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  • 1
    Publication Date: 2018-01-03
    Description: Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the stage of intestinal differentiation and further identifying hIOs derived from hPSCs. Here, 2 fluorescent biosensors were developed based on human induced pluripotent stem cell (hiPSC) lines that stably expressed fluorescent reporters driven by intestine-specific gene promoters Krüppel-like factor 5 monomeric Cherry (KLF5 mCherry ) and intestine-specific homeobox enhanced green fluorescence protein (ISX eGFP ). Then hIOs were efficiently induced from those transgenic hiPSC lines in which mCherry– or eGFP–expressing cells, which appeared during differentiation, could be identified in intact living cells in real time. Reporter gene expression had no adverse effects on differentiation into hIOs and proliferation. Using our reporter system to screen for hIO differentiation factors, we identified DMH1 as an efficient substitute for Noggin. Transplanted hIOs under the kidney capsule were tracked with fluorescence imaging (FLI) and confirmed histologically. After orthotopic transplantation, the localization of the hIOs in the small intestine could be accurately visualized using FLI. Our study establishes a selective system for monitoring the in vitro differentiation and for tracking the in vivo localization of hIOs and contributes to further improvement of cell-based therapies and preclinical screenings in the intestinal field.—Jung, K. B., Lee, H., Son, Y. S., Lee, J. H., Cho, H.-S., Lee, M.-O., Oh, J.-H., Lee, J., Kim, S., Jung, C.-R., Kim, J., Son, M.-Y. In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells.
    Print ISSN: 0892-6638
    Electronic ISSN: 1530-6860
    Topics: Biology
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  • 2
    Publication Date: 2018-03-16
    Description: Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC). Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2–5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes ( n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49). Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1 – ERBB2 – , 48% ESR1 + ERBB2 – , and 27% ERBB2 + . Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation ( MKI67 ) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1 /ER (27%) and ERBB2 /HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation ( MKI67 ) status had significantly reduced progression-free survival ( P = 0.0011) and overall survival ( P = 0.0095) compared with patients with low proliferative CTCs. Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486–99. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    Publication Date: 2018-01-06
    Description: Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia, Published online: 05 January 2018; doi:10.1038/leu.2017.312 Generation of a multi-antigen-directed immune response for durable control of acute lymphoblastic leukemia
    Print ISSN: 0887-6924
    Electronic ISSN: 1476-5551
    Topics: Medicine
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  • 4
    Publication Date: 2018-05-31
    Description: Background: Pancreatic cancer is a highly lethal malignancy with a poor prognosis. This study was set up to investigate the combined effect of gemcitabine and fisetin, a natural flavonoid from plants, on human pancreatic cancer cells. Meterials and Methods: Cytotoxic effect of fisetin in combination with gemcitabine on MiaPaca-2 cells was evaluated by the MTT assay, caspase 3/7 assay and propidium iodide/Annexin V. Extracellular signal-regulated kinase (ERK)-v-myc avian myelocytomatosis viral oncogene homolog (MYC) pathway was investigated by western blotting and quantitative real-time polymerase chain reaction. Results: Combination treatment with fisetin and gemcitabine inhibited the proliferation of pancreatic cancer cells within 72 h and induced apoptosis, as indicated by activation of caspase 3/7. Fisetin down-regulated ERK at the protein and mRNA levels, and reduced ERK-induced MYC instability at the protein level. Conclusion: Fisetin sensitized human pancreatic cancer cells to gemcitabine-induced cytotoxicity through inhibition of ERK-MYC signaling. These results suggest that the combination of fisetin and gemcitabine could be developed as a novel potent therapeutic.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 5
    Publication Date: 2018-07-04
    Description: Background/Aim: Melatonin, an endogenously secreted indoleamine hormone that is produced in the pineal gland, is known to possess antitumor effect via various mechanisms including induction of apoptosis and pro-oxidant effects in various cancer cells, including colorectal cancer (CRC). In our study, we hypothesized that melatonin enhances the anticancer effects via suppression of PrP C and PINK1 levels, thereby increasing superoxide production. Materials and Methods: To investigate the antitumor effects of melatonin in CRC cells, assessing its effects on mitochondrial dysfunction, production of superoxide, induction of endoplasmic reticulum stress, and cellular apoptosis were assessed. Results: Melatonin was found to decrease the expression of PrP C and PINK1, and increase superoxide accumulation in the mitochondria. In addition, PrP C -knockdown potentiated the effects of melatonin resulting further in significantly reduced expression of PINK1 and increased superoxide production in CRC. si-PRNP-transfected CRC cells treated with melatonin increased the production of intracellular superoxide and induced endoplasmic reticulum stress associated protein, and apoptosis. Conclusion: Melatonin induces mitochondria-mediated cellular apoptosis in CRC cancer cells via a PrP C -dependent pathway. PrP C knockdown combined with melatonin amplifies the effects of melatonin, suggesting a novel therapeutic strategy in targeting CRC cells.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 6
    Publication Date: 2018-01-14
    Description: The Hippo signaling pathway, which is highly conserved in organisms ranging from Drosophila to mammals, plays a key role in organ size control, cellular proliferation, survival and tumorigenesis 1 Yes-associated protein (YAP) is the major downstream effector of Hippo signaling pathway and transcriptional co-activator with PDZ-binding motif (TAZ) is a YAP paralog. Recently, Zhang et al . found that YAP/TAZ acts as natural inhibitors of TANK binding kinase 1 (TBK1), which is a key component for cytosolic nucleic acid sensing antiviral defense and antiviral physiology 2 This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 7
    Publication Date: 2018-01-25
    Description: Recent advances in wearable electronics combined with wireless communications are essential to the realization of medical applications through health monitoring technologies. For example, a smart contact lens, which is capable of monitoring the physiological information of the eye and tear fluid, could provide real-time, noninvasive medical diagnostics. However, previous reports concerning the smart contact lens have indicated that opaque and brittle components have been used to enable the operation of the electronic device, and this could block the user’s vision and potentially damage the eye. In addition, the use of expensive and bulky equipment to measure signals from the contact lens sensors could interfere with the user’s external activities. Thus, we report an unconventional approach for the fabrication of a soft, smart contact lens in which glucose sensors, wireless power transfer circuits, and display pixels to visualize sensing signals in real time are fully integrated using transparent and stretchable nanostructures. The integration of this display into the smart lens eliminates the need for additional, bulky measurement equipment. This soft, smart contact lens can be transparent, providing a clear view by matching the refractive indices of its locally patterned areas. The resulting soft, smart contact lens provides real-time, wireless operation, and there are in vivo tests to monitor the glucose concentration in tears (suitable for determining the fasting glucose level in the tears of diabetic patients) and, simultaneously, to provide sensing results through the contact lens display.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 8
    Publication Date: 2018-08-02
    Description: AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak –/– mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak –/– mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak –/– mice developed lung tumors, and Ahnak –/– mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak –/– lungs, and the depletion of AMs in Ahnak –/– lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer. Implications: The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. Mol Cancer Res; 16(8); 1287–98. ©2018 AACR .
    Print ISSN: 1541-7786
    Electronic ISSN: 1557-3125
    Topics: Medicine
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  • 9
    Publication Date: 2018-03-16
    Description: Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER + breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446–460 of the C2 domain, suggesting these residues are critical for p110α function. Experimental Design: A computational structural model of PIK3CA delP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CA delP447-L455 and PIK3CA H450_P458del were used to understand the phenotype of C2 domain deletions. Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor–independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment. Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426–35. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    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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