Grid composite meta-surface absorber with thermal isolation structure for terahertz detection.

This paper specifically focuses on the absorber, the critical component responsible for the detector's response performance. The meta-surface absorber combines two resonant structures and achieves over 80% absorptance around 210 GHz, resulting in a broad operating frequency range. FR-4 is selected as the dielectric layer to be compatible with standard printed circuit board (PCB) technology, which reduces the overall fabrication time and cost. The absorbing unit and array layout are symmetrically designed, providing stable absorptance performance even under incident waves of different polarization angles. The polarization-insensitive absorptance characteristic further enhances the compatibility between the absorber and the detector in the application scenario. Furthermore, the thermal insulation performance of the absorber is ensured by introducing thermal insulation gaps. After completing fabrication through PCB technology, testing revealed that the absorber maintained excellent absorptance performance within its primary operating frequency range. This performance consistency closely matched the simulation results.

Prognostic implication of NOTCH1 in early stage oral squamous cell cancer with occult metastases.

OBJECTIVE: The objective of this study was to explore the prognostic value of cancer stem cell markers, namely CD133, NANOG, and NOTCH1, in early stage oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: One hundred forty-four patients with early stage (cT1T2N0) OSCC were identified from a pre-existing database of patients with oral cancer. We examined the impact of the immunohistochemical expression of CD133, NANOG, and NOTCH1 in OSCC. Overall survival (OS) curves were calculated using the Kaplan-Meier method. Predictors of outcome were identified using multivariate analysis. RESULTS: We found that CD133, NANOG, and NOTCH1 were significantly associated with lymph node metastasis, and NOTCH1 was also significantly associated with depth of invasion and locoregional recurrence. CONCLUSIONS: NOTCH1 was identified as an independent prognostic factor for OS. CLINICAL RELEVANCE: NOTCH1 might prove to be a useful indicator for high-risk patients with occult metastases from early stage OSCC.

Mapping enhancer and chromatin accessibility landscapes charts the regulatory network of Alzheimer's disease.

BACKGROUND: Enhancers are regulatory elements that target and modulate gene expression and play a role in human health and disease. However, the roles of enhancer regulatory circuit abnormalities driven by epigenetic alterations in Alzheimer's disease (AD) are unclear. METHODS: In this study, a multiomic integrative analysis was performed to map enhancer and chromatin accessibility landscapes and identify regulatory network abnormalities in AD. We identified differentially methylated enhancers and constructed regulatory networks across brain regions using AD brain tissue samples. Through the integration of snATAC-seq and snRNA-seq datasets, we mapped enhancers with DNA methylation alterations (DMA) and chromatin accessibility landscapes. Core regulatory triplets that contributed to AD neuropathology in specific cell types were further prioritized. RESULTS: We revealed widespread DNA methylation alterations (DMA) in the enhancers of AD patients across different brain regions. In addition, the genome-wide transcription factor (TF) binding profiles showed that enhancers with DMA are pervasively regulated by TFs. The TF-enhancer-gene regulatory network analysis identified core regulatory triplets that are associated with brain and immune cell proportions and play important roles in AD pathogenesis. Enhancer regulatory circuits with DMA exhibited distinct chromatin accessibility patterns, which were further characterized at single-cell resolutions. CONCLUSIONS: Our study comprehensively investigated DNA methylation-mediated regulatory circuit abnormalities and provided novel insights into the potential pathogenesis of AD.

Epigenetically regulated lncRNAs dissect the intratumoural heterogeneity and facilitate immune evasion of glioblastomas.

Background: Glioblastomas are the most common and malignant central nervous system (CNS) tumors that occupied a highly heterogeneous tumor microenvironment (TIME). Long noncoding RNAs (lncRNAs), whose expression can be modified by DNA methylation, are emerging as critical regulators in the immune system. However, knowledge about the epigenetic changes in lncRNAs and their contribution to the immune heterogeneity of glioma is still lacking. Methods: In this study, we integrated paired methylome and transcriptome datasets of glioblastomas and identified 2 robust immune subtypes based on lncRNA methylation features. The immune characteristics of glioma subtypes were compared. Furthermore, immune-related lncRNAs were identified and their relationships with immune evasion were evaluated. Results: Glioma immunophenotypes exhibited distinct immune-related characteristics as well as clinical and epigenetic features. 149 epigenetically regulated (ER) lncRNAs were recognized that possessed inverse variation in epigenetic and transcriptional levels between glioma subtypes. Immune-related lncRNAs were further identified through the investigation of their correlation with immune cell infiltrations and immune-related pathways. In particular, the 'Hot' glioma subtype with higher immunoactivity while a worse survival outcome was found to character immune evasion features. We finally prioritized candidate ER lncRNAs associated with immune evasion markers and response to glioma immunotherapy. Among them, CD109-AS1 and LINC02447 were validated as novel immunoevasive biomarkers for glioma through in vitro experiments. Conclusion: In summary, our study systematically reveals the crosstalk among DNA methylation, lncRNA, and immune regulation in glioblastomas, and will facilitate the development of epigenetic immunotherapy approaches.

A sub-pathway-based approach for identifying drug response principal network.

MOTIVATION: The high redundancy of and high degree of cross-talk between biological pathways hint that a sub-pathway may respond more effectively or sensitively than the whole pathway. However, few current pathway enrichment analysis methods account for the sub-pathways or structures of the tested pathways. We present a sub-pathway-based enrichment approach for identifying a drug response principal network, which takes into consideration the quantitative structures of the pathways. RESULT: We validated this new approach on a microarray experiment that captures the transcriptional profile of dexamethasone (DEX)-treated human prostate cancer PC3 cells. Compared with GeneTrail and DAVID, our approach is more sensitive to the DEX response pathways. Specifically, not only pathways but also the principal components of sub-pathways and networks related to prostate cancer and DEX response could be identified and verified by literature retrieval.

DBGSA: a novel method of distance-based gene set analysis.

When compared with single gene functional analysis, gene set analysis (GSA) can extract more information from gene expression profiles. Currently, several gene set methods have been proposed, but most of the methods cannot detect gene sets with a large number of minor-effect genes. Here, we propose a novel distance-based gene set analysis method. The distance between two groups of genes with different phenotypes based on gene expression should be larger if a certain gene set is significantly associated with the given phenotype. We calculated the distance between two groups with different phenotypes, estimated the significant P-values using two permutation methods and performed multiple hypothesis testing adjustments. This method was performed on one simulated data set and three real data sets. After a comparison and literature verification, we determined that the gene resampling-based permutation method is more suitable for GSA, and the centroid statistical and average linkage statistical distance methods are efficient, especially in detecting gene sets containing more minor-effect genes. We believe that this distance-based method will assist us in finding functional gene sets that are significantly related to a complex trait. Additionally, we have prepared a simple and publically available Perl and R package (http://bioinfo.hrbmu.edu.cn/dbgsa or http://cran.r-project.org/web/packages/DBGSA/).

Prognostic Implications and Immune Infiltration Characteristics of Chromosomal Instability-Related Dysregulated CeRNA in Lung Adenocarcinoma.

An accumulating body of research indicates that long-noncoding RNAs (lncRNAs) regulate the target genes and act as competitive endogenous RNAs (ceRNAs) playing an indispensable role in lung adenocarcinoma (LUAD). LUAD is frequently accompanied by the feature of chromosomal instability (CIN); however, CIN-related ceRNAs have not been investigated yet. We systematically analyzed and integrated CIN-related dysregulated ceRNAs characteristics in LUAD samples for the first time. In TCGA LUAD cohort, CIN in tumor samples was significantly higher than that in those of adjacent, and patients with high CIN risk tended to have worse clinical outcomes. We constructed a double-weighted CIN-related dysregulated ceRNA network, in which edge weight and node weight represented the disorder extent of ceRNA and the correlation of RNA expression level and prognosis, respectively. After module mining and analysis, a potential prognostic biomarker composed of 12 RNAs (8 mRNAs and 4 lncRNAs) named CIN-related dysregulated ceRNAs (CRDC) was obtained. The CRDC risk score had a positive relation with clinical stage and CIN, and patients with high CRDC risk scores exhibited poor prognosis. Moreover, CRDC tended to be an independent risk factor with high robustness to overcome the effect of multicollinearity among other explanatory variables for disease-specific survival (DSS) in TCGA and two GEO cohorts. The result of functional analysis indicated that CRDC was involved in multiple cancer progresses, especially immune-related pathways. The patients with lower CRDC risk had higher B cell, T cell CD4+, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cell infiltration than the patients with higher CRDC risk. Meanwhile, patients with lower CRDC risk could get more benefits from immunological therapy. The results suggested that the CRDC could be a potential prognostic biomarker and an immunotherapy predictor for lung adenocarcinoma.

Comprehensive Analysis of the Carcinogenic Process, Tumor Microenvironment, and Drug Response in HPV-Positive Cancers.

Human papillomavirus (HPV) is a common virus, and about 5% of all cancers worldwide is caused by persistent high-risk HPV infections. Here, we reported a comprehensive analysis of the molecular features for HPV-related cancer types using TCGA (The Cancer Genome Atlas) data with HPV status. We found that the HPV-positive cancer patients had a unique oncogenic process, tumor microenvironment, and drug response compared with HPV-negative patients. In addition, HPV improved overall survival for the four cancer types, namely, cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). The stronger activity of cell-cycle pathways and lower driver gene mutation rates were observed in HPV-positive patients, which implied the different carcinogenic processes between HPV-positive and HPV-negative groups. The increased activities of immune cells and differences in metabolic pathways helped explain the heterogeneity of prognosis between the two groups. Furthermore, we constructed HPV prediction models for different cancers by the virus infection score (VIS) which was linearly correlated with HPV load and found that VIS was associated with drug response. Altogether, our study reveals that HPV-positive cancer patients have unique molecular characteristics which help the development of precision medicine in HPV-positive cancers.

The synergistic interaction landscape of chromatin regulators reveals their epigenetic regulation mechanisms across five cancer cell lines.

Chromatin regulators (CRs) regulate the gene transcription process through combinatorial patterns, which currently remain obscure for pan-cancer. This study identified the interaction of CRs and constructed CR-CR interaction networks across five tumor cell lines. The global interaction analysis revealed that CRs tend to function in synergistically. In addition, common and specific CRs in interaction networks were identified, and the epigenetic processes of these CRs in regulating gene transcription were analyzed. Common CRs have conserved binding sites but cooperate with different partners in multiple tumor cell lines. They also participate in gene transcription regulation, through mediation of different histone modifications (HMs). Specific CRs, ATF2 and PRDM10 were found to distinguish liver cancer samples with different prognosis. PRDM10 participates in gene transcription regulation, by exertion of influence on the DNA methylation level of liver cancer. Through analysis of the edges in the CR-CR interaction networks, it was found EP300-TAF1 has genome-wide distinct signaling patterns, which exhibit different effects on downstream targets. This analysis provides novel insights for the understanding of synergistic mechanism of CRs function, as controllers of gene transcription across cancer types.

The Influence of the Different Repair Methods on the Electrical Properties of the Normally off p-GaN HEMT.

The influence of the repair process on the electrical properties of the normally off p-GaN high-electron-mobility transistor (HEMT) is studied in detail in this paper. We find that the etching process will cause the two-dimensional electron gas (2DEG) and the mobility of the p-GaN HEMT to decrease. However, the repair process will gradually recover the electrical properties. We study different repair methods and different repair conditions, propose the best repair conditions, and further fabricate the p-GaN HEMTs devices. The threshold voltage of the fabricated device is 1.6 V, the maximum gate voltage is 7 V, and the on-resistance is 23 Ω·mm. The device has a good performance, which proves that the repair conditions can be successfully applied to the fabricate of the p-GaN HEMT devices.

The Functional Characterization of Epigenetically Related lncRNAs Involved in Dysregulated CeRNA-CeRNA Networks Across Eight Cancer Types.

Numerous studies have demonstrated that lncRNAs could compete with other RNAs to bind miRNAs, as competing endogenous RNAs (ceRNAs), to regulate each other. On the other hand, ceRNAs were found to be recurrently dysregulated in cancer status. However, limited studies considered the upstream epigenetic regulatory factors that disrupted the normal competing mechanism. In the present study, we constructed the lncRNA-associated dysregulated ceRNA networks across eight cancer types. lncRNAs in the individual dysregulated network and pan-cancer core dysregulated ceRNA subnetwork were found to play more important roles than mRNAs. Integrating lncRNA methylation profiles, we identified 49 epigenetically related (ER) lncRNAs involved in the dysregulated ceRNA networks, including 18 epigenetically activated (EA) lncRNAs, 18 epigenetically silenced (ES) lncRNAs, and 13 rewired ER lncRNAs across eight cancer types. Furthermore, we evaluated the epigenetic regulating patterns of these lncRNAs and screened nine pan-cancer ER lncRNAs (six EA and three ES lncRNAs). The nine lncRNAs were found to regulate the cancer hallmarks by competing with mRNAs. Moreover, we found that integrating the expression and methylation profiles of the nine lncRNAs could predict cancer incidence in eight cancer types robustly and the cancer outcome of several cancer types. These results provide an improved understanding of methylation regulation to ceRNA and offer novel potential molecular therapeutic targets for the diagnosis and prognosis across different cancer types.

Pharmacokinetics of luteolin and tetra-acetyl-luteolin assayed by HPLC in rats after oral administration.

Accurate and reproducible HPLC methods were developed and validated for the determination of concentrations of luteolin (LT) and tetra-acetyl-luteolin (TALT) in rat plasma. HPLC analyses were performed on an Agilent TC-C(18) column protected by a guard Agilent Zorbax Eclipse Plus. The mobile phase for LT was a binary mixture of acetonitrile-water (40:60, v/v) containing 0.5% phosphoric acid at a flow rate of 1.0 mL/min, and that for TALT was a binary mixture of methanol-water (70 : 30, v/v) containing 0.5% glacial acetic acid at the same flow rate. The UV detection wavelength for both analytes was set at 350 nm. The calibration curve was linear over the range of 40-1800 ng/mL, the lower limit of quantitation was 40 ng/mL and the lower limit of detection was 20 ng/mL for both LT and TALT. The intra- and inter-day precision (RSD) values for all samples were within 7.9%. The concentration-time curves of LT and TALT after oral administration (30 mg/kg) were both fitted to a two-compartment model. The pharmacokinetic characteristics of TALT were better than that of LT in the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC).

Identification of Autophagy-Associated Biomarkers and Corresponding Regulatory Factors in the Progression of Colorectal Cancer.

Autophagy is a self-degradation process that maintains homeostasis against stress in cells. Autophagy dysfunction plays a central role in the development of tumors, such as colorectal cancer (CRC). In this study, autophagy-related differentially expressed genes, their downstream functions, and upstream regulatory factors including RNA-binding proteins (RBP) involved in programmed cell death in the CRC were investigated. Transcription factors (TFs) and miRNAs have been shown to mainly regulate autophagy genes. Interestingly, we found that some of the RBP in the CRC, such as DDX17, SETDB1, and POLR3A, play an important regulatory role in maintaining autophagy at a basal level during growth by acting as TFs that regulate autophagy. Promoter methylations showed negative regulations on differentially expressed autophagy gene (DEAG), while copy number variations revealed a positive role in them. A proportional hazards regression analysis indicated that using autophagy-related prognostic signature can divide patients into high-risk and low-risk groups. Autophagy associated FDA-approved drugs were studied by a prognostic network. This would contribute to the identifications of new potential molecular therapeutic targets for CRC.

Contributions of Gene Modules Regulated by Essential Noncoding RNA in Colon Adenocarcinoma Progression.

Noncoding RNAs (ncRNAs), especially microRNA (miRNA) and long noncoding RNA (lncRNA), have an impact on a variety of important biological processes during colon adenocarcinoma (COAD) progression. This includes chromatin organization, transcriptional and posttranscriptional regulation, and cell-cell signaling. The aim of this study is to identify the ncRNA-regulated modules that accompany the progression of COAD and to analyze their mechanisms, in order to screen the potential prognostic biomarkers for COAD. An integrative molecular analysis was carried out to identify the crosstalks of gene modules between different COAD stages, as well as the essential ncRNAs in the posttranscriptional regulation of these modules. 31 ncRNA regulatory modules were found to be significantly associated with overall survival in COAD patients. 17 out of the 31 modules (in which ncRNAs played essential roles) had improved the predictive ability for COAD patient survival compared to only the mRNAs of those modules, which were enriched in the core cancer hallmark pathways with closer interactions. These suggest that the ncRNAs' regulatory modules not only exhibit close relation to COAD progression but also reflect the dynamic significant crosstalk of genes in the modules to the different malignant extent of COAD.

Detection of deregulated pathways to lymphatic metastasis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignancy, in which lymph node metastasis is a major determinant of outcome. The pathway deregulation resulting from a large number of somatic genetic alterations in the development of the tumor, plays an important role in lymphatic metastasis process. To detect the deregulated pathways to lymphatic metastasis in OSCC, we performed pathway-oriented analysis using gene expression profile from 16 samples without lymphatic metastasis and 27 samples with lymphatic metastasis. We identified seven significantly (p < 0.05) deregulated pathways: the erythropoietin (EPO) Signaling Pathway, Signaling Pathway from G-Protein Families, Cytokine-cytokine receptor interaction, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, Ribosome, Colorectal cancer, B cell receptor signaling pathway. The biological relevance of these pathways to OSCC is the focus of ongoing studies, as well as complex interactions and crosstalk between them. These pathways might provide additional clues about factors that regulate the course for OSCC patients and might offer new opportunities for therapeutic intervention.

Expression of PIWIL2 in oral cancer and leukoplakia: Prognostic implications and insights from tumors.

PIWIL2 is a human Argonaute protein, which is guided by small RNAs to its targets, plays a role in germ cell maintenance and has been proposed to be expressed in precancerous stem cells and tumor stem cells. However, the significance of PIWIL2 expression in oral cancer and precancerous lesions has not been investigated. In this study, we analyzed the expression of the stem cell protein PIWIL2 in oral squamous-cell carcinoma (OSCC) and in premalignant oral leukoplakia (OL) with predominant expression in malignant and premalignant tissues. In the evaluated patients, we found that PIWIL2 was associated significantly with OSCC prognosis and OL. Furthermore, PIWIL2 was found to be expressed in tumor epithelial cells and macrophages in the tumor microenvironment, which are not derived from enlarged lymph nodes. Cytological experiments confirmed that the human squamous cell carcinoma cell line SCC-25, can promote the PIWIL2 and Nanog level in THP-1 cells, which are extensively used to study the modulation of monocytes and macrophages. Our findings showed that PIWIL2 can predict effectively OSCC prognosis and OL with a high risk of OSCC development and substantiate the deduction that cancer stem(-like) cells in oral cancer have the ability to reconstitute the heterogeneity of the bulk tumor and contribute to poor outcome and immunosuppression.

Imaging c-Met expression using 18F-labeled binding peptide in human cancer xenografts.

OBJECTIVES: c-Met is a receptor tyrosine kinase shown inappropriate expression and actively involved in progression and metastasis in most types of human cancer. Development of c-Met-targeted imaging and therapeutic agents would be extremely useful. Previous studies reported that c-Met-binding peptide (Met-pep1, YLFSVHWPPLKA) specifically targets c-Met receptor. Here, we evaluated 18F-labeled Met-pep1 for PET imaging of c-Met positive tumor in human head and neck squamous cell carcinoma (HNSCC) xenografted mice. METHODS: c-Met-binding peptide, Met-pep1, was synthesized and labeled with 4-nitrophenyl [18F]-2-fluoropropionate ([18F]-NPFP) ([18F]FP-Met-pep1). The cell uptake, internalization and efflux of [18F]FP-Met-pep1 were assessed in UM-SCC-22B cells. In vivo pharmacokinetics, blocking and biodistribution of the radiotracers were investigated in tumor-bearing nude mice by microPET imaging. RESULTS: The radiolabeling yield for [18F]FP-Met-pep1 was over 55% with 97% purity. [18F]FP-Met-pep1 showed high tumor uptake in UM-SCC-22B tumor-bearing mice with clear visualization. The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides. Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was also observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes. Ex vivo biodistribution showed similar results that were consistent with microPET imaging data. CONCLUSIONS: These results suggest that 18F-labeled c-Met peptide may potentially be used for imaging c-Met positive HNSCC cancer in vivo and for c-Met-targeted cancer therapy.

Hierarchical Carbon Micro/Nanonetwork with Superior Electrocatalysis for High-Rate and Endurable Vanadium Redox Flow Batteries.

Vanadium redox flow batteries (VRFBs) are receiving increasing interest in energy storage fields because of their safety and versatility. However, the electrocatalytic activity of the electrode is a pivotal factor that still restricts the power and cycling capabilities of VRFBs. Here, a hierarchical carbon micro/nanonetwork (HCN) electrode codoped with nitrogen and phosphorus is prepared for application in VRFBs by cross-linking polymerization of aniline and physic acid, and subsequent pyrolysis on graphite felt. Due to the hierarchical electron pathways and abundant heteroatom active sites, the HCN exhibits superior electrocatalysis toward the vanadium redox couples and imparts the VRFBs with an outstanding energy efficiency and extraordinary stability after 2000 cycles at 250 mA cm-2 and a discharge capacity of 10.5 mA h mL-1 at an extra-large current density of 400 mA cm-2. Such a micro/nanostructure design will force the advancement of durable and high-power VRFBs and other electrochemical energy storage devices.

Detection of dysregulated competing endogenous RNA modules associated with clear cell kidney carcinoma.

Recent evidence has suggested that competitive endogenous RNAs (ceRNAs) are important regulatory molecules in clear cell kidney carcinoma (KIRC) and their dysregulation may contribute to cancer pathogenesis. However, the critical roles of dysregulated ceRNAs in KIRC remain unknown. In the present study, a KIRC dysregulated ceRNA­ceRNA network (KDCCNet) was constructed based on the 'ceRNA hypothesis' by integrating microRNA regulation and expression profiles in cancerous and normal tissues. Two dysregulated patterns of ceRNAs interaction (gain and loss) exist in KDCCNet. The two modules, which are 95% loss interactions and 97% gain interactions, were demonstrated to be able to distinguish normal samples from cancer samples. Two long non­coding (lnc)­RNAs (glucuronidase ß pseudogene 11 and LIFR antisense RNA 1) demonstrated significant associations with KIRC prognosis. The present study of the KDCCNet revealed a novel biological mechanism for KIRC and provides novel lncRNAs as candidate prognostic biomarkers.

In situ memory T cells and patterns of invasion predict outcome in patients with early-stage oral squamous cell carcinoma.

PURPOSE: The objective of this study was to explore the prognostic value of in situ memory T cells and patterns of invasion (POI) in early stage oral squamous cell carcinoma (OSCC). METHODS: One hundred fifty-seven patients with early stage (cT1T2N0) OSCC were identified from a pre-existing database of patients with oral cancer and were classified by POI according to hematoxylin-eosin staining. We examined the impact of the immunohistochemical expression of CD45RO in OSCC. Overall survival (OS) curves were calculated using the Kaplan-Meier method. RESULTS: Margin status was significantly associated with local recurrence in early stage OSCC (p= 0.000), and depth of invasion was also associated with regional recurrence (2 mm: p= 0.034; 4 mm: p= 0.015). The expression of CD45RO (p= 0.021) and POI (p= 0.027) individually was associated with OS, and patients in the group with combination score tended to have worse OS (p= 0.012). CONCLUSION: Combined evaluation of POI and CD45RO might prove to be a useful indicator for high-risk patients with occult metastases from early stage OSCC.