIMH NIH HHS/ -- P50 GM085764/GM/NIGMS NIH HHS/ -- R01 GM041804/GM/NIGMS NIH HHS/ -- R01 GM074868/GM/NIGMS NIH HHS/ -- R01 GM096873/GM/NIGMS NIH HHS/ -- R01 MH051573/MH/NIMH NIH HHS/ -- R01 MH082945/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 31;337(6098):1094-7. doi: 10.1126/science.1223710. Epub 2012 Jul 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22798407" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3 Cells ; Amino Acid Sequence ; Animals ; Carbazoles/chemistry/isolation & purification/*pharmacology ; Cell Line, Tumor ; Circadian Clocks/*drug effects ; Cryptochromes/*agonists/metabolism ; Gluconeogenesis/drug effects/genetics ; Glucose-6-Phosphatase/genetics ; HEK293 Cells ; Hepatocytes/drug effects/metabolism ; Humans ; Liver/cytology/drug effects/metabolism ; Mice ; Molecular Sequence Data ; Phosphoenolpyruvate Carboxykinase (GTP)/genetics ; Protein Stability/drug effects ; Proteolysis/drug effects ; *Small Molecule Libraries ; Sulfonamides/chemistry/isolation & purification/*pharmacology
    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: 2018-02-06
    Description: Direct observation of a two-dimensional hole gas at oxide interfaces Direct observation of a two-dimensional hole gas at oxide interfaces, Published online: 05 February 2018; doi:10.1038/s41563-017-0002-4 A SrTiO3/LaAlO3/SrTiO3 heterostructure is fabricated in high oxygen partial pressure to prevent oxygen vacancy formation. Electrical transport and electron holography directly observes a highly mobile two dimensional hole gas at the top interface.
    Print ISSN: 1476-1122
    Electronic ISSN: 1476-4660
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 10
    Publication Date: 2013-09-14
    Description: Throughout human history, textiles have been integral to daily life, but their exploration in catalysis has been rare. Herein, we show a facile and permanent immobilization of organocatalysts on the textile nylon using ultraviolet light. The catalyst and the textile material require no chemical modification for the immobilization. All of the prepared textile-immobilized organocatalysts (a Lewis basic, a Bronsted acidic, and a chiral organocatalyst) display excellent stability, activity, and recyclability for various organic transformations. Very good enantioselectivity (〉95:5 enantiomeric ratio) can be maintained for more than 250 cycles of asymmetric catalysis. Practical and straightforward applications of textile organocatalysis may be beneficial for various fields by offering inexpensive and accessible functionalized catalytic materials.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Ji-Woong -- Mayer-Gall, Thomas -- Opwis, Klaus -- Song, Choong Eui -- Gutmann, Jochen Stefan -- List, Benjamin -- New York, N.Y. -- Science. 2013 Sep 13;341(6151):1225-9. doi: 10.1126/science.1242196.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institut fur Kohlenforschung, Mulheim an der Ruhr, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24031014" 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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