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  • 1
    Publication Date: 2018-04-27
    Description: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV + -DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV + -DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV + -DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV + -DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2 , and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV + -DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.
    Keywords: Immunobiology and Immunotherapy, Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-04-14
    Description: We report a general strategy for obtaining high-quality, large-area metal-chalcogenide semiconductor films from precursors combining chelated metal salts with chalcoureas or chalcoamides. Using conventional organic solvents, such precursors enable the expeditious formation of chalco-gels, which are easily transformed into the corresponding high-performance metal-chalcogenide thin films with large, uniform areas. Diverse metal chalcogenides and their alloys (MQ x : M = Zn, Cd, In, Sb, Pb; Q = S, Se, Te) are successfully synthesized at relatively low processing temperatures (〈400°C). The versatility of this scalable route is demonstrated by the fabrication of large-area thin-film transistors (TFTs), optoelectronic devices, and integrated circuits on a 4-inch Si wafer and 2.5-inch borosilicate glass substrates in ambient air using CdS, CdSe, and In 2 Se 3 active layers. The CdSe TFTs exhibit a maximum field-effect mobility greater than 300 cm 2 V –1 s –1 with an on/off current ratio of 〉10 7 and good operational stability (threshold voltage shift 〈 0.5 V at a positive gate bias stress of 10 ks). In addition, metal chalcogenide–based phototransistors with a photodetectivity of 〉10 13 Jones and seven-stage ring oscillators operating at a speed of ~2.6 MHz (propagation delay of 〈 27 ns per stage) are demonstrated.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 3
    Publication Date: 2018-11-06
    Description: Background/Aim: High-carbohydrate diets are generally provided to post-pancreatectomy cancer patients. Low energy density of this diet may obstruct proper energy intake and recovery. This study aimed to assess the effects of high-fat, high-energy ketogenic diet (KD) in these patients. Patients and Methods: After pancreatectomy, 9 patients were provided with general diet (GD) while 10 were served KD. Meal compliance, energy intake rate, meal satisfaction and presence of complications were monitored throughout hospital stay. Data on nutritional status, serum lipids and body composition were collected and compared between groups. Results: Meal compliance, energy intake rate and meal satisfaction score were higher in KD. There were no differences in complications, nutritional status and serum lipids. The decrease in body cell mass (BCM) was greater in GD. Conclusion: Post-pancreatectomy cancer patients who consumed KD had a higher energy intake and BCM. These results suggest the potential use of KD as an adjuvant anti-cancer therapy.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 4
    Publication Date: 2018-11-10
    Description: Pulse oximetry sensors have been playing a key role as devices to monitor elemental yet critical human health states. Conventional pulse oximetry sensors, however, have relatively large power consumption, impeding their use as stand-alone, continuous monitoring systems that can easily be integrated with everyday life. Here, we exploit the design freedom offered by organic technologies to realize a reflective patch-type pulse oximetry sensor with ultralow power consumption. On the basis of flexible organic light-emitting diodes and organic photodiodes designed via an optical simulation of color-sensitive light propagation within human skin, the proposed monolithically integrated organic pulse oximetry sensor heads exhibit successful operation at electrical power as low as 24 μW on average. We thereby demonstrate that organic devices not only have form factor advantages for such applications but also hold great promise as enablers for all-day wearable health monitoring systems.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    Publication Date: 2018-07-31
    Description: Background/Aim: Capecitabine is a pro-drug of 5-fluorouracil (5-FU), and is an orally available chemotherapeutic used to treat colorectal cancer (CRC). Recently, research has focused on improving its efficacy at lower doses in order to minimize its well-known toxicities. In this study, we investigated the possibility of improving the antitumor effect of capecitabine against CRC by destabilizing focal adhesion kinase (FAK) signaling. Materials and Methods: Optimal dosages for capecitabine and lactate calcium salt (LCS) were determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MTT assay. The viability of CRC cells was investigated by MTT and clonogenic assays after single or combination treatment with capecitabine and LCS. Western blot analyses were used to determine changes in the expression of components of the FAK and AKT signaling cascade, and this information was used to elucidate the underlying mechanism. A xenograft model was established to evaluate the antitumor efficacy of the combination treatment, as well as its necrotic effect and organ toxicity. Results: The addition of LCS to capecitabine treatment led to an increase in the proteolysis of the FAK signaling cascade components, including SRC proto-oncogene, non-receptor tyrosine kinase; AKT serine/threonine kinase 1; and nuclear factor-kappa B, resulting in a decrease in the viability and clonogenic ability of CRC cells. In vivo antitumor efficacy, including tumor necrosis, was significantly increased with the combination treatment relative to both single treatments, and no organ toxicity was found in any experimental group. Conclusion: The addition of LCS increased the anticancer efficacy of capecitabine at a lower dose than is currently used in human patients.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 6
    Publication Date: 2018-04-04
    Description: Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca 2+ -dependent apoptosis during glucose deprivation. Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha ( CaMK2α ) gene knockdown, and investigated the role of nuclear factor kappa B (NFB) in CSCs during time-dependent Ca 2+ -mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy- d -glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA). Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFB activation. Combined treatment with 2-deoxy- d -glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone. Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677–90. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 7
    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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  • 8
    Publication Date: 2016-01-19
    Description: Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seung-Kyun -- Murphy, Rory K J -- Hwang, Suk-Won -- Lee, Seung Min -- Harburg, Daniel V -- Krueger, Neil A -- Shin, Jiho -- Gamble, Paul -- Cheng, Huanyu -- Yu, Sooyoun -- Liu, Zhuangjian -- McCall, Jordan G -- Stephen, Manu -- Ying, Hanze -- Kim, Jeonghyun -- Park, Gayoung -- Webb, R Chad -- Lee, Chi Hwan -- Chung, Sangjin -- Wie, Dae Seung -- Gujar, Amit D -- Vemulapalli, Bharat -- Kim, Albert H -- Lee, Kyung-Mi -- Cheng, Jianjun -- Huang, Younggang -- Lee, Sang Hoon -- Braun, Paul V -- Ray, Wilson Z -- Rogers, John A -- F31MH101956/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 4;530(7588):71-6. doi: 10.1038/nature16492. Epub 2016 Jan 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Republic of Korea. ; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Engineering Science and Mechanics, Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Institute of High Performance Computing, Singapore 138632, Singapore. ; Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Biomicrosystem Technology, Korea University, Seoul 136-701, South Korea. ; Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-713, South Korea. ; Weldon School of Biomedical Engineering, School of Mechanical Engineering, The Center for Implantable Devices, Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Mechanical Engineering, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Mechanical Engineering, Civil and Environmental Engineering, Materials Science and Engineering, and Skin Disease Research Center, Northwestern University, Evanston, Illinois 60208, USA. ; Department of Biomedical Engineering, College of Health Science, Korea University, Seoul 136-703, South Korea. ; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26779949" target="_blank"〉PubMed〈/a〉
    Keywords: *Absorbable Implants/adverse effects ; Administration, Cutaneous ; Animals ; Body Temperature ; Brain/*metabolism/surgery ; Electronics/*instrumentation ; Equipment Design ; Hydrolysis ; Male ; Monitoring, Physiologic/adverse effects/*instrumentation ; Organ Specificity ; Pressure ; *Prostheses and Implants/adverse effects ; Rats ; Rats, Inbred Lew ; *Silicon ; Telemetry/instrumentation ; Wireless Technology/instrumentation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2011-02-19
    Description: Controlling the electromagnetic properties of materials, going beyond the limit that is attainable with naturally existing substances, has become a reality with the advent of metamaterials. The range of various structured artificial 'atoms' has promised a vast variety of otherwise unexpected physical phenomena, among which the experimental realization of a negative refractive index has been one of the main foci thus far. Expanding the refractive index into a high positive regime will complete the spectrum of achievable refractive index and provide more design flexibility for transformation optics. Naturally existing transparent materials possess small positive indices of refraction, except for a few semiconductors and insulators, such as lead sulphide or strontium titanate, that exhibit a rather high peak refractive index at mid- and far-infrared frequencies. Previous approaches using metamaterials were not successful in realizing broadband high refractive indices. A broadband high-refractive-index metamaterial structure was theoretically investigated only recently, but the proposed structure does not lend itself to easy implementation. Here we demonstrate that a broadband, extremely high index of refraction can be realized from large-area, free-standing, flexible terahertz metamaterials composed of strongly coupled unit cells. By drastically increasing the effective permittivity through strong capacitive coupling and decreasing the diamagnetic response with a thin metallic structure in the unit cell, a peak refractive index of 38.6 along with a low-frequency quasi-static value of over 20 were experimentally realized for a single-layer terahertz metamaterial, while maintaining low losses. As a natural extension of these single-layer metamaterials, we fabricated quasi-three-dimensional high-refractive-index metamaterials, and obtained a maximum bulk refractive index of 33.2 along with a value of around 8 at the quasi-static limit.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Muhan -- Lee, Seung Hoon -- Kim, Yushin -- Kang, Seung Beom -- Shin, Jonghwa -- Kwak, Min Hwan -- Kang, Kwang-Young -- Lee, Yong-Hee -- Park, Namkyoo -- Min, Bumki -- England -- Nature. 2011 Feb 17;470(7334):369-73. doi: 10.1038/nature09776.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-751, South Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331038" 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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  • 10
    Publication Date: 2018-10-12
    Description: Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCT D21 ). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCT D21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCT D21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCT D21 (VAF 0.2% -post-HCT D21 ) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P 〈 .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF 0.2% -post-HCT D21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P = .003) and relapse incidence (HR, 4.75; P 〈 .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.
    Keywords: Transplantation, Myeloid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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