Enhanced synergistic antitumor effect of a DNA vaccine with anticancer cytokine, MDA-7/IL-24, and immune checkpoint blockade

MDA-7/IL-24 cytokine has shown potent antitumor properties in various types of cancer without exerting any significant toxicity on healthy cells. It has also been proved to encompass pro-immune Th1 cytokine-like behavior. Several E7 DNA vaccines have developed against human papillomavirus (HPV)-related cervical cancer. However, the restricted immunogenicity has limited their clinical applications individually. To address this deficiency, we investigated whether combining the E7 DNA vaccine with MDA-7/IL-24 as an adjuvant would elicit efficient antitumor responses in tumor-bearing mouse models. Next, we evaluated how suppression of immunosuppressive IL-10 cytokine would enhance the outcome of our candidate adjuvant vaccine. Methods For this purpose, tumor-bearing mice received either E7 DNA vaccine, MDA-7/IL-24 cytokine or combination of E7 vaccine with MDA-7/IL-24 adjuvant one week after tumor challenge and boosted two times with one-week interval. IL-10 blockade was performed by injection of anti-IL-10 mAb before each immunization. One week after the last immunization, mice were sacrificed and the treatment efficacy was evaluated through immunological and immunohistochemical analysis. Moreover, the condition of tumors was monitored every two days for six weeks intervals from week 2 on, and the tumor volume was measured and compared within different groups. Results A highly significant synergistic relationship was observed between the E7 DNA vaccine and the MDA-7/IL-24 cytokine against HPV-16+ cervical cancer models. An increase in proliferation of lymphocytes, cytotoxicity of CD8+ T cells, the level of Th1 cytokines (IFN-γ, TNF-α) and IL-4, the level of apoptotic markers (TRAIL and caspase-9), and a decrease in the level of immunosuppressive IL-10 cytokine, together with the control of tumor growth and the induction of tumor regression, all prove the efficacy of adjuvant E7&IL-24 vaccine when compared to their individual administration. Surprisingly, vaccination with the DNA E7&IL-24 significantly reduced the population of Regulatory T cells (Treg) in the spleen of immunized mice compared to sole administration and control groups. Moreover, IL-10 blockade enhanced the effect of the co-administration by eliciting higher levels of IFN-γ and caspase-9, reducing Il-10 secretion and provoking the regression of tumor size. Conclusion The synergy between the E7 DNA vaccine and MDA-7/IL-24 suggests that DNA vaccines’ low immunogenicity can be effectively addressed by coupling them with an immunoregulatory agent. Moreover, IL-10 blockade can be considered a complementary treatment to improve the outcome of conventional or novel cancer therapies

Modeling the Urban Freight-Transportation System Using the System Dynamics Approach

The dynamic and complex interactions between the urban freight-transportation system and population, economy, traffic flow, fuel consumption, and environmental pollution, make policymaking in this system one of the fundamental challenges of urban management. In this regard, a systemic approach in urban freight-transportation system modelling should be considered to solve the problems of the system. One of the main problems of this system is the mismatch between the freight-transportation capacity and the total freight-transportation demand. Considering the lack of sufficient studies in the field of macro and quantitative modeling of this system, the main goal of this article is to model the urban freight-transportation system in order to identify the factors affecting the urban freight-transportation demand and capacity. The main focus of the research is to develop quantitative scenarios which balance the freight-transportation capacity and freight-transportation demand. The urban freight-transportation system is modelled by the System Dynamics (SD) approach and their basic behaviors; as well as this the results of some policy-making scenarios are simulated. The model is validated by the real data of Shiraz. Five quantitative scenarios are designed with two approaches of managing the freight-transportation demand and freight-transportation-capacity sectors. The scenarios are based on four control variables, including the distribution coefficient, trip numbers, vehicle capacity, and vehicle numbers. The simulation results show that the total gap between freight-transportation capacity and freight-transportation demand will decrease by optimizing each of the control variables. However, the combined scenario is the most applicable policy in order to maintain the balance between freight-transportation capacity and demand. Generally, the proposed model can be used to design different quantitative scenarios in order to optimize the freight-transportation system’s performance. This study can also help policymakers to manage the urban freight-transportation system more efficiently

Molecular interaction of fibrinogen with zeolite nanoparticles

International audienceFibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377–394), located in D-domain, showed the highest level of exposure compared to other sequences/residues