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The recurrence of patients with epithelial ovarian cancer (EOC) is largely attributed to tumour cells escaping from the surveillance of immune cells. However, to date there is a lack of studies that have systematically evaluated the associations between the infiltration fraction of immune cells and the recurrence risk of EOC. Based on the micro-ribonucleic acid (microRNA) expression profiles of 441 EOC patients, we constructed a microRNA-based panel with recurrence prediction potential using non-negative matrix factorization consensus clustering. Then, we evaluated the association between recurrence risk and infiltration proportions among 10 immune cell types by CIBERSORT and a multivariable Cox regression model. As a result, we identified a 72-microRNA-based panel that could stratify patients into high and low risk of recurrence. The infiltration of plasma cells and M1 macrophages was consistently significantly associated with the risk of recurrence in patients with EOC. Plasma cells were significantly associated with a decreased risk of relapse [hazard ratio (HR) = 0.58, p = 0.006), while M1 macrophages were associated with an increased risk of relapse (HR = 1.59, p = 0.003). Therefore, the 72-microRNA-based panel, M1 macrophages and plasma cells may hold potential to serve as recurrence predictors of EOC patients in clinical practice.

For the commercialization of wireless electric vehicle (EV) chargers, the metal object detection and coil alignment are needed for the safe and efficient operation of chargers. This article proposes a dual-purpose method for the simultaneous metal object detection and coil alignment using a planar coil array before the start of wireless EV charging. Magnetic induction tomography (MIT) is adopted to reconstruct the images of metal objects and the location of the objects is calculated using the image processing algorithms. The receiving coil in the EV is visualized using the induced voltage map from the coil array and the coil position is computed using characteristic points of the map. First, the structure of the coil array is optimized using the finite element model (FEM) and $4\times $ 4 coil elements are used. Then the FEM simulation is conducted for the feasibility study of the proposed method. Finally, an experimental setup of the wireless charging is designed for further verification. For the metal object detection, eight experimental cases prove that the proposed method is able to detect and visualize metal objects with different numbers and different shapes. In addition, the maximum location error for all metal objects is 6.27 mm. For the coil alignment, the location error of the receiving coil is less than 2 cm. The proposed method can help to remove metal objects and assist the driver during the parking, which meets the requirement for wireless EV charging.

Background: Understanding how cells respond to mitotic poisons is of great biomedical and clinical significance. However, it remains unknown how cell-death or survival is determined during exposure to anti-mitotic drugs. Methods: The biological effects of SLC39A6 (LIV-1) and GrpE-like 1 (GRPEL1) on mitotic exit and apoptosis were evaluated both in vitro and in vivo using flow cytometry, western blotting, xenografts and time-lapse imaging. The interactions between proteins and the ubiquitination of GRPEL1 were assessed by GST pull down, immunoprecipitation and mass spectrometry analysis. The expression of LIV-1 in cancers was assessed by immunohistochemistry. Findings: Overexpression of LIV-1 led to direct apoptosis. Depleted for LIV-1 evade anti-mitotic agent-induced killing through a rapid exit from arrested mitosis. LIV-1 interacts with GRPEL1 and Stabilizes GRPEL1 Protein by Preventing Ubiquitylation of GRPEL1. LIV-1-GRPEL1 axis depletion works to reduce the mitotic arrest by inducing PP2A-B55α phosphates activity, while inhibit apoptosis by banding AIF and preventing the latter's release into the nucleus. Loss of function in this axis was frequent in multiple types of human epithelial cancer. Interpretation: These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55α and AIF. Its discovery constitutes a conceptual advance for the decisive mechanism of cell fate during damaged mitosis. Fund: National Clinical Research Center for Obstetric and Gynecologic Diseases, the National Natural Science Foundation of China. Keywords: LIV-1-GRPEL1 axis, Mitotic exit, Apoptosis, Anti-mitotic agents, Human cancer

Investigations into drying kinetics of biomass in fluidized bed dryers are essential for the control of drying processes, enhancing productivity and reducing energy consumption. However, there is limited research on drying characteristics of biomass at different bubble locations due to complex hydrodynamics around bubbles in the bed. In this paper, a new method is proposed by combining electrostatic sensing and digital imaging techniques to obtain moisture contents, drying models, moisture diffusivities, activation energies and mass transfer coefficients of biomass at different bubble locations. Experimental tests were conducted on a laboratory-scale fluidized bed dryer for different air velocities at a range of air temperatures. Five mathematical drying models are evaluated in the paper. It is found that the Page drying model is most suitable for describing the drying process of biomass in the fluidized bed. The results also show that the mass transfer coefficient of biomass at the interior and boundary of the bubble is higher than that at the exterior of the bubble. In addition, although the mass transfer coefficient increases with the air temperature and air velocity, the highest air temperature and highest air velocity are not optimal conditions. For example, a bubble flow turns into a slug flow or plug flow at an air velocity of 0.56 m/s and an air temperature of 75 °C.

Drug resistance is the predominant cause of mortality in late-stage patients with ovarian cancer. Histone deacetylase inhibitors (HDACis) have emerged as a novel type of second line drug with high specificity for tumor cells, including ovarian cancer cells. However, HDACis usually exhibit relatively low potencies when used as a single agent. The majority of current clinical trials are combination strategies. These strategies are more empirical than mechanism-based applications. Previously, it was reported that the adhesion molecule cluster of differentiation 146 (CD146) is significantly induced in HDACi-treated tumor cells. The present study additionally confirmed that the induction of CD146 is a common phenomenon in vorinostat-treated ovarian cancer cells. AA98, an anti-CD146 monoclonal antibody (mAb), was used to target CD146 function. Synergistic antitumoral effects between AA98 and vorinostat were examined in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the protein kinase B (Akt) pathway was determined by western blotting. The present study found that targeting of CD146 substantially enhanced vorinostat-induced killing via the suppression of activation of Akt pathways in ovarian cancer cells. AA98 in combination with vorinostat significantly inhibited cell proliferation and increased apoptosis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and prolong survival in ovarian cancer. These data suggest that an undesired induction of CD146 may serve as a protective response to offset the antitumor efficacy of vorinostat. By contrast, targeting CD146 in combination with vorinostat may be exploited as a novel strategy to more effectively kill ovarian cancer cells.

Recent advances in tumor metabolism have revealed that metabolic reprogramming could dramatically promote caner metastasis. However, the relation and mechanism between metastasis and metabolic reprogramming are not thoroughly explored. Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of FAM210B in human cancer cells. Human ovarian cancer xenograft model was used to determine the effects of inhibiting FAM210B by shRNA on tumor metastasis. Microarray analysis was used to determine the target genes of FAM210B. FAM210B cellular localization was performed by mitochondria isolation and mitochondria protein extraction. To detect FAM210B-mediated metabolic reprogramming, oxygen consumption rate and extracellular acidification rate were measured. Our previous study screened a novel cancer progression-suppressor gene, FAM210B, which encodes an outer mitochondrial membrane protein, by the suppression of mortality by antisense rescue technique (SMART). Here we demonstrated that FAM210B loss was significantly associated with cancer metastasis and decreased survival in a clinical setting. Additionally, it was found that low expression of FAM210B was significantly correlated with decreased survival and enhanced metastasis in vivo and in vitro, and the loss of FAM210B led to an increased mitochondrial respiratory capacity and reduced glycolysis through the downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which activated the EMT program and enhanced migratory and invasive properties. Collectively, our data unveil a potential metabolic target and mechanism of cancer metastasis.

Background: Understanding how cells respond to mitotic poisons is of great biomedical and clinical significance. However, it remains unknown how cell-death or survival is determined during exposure to anti-mitotic drugs. Methods: The biological effects of LIV-1 and GRPEL1 on mitotic exit and apoptosis were evaluated both in vitro and in vivo using flow cytometry, western blotting, xenografts and time-lapse imaging. The interactions between proteins and the ubiquitination of GRPEL1 were assessed by GST pull down, immunoprecipitation and mass spectrometry analysis. The expression of LIV-1 in cancers was assessed by immunohistochemistry. Findings: Overexpression of LIV-1 led to direct apoptosis. Depleted for LIV-1 evade anti-mitotic agent-induced killing through a rapid exit from arrested mitosis. LIV-1 interacts with GRPEL1 and Stabilizes GRPEL1 Protein by Preventing Ubiquitylation of GRPEL1. LIV-1-GRPEL1 axis regulate mitotic exit through inhibiting PP2A-B55I± phosphates activity, and promot apoptosis partially through the release of AIF. Loss of function in this axis was frequent in multiple types of human epithelial cancer. Interpretation: These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55I± and AIF. Its discovery constitutes a conceptual advance for the decisive mechanism of cell fate during damaged mitosis. Funding Statement: National Clinical Research Center for Obstetric and Gynecologic Diseases, the National Natural Science Foundation of China. Declaration of Interests: The authors declare that there are no conflicts of interest with this work. Ethical Approval Statement: All animals were obtained from BEIJING HFK BIOSCIENCE Co., Ltd. (Beijing, China), and experiments were approved by the Committee on the Ethics of Animal Experiments of Tongji Medical College. Mice were maintained in the accredited animal facility of Tongji Medical College.

Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.

Background Ubiquinol-cytochrome C reductase core protein II (QCR2) is essential for mitochondrial functions, yet, its role in cancer development has remained elusive. Methods The expression of QCR2 in cancer patients was assessed by immunohistochemistry. The proliferation of cancer cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. The biological function of QCR2 and PHB were determined using western blotting, RT-qPCR, microarray analysis and xenografts. The interactions between proteins and the ubiquitination of p53 were assessed by immunoprecipitation, mass spectrometry analysis and GST pull down. The subcellular location of PHB and QCR2 was assessed by immunoblotting and immunofluorescence. Finding The expression of QCR2 is upregulated in multiple human tumors. Suppression of QCR2 inhibits cancer cell growth by activating p53 signaling and inducing p21-dependent cell cycle arrest and senescence. QCR2 directly interacts with PHB in the mitochondria. Overexpression of QCR2 inhibits PHB binding to p53 in the nucleus, and facilitates p53 ubiquitination and degradation, consequently leading to tumorigenesis. Also, increased QCR2 and decreased PHB protein levels are well correlated with decreased expression of p21 in cervical cancer tissues. Interpretation These results identify a novel role for QCR2, together with PHB, in negative regulation of p53 stability and activity, thus promote cervical carcinogenesis. Fund “973” Program of China, the National Science-technology Supporting Plan Projects, the National Natural Science Foundation of China, National Science and Technology Major Sub-Project and Technical Innovation Special Project of Hubei Province.

In this paper, we apply the model of the extended linear expenditure system to measure housing affordability of urban households in Beijing, and calculate the affordable housing areas of urban households which are on different income levels in Beijing in 2014 and 2004. In this study, we find that, the household disposable incomes of urban households in Beijing increase along with the development of economy, all income levels of urban households in Beijing can cover the expenditures of their basic life needs, and housing affordability of urban households of different income levels in Beijing is increasing as well. The increasing disposable incomes enhanced the housing affordability of urban households in Beijing from the year 2004 to the year 2014, and all income levels of urban households in Beijing have improved their housing conditions. However, from the view of the affordable housing squares, their housing conditions depend on the housing price closely. If the growth of house price is faster than the growth of housing affordability, the affordable housing squares will decrease, and the housing condition of urban households in Beijing will be worse from 2004 to 2014. And the comparison between 2013 and 2014 shows the housing affability problem has been relieved.

VX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

The authors would like to correct Fig 1, as errors were introduced in the preparation of this figure for publication. In Fig 1C, the panels for HeLa at 7 days and at 10 days appear to be identical. The authors have provided a corrected version of Fig 1 here. Fig 1 The increasing effect of colony formation and drug-resistance in HeLa/TSA. The authors confirm that these changes do not alter their findings. The authors have provided the underlying images for all figures in the original article as Supporting Information.

Recent advances in tumor metabolism have revealed that metabolic reprogramming could dramatically promote caner metastasis. However, the relation and mechanism between metastasis and metabolic reprogramming are not thoroughly explored. Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of FAM210B in human cancer cells. Human ovarian cancer xenograft model was used to determine the effects of inhibiting FAM210B by shRNA on tumor metastasis. Microarray analysis was used to determine the target genes of FAM210B. FAM210B cellular localization was performed by mitochondria isolation and mitochondria protein extraction. To detect FAM210B-mediated metabolic reprogramming, oxygen consumption rate and extracellular acidification rate were measured. Our previous study screened a novel cancer progression-suppressor gene, FAM210B, which encodes an outer mitochondrial membrane protein, by the suppression of mortality by antisense rescue technique (SMART). Here we demonstrated that FAM210B loss was significantly associated with cancer metastasis and decreased survival in a clinical setting. Additionally, it was found that low expression of FAM210B was significantly correlated with decreased survival and enhanced metastasis in vivo and in vitro, and the loss of FAM210B led to an increased mitochondrial respiratory capacity and reduced glycolysis through the downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which activated the EMT program and enhanced migratory and invasive properties. Collectively, our data unveil a potential metabolic target and mechanism of cancer metastasis.

In a previous study, we used a functional gene screen approach to identify the key genes responsible for the tumor-selective action of trichostatin A (TSA), of which LIV1, a novel zinc transporter, was isolated by its marked ability to confer resistance against TSA-induced apoptosis. The aim of the present study was to investigate the effect of LIV1 expression on the sensitivity of ovarian cancer cells to TSA. We tested the induction of LIV1 in ovarian cancer cells and clinical samples after TSA treatment by real-time PCR and western blot analysis. We investigated the effect of LIV1 expression on the sensitivity of ovarian cancer cells to TSA by MTT assay, flow cytometry and colony forming assays. Finally, we analyzed the mechanism of LIV1 in ovarian cancer cells by western blot analysis. We found that the levels of LIV1 mRNA and protein were significantly upregulated after TSA treatment. The viability and colony forming rates of the ovarian cancer cells transfected with AS-LIV1 (pCEP4 carrying antisense LIV1 cDNA) were obviously higher than the rates of the control as detected by MTT and colony forming assays, which could be reversed by FL-LIV1 (pCEP4 carrying full-length LIV1 cDNA). The apoptotic rate of the AS-LIV1 cells was markedly lower than the rate of the control as determined FACS. Using western blot analysis, we demostrated that the inhibition of TSA-induced apoptosis by knockdown of LIV1 might be associated with decreased endogenous levels of Bcl-2, enhanced levels of Bax and cleavage of procaspase-3. The present study suggests that the drug resistance of ovarian cancer cells to TSA may be related to expression of the LIV1 gene, and targeting LIV1 could be exploited as a novel strategy to more effectively kill ovarian cancer cells.

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.

Hec1, a member of the Ndc80 kinetochore complex, is highly expressed in cancers. The aim of this study was to explore the role and mechanism of action of Hec1 with respect to the cytotoxicity of paclitaxel in ovarian cancer.Thirty ovarian cancer samples and 6 normal ovarian samples were collected. Hec1 expression in these samples was determined with immunohistochemistry. Ovarian cancer cell lines A2780, OV2008, C13K, SKOV3, and CAOV3 and A2780/Taxol were examined. Cell apoptosis and cell cycle analysis were detected with flow cytometric technique. siRNA was used to delete Hec1 in the cells. The expression of related mRNAs and proteins was measured using RT-PCR and Western blot analysis, respectively.Hec1 expression was significantly higher in ovarian cancer samples than in normal ovarian samples, and was associated with paclitaxel-resistance and poor prognosis. Among the 6 ovarian cancer cell lines examined, Hec1 expression was highest in paclitaxel-resistant A2780/Taxol cells, and lowest in A2780 cells. Depleting Hec1 in A2780/Taxol cells with siRNA decreased the IC50 value of paclitaxel by more than 10-fold (from 590±26.7 to 45.6±19.4 nmol/L). Depleting Hec1 in A2780 cells had no significant effect on the paclitaxel sensitivity. In paclitaxel-treated A2780/Taxol cells, depleting Hec1 significantly increased the cleaved PARP and Bax protein levels, and decreased the Bcl-xL protein level.Hec1 overexpression is associated with the progression and poor prognosis of ovarian cancer. Inhibition of Hec1 expression can sensitize ovarian cancer cells to paclitaxel.

This study was aimed to explore the influence of breast cancer associated fibroblasts (CAFs) in migration and invasion of breast cancer cell line MCF-7, and investigate whether hepatocyte growth factor (HGF) is involved in this process. Primary breast CAFs and their corresponding normal breast fibroblasts (NFs) were obtained by collagenase digestion. On the basis of the co-culture, the migration and invasion capacity of MCF-7 cells was compared between CAFs and NFs by Transwell. The difference in the HGF expression between them was detected by ELISA. The secretion of HGF was knocked down by using RNA interference technology in CAFs. Then the changes of migration and invasion capacity of MCF-7 cells were investigated by Transwell. Eventually, we isolated high-purity CAFs and NFs, and the CAFs had a stronger ability in promoting MCF-7 migration and invasion than the NFs. ELISA results demonstrated that CAFs secreted higher HGF, and the capacity of MCF-7 migration and invasion was declined after knocking down the secretion of HGF in CAFs by RNA interference. It is suggested that CAFs can promote MCF-7 migration and invasion through HGF in vitro.

In this paper, we apply the model of the extended linear expenditure system to measure housing affordability of urban households in Beijing, and calculate the affordable housing areas of urban households which are on different income levels in Beijing in 2013 and 2004. In this study, we find that, the household disposable incomes of urban households in Beijing increase along with the development of economy, all income levels of urban households in Beijing can cover the expenditures of their basic life needs, housing affordability of urban households of different income levels in Beijing is increasing. However, because the growth of house prices is faster than the growth of disposable income of urban households in Beijing, the affordable housing areas of urban residents in Beijing is decreasing. To solve the housing problem in Beijing, the government must find ways to increase households’ income and carry out efficient ways to control the growth of housing price.