Pyruvate kinase M2 (PKM2) regulates glycolysis and oxidative phosphorylation; however, the role of PKM2 in ovarian cancer remains largely unknown. We investigated whether ovarian cancer metabolism ...could provide insight into the development of therapeutic strategies. We performed immunohistochemical staining for PKM2 on a tissue microarray for multivariate analysis. It revealed that patients exhibiting higher PKM2 expression were significantly associated with malignancy groups (p < 0.001) and pathogenesis models (p < 0.001), had poor progression-free survival rates (p = 0.01) as compared with patients exhibiting lower PKM2 levels, and yielded a hazard ratio of death of 2.02 (95% confidence interval: 0.70-5.85). In cell lines, PKM2 inhibitor significantly inhibited the glycolytic rate according to cellular glucose consumption (p < 0.001). We also utilized Seahorse assays to assess metabolism-related cell-specific factors and the impact of PKM2 inhibitors. Energy shifts as per Seahorse analysis showed attenuation of the extracellular acidification rate (p < 0.05) and no significant difference in oxygen-consumption rate in SKOV3 cells. Treatment with PKM2 inhibitor suppressed ovarian cancer growth and cell migration in vitro and inhibited tumor growth without significant toxicity in a xenograft study. PKM2 inhibition disturbed Warburg effects and inhibited ovarian cancer cell growth. Targeting PKM2 may constitute a promising therapy for patients with ovarian cancer, and clinical trials involving shikonin are warranted.
Ovarian high‐grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of ...cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem‐like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3‐driven stemness phenotypes, and enhanced apoptosis of GATA3‐expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future.
What's new?
Cancer stem cells (CSCs) routinely evade conventional cancer therapies and fuel tumor regrowth. However, while CSC targeting is an appealing therapeutic strategy, studies are needed to better understand CSC differentiation. Here, in multipotent CSCs from ovarian high‐grade serous carcinomas (HGSCs), complexes consisting of the stemness regulator GATA3 and the histone demethylase UTX were found to maintain cancer stemness via epigenetic activation of c‐MYC, CD44, and NANOG. GATA3 was further identified as an independent risk factor in early‐stage ovarian HGSC. The results suggest that GATA3 is a prognostic marker in ovarian tumorigenesis and that targeting GATA3/UTX is a promising therapeutic approach.
Hashtag is an important advertising tool and a must-have feature for social media nowadays. In the past, many hashtag recommendation methods have been proposed from different perspectives of images, ...texts, and users. However, most previous works consider neither the mutual influence between multi-modalities, nor the visual similarity between images. In this paper, we devise a novel model, named Triplet-Attention Graph Network (TAGNet). The rationale behind our method is that visually similar images share some common hashtags. Therefore, we build an image graph, and apply a new Aggregated Graph Convolution (AGC) module to propagate information in a collective way. Furthermore, it is noted that text and user also have rich content information within posts, and we hence propose a Triplet Attention (TA) module to incorporate multi-modalities into node features. Experiments on the large-scale dataset collected from Instagram show that TAGNet achieved significant improvement in recall rate over the best state-of-the-art method.
Background
Respiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL‐33 is elevated and promotes immune cell activation, leading to the development ...of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL‐33‐activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection‐triggered pathophysiology.
Methods
The role of IL‐33/ILC2 axis in RSV‐induced AHR inflammation and eosinophilia were evaluated in the IL‐33‐deficient and YetCre‐13 Rosa‐DTA mice. Myeloid‐specific, IL‐33‐deficient or ST2‐deficient mice were employed to examine the role of IL‐33 and ST2 signaling in myeloid cells.
Results
We found that IL‐33‐activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2‐derived IL‐13 was sufficient for RSV‐driven AHR, since reconstitution of wild‐type ILC2 rescued RSV‐driven AHR in IL‐13‐deficient mice. Meanwhile, myeloid cell‐derived IL‐33 was required for airway inflammation, ST2+ myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL‐33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL‐33 signaling.
Conclusions
This study highlights the importance of IL‐33‐activated ILC2s in mediating RSV‐triggered AHR and eosinophilia. In addition, IL‐33 signaling in myeloid cells is crucial for airway inflammation.
Respiratory syncytial virus induces ILC2 to produce IL‐5 and IL‐13 through IL‐33, which is crucial for the development of airway hyperreactivity and airway inflammation. Myeloid cell‐derived IL‐33 and suppression of tumorigenicity 2‐positive myeloid cells contribute to cytokine production and cellular inflammation in airway. Both ILC2 and myeloid cell IL‐33 signaling contribute to local and peripheral eosinophilia.
Aqueous zinc-based energy storage devices possess superior safety, cost-effectiveness, and high energy density; however, dendritic growth and side reactions on the zinc electrode curtail their ...widespread applications. In this study, these issues are mitigated by introducing a polyimide (PI) nanofabric interfacial layer onto the zinc substrate. Simulations reveal that the PI nanofabric promotes a pre-desolvation process, effectively desolvating hydrated zinc ions from Zn(H
O)
to Zn(H
O)
before approaching the zinc surface. The exposed zinc ion in Zn(H
O)
provides an accelerated charge transfer process and reduces the activation energy for zinc deposition from 40 to 21 kJ mol
. The PI nanofabric also acts as a protective barrier, reducing side reactions at the electrode. As a result, the PI-Zn symmetric cell exhibits remarkable cycling stability over 1200 h, maintaining a dendrite-free morphology and minimal byproduct formation. Moreover, the cell exhibits high stability and low voltage hysteresis even under high current densities (20 mA cm
, 10 mAh cm
) thanks to the 3D porous structure of PI nanofabric. When integrated into full cells, the PI-Zn||AC hybrid zinc-ion capacitor and PI-Zn||MnVOH@SWCNT zinc-ion battery achieve impressive lifespans of 15000 and 600 cycles with outstanding capacitance retention. This approach paves a novel avenue for high-performance zinc metal electrodes.
This paper describes a video coding technology proposal submitted by MediaTek in April 2018 in response to a joint call for proposals (CfP) issued by ITU-T VCEG and ISO/IEC MPEG. The proposal uses ...the conventional block-based hybrid coding approach with a breakthrough design of block structure, substantial improvements of coding tools, and new inventions of loop filtering techniques. First, the block structure is designed using a highly flexible partitioning scheme, where each coding tree unit in a picture is split into multiple coding units (CUs) by a recursive quaternary tree followed by a recursive binary-ternary tree. The prediction unit (PU) and transform unit (TU) concepts are unified with the CU concept, i.e., PU and TU are basically the same as CU. Moreover, inter prediction, intra prediction, transform, quantization, in-loop filtering, and entropy coding are all improved. Finally, new loop filtering techniques are invented, where the proposed convolutional neural network loop filtering is of particular interest. The proposed video codec achieves 43.81% average bit rate savings based on objective measures compared to the High Efficiency Video Coding (HEVC) anchors and is among the best-performing CfP responses both objectively and subjectively. It has been partially adopted into the working draft of the Versatile Video Coding (VVC) standard.
Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of ...biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high‐methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL‐6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3‐O‐sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.
What's new?
Most targeted therapies for epithelial ovarian cancer are ineffective. For precision medicine to be effective, companion diagnostic tests are needed. Through integrative epigenomics, here the authors discovered and validated the epigenetic signature of NEFH/HS3ST2 as a stratifying prognostic factor. Mechanistic investigations of HS3ST2 revealed inhibitory effects on various oncogenic signals and malignant phenotypes. Low HS3ST2 and overexpression of oncogenic ligands synergized to confer a poor outcome. Furthermore, 3‐O‐sulfation of heparan sulfate by HS3ST2 made ovarian cancer cells intrinsically sensitive to oncogenic signals, suggesting the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.
Oral submucous fibrosis (OSF) is considered as a pre‐cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid ...and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial–mesenchymal transition (EMT)‐related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E‐box binding homeobox 1 (ZEB1), which is a well‐known transcriptional factor in EMT, in OSF tissues and its role in arecoline‐induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker α‐smooth muscle actin (α‐SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of α‐SMA‐positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the α‐SMA promoter in BMFs was increased by arecoline. The promoter activity of α‐SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline‐induced α‐SMA promoter activity and collagen contraction of BMFs. Long‐term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of α‐SMA and myofibroblast activity. Inhibition of insulin‐like growth factor receptor‐1 could suppress arecoline‐induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid–associated OSF by activating the α‐SMA promoter and inducing myofibroblast transdifferentiation from BMFs.
Thrombospondin‐1 (TSP1) is involved in corneal wound healing caused by chemical injury. Herein, we examined the effects of TSP1 on hypoxia‐induced damages and wound‐healing activity in human corneal ...epithelial (HCE) cells. Exosomal protein expression was determined using liquid chromatography‐tandem mass spectrometry, and HCE cell migration and motility were examined through wound‐healing assay and time‐lapse microscopy. Reestablishment of cell junctions by TSP1 was assessed through confocal microscopy and 3D image reconstruction. Our results show that CoCl2‐induced hypoxia promoted HCE cell death by paraptosis. TSP1 protected these cells against paraptosis by attenuating mitochondrial membrane potential depletion, swelling and dilation of endoplasmic reticulum and mitochondria, and mitochondrial fission. Exosomes isolated from HCE cells treated with TSP1 contained wound healing‐associated proteins that were taken up by HCE cells to promote tissue remodeling and repair. TSP1 protected HCE cells against hypoxia‐induced damages and inhibited paraptosis progression by promoting cell migration, cell‐cell adhesion, and extracellular matrix remodeling. These findings indicate that TSP1 ameliorates hypoxia‐induced paraptosis in HCE cells and promotes wound healing and remodeling by regulating exosomal protein expression. TSP1 may, therefore, play important roles in the treatment of hypoxia‐associated corneal diseases.
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