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  • 1
    Publication Date: 2018-08-31
    Description: Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders ( P = .007). Frequently mutated genes at diagnosis were ASXL1 , IKZF1 , and RUNX1 . The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9 (33%) of 27 vs 2 (11%) of 19 optimal responders ( P = .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations cooccurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Ph translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.
    Keywords: Myeloid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-10-02
    Description: Purpose: Gastric adenoma (GA) is a premalignant lesion that precedes intestinal-type gastric carcinoma (GC). However, genetic progression mechanisms from GA to GC have not been clarified. Experimental Design: We performed whole-exome sequencing–based mutational analyses for 15 synchronous pairs of attached GAs and GCs. Results: There was no significant difference in the number of driver mutations or copy-number alterations between GAs and GCs. Well-known mutations of TP53, APC, RNF43, and RPL22 were recurrently detected in synchronous GA/GC pairs. In addition, we discovered novel KDM6A, PREX2, FAT1, KMT2C, GLI3, and RPL22 mutations and hypermutation in GAs, but did not identify recurrent drivers for GA-to-GC progression. Clonal structure analyses revealed that most GA/GC pairs exhibit parallel evolution with early divergence rather than stepwise evolution during GA-to-GC progression. Of note, three cases were identified as clonally nonrelated GA/GC pairs despite the lack of histologic differences. We found differences in dominant mutational signatures 1, 6, 15, and 17 in GA/GC trunks, GA branches, and GC branches. Compared with our previous work on synchronous colon adenoma/carcinoma genome structures, where most drivers were in the trunk with parallel evolution, synchronous GA/GC genomes showed a different model of parallel evolution, with many drivers in the branches. Conclusions: The preferred sequence of mutational events during GA-to-GC progression might be more context-dependent than colon adenoma progression. Our results show that nonclonal synchronous GA/GC is common and that GA genomes have already acquired distinct genomic alterations, suggesting caution in the diagnosis of synchronous GA and GC, especially in residual or recurrent cases. Clin Cancer Res; 24(19); 4715–25. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    Publication Date: 2018-03-06
    Description: BACKGROUND: Scrub typhus and severe fever with thrombocytopenia syndrome (SFTS) are the most common tick-borne illnesses in South Korea. Early differentiation of SFTS from scrub typhus in emergency departments is essential but difficult because of their overlapping epidemiology, shared risk factors, and similar clinical manifestations. METHODS: We compared the diagnostic performance of one-step isothermal nucleic acid amplification with bio-optical sensor detection (iNAD) under isothermal conditions, which is rapid (20–30 min), with that of real-time PCR, in patients with a confirmed tick-borne illness. Fifteen patients with confirmed SFTS who provided a total of 15 initial blood samples and 5 follow-up blood samples, and 21 patients with confirmed scrub typhus, were evaluated. RESULTS: The clinical sensitivity of iNAD (100%; 95% CI, 83–100) for SFTS was significantly higher than that of real-time PCR (75%; 95% CI, 51–91; P = 0.047), while its clinical specificity (86%; 95% CI, 65–97) was similar to that of real-time PCR (95%; 95% CI, 77–99; P = 0.61). The clinical sensitivity of iNAD for scrub typhus (100%; 95% CI, 81–100) was significantly higher than that of real-time PCR for scrub typhus (67%; 95% CI, 43–85; P = 0.009), while its clinical specificity (90%; 95% CI, 67–98) was similar to that of real-time PCR (95%; 95% CI, 73–100; P 〉 0.99). CONCLUSIONS: iNAD is a valuable, rapid method of detecting SFTS virus and Orientia tsutsugamushi with high clinical sensitivity and specificity.
    Keywords: Molecular Diagnostics and Genetics
    Print ISSN: 0009-9147
    Electronic ISSN: 1530-8561
    Topics: Medicine
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  • 4
    Publication Date: 2018-11-02
    Description: Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC ( n = 11) and mouse models of HCC ( n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa , and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFN score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes ( Cd276 and Nectin2/ Pvrl2 ) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene ( Cd86 ) in the DEN model might be accountable for the lack of predictive response to immunotherapy. Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713–23. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 5
    Publication Date: 2014-02-22
    Description: The high cost of powerful, large-stroke, high-stress artificial muscles has combined with performance limitations such as low cycle life, hysteresis, and low efficiency to restrict applications. We demonstrated that inexpensive high-strength polymer fibers used for fishing line and sewing thread can be easily transformed by twist insertion to provide fast, scalable, nonhysteretic, long-life tensile and torsional muscles. Extreme twisting produces coiled muscles that can contract by 49%, lift loads over 100 times heavier than can human muscle of the same length and weight, and generate 5.3 kilowatts of mechanical work per kilogram of muscle weight, similar to that produced by a jet engine. Woven textiles that change porosity in response to temperature and actuating window shutters that could help conserve energy were also demonstrated. Large-stroke tensile actuation was theoretically and experimentally shown to result from torsional actuation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haines, Carter S -- Lima, Marcio D -- Li, Na -- Spinks, Geoffrey M -- Foroughi, Javad -- Madden, John D W -- Kim, Shi Hyeong -- Fang, Shaoli -- Jung de Andrade, Monica -- Goktepe, Fatma -- Goktepe, Ozer -- Mirvakili, Seyed M -- Naficy, Sina -- Lepro, Xavier -- Oh, Jiyoung -- Kozlov, Mikhail E -- Kim, Seon Jeong -- Xu, Xiuru -- Swedlove, Benjamin J -- Wallace, Gordon G -- Baughman, Ray H -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):868-72. doi: 10.1126/science.1246906.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Alan G. MacDiarmid NanoTech Institute, University of Texas at Dallas, Richardson, TX 75083, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24558156" target="_blank"〉PubMed〈/a〉
    Keywords: *Cotton Fiber ; Humans ; Muscles/chemistry/ultrastructure ; *Nylons ; Polymers ; Porosity ; *Tensile Strength ; *Torsion, Mechanical
    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: 2015-10-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moon, Il-Ju -- Kim, Sung-Hun -- Wang, Chunzai -- England -- Nature. 2015 Oct 29;526(7575):E4-5. doi: 10.1038/nature15546.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Typhoon Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju 690-756, South Koreaijmoon@jejunu.ac.kr. ; NOAA/Atlantic Oceanographic and Meteorological Laboratory, Miami, Florida 33149, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26511582" 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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  • 7
    Publication Date: 2018-11-16
    Description: Although polycrystalline hexagonal boron nitride (PC-hBN) has been realized, defects and grain boundaries still cause charge scatterings and trap sites, impeding high-performance electronics. Here, we report a method of synthesizing wafer-scale single-crystalline hBN (SC-hBN) monolayer films by chemical vapor deposition. The limited solubility of boron (B) and nitrogen (N) atoms in liquid gold promotes high diffusion of adatoms on the surface of liquid at high temperature to provoke the circular hBN grains. These further evolve into closely packed unimodal grains by means of self-collimation of B and N edges inherited by electrostatic interaction between grains, eventually forming an SC-hBN film on a wafer scale. This SC-hBN film also allows for the synthesis of wafer-scale graphene/hBN heterostructure and single-crystalline tungsten disulfide.
    Keywords: Materials Science
    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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  • 8
    Publication Date: 2016-02-26
    Description: Maintaining high crop yields in an environmentally sustainable manner requires the development of disease-resistant crop varieties. We describe a method to engineer disease resistance in plants by means of an endogenous disease resistance gene from Arabidopsis thaliana named RPS5, which encodes a nucleotide-binding leucine-rich repeat (NLR) protein. RPS5 is normally activated when a second host protein, PBS1, is cleaved by the pathogen-secreted protease AvrPphB. We show that the AvrPphB cleavage site within PBS1 can be substituted with cleavage sites for other pathogen proteases, which then enables RPS5 to be activated by these proteases, thereby conferring resistance to new pathogens. This "decoy" approach may be applicable to other NLR proteins and should enable engineering of resistance in plants to diseases for which we currently lack robust genetic resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Sang Hee -- Qi, Dong -- Ashfield, Tom -- Helm, Matthew -- Innes, Roger W -- R01 GM046451/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):684-7. doi: 10.1126/science.aad3436.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Indiana University, Bloomington, IN 47405, USA. ; Department of Biology, Indiana University, Bloomington, IN 47405, USA. rinnes@indiana.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912853" target="_blank"〉PubMed〈/a〉
    Keywords: *Arabidopsis/genetics/metabolism/microbiology ; Arabidopsis Proteins/genetics/*metabolism ; Bacterial Proteins/metabolism ; Disease Resistance/*genetics ; Genetic Engineering/methods ; Peptide Hydrolases/genetics/metabolism ; Plant Diseases/genetics/microbiology/*prevention & control ; Plants, Genetically Modified/genetics/metabolism/microbiology ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; *Proteolysis ; Pseudomonas syringae/metabolism/pathogenicity ; Transgenes
    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: 2018-05-02
    Description: In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and -glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R 2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303–12. ©2018 AACR .
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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  • 10
    Publication Date: 2018-05-16
    Description: Objectives Secondhand smoke (SHS) exposure is associated with cardiovascular disease. This study aims to determine the association between SHS exposure estimated by questionnaire and hypertension in Korean never smokers. Setting Korean National Health and Nutrition Examination Survey (KNHANES) V was conducted from 2010 to 2012. Participants We selected the never smokers aged over 20 years who answered the question about the SHS exposure. Primary and secondary measures SHS exposure in both the home and work place was estimated using a self-reporting questionnaire. We investigated the association between SHS exposure and hypertension by using multivariate analysis. And we evaluated the mean systolic and diastolic blood pressure values according to SHS exposure after adjusting for possible confounding factors. All analyses were stratified by women and men. Results There were 10 532 (women 8987 and men 1545) never smokers. We divided the subjects into three groups according to the amount of SHS exposure: none—group I, 〈2 hour/day—group II and ≥2 hour/day—group III. Using multivariate analysis, hypertension was more commonly associated with group III than group I in women (adjusted OR 1.50, 95% CI 1.00 to 2.04, p=0.011). Adjusted mean systolic and diastolic blood pressure values in women who were not taking antihypertensive medication were significantly elevated in group III by 2.3 and 1.7 mm Hg, respectively. Conclusion SHS exposure is significantly associated with hypertension in women never smokers.
    Keywords: Open access, Smoking and tobacco
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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