Comprehensive Analysis of the Relationships Between Tumor Mutation Burden With Immune Infiltrates in Cervical Cell Carcinoma.

We aimed to investigate the prognosis of tumor mutation burden (TMB) in cervical cell carcinoma (CCC) and its potential association with tumor-infiltrating immune cells. The data from TCGA were analyzed, and higher TMB levels conferred high overall survival time, associated with higher T staging (p = 0.006) and older age (p = 2.961e-04). Through "CIBERSORT" package and Wilcoxon rank-sum test, the high TMB group exhibited higher levels of infiltration of T cell CD8 (p = 0.008), T cell CD4 memory activation (p = 0.006), T cell follicular assistance (p = 0.018), and Macrophage M1 (p = 0.037). In addition, 478 TMB-associated differentially expressed genes were identified, and two hub TMB-associated immune genes were identified, including CLEC3B and COL4A2. The TMB prognostic model (TMBPM) based on two hub immune genes showed robust prognostic capability in both training set and testing sets, and the higher the TMBPM score, the worse the prognosis. Finally, survival time was higher for high CLEC3B expression levels (p = 0.038) and lower for high COL4A2 expression levels (p = 0.033). Notably, there is an association between the expression of these two genes and immune infiltration in CCC. CLEC3B expression was most significantly positively correlated with B cells, CD4+ T cells, and Macrophage infiltration. COL4A2 expression was most significantly positively correlated with the presence of Macrophage and Dendritic cell infiltration. In addition, we observed that CLEC3B and COL4A carry mutations in multiple forms that normally suppress immune infiltration, including B cells, CD8+ T cells, and Macrophages.

Integrative bioinformatics analysis of a prognostic index and immunotherapeutic targets in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most common malignancies. The immunogenomic landscape signature significantly correlates with the progression and prognosis of RCC. Novel therapeutic targets and prognostic indices in RCC are highly desirable. The TCGA database enables comprehensive immunogenomic landscape analysis. Differentially expressed immune-related genes (IRGs) were obtained from TCGA and GO analyses, and KEGG pathway analyses were performed to explore their functions and molecular mechanisms. Multivariable Cox analysis was utilized to calculate the risk score of each patient and locate survival-associated IRGs, thereby constructing a novel immune-related gene-based prognostic index (IRGPI). The correlation between IRGPI and immune cell infiltration was also investigated. A total of 41 differentially expressed IRGs were notably related to prognosis in RCC. GO functions and KEGG pathway analyses demonstrated that these genes were primarily associated with the tumour immune response and cytokine-cytokine receptor interaction pathway. An IRGPI based on seventeen survival-associated differentially expressed IRGs was constructed and exhibited a moderate predictive value in the prognosis of RCC patients and a powerful identification ability in refining the risk stratification of RCC patients. A close correlation was found between IRGPI and specific clinicopathological parameters, including age, gender, pathological stage, tumour stage, lymph node metastasis and distant metastasis. A positive correlation was found between IRGPI and the infiltration levels of neutrophils, dendritic cells, CD8+ T cells and B cells. Our results demonstrated the clinical significance and potential function of IRGs, providing additional data for prognostic risk prediction and immunotherapeutic target selection in RCC.

Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent malignancies with high incidence and mortality. The circadian clock, which is also involved in the regulation of the immune system and tumor microenvironment, is an internal timing system that allows organisms to adjust biological processes and behaviors according to geophysical time. RESULT: A wide range of circadian clock genes are epigenetically altered in KIRC, and associated with the overall survival and disease-free survival of patients. SNV analysis revealed missense mutation and splice site to be the most common variant types of circadian clock genes in KIRC. Several circadian clock genes were involved in the regulation of some cancer-related hallmark pathways, including apoptosis and cell cycle pathway. Further, immune infiltrates analysis not only revealed that the expression of circadian clock genes is associated with immune cell infiltrates, but also that somatic copy-number alteration of circadian clock genes could inhibit the immune infiltrates. Moreover, enrichment analysis implied that the circadian clock genes could regulate transcription factor activity and circadian rhythm in KIRC. CONCLUSION: Our results demonstrate the potential of chrono-immunotherapy as a candidate option for the management of KIRC. METHOD: Multi-omics analysis was performed to comprehensively determine the roles of core circadian clock genes in KIRC.

Mining therapeutic and prognostic significance of STATs in renal cell carcinoma with bioinformatics analysis.

Renal cell carcinoma is one of the most common malignancies with high morbidity and mortality. STAT proteins play a significant role in cell biological behavior and immune response associated with cancer progression. In our study, the datasets analyzed for the expression and potential functions can be found in several bioinformatics analysis tools. We found that STAT1/2/4/6 were upregulated in RCC while STAT3/5B were downregulated. The expression of STAT2/4/5B were significantly associated with the pathological stage of RCC patients. RCC patients with high expression of STAT2/4 and low/medium expression of STAT5B had a poor overall survival. The function of STATs and the neighboring genes mainly enriched in JAK-STAT signaling pathway and NOD-like receptor signaling pathway. Several transcription factor, kinase, and miRNA targets were identified. Close correlations were obtained between immune cell infiltration and STATs in RCC. Our results have provided novel insights for the selection of immunotherapeutic targets and prognostic biomarkers.

Ultrasensitive Ebola Virus Antigen Sensing via 3D Nanoantenna Arrays.

Sensitive detection of pathogens is crucial for early disease diagnosis and quarantine, which is of tremendous need in controlling severe and fatal illness epidemics such as of Ebola virus (EBOV) disease. Serology assays can detect EBOV-specific antigens and antibodies cost-effectively without sophisticated equipment; however, they are less sensitive than reverse transcriptase polymerase chain reaction (RT-PCR) tests. Herein, a 3D plasmonic nanoantenna assay sensor is developed as an on-chip immunoassay platform for ultrasensitive detection of Ebola virus (EBOV) antigens. The EBOV sensor exhibits substantial fluorescence intensity enhancement in immunoassays compared to flat gold substrate. The nanoantenna-based biosensor successfully detects EBOV soluble glycoprotein (sGP) in human plasma down to 220 fg mL-1 , a significant 240 000-fold sensitivity improvement compared to the 53 ng mL-1 EBOV antigen detection limit of the existing rapid EBOV immunoassay. In a mock clinical trial, the sensor detects sGP-spiked human plasma samples at two times the limit of detection with 95.8% sensitivity. The results combined highlight the nanosensor's extraordinary capability of detecting EBOV antigen at ultralow concentration compared to existing immunoassay methods. It is a promising next-generation bioassay platform for early-stage disease diagnosis and pathogen detection for both public health and national security applications.

Enhancement and electric charge-assisted tuning of nonlinear light generation in bipolar plasmonics.

We propose and experimentally demonstrate a new plasmonic nonlinear light generation (NLG) structure, termed plasmonic-enhanced, charge-assisted second-harmonic generator (p-CASH), that not only achieves high second-harmonic generation (SHG) enhancement (76-fold), large SHG tunability by bias (8%/V), wide tuning range (280%), 7.8 × 10(-9) conversion efficiency, and high stability but also exhibits a SHG tuning, that is bipolar rather than unipolar, not due to the third-order nonlinear polarization term, hence fundamentally different from the classic electric field induced SHG-tuning (EFISH). We propose a new SHG tuning mechanism: the second-order nonlinear polarization term enhanced by plasmonic effects, changed by charge injection and negative oxygen vacancies movement, and is nearly 3 orders of magnitude larger than EFISH. p-CASH is a bipolar parallel-plate capacitor with thin layers of plasmonic nanostructures, a TiOx (semiconductor and nonlinear) and a SiO2 (insulator) sandwiched between two electrodes. Fabrication of p-CASH used nanoimprint on 4″ wafer and is scalable to wallpaper-sized areas. The new structure, new properties, and new understanding should open up various new designs and applications of NLG in various fields.

Enhancement of immunoassay's fluorescence and detection sensitivity using three-dimensional plasmonic nano-antenna-dots array.

Protein detection is universal and vital in biological study and medical diagnosis (e.g., cancer detection). Fluorescent immunoassay is one of the most widely used and most sensitive methods in protein detection (Giljohann, D. A.; Mirkin, C. A. Nature2009, 462, 461-464; Yager, P.; et al. Nature2006, 442, 412-418). Improvements of such assays have many significant implications. Here, we report the use of a new plasmonic structure and a molecular spacer to enhance the average fluorescence of an immunoassay of Protein A and human immunoglobulin G (IgG) by over 7400-fold and the immunoassay's detection sensitivity by 3,000,000-fold (the limit of detection is reduced from 0.9 × 10(-9) to 0.3 × 10(-15) molar (i.e., from 0.9 nM to 300 aM), compared to identical assays performed on glass plates). Furthermore, the average fluorescence enhancement has a dynamic range of 8 orders of magnitude and is uniform over the entire large sample area with a spatial variation ±9%. Additionally, we observed that, when a single molecule fluorophore is placed at a "hot spot" of the plasmonic structure, its fluorescence is enhanced by 4 × 10(6)-fold, thus indicating the potential to further significantly increase the average fluorescence enhancement and the detection sensitivity. Together with good spatial uniformity, wide dynamic range, and ease to manufacture, the giant enhancement in immunoassay's fluorescence and detection sensitivity (orders of magnitude higher than previously reported) should open up broad applications in biology study, medical diagnosis, and others.

Direct near-field optical imaging of UV bowtie nanoantennas.

We report near-field optical imaging of bowtie nanoantennas obtained using a UV near-field scanning optical microscope (NSOM). A strong and highly localized UV intensity profile was observed at the antenna gap due to the localized surface plasmon resonance. The relationship of optical field enhancement and antenna size is discussed based on numerical simulations and NSOM experiments.

Direct mapping of the UV surface plasmons.

Researchers employed various well-developed concepts from conventional optics in designing novel plasmonic devices, which allow us to construct a framework to describe the propagation, diffraction, and interference of surface plasmon polaritons (SPPs) on a chip. Here we present what we believe to be the first direct mapping of the UV SPPs on an Al2O3/Al surface using a UV-compatible near-field scanning optical microscope system. UV SPP modes launched by one-dimensional slits or two-dimensional groove arrays and corresponding interference phenomenon were both observed, which may enrich the studies on subwavelength optics on a chip.