Abstract BACKGROUND The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear. METHODS We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis. RESULTS We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database. CONCLUSIONS miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.
This study analyzes user acceptance behavior of 3DTV by focusing on variables that influence attitudes and intention to adopt. Structural equation modeling is used to construct a predictive model of attitudes toward 3DTV. Individuals' responses to questions about attitude and intention to use 3DTV were collected and analyzed. The model shows significant roles for social presence and flow, both of which affect attitude as well as perceived usefulness and perceived enjoyment. This set of factors is key to users' expectations of 3DTV. Given the significant role of social presence, the study attempts to conceptualize social presence in the 3DTV context. The findings imply that social presence may be enhanced by illusions of advanced technical manipulation, but it can be more effectively enhanced by a sense of belonging or emotional connection. Specific design features and characteristics of 3DTV services can be utilized to achieve meaningful social presence. The proposed model brings together extant research on 3DTV and supports eventual 3D acceptance.
Resolving the design rule checking (DRC) violations at the pre-route stage is critically important to reduce the time-consuming design closure process at the post-route stage. Recently, noticeable methodologies have been proposed to predict DRC hotspots using Machine Learning based prediction models. However, little attention has been paid to how the predicted DRC violations can be effectively resolved. In this paper, we propose a pre-route DRC violation resolution methodology that is tightly coupled with fully compatible prediction model. Precisely, we devise different resolution strategies for two types of DRC violations: (1) pin accessibility (PA)-related and (2) routing congestion (RC)-related. To this end, we develop a fully predictable ML-based model for both PA and RC-related DRC violations, and propose completely different resolution techniques to be applied depending on the DRC violation type informed by the compatible prediction model such that for (1) PA-related DRC violation, we extract the DRC violation mitigating regions, then improve placement by formulating the whitespace redistribution problem on the regions into an instance of Bayesian Optimization problem to produce an optimal cell perturbation, while for (2) RC-related DRC violation, we manipulate the routing resources within the regions that have high potential for the occurrence of RC-related DRC violation. Through experiments, it is shown that our methodology is able to resolve the number of DRC violations by 26.54%, 25.28%, and 20.34% further on average over that by a conventional flow with no resolution, a commercial ECO router, and a state-of-the-art academic predictor/resolver, respectively, while maintaining comparable design quality.
Abstract Glioblastoma multiforme (GBM) is an aggressive malignancy classified by the World Health Organization as a grade IV glioma. Despite the availability of aggressive standard therapies, most patients experience recurrence, for which there are currently no effective treatments. We aimed to conduct a phase I/IIa clinical trial to investigate the safety and efficacy of adoptive, ex-vivo-expanded, and activated natural killer cells and T lymphocytes from peripheral blood mononuclear cells of patients with recurrent GBM. This study was a single-arm, open-label, investigator-initiated trial on 14 patients recruited between 2013 and 2017. The immune cells were administered via intravenous injection 24 times at 2-week intervals after surgical resection or biopsy. The safety and clinical efficacy of this therapy was examined by assessing adverse events and comparing 2-year overall survival (OS). Transcriptomic analysis of tumor tissues was performed using NanoString to identify the mechanism of therapeutic efficacy. No grade 4 or 5 severe adverse events were observed. The most common treatment-related adverse events were grade 1 or 2 in severity. The most severe adverse event was grade 3 fever. Median OS was 22.5 months, and the median progression-free survival was 10 months. Five patients were alive for over 2 years and showed durable response with enhanced immune reaction transcriptomic signatures without clinical decline until the last follow-up after completion of the therapy. In conclusion, autologous adoptive immune-cell therapy was safe and showed durable response in patients with enhanced immune reaction signatures. This therapy may be effective for recurrent GBM patients with high immune response in their tumor microenvironments. Trial registration: The Korea Clinical Research Information Service database: KCT0003815, Registered 18 April 2019, retrospectively registered.
(1) Background: The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear; (2) Methods: We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis; (3) Results: We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database; (4) Conclusions: miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.
Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1β secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein-protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.
In the study of leadership within the private sector in China, few scholars have tried to link ancient Chinese teachings to the present leadership style beyond the level of highlighting Confucianism and/or militarist philosophy. This study argues that Mohist teachings are the foundation of Ma Yun's leadership in https://Alibaba.com">Alibaba.com. Using three propositions of (a) Ma Yun's motivation to become a start-up CEO, (b) structuring his business using his inter-national skills and linguistic competences and (c) shaping his leader-ship style based on the Mohist teachings, one of the minority schools of ancient Chinese philosophy, this paper finds that innovative firms in China such as https://Alibaba.com">Alibaba.com deliberately shies themselves from conventional symbols of Confucianism or militarist teachings to accommodate Western managerial in the name of unpopular ancient Chinese teachings. The result of Ma Yun's leadership is successful corporate social responsibility (CSR) performance amid rapid innovation within his company. Our results show that Ma Yun's Mohist quality and balance of justice and interests are the most effective measurement indicators of Ma Yun's internal operations; values of eloquent rhetoric, a chivalrous spirit, and mutual love have promoted Alibaba's external reputation and expansion and constitute important indicators.
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