Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their ...inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
This paper presents a new approach, called band subset selection (BSS)-based hyperspectral anomaly detection (AD), which selects multiple bands simultaneously as a band subset rather than selecting ...multiple bands one at a time as the tradition band selection (BS) does, referred to as sequential multiple BS (SQMBS). Its idea is to first use virtual dimensionality (VD) to determine the number of multiple bands, nBS needed to be selected as a band subset and then develop two iterative process, sequential BSS (SQ-BSS) algorithm and successive BSS (SC-BSS) algorithm to find an optimal band subset numerically among all possible nBS combinations out of the full band set. In order to terminate the search process the averaged least-squares error (ALSE) and 3-D receiver operating characteristic (3D ROC) curves are used as stopping criteria to evaluate performance relative to AD using the full band set. Experimental results demonstrate that BSS generally performs better background suppression while maintaining target detection capability compared to target detection using full band information.
This paper develops a new Neyman-Pearson detection approach, to be called band-specified virtual dimensionality (BSVD), to estimating the number of bands required by band selection (BS), ...<inline-formula> <tex-math notation="LaTeX">n_{\mathrm {BS}} </tex-math></inline-formula>, as well as finding desired bands at the same time. Its idea is derived from target-specified virtual dimensionality (TSVD) where targets under hypotheses as signal sources in TSVD are replaced with bands as signal sources and the test statistics derived for a Neyman-Pearson detector (NPD) is signal-to-noise ratio (SNR) that is used to derive orthogonal subspace projection (OSP) approach for hyperspectral image classification and dimensionality reduction. Accordingly, the resulting virtual dimensionality is referred to as OSP-based BSVD. Several benefits resulting from BSVD cannot be offered by the traditional BS methods. One is its direct approach to dealing with <inline-formula> <tex-math notation="LaTeX">n_{\mathrm {BS}} </tex-math></inline-formula>. Another is no-search strategy needed for finding optimal bands. Instead, it uses NPD to determine and rank desired bands for band prioritization. Most importantly, it determines <inline-formula> <tex-math notation="LaTeX">n_{\mathrm {BS}} </tex-math></inline-formula> and finds desired bands simultaneously and progressively.
Cinnamomum osmophloeum Kanehira is a Taiwan native plant that belongs to genus Cinnamomum and is also known as pseudocinnamomum or indigenous cinnamon. Its leaf is traditionally used by local people ...in cooking and as folk therapy. We previously demonstrated the chemical composition and anti-inflammatory effect of leaf essential oil of Cinnamomum osmophloeum Kanehira of linalool chemotype in streptozotocin-induced diabetic rats and on endotoxin-injected mice. The aim of the present study is to evaluate whether cinnamaldehyde and linalool the active anti-inflammatory compounds in leaf essential oil of Cinnamomum osmophloeum Kanehira. Before the injection of endotoxin, C57BL/6 mice of the experimental groups were administered cinnamaldehyde (0.45 or 0.9 mg/kg body weight) or linalool (2.6 or 5.2 mg/kg body weight), mice of the positive control group were administered the leaf essential oil (13 mg/kg body weight), and mice of the negative group were administered vehicle (corn oil, 4 mL/kg body weight) by gavage every other day for two weeks. All mice received endotoxin (i.p. 10 mg/mL/kg body weight) the next day after the final administration and were killed 12 h after the injection. Normal control mice were pretreated with vehicle followed by the injection with saline. None of the treatment found to affect body weight or food or water intake of mice before the injection of endotoxin. Cinnamaldehyde and linalool were found significantly reversed endotoxin-induced body weight loss and lymphoid organ enlargement compared with vehicle (P < 0.05). Both compounds also significantly lowered endotoxin-induced levels of peripheral nitrate/nitrite, interleukin (IL)-1β, IL-18, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and High-mobility group box 1 protein (HMGB-1), and levels of nitrate/nitrite, IL-1β, TNF-α, and IFN-γ in spleen and mesenteric lymph nodes (MLNs) (P < 0.05). Endotoxin-induced expression of toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), myeloid differentiation protein 2 (MD2), Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and caspase-1 in spleen and mesenteric lymph nodes (MLNs) were inhibited by all tested doses of cinnamaldehyde and linalool (P < 0.05). Subsequently, the activation of nuclear factor (NF)-κB and the activity of caspase-1 in spleen and MLNs were also suppressed by these two compounds (P < 0.05). In addition, cinnamaldehyde and linalool at the dose equivalent to their corresponding content in the tested dose of the leaf essential oil, which was 0.9 mg/kg and 5.2 mg/kg, respectively, showed similar or slightly less inhibitory activity for most of these inflammatory parameters compared with that of the leaf essential oil. Our data confirmed the potential use of leaf essential oil of Cinnamomum osmophloeum Kanehira as an anti-inflammatory natural product and provide evidence for cinnamaldehyde and linalool as two potent agents for prophylactic use in health problems associated with inflammations that being attributed to over-activated TLR4 and/or NLRP3 signaling pathways.
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Anomaly detection (AD) generally finds targets that are spectrally distinct from their surrounding neighborhoods but cannot discriminate its detected targets one from another. It cannot even perform ...classification because there is no prior knowledge about the data. This paper presents a new approach to AD, to be called a posteriori AD for unlabeled anomaly classification where a posteriori indicates that information obtained directly from processing data is used as new information for subsequent data processing. In particular, a posteriori AD uses a Gaussian filter to capture spatial correlation of detected anomalies as a posteriori information which is included as new information for further AD. In doing so, a posteriori AD develops an iterative version of AD, referred to as iterative anomaly detection (IAD), which implements AD by feeding back Gaussian-filtered AD maps in an iterative manner. It then uses an unsupervised target detection algorithm to identify spectrally distinct anomalies that can be used to specify particular anomaly classes. To terminate IAD, an automatic stopping rule is also derived. Finally, it uses identified distinct anomalies as desired target signatures to implement constrained energy minimization (CEM) to classify all detected anomalies into unlabeled classes. The experimental results show that a posteriori AD is indeed very effective in unlabeled anomaly classification.
Non‐small‐cell lung cancer (NSCLC) accounts for the majority of the lung cancer cases that have become a leading cause of cancer deaths worldwide. Overexpression of transcription factor forkhead box ...M1 (FOXM1) is involved in the inauspicious development of several types of cancer, including lung tumor aggressiveness. Our laboratory has previously found that MED28, a Mediator subunit for transcriptional activation, modulates cell growth, epithelial‐mesenchymal transition, migration, and invasion in human breast cancer cells. The objective of the current study is to investigate the potential role of MED28 and FOXM1 in NSCLC. In addition to A549 and PC9 cells, we also used a doxycycline‐inducible system to generate FOXM1‐overexpressed A549‐DN cells, and we explored the connection of MED28 with FOXM1 and their effect on migration. Herein, we report that the increased expression levels of both MED28 and FOXM1 elevated the expression of matrix metalloproteinase 2 (MMP2), a metastasis marker, which enhanced cell migration and matrigel invasion of NSCLC cells. Furthermore, MED28 interacted with FOXM1, and both exhibited a mutual effect on the expression and subcellular localization. Moreover, MED28 small interfering RNA‐mediated MMP2 gene suppression could be attenuated by inducible expression of a constitutively active form of FOXM1, which consequently restored the migration and invasion ability of NSCLC cells. Our data indicate that MED28 interacts with FOXM1, and each affects the expression and localization of the other, and, more importantly, both regulate MMP2‐dependent migration and invasion in human lung cancer cells.
The authors reported a mutual effect of MED28, a Mediator subunit, and forkhead box M1 (FOXM1), a transcription factor, in matrix metalloproteinase 2 (MMP2)‐dependent migration and invasion in human non‐small‐cell lung cancer (NSCLC) cells. These findings highlight the significance of MED28 in human lung cancer cells in addition to the previous publications in human breast cancer cells.
Treatment of triple‐negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. ...Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen‐inducible gene‐6 (MIG‐6) has long been thought of as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncover that MIG‐6 is upregulated in TNBC and that MIG‐6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays reveal that MIG‐6 drives glucose metabolism reprogramming toward glycolysis. Mechanistically, MIG‐6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein expression and the subsequent upregulation of GLUT1 and other HIF1α‐regulated glycolytic genes, substantiating the comprehensive regulation of MIG‐6 in glucose metabolism. Moreover, our mouse studies demonstrate that MIG‐6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG‐6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC.
SYNOPSIS
MIG‐6 is upregulated in TNBC and promotes tumor growth by fueling glycolytic flux via the HIf1α‐Glut1 pathway.
MIG‐6 levels correlate with disease progression and bad prognosis in TNBC patients.
Depletion of MIG‐6 restricts TNBC cell proliferation and TNBC xenograft growth in mice.
MIG‐6 promotes aerobic glycolysis by promoting GLUT1 transcription.
MIG‐6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein, which in turn upregulates GLUT1.
MIG‐6 is upregulated in TNBC and promotes tumor growth by fueling glycolytic flux via the HIf1α‐Glut1 pathway.
With the exponential growth of web multimedia contents, the Internet is rife with near-duplicate videos, the video copies applied with visual/temporal transformations and/or post productions. Two ...critical issues, copyright infringement and search result redundancy, arise accordingly. To resolve these problems, this paper proposes a spatiotemporal pattern-based approach under the hierarchical filter-and-refine framework for efficient and effective near-duplicate video retrieval and localization . Firstly, non-near-duplicate videos are fast filtered out through a computationally efficient data structure, termed pattern -based index tree (PI-tree). Then, an m- pattern -based dynamic programming (mPDP) algorithm is designed to localize near-duplicate segments and to re-rank the videos retrieved. The influence of time shift misalignment can be alleviated by time-shift m-pattern similarity (TPS) measurement. Comprehensive experiments on the five datasets are conducted to verify the effectiveness, efficiency, robustness, and scalability of the proposed approach. Convincing results demonstrate that our proposed approach outperforms the state-of-the-art approaches in terms of mean average precision (MAP) and normalized detection cost rate (NDCR) on the testing datasets. Furthermore, the proposed approach can achieve high quality of near-duplicate video localization in terms of quality frames (QF) and mean F1.
LKB1 is activated by forming a heterotrimeric complex with STRAD and MO25. Recent studies suggest that LKB1 has pro-oncogenic functions, besides acting as a tumor suppressor. How the LKB1 activity is ...maintained and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by Skp2-SCF ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating Skp2-SCF ubiquitin ligase. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy-stress-induced cell survival. We also detected overexpression of Skp2 and LKB1 in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcomes. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth in vivo. Our study provides new insights into the upstream regulation of LKB1 activation and suggests a potential target, the Ras/Skp2/LKB1 axis, for cancer therapy.
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•LKB1 ubiquitination is critical for maintaining its activity and complex integrity•Ras activates the Skp2-SCF to induce polyubiquitination and activation of LKB1•LKB1 polyubiquitination is important for cell survival under metabolic stress•Overexpression of LKB1 and Skp2 is found in HCC and predicts poor survival outcomes
Lee et al. describe the role of Ras/Skp2/LKB1/AMPK axis in cancer cell survival under energy stress, showing that K63-linked LKB1 polyubiquitination by Skp2-SCF ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. Oncogenic Ras acts as the upstream regulator.
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