Good Cop, Bad Cop: The Opposing Effects of Macrophage Activation State on Maintaining or Damaging Functional ß-Cell Mass.

Loss of functional ß-cell mass is a hallmark of Type 1 and Type 2 Diabetes. Macrophages play an integral role in the maintenance or destruction of pancreatic ß-cells. The effect of the macrophage ß-cell interaction is dependent on the activation state of the macrophage. Macrophages can be activated across a spectrum, from pro-inflammatory to anti-inflammatory and tissue remodeling. The factors secreted by these differentially activated macrophages and their effect on ß-cells define the effect on functional ß-cell mass. In this review, the spectrum of macrophage activation is discussed, as are the positive and negative effects on ß-cell survival, expansion, and function as well as the defined factors released from macrophages that impinge on functional ß-cell mass.

Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers.

Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01).Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845-56. ©2018 AACR.

Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-α (TNFα) plays a critical role. Etanercept, a recombinant fusion protein of human soluble tumor necrosis factor receptor II (hsTNFR) linked to the Fc portion of human IgG1, is used to treat RA based on the rationale that sTNFR binds TNFα and blocks TNFα-mediated inflammation. We compared hsTNFR protein delivery from genetically engineered human mesenchymal stem cells (hMSCs) with etanercept. Blocking TNFα-dependent intercellular adhesion molecule-1 expression on transduced hMSCs and inhibition of nitric oxide production from TNFα-treated bovine chondrocytes by conditioned culture media from transduced hMSCs demonstrated the functionality of the hsTNFR construction. Implanted hsTNFR-transduced mesenchymal stem cells (MSCs) reduced mouse serum circulating TNFα generated from either implanted TNFα-expressing cells or lipopolysaccharide induction more effectively than etanercept (TNFα, 100%; interleukin [IL]-1α, 90%; and IL-6, 60% within 6 hours), suggesting faster clearance of the soluble tumor necrosis factor receptor (sTNFR)-TNFα complex from the animals. In vivo efficacy of sTNFR-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the antibody-induced arthritis BalbC/SCID mouse model, intramuscular injection of hsTNFR-transduced hMSCs reduced joint inflammation by 90% compared with untransduced hMSCs; in the collagen-induced arthritis Fischer rat model, both sTNFR-transduced rat MSCs and etanercept inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not interferon γ, to inhibit hMSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data support the utility of hMSCs as therapeutic gene delivery vehicles and their potential to be used in alleviating inflammation within the arthritic joint.

Particle-in-Cell (PIC) simulation of CW industrial heating magnetron.

Modern CW industrial heating magnetrons are capable for producing as high as 300 kW of continuous-wave microwave power at frequencies around 900 MHz and are sold commercially [Wynn et al., 2004]. However, to utilize these magnetrons in some specific research and scientific applications being of interest for the Air Force, the necessary adaptation and redesign are required. It means that the detailed knowledge of principles of their operation and full understanding of how the changes of the design parameters affect their operational characteristics are necessary. We have developed and tested computer model of a 10-vane high-power strapped magnetron, which geometrical dimensions and design parameters are close to those of the California Tube Laboratory's commercially produced CWM-75/100L tube. The computer model is built by using the 3-D Improved Concurrent Electromagnetic Particle-in-Cell (ICEPIC) code. Simulations of the strapped magnetron operation are performed and the following operational characteristics are obtained during the simulation: frequency and mode of magnetron oscillations, output microwave power and efficiency of magnetron operation, anode current and anode-cathode voltage dynamics. The developed computer model of a non-relativistic high-power strapped magnetron may be used by the industrial magnetron community for designing following generations of the CW industrial heating high-power magnetrons.