Molecular Mechanisms in Clear Cell Renal Cell Carcinoma: Role of miRNAs and Hypermethylated miRNA Genes in Crucial Oncogenic Pathways and Processes

Clear cell renal cell carcinoma (ccRCC) is the third most common urological cancer, and it has the highest mortality rate. The increasing drug resistance of metastatic ccRCC has resulted in the search for new biomarkers. Epigenetic regulatory mechanisms, such as genome-wide DNA methylation and inhibition of protein translation by interaction of microRNA (miRNA) with its target messenger RNA (mRNA), are deeply involved in the pathogenesis of human cancers, including ccRCC, and may be used in its diagnosis and prognosis. Here, we review oncogenic and oncosuppressive miRNAs, their putative target genes, and the crucial pathways they are involved in. The contradictory behavior of a number of miRNAs, such as suppressive and anti-metastatic miRNAs with oncogenic potential (for example, miR-99a, miR-106a, miR-125b, miR-144, miR-203, miR-378), is examined. miRNAs that contribute mostly to important pathways and processes in ccRCC, for instance, PI3K/AKT/mTOR, Wnt-β, histone modification, and chromatin remodeling, are discussed in detail. We also separately consider their participation in crucial oncogenic processes, such as hypoxia and angiogenesis, metastasis, and epithelial-mesenchymal transition (EMT). The review also considers the interactions of long non-coding RNAs (lncRNAs) and miRNAs of significance in ccRCC. Recent advances in the understanding of the role of hypermethylated miRNA genes in ccRCC and their usefulness as biomarkers are reviewed based on our own data and those available in the literature. Finally, new data and perspectives concerning the clinical applications of miRNAs in the diagnosis, prognosis, and treatment of ccRCC are discussed

HiCIRF: a high-fidelity HF channel simulation

A high-fidelity HF channel simulation has been developed that is suitable for Over-the-Horizon Radar (OTHR) and HF communication system design studies and test planning. The simulation capability is called HiCIRF, for High-frequency Channel Impulse Response Function. HiCIRF provides simulated HF signals corresponding to transmissions from individual transmitter array elements to individual receiver array elements for propagation through the naturally disturbed or undisturbed ionospheric channel. Both one-way link geometries and two-way radar geometries can be simulated. HiCIRF incorporates numerical ray tracing and stochastic signal structure computations to realistically simulate signal scatter by small-scale ionization structure. Stochastic signal generation is employed to generate signal realizations that can be used for OTHR array design and advanced signal processing studies.L.J. Nickisch, Gavin St. John, Sergey V. Fridman, Mark A. Hausman and C.J. Colema

HiCIRF: a high-fidelity HF channel simulation

A high-fidelity HF channel simulation has been developed that is suitable for Over-the-Horizon Radar (OTHR) and HF communication system design studies and test planning. The simulation capability is called HiCIRF, for High-frequency Channel Impulse Response Function. HiCIRF provides simulated HF signals corresponding to transmissions from individual transmitter array elements to individual receiver array elements for propagation through the naturally disturbed or undisturbed ionospheric channel. Both one-way link geometries and two-way radar geometries can be simulated. HiCIRF incorporates numerical ray tracing and stochastic signal structure computations to realistically simulate signal scatter by small-scale ionization structure. Stochastic signal generation is employed to generate signal realizations that can be used for OTHR array design and advanced signal processing studies.L.J. Nickisch, Gavin St. John, Sergey V. Fridman, Mark A. Hausman and C.J. Colema

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Pulsed Corona Plasma Technology for Treating VOC Emissions from Pulp Mills

ABSTRACT Under the DOE Office of Industrial Technologies Forest Products program various plasma technologies were evaluated under project FWP 49885 &quot;Experimental Assessment of Low-Temperature Plasma Technologies for Treating Volatile Organic Compound Emissions from Pulp Mills and Wood Products Plants&quot;. The heterogeneous pulsed corona discharge was chosen as the best non-equilibrium plasma technology for control of the vent emissions from HVLC Brownstock Washers. The technology for removal of Volatile Organic Compounds (VOCs) from gas emissions with conditions typical of the exhausts of the paper industry by means of pulsed corona plasma techniques presented in this work. For the compounds of interest in this study (methanol, acetone, dimethyl sulfide and α -pinene), high removal efficiencies were obtained with power levels competitive with the present technologies for the VOCs removal. Laboratory experiments were made using installation with the average power up to 20 W. Pilot plant prepared for on-site test has average plasma power up to 6.4 kW. The model of the Pilot Plant operation is presented

Pulsed Corona Plasma Technology for Treating VOC Emissions from Pulp Mills

Under the DOE Office of Industrial Technologies Forest Products program various plasma technologies were evaluated under project FWP 49885 ''Experimental Assessment of Low-Temperature Plasma Technologies for Treating Volatile Organic Compound Emissions from Pulp Mills and Wood Products Plants''. The heterogeneous pulsed corona discharge was chosen as the best non-equilibrium plasma technology for control of the vent emissions from HVLC Brownstock Washers. The technology for removal of Volatile Organic Compounds (VOCs) from gas emissions with conditions typical of the exhausts of the paper industry by means of pulsed corona plasma techniques presented in this work. For the compounds of interest in this study (methanol, acetone, dimethyl sulfide and ? -pinene), high removal efficiencies were obtained with power levels competitive with the present technologies for the VOCs removal. Laboratory experiments were made using installation with the average power up to 20 W. Pilot plant prepared for on-site test has average plasma power up to 6.4 kW. The model of the Pilot Plant operation is presented

LncRNAs in the Regulation of Genes and Signaling Pathways through miRNA-Mediated and Other Mechanisms in Clear Cell Renal Cell Carcinoma

The fundamental novelty in the pathogenesis of renal cell carcinoma (RCC) was discovered as a result of the recent identification of the role of long non-coding RNAs (lncRNAs). Here, we discuss several mechanisms for the dysregulation of the expression of protein-coding genes initiated by lncRNAs in the most common and aggressive type of kidney cancer—clear cell RCC (ccRCC). A model of competitive endogenous RNA (ceRNA) is considered, in which lncRNA acts on genes through the lncRNA/miRNA/mRNA axis. For the most studied oncogenic lncRNAs, such as HOTAIR, MALAT1, and TUG1, several regulatory axes were identified in ccRCC, demonstrating a number of sites for various miRNAs. Interestingly, the LINC00973/miR-7109/Siglec-15 axis represents a novel agent that can suppress the immune response in patients with ccRCC, serving as a valuable target in addition to the PD1/PD-L1 pathway. Other mechanisms of action of lncRNAs in ccRCC, involving direct binding with proteins, mRNAs, and genes/DNA, are also considered. Our review briefly highlights methods by which various mechanisms of action of lncRNAs were verified. We pay special attention to protein targets and signaling pathways with which lncRNAs are associated in ccRCC. Thus, these new data on the different mechanisms of lncRNA functioning provide a novel basis for understanding the pathogenesis of ccRCC and the identification of new prognostic markers and targets for therapy