Coupled Model and Node Importance Evaluation of Electric Power Cyber-Physical Systems Considering Carbon Power Flow

To improve the distributed carbon emission optimization control capability of the smart distribution network system, thereby reducing the carbon emissions in the distribution process, it is a very important issue to comprehensively analyze the importance of the node carbon emission flow of the smart distribution network. This paper transforms the power grid into a carbon emission flow network through power flow calculations: Based on the complex network theory, it determines the coupling scale of the two networks by means of the correlation coefficient method and the correlation matrix method, and establishes a coupling network model based on the carbon emission flow network; Combining the different business characteristics of carbon emission flow and information flow, an evaluation index system considering the dual-network coupling scale is established, and a multi-indicator comprehensive evaluation method that combines the Topsis and grey relational analysis method, that can objectively evaluate indicators that contain subjective components was proposed; The obtained node importance values can be used to determine the relative key line, greater sum node importance values represent a greater carbon emission impact of the line, providing a sequential basis for the carbon reduction and restructuring of the distribution network; Taking the 3-machine 9-node system as an example, the carbon flow distribution in the corresponding network is calculated, and the comprehensive importance value of the coupling node is calculated to analyze the rationality of this method

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers

Abstract Background Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3. Methods Serum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers. Results HER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo. Conclusions In addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones

Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression

Background The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.Methods We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo.Results MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs.Conclusion These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers

FIGURE 2 from Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent “NoGlow” Mice

Mutant GFP and luciferase induce immune responses comparable with wild-type (WT) proteins. A, WT male Balb/c mice were vaccinated with Ad encoding WT or mutant copies of GFP (ΔT64; n = 5/group) and serum antibody responses were measured after 3 weeks. Mice showed equivalent anti-GFP responses whether vaccinated with WT or mutant GFP. B, WT female C57Bl/6 mice were vaccinated with Ad-GFP-Luc WT or Ad-Luc mutant (G315A; n = 5/group) and serum antibody responses were measured after 3 weeks revealing similar levels of anti-Luc antibodies. P values for A, B are at 1:50 dilution by two-way ANOVA with Tukey multiple comparisons test. C, Male WT Balb/c mice were vaccinated with Ad encoding WT or mutant GFP (ΔT64) or Luc (H245R) and anti-GFP or -Luc T-cell responses in the spleens were detected after 3 weeks via ELISpot. Both WT and mutant forms of GFP and Luc were able to elicit robust T-cell responses compared with mice naïve for the respective antigen. P values were determined by two-way ANOVA with Tukey post hoc analysis. D, E0771 GFP-Luc cells were implanted in MFPs of female WT C57Bl/6 mice and were vaccinated with Ad encoding WT GFP, mutant GFP (ΔT64), WT Luc, mutant Luc (ΔH245), or LacZ control (n = 5 per group) after three days. Compared with LacZ control vaccination, GFP WT/mutant, or Luc WT/mutant vaccines resulted in a comparable reduction in tumor growth. P values are at time of euthanasia by two-way ANOVA with Tukey multiple comparisons test. All P values represent mean ± SEM.</p

FIGURE 6 from Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent “NoGlow” Mice

NoGlow mice reveal unappreciated metastatic dynamics independent of the primary tumor. A, Tumor growth of triple transgenic (3 ×) B16-F10 cells (105) after subcutaneous implantation into the flank of WT C57Bl/6 (n = 2), CAG-driven Full-body WT GFP/Luc expressing mice (n = 3), CMV cre littermates positive (n = 8) or negative (n = 5) for the NoGlow construct, or SCID beige (n = 5) mice. B, Bioluminescence imaging of lungs at the time of euthanasia for each mouse from A. Robust signal is detected only in NoGlow+ lungs. *Indicates no detectable primary tumor at the end of experiment. C, Bioluminescence intensity of individual lungs from B. NoGlow+ lungs contained significantly more positive Luc signal than SCID, WT, or NoGlow− animals. D, Plot of tumor volume at time of euthanasia (x) by total lung radiance (y) for individual animals from A. P values were determined by one-way ANOVA with Tukey correction. All P values represent mean ± SEM.</p

FIGURE 7 from Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent “NoGlow” Mice

Summary of tumor behavior in differentially tolerant animal models. A, Xenoantigen-bearing tumor cells implanted orthotopically into immune-deficient mice typically grow and metastasize as expected and can be easily observed with fluorescence/bioluminescence. B, Conversely, in immune-competent animals the presence of foreign immunogens often results in complete rejection of the primary tumor, or severely restricts expression of immunogenic antigens and limits the utility of reporter proteins. C, However, NoGlow mice are tolerant to foreign GFP, Luciferase, and rtTA, thus allowing primary tumor growth and de novo metastasis of xenoantigen-expressing tumor cells.</p

Figure S1 from Overcoming Xenoantigen Immunity to Enable Cellular Tracking and Gene Regulation with Immune-competent “NoGlow” Mice

Additional E0771 tumor growth in WT, GH, and CAG Luc-GFP mice; MMTV CAG HER2 Ad-HER2 vaccination T cell responses.</p