Anisotropic Semicrystalline Homopolymer Dielectrics for High-Temperature Capacitive Energy Storage.

High-temperature dielectric polymers are in high demand for powering applications in extreme environments. Here, we have developed high-temperature homopolymer dielectrics with anisotropy by leveraging the hierarchical structure in semicrystalline polymers. The lamellae have been aligned parallel to the surface in the dielectric films. This structural arrangement resembles the horizontal alignment of nanosheet fillers in polymer nanocomposites and nanosheet-like lamellae in block copolymers, which has been proven to provide the optimal topological structure for electrical energy storage. The unique ordering of lamellae in our dielectric films endue a significantly increased breakdown strength and a reduced leakage current compared to amorphous films. This novel approach of enhancing the capacitive energy storage properties by controlled orientation of lamellae in homopolymer offers a new perspective for the design of high-temperature polymer dielectrics.

Hydrogen Bonding of Aramid Boosts High-Temperature Capacitive Properties of Polyetherimide Blends.

Polyetherimide (PEI) is the state-of-the-art commercial high-temperature polymer dielectric with excellent thermal and chemical stability and relatively high high-temperature capacitive energy storage properties. The rotation of the dipoles in the PEI chains brings the ß-relaxation which seriously increases the leakage current and decreases the charge-discharge efficiency. In this work, hydrogen bonds have been introduced to limit the dipole rotation of PEI by blending aramids [1,4-poly(ether fluoromethyl naphthalene amide), PNFA] into the PEI matrix. By introducing 10 wt % PNFA, the ß-relaxation of the blend has been significantly reduced which could be observed from the dielectric spectrum. To explore the mechanism of limited ß-relaxation, we analyze the hydrogen bonds in the blend films by infrared spectroscopy and found that the maximum content of hydrogen-bonded carbonyl formed between PNFA and PEI chains was 14.3% when the content of PNFA was 30 wt %. The content of hydrogen bonds formed between PNFA and PEI was positively correlated with the energy storage performance of the blends. The maximum discharged energy density with an efficiency above 90% of the blend film with 30 wt % PNFA reaches 4.1 J cm-3 at 150 °C, which is about 350% higher than that of pristine PEI. This work shows that composing hydrogen bonds by the blending method could be a viable strategy for enhancing the high-temperature energy storage performance of polymer dielectrics, which could be achieved by large-scale preparation and has feasible industrial production prospects.

Improving the malignancy prediction of breast cancer based on the integration of radiomics features from dual-view mammography and clinical parameters.

Radiomics has been a promising imaging biomarker for many malignant diseases. We developed a novel radiomics strategy that incorporating radiomics features extracted from dual-view mammograms and clinical parameters for identifying benign and malignant breast lesions, and validated whether the radiomics assessment could improve the accurate diagnosis of breast cancer. A total of 380 patients (mean age, 52 ± 7 years) with 621 breast lesions utilizing mammograms on craniocaudal (CC) and mediolateral oblique (MLO) views were randomly allocated into the training (n = 486) and testing (n = 135) sets in this retrospective study. A total of 1184 and 2368 radiomics features were extracted from single-position region of interest (ROI) and position-paired ROI, separately. Clinical parameters were then combined for better prediction. Recursive feature elimination and least absolute shrinkage and selection operator methods were applied to select optimal predictive features. Random forest was used to conduct the predictive model. Intraclass correlation coefficient test was used to assess repeatability and reproducibility of features. After preprocessing, 467 radiomics features and clinical parameters remained in the single-view and dual-view models. The performance and significance of models were quantified by the area under the curve (AUC), sensitivity, specificity, and accuracy. The correlation analysis between variables was evaluated using the correlation ratio and Pearson correlation coefficient. The model using a combination of dual-view radiomics and clinical parameters achieved a favorable performance (AUC: 0.804, 95% CI: 0.668-0.916), outperformed single-view model and model without clinical parameters. Incorporating with radiomics features of dual-view (CC&MLO) mammogram, age, breast density, and type of suspicious lesions can provide a noninvasive approach to evaluate the malignancy of breast lesions and facilitate clinical decision-making.

A Immune-Related Signature Associated with TME Can Serve as a Potential Biomarker for Survival and Sorafenib Resistance in Liver Cancer.

OBJECTIVE: Although many curative treatments are being applied in the clinic, a significant number of patients with liver hepatocellular carcinoma (LIHC) suffer from drug resistance. The tumour microenvironment (TME) has been found to be closely associated with resistance, suggesting that identification of predictive biomarkers related to the TME for resistance in LIHC will be very rewarding. However, there has been no study dedicated to identifying a TME-related biomarker that has the potential to predict resistance in LIHC. METHODS: An integrated analysis was conducted based on data of patients with LIHC suffering from drug resistance from the TCGA database and four GEO datasets. Subsequently, we also validated the expression levels of the identified genes in paraffin-embedded LIHC samples by immunohistochemistry. RESULTS: In this study, we developed a robust and acute TME-related signature consisted of five immune-related genes (FABP6, CD4, PRF1, EREG and COLEC10) that could independently predict both the RFS and OS of LIHC patients. Moreover, the TME-related signature was significantly associated with the immune score, immune cytolytic activity (CYT), HLA, interferon (IFN) response and tumour-infiltrating lymphocytes (TILs), and it might influence tumour immunity mainly by affecting B cells, CD8+ T cells and dendritic cells. Furthermore, our analysis also indicated that the TME-related signature was correlated with the immunotherapy response and had an enormous potential to predict sorafenib resistance in LIHC. CONCLUSION: Our findings demonstrated a TME-related signature which can independently predict both the RFS and OS of LIHC patients, highlighting the predictive potential of the signature for immunotherapy response and sorafenib resistance, potentially enabling more precise and personalized sorafenib treatment in LIHC in the future.

Advances in cancer treatment: a new therapeutic target, Annexin A2.

Annexin A2 (ANXA2) is a calcium regulated phospholipid-binding protein. It is expressed in some tumor cells, endothelial cells, macrophages, and mononuclear cells, affecting cell survival and mediating interactions between intercellular and extracellular microenvironment. Aberrant expression of ANXA2 can be used as a potential predictive factor, diagnostic biomarker and therapeutic target in cancer therapy. Investigators used various technologies to target ANXA2 in a preclinical model of human cancers and demonstrated encouraging results. In this review article, we discuss the diagnosis and prognosis latent capacity of ANXA2 in progressive cancers, focus on the exploration of restorative interventions targeting ANXA2 in cancer treatment. Further, we comment on a promising candidate therapy that is conceivable for clinical translation.

m6A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma.

Accumulating evidence has proven that N6-methyladenosine (m6A) RNA methylation plays an essential role in tumorigenesis. However, the significance of m6A RNA methylation modulators in the malignant progression of papillary renal cell carcinoma (PRCC) and their impact on prognosis has not been fully analyzed. The present research set out to explore the roles of 17 m6A RNA methylation regulators in tumor microenvironment (TME) of PRCC and identify the prognostic values of m6A RNA methylation regulators in patients afflicted by PRCC. We investigated the different expression patterns of the m6A RNA methylation regulators between PRCC tumor samples and normal tissues, and systematically explored the association of the expression patterns of these genes with TME cell-infiltrating characteristics. Additionally, we used LASSO regression to construct a risk signature based upon the m6A RNA methylation modulators. Two-gene prognostic risk model including IGF2BP3 and HNRNPC was constructed and could predict overall survival (OS) of PRCC patients from the Cancer Genome Atlas (TCGA) dataset. The prognostic signature-based risk score was identified as an independent prognostic indicator in Cox regression analysis. Moreover, we predicted the three most significant small molecule drugs that potentially inhibit PRCC. Taken together, our study revealed that m6A RNA methylation regulators might play a significant role in the initiation and progression of PRCC. The results might provide novel insight into exploration of m6A RNA modification in PRCC and provide essential guidance for therapeutic strategies.

Analysis of immune subtypes based on immunogenomic profiling identifies prognostic signature for cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is the most invasive form of skin cancer with poor prognosis. Growing evidence has demonstrated that tumor immune microenvironment plays a key contributing role in tumorigenesis and predicting clinical outcomes. The aim of this study was to recognize immune classification and a reliable prognostic signature for patients with SKCM. By using single-sample gene set enrichment (ssGSEA) and hierarchical clustering analyses, we evaluated the immune infiltration landscape of SKCM afflicted patients from The Cancer Genome Atlas (TCGA) dataset and named two SKCM subtypes: Immunity-high and Immunity-low. The Immunity-high subgroup was characterized by up-regulation of immune response and favorable survival probability. Seven candidate small molecule drugs which potentially reverse SKCM immune status were identified by using Connectivity map (CMap) database. A prognostic five-immune-associated gene (IAG) signature consisting IFITM1, TNFSF13B, APOBEC3G, CCL8 and KLRK1 with high predictive value was established using the LASSO Cox regression analysis in training set, and validated in testing set as well as Gene Expression Omnibus (GEO) external validation cohort (P < 0.05). Lower tumor purity and active immune-related signaling pathways were obviously presented in low-risk group. Furthermore, a novel composite nomogram based upon the five-IAG signature and other clinical parameters was built with excellent calibration curves. Collectively, comprehensively characterizing the SKCM subtypes based upon immune microenvironment landscape and development of a survival-related IAG signature may provide a promising avenue for improving individualized treatment design and prognosis prediction for patients with SKCM.

Development of an IFNγ response-related signature for predicting the survival of cutaneous melanoma.

BACKGROUND: The tumor microenvironment (TME) plays a critical role in tumorigenesis, development, and therapeutic efficacy. Major advances have been achieved in the treatment of various cancers through immunotherapy. Nevertheless, only a minority of patients have positive responses to immunotherapy, which is partly due to conditions of the immunosuppressive microenvironment. Therefore, it is essential to identify prognostic biomarkers that reflect heterogeneous landscapes of the TME. METHODS AND MATERIALS: Based upon the ESTIMATE algorithm, we evaluated the infiltrating levels of immune and stromal components derived from patients afflicted by various types of cancer from The Cancer Genome Atlas database (TCGA). According to respective patient immune and stromal scores, we categorized cases into high- and low-scoring subgroups for each cancer type to explore associations between TME and patient prognosis. Gene Set Enrichment Analyses (GSEA) were conducted and genes enriched in IFNγ response signaling pathway were selected to facilitate establishment of a risk model for predicting overall survival (OS). Furthermore, we investigated the associations between the prognostic signature and tumor immune infiltration landscape by using CIBERSORT algorithm and TIMER database. RESULTS: Among the cancers assessed, the immune scores for skin cutaneous melanoma (SKCM) were the most significantly correlated with patients' survival time (P < .0001). We identified and validated a five-IFNγ response-related gene signature (UBE2L6, PARP14, IFIH1, IRF2, and GBP4), which was closely correlated with the prognosis for SKCM afflicted patients. Multivariate Cox regression analysis indicated that this risk model was an independent prognostic factor for SKCM. Tumor-infiltrating lymphocytes and specific immune checkpoint molecules had notably differential levels of expression in high- compared to low-risk samples. CONCLUSION: In this study, we established a novel five-IFNγ response-related gene signature that provided a better and increasingly comprehensive understanding of tumor immune landscape, and which demonstrated good performance in predicting outcomes for patients afflicted by SKCM.

Identification of the prognostic value of immune gene signature and infiltrating immune cells for esophageal cancer patients.

BACKGROUND: Esophageal cancer (ESCA) is one of the deadliest solid malignancies with worse survival rate worldwide. Here, we aimed to establish an immune-gene prognostic signature for predicting patients' survival and providing accurate targets for personalized therapy or immunotherapy. METHODS: Gene expression profile of patients with ESCA were download from The Cancer Genome Atlas (TCGA) database (dataset 1: n = 159) and immune-related genes from the ImmPORT database. Dataset 1 was subdivided into two groups (dataset 2: n = 80; dataset 3: n = 79). Kaplan-Meier and receiver operating characteristic (ROC) curves were plotted to validate the predictive effect of the prognostic signature on the three datasets. TIMER and CIBERSORT analysis were used to evaluate the correlation between the prognostic signature and infiltrating immune cells. RESULTS: We constructed a prognostic signature composed of six immune genes (HSPA6, S100A12, FABP3, DKK1, OSM and NR2F2). Kaplan-Meier curves validated the good predictive ability of the prognostic signature in datasets 1, 2 and 3 (P = 0.0034, P = 0.0081, and P = 0.0363, respectively). The area under the curve (AUC) of the ROC curves validated the predictive accuracy of the immune signature (AUCs = 0.757, 0.800, and 0.701, respectively). We also revealed the good prognostic value of the immune cells, including activated memory CD4 T cells, T follicular helper cells and monocytes. Potential target drugs, including Olopatadine and Amlexanox, were identified for clinical therapies to improve patients' survival outcomes. CONCLUSION: Our study indicated that the immune-related prognostic signature could serve as a novel biomarker for predicting patients' prognosis and providing new immunotherapy targets in ESCA.

Preparation and Properties of Novel Cross-Linked Fluorinated Poly(aryl ether) with Low Dielectric Constant and High Thermal Stability.

Fluorinated poly(aryl ether)s (FPAEs) have attracted much attention due to their high thermal stability, excellent mechanical strength, and low dielectric constant. High-molecular-weight fluorinated poly(aryl ether) containing phenylethynyl (FPAE-PE) is successfully synthesized by nucleophilic substitution between 3-ethynylphenol and FPAE. The cross-linked fluorinated poly(aryl ether) (C-FPAE-PE) is prepared by thermal treatment of FPAE-PE at 300 °C. The thermal stability, dynamic thermomechanical property, and dielectric performance of C-FPAE-PE are systematically studied. C-FPAE-PE has excellent heat resistance with 5% weight loss temperature (Td5% ) at 490 °C in air and high thermomechanical properties with storage modulus retention of 50% at 215 °C. C-FPAE-PE displays low and steady dielectric constant of 2.4 and dielectric loss of 0.004 at 215 °C, exhibiting potential applications in the field of microelectronics, communication technology, and energy storage as high-temperature low dielectric materials.

Regulation and role of post-translational modifications of enhancer of zeste homologue 2 in cancer development.

Post-translational modifications (PTMs) are critical molecular events which alter protein conformation after their synthesis and diversity protein properties by modulating their stability, localization, interacting partners or the activity of their substrates, consequently exerting pivotal roles in regulating the functions of many important eukaryotic proteins. It has been well acknowledged that PTMs are of great importance in a broad range of biological processes such as gene regulation, cell proliferation, differentiation and apoptosis, tissue development, diseases, tumor progression and drug resistance. As the core and contributing catalytic subunit of Polycomb repressive complex 2(PRC2), Enhancer of zeste homolog 2 (EZH2) is a master epigenetic regulator, often serving as a highly conserved histone methyltransferase (HMTase) to induce histone H3 lysine 27 trimethylation (H3K27me3) and repress gene transcription and expression. Dysregulated EZH2 expression is frequently associated with cancer development and poor prognosis in a wide variety of cancers. Considered its essential role in carcinogenesis, EZH2 is a potential candidate for cancer targeted therapy. Remarkably, mounting evidence highlights that EZH2 expression, activity and stability can be regulated by PTMs including phosphorylation, acetylation, ubiquitination, sumoylation and GlcNAcylation aside from its well-validated modifications in transcriptional and post-transcriptional levels. However, the precise regulatory mechanisms underlying EZH2 PTMs and whether other types of PTMs orchestrate in EZH2 remain largely unclear. In this review, we summarize current advances in the understanding of EZH2 regulation by PTMs and their associated biological functions during tumorigenesis.

Knockdown of p53 combined with expression of the catalytic subunit of telomerase is sufficient to immortalize primary human ovarian surface epithelial cells.

Ovarian cancer is developed from a single layer of thin epithelial cells covering the surface of ovary, named human ovarian surface epithelial cells. Like all primary human cells, human ovarian surface epithelial cells have a finite life span and will go into senescence and eventually die when cultured in vitro. Immortalized human ovarian surface epithelial cells will provide an important model system with which to study ovarian cancer initiation and progression. Here, we show that silencing p53 expression with retrovirus-mediated small interfering RNA can delay the senescence and extend cell passage number, but is not sufficient to immortalize normal ovarian surface epithelial cells. Introduction of the catalytic subunit of telomerase is similarly insufficient to achieve immortalization. However, concurrent disruption of p53 expression with small interfering RNA retroviral constructs and ectopic expression of the catalytic subunit of telomerase was sufficient to induce cellular immortalization in 3 of 3 human ovarian surface epithelial cell cultures tested. The immortalization is associated with increased telomerase activity and telomere length, and attenuated response of cell-cycle regulatory proteins to irradiation. The resultant immortal cells continued to express the same specific cytokeratins 8 and 18 as parental cells did, indicating that the epithelial characters are still maintained in the immortal cells. In addition, the immortalized cells are non-tumorigenic and nearly diploid, which is in constrast with one immortalized by SV40 T/t antigens and hTERT. As both p53 pathway dysfunction and activation of telomerase are commonly present in human ovarian cancer, these immortal cells provide an authetic cell model system for the study of the human ovarian cancer initiation, progression, differentiation and chemoprevention.

The carboxyl-terminal of BRCA1 is required for subnuclear assembly of RAD51 after treatment with cisplatin but not ionizing radiation in human breast and ovarian cancer cells.

BRCA1 plays an important role in maintaining genomic stability through its involvement in DNA repair. Although it is known that BRCA1 and RAD51 form distinct DNA repair subnuclear complexes, or foci, following environmental insults to the DNA, the role of BRCA1 in this process remains to be characterized. The purpose of the study was therefore to determine the role of BRCA1 in the formation of RAD51 foci following treatment with cisplatin and ionizing radiation. We found that although a functional BRCA1 is required for the subnuclear assembly of BRCA1 foci following treatment with either ionizing radiation or cisplatin, a functional BRCA1 is required for RAD51 foci to form following treatment with cisplatin but not with ionizing radiation. Similar results were obtained in SKOV-3 cells when the level of BRCA1 expression was knocked down by stable expression of a retrovirus-mediated small-interfering RNA against BRCA1. We also found that the carboxyl-terminal of BRCA1 contains uncharacterized phosphorylation sites that are responsive to cisplatin. The functional BRCA1 is also required for breast and ovarian cancer cells to mount resistance to cisplatin. These results suggest that the carboxyl-terminal of BRCA1 is required for the cisplatin-induced recruitment of RAD51 to the DNA-damage site, which may contribute to cisplatin resistance.

Telomerase in breast cancer: a critical evaluation.

Human chromosomes have highly specialized structures at their ends termed telomeres, repetitive, non-coding DNA sequences (5'-TTAGGG-3'), ranging in size from 5 to 20 kb in human cells. These highly specialized structures prevent chromosome ends from being recognized as double-strand DNA breaks, and they also provide protection from destabilizing agents. The mechanism for maintaining telomere integrity is controlled by telomerase, a ribonucleoprotein enzyme that specifically restores telomere sequences lost during replication by using an intrinsic RNA component as a template for polymerization. Telomerase has two core functional components required for its activity: the catalytic subunit of human telomerase reverse transcriptase (hTERT) and a telomerase RNA template (hTR). Telomerase is activated in the majority of immortal cell lines in culture and in most malignant tumors. This review outlines our current understanding of telomerase in breast cancer development and critically evaluates potential utilities in diagnosis, prognosis, and therapy.

Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1.

BRCA1, the gene responsible for approximately half of all cases of hereditary breast cancer and almost all cases of combined hereditary breast and ovarian cancer, has been implicated in the maintenance of genomic stability through DNA repair. This function is mediated, at least in part, through two tandem BRCA1 C-terminal (BRCT) repeats. The role of BRCA1 in the development of ovarian cancer is poorly understood, partially owing to the lack of ovarian cancer cell lines with defective BRCA1. The purpose of this study was to further characterize an endometrioid ovarian cancer cell line, SNU-251, which was previously reported to carry a nonsense mutation (from G to A) at amino acid 1815 of BRCA1. In addition, we examined the role of BRCA1 in the cell cycle and in the responses to the chemotherapy drug paclitaxel and ionizing radiation. Loss of the C-terminal 49 amino acids due to this point mutation did not affect the expression of the truncated BRCA1 protein, but caused a loss of transcriptional activation of the endogenous p21(WAF1/CIP1) gene, and could not sustain arrest in the G(2)/M phase of the cell cycle. The BRCA1 mutation in SNU-251 cells inhibited BRCA1 subnuclear assembly for DNA-damage repair and increased cellular sensitivity to ionizing radiation and paclitaxel. This sensitivity was reversed by reintroduction of ectopic wild-type BRCA1. Our results suggest that the deletion of the C-terminal 49 amino acids of BRCA1 results in a loss of BRCA1 function in the SNU-251 cell line. BRCA1 helps to mediate the resistance to both radiation and paclitaxel. Therefore, SNU-251 may be a useful model for studying the molecular mechanism of BRCA1 in the resistance of ovarian cancer to ionizing radiation and chemotherapy treatment and in the development of hereditary human ovarian cancer.

Inhibition of human telomerase reverse transcriptase gene expression by BRCA1 in human ovarian cancer cells.

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is responsible for the synthesis and maintenance of the telomeric repeats at the distal ends of human chromosomes. Telomerase expression is repressed in normal human cells and is activated in immortal cells and during tumorigenesis, but the mechanism by which telomerase expression is regulated is not fully understood. Previous studies have shown that c-Myc stimulates hTERT transcription through the binding sites located on the hTERT promoter. In this study, we sought to determine whether BRCA1 inhibits hTERT transcription through its direct interaction with c-Myc. In ovarian cancer cells, c-Myc increased hTERT expression by threefold and BRCA1 completely abrogated this activity. A mutation in the c-Myc-binding site (E-box) of the hTERT promoter resulted in the loss of activation by c-Myc and in the loss of inhibition by BRCA1. Deletion of the c-Myc-binding domain in BRCA1 resulted in the loss of BRCA1's ability to inhibit transcription of the hTERT promoter. In addition, BRCA1 associates with c-Myc and inhibits the binding activity of c-Myc to the hTERT promoter. Our data indicate that BRCA1 is involved in regulating cellular immortalization through the modulation of c-Myc on the hTERT promoter.