Abstract Systemic chemotherapy given at maximum tolerated doses (MTD) has been the mainstay of cancer treatment for more than half a century. In some chemosensitive diseases such as hematologic ...malignancies and solid tumors, MTD has led to complete remission and even cure. The combination of maintenance therapy and standard MTD also can generate good disease control; however, resistance to chemotherapy and disease metastasis still remain major obstacles to successful cancer treatment in the majority of advanced tumors. Metronomic chemotherapy, defined as frequent administration of chemotherapeutic agents at a non-toxic dose without extended rest periods, was originally designed to overcome drug resistance by shifting the therapeutic target from tumor cells to tumor endothelial cells. Metronomic chemotherapy also exerts anti-tumor effects on the immune system (immunomodulation) and tumor cells. The goal of immunotherapy is to enhance host anti-tumor immunities. Adding immunomodulators such as metronomic chemotherapy to immunotherapy can improve the clinical outcomes in a synergistic manner. Here, we review the anti-tumor mechanisms of metronomic chemotherapy and the preliminary research addressing the combination of immunotherapy and metronomic chemotherapy for cancer treatment in animal models and in clinical setting.
Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes (ATG). Autophagy is a "double-edged ...sword" in tumors. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy. Therapies aiming at autophagy to enhance the immune responses and anti-tumor effects of immunotherapy have become the prospective strategy, with enhanced antigen presentation and higher sensitivity to CTLs. However, the induction of autophagy may also benefit tumor cells escape from immune surveillance and result in intrinsic resistance against anti-tumor immunotherapy. Increasing studies have proven the optimal use of either ATG inducers or inhibitors can restrain tumor growth and progression by enhancing anti-tumor immune responses and overcoming the anti-tumor immune resistance in combination with several immunotherapeutic strategies, indicating that induction or inhibition of autophagy might show us a prospective therapeutic strategy when combined with immunotherapy. In this article, the possible mechanisms of autophagy regulating immune system, and the potential applications of autophagy in tumor immunotherapy will be discussed.
Maslinic acid is a pentacyclic triterpenoid that is distributed in the peel of olives. Previous studies found that maslinic acid inhibited inflammatory response and antioxidant effects. We ...investigated whether maslinic acid ameliorates nonalcoholic fatty liver disease in mice with high‐fat‐diet (HFD)‐induced obesity and evaluated the regulation of lipogenesis in hepatocytes. Male C57BL/6 mice fed a normal diet or HFD (60% fat, w/w) were tested for 16 wk. After the fourth week, mice were injected intraperitoneally with maslinic acid for 12 wk. In another experiment, HepG2 cells were treated with oleic acid to induce lipid accumulation or maslinic acid to evaluate lipogenesis. Maslinic acid significantly reduced body weight compared with HFD‐fed mice. Maslinic acid reduced liver weight and liver lipid accumulation and improved hepatocyte steatosis. Furthermore, serum glucose, leptin, and free fatty acid concentrations significantly reduced, but the serum adiponectin concentration was higher, in the maslinic acid group than in the HFD group. In liver tissue, maslinic acid suppressed transcription factors involved in lipogenesis and increased adipose triglyceride lipase. In vitro, maslinic acid decreased lipogenesis by activating AMPK. These findings suggest that maslinic acid acts against hepatic steatosis by regulating enzyme activity involved in lipogenesis, lipolysis, and fatty acid oxidation in the liver.—Liou, C.‐J., Dai, Y.‐W., Wang, C.‐L., Fang, L.‐W., Huang, W.‐C. Maslinic acid protects against obesity‐induced nonalcoholic fatty liver disease in mice through regulation of the Sirt1/AMPK signaling pathway. FASEB J. 33, 11791‐11803 (2019). www.fasebj.org
•Thermal conductivity of PU foam is measured under various environments by TPS method.•Spectral extinction coefficient of PU foam is measured by FTIR.•Thermal conductivity of PU foam increases ...non-monotonically with temperature.•Thermal conductivity of PU foam increases as high as 10–18% in moist air.•Radiative thermal conductivity of PU foam can be calculated by Rosseland model.
Polyurethane foams are widely used in energy conservation field and thermal conductivity is one of the most important properties. To reveal and optimize the thermal insulation performance of PU foams, the thermal conductivity of five PU foam samples formed by blowing agents of CP, CP+IP, CP+245fa and CP+245fa+LBA are measured using transient plane source method under various environment. Influences of temperature, humidity, water uptake, alternate high and low temperature, long time storage at high temperature and gas pressure of the atmosphere on the thermal conductivity of PU forms are investigated comprehensively. The mechanism of temperature that affects the thermal conductivity of PU foams is discussed. Fourier transform infrared spectroscopy is adopted to measure the spectral extinction coefficients of these five samples. With the spectral extinction coefficient, the radiative thermal conductivity is calculated from Rosseland model. Then the contributions of radiative heat transfer to the effective thermal conductivity are decomposed. The thermal conductivity of five foams increases non-monotonically with temperature. When stored in moist air, thermal conductivity can increase as high as 10–18%. Radiative thermal conductivity contributes 3.6–4.1% at −40°C, 7.3–9.0% at 20°C and 9.1–11.8% at 70°C to the effective thermal conductivity.
Although immune cell therapy has long been used for treating solid cancer, its efficacy remains limited. Interferon (IFN)-producing killer dendritic cells (IKDCs) exhibit cytotoxicity and present ...antigens to relevant cells; thus, they can selectively induce tumor-associated antigen (TAA)-specific CD8 T cells and may be useful in cancer treatment. Various protocols have been used to amplify human IKDCs from peripheral sources, but the complexity of the process has prevented their widespread clinical application. Additionally, the induction of TAA-specific CD8 T cells through the adoptive transfer of IKDCs to immunocompromised patients with cancer may be insufficient. Therefore, we developed a method for generating an immune cell-based regimen, Phyduxon-T, comprising a human IKDC counterpart (Phyduxon) and expanded TAA-specific CD8 T cells.
Peripheral blood mononuclear cells from ovarian cancer patients were cultured with human interleukin (hIL)-15, hIL-12, and hIL-18 to generate Phyduxon-T. Then, its phenotype, cytotoxicity, and antigen-presenting function were evaluated through flow cytometry using specific monoclonal antibodies.
Phyduxon exhibited the characteristics of both natural killer and dendritic cells. This regimen also exhibited cytotoxicity against primary ovarian cancer cells and presented TAAs, thereby inducing TAA-specific CD8 T cells, as evidenced by the expression of 4-1BB and IFN-γ. Notably, the Phyduxon-T manufacturing protocol effectively expanded IFN-γ-producing 4-1BB
TAA-specific CD8 T cells from peripheral sources; these cells exhibited cytotoxic activities against ovarian cancer cells.
Phyduxon-T, which is a combination of natural killer cells, dendritic cells, and TAA-specific CD8 T cells, may enhance the efficacy of cancer immunotherapy.
Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. ...Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.
Internet of things (IoT) is one of the most emerging technologies nowadays and it is one of the key enablers of industrial cyber physical system (CPSs). It has started to participate in almost every ...aspect of our social life, ranging from financial transactions to the healthcare system, communication to national security, battlefield to smart homes, and so on. However, the wide deployment of IoT suffers certain issues as well, such as interoperability, compatibility, heterogeneity, large amount of data, processing of heterogeneous data etc. Among others, energy efficiency and security are the utmost prominent issues. Scarce computing resources of IoT devices put hindrances on information sharing across edge or IoT network. Indeed, unintentional or malicious interference with IoT data may lead to severe concerns. In this study, the researcher exploits the potential benefits of a blockchain system and integrates it with software-defined networking (SDN) while justifying energy and security issues. More in detail, the researcher proposed a new routing protocol with the cluster structure for IoT networks using blockchain-based architecture for SDN controller. The proposed architecture obviates proof-of-work (PoW) with private and public blockchains for Peer-to-Peer (P2P) communication between SDN controllers and IoT devices. In addition to this, distributed trust-based authentication mechanism makes blockchain even more adoptive for IoT devices with limited resources. The experimental results show that the proposed cluster structure based routing protocol outperforms the state-of-the-art Ad-hoc On-demand Distance Vector (AODV), Destination-Sequenced Distance Vector (DSDV), Secure Mobile Sensor Network (SMSN), Energy efficient secured cluster based distributed fault diagnosis (EESCFD), and Ad-hoc On-demand Multipath Distance Vector (AOMDV), in terms of energy consumption, network throughput, and packet latency. Proposed protocol help overcome the issues especially, energy management and security of the next generation industrial cyber physical systems.
Rapid and accurate detection of SARS-CoV-2 infection is the cornerstone of prompt patient care. However, the reliability of the antigen rapid diagnostic test (Ag-RDT) in the diagnosis of SARS-CoV-2 ...infection remains inconclusive. We conducted a field evaluation of Ag-RDT performance during the Shanghai Coronavirus disease 2019 (COVID-19) quarantine and screened 7225 individuals visiting our Emergency Department. 83 asymptomatic SARS-CoV-2 (+) individuals were enrolled in the current study. Simultaneously, Ag-RDT was performed to evaluate its testing performance. For the Ag-RDT(-) cases, the average cycle threshold (Ct) values of the N gene were 27.26 + or - 4.59, which were significantly higher than the Ct value (21.9 + or - 4.73) of the Ag-RDT(+) individuals (p < 0.0001). The overall sensitivity of Ag-RDT versus that of RT-PCR was 43.37%. The Ag-RDT(+) individuals regarding the N gene's Ct value were 16 cases in the < 20 range, 12 in 20-25, 5 in 25-30, and 3 in 30-35. The corresponding sensitivity was 84.21%, 52.17%, 21.74% and 16.67%, respectively. Meanwhile, sampling had a straight specificity of 100% regardless of the Ct value. The Ag-RDT were extremely sensitive in asymptomatic COVID-19 individuals with a Ct value < 20.
Background
Signet ring cell adenocarcinoma is a histological classification based on the WHO classification. The presence of this specific histological type is associated with a worse pathological ...appearance. The prognosis of signet ring cell adenocarcinoma in gastric cancer patients after curative surgery is still under debate.
Methods
From January 1988 to December 2012, a total of 2971 patients, including 819 early and 2152 advanced gastric cancer patients underwent curative resection for gastric cancer. Among them, there were 185 cases of signet ring cell adenocarcinoma in early gastric cancer patients, while there were 570 cases in advanced gastric cancer patients.
Results
The overall incidence of signet ring cell adenocarcinoma was 25.4%. Our results showed that the 5-year overall survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 90.7 and 83.2%, respectively (
P
= 0.001). The 5-year disease-free survival rates of early gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 87.4 and 81.6%, respectively (
P
= 0.003). The 5-year overall survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 32.1 and 37.9%, respectively (
P
= 0.041). The 5-year disease-free survival rates of advanced gastric cancer patients with signet ring cell adenocarcinoma and non-signet ring cell adenocarcinoma were 28.6 and 35.2%, respectively (
P
= 0.037). Signet ring cell adenocarcinoma was an independent predictor for overall survival in advanced gastric cancer (
P
= 0.017).
Conclusion
The clinical features and prognosis of signet ring cell adenocarcinoma are different between early and advanced gastric cancer. Signet ring cell adenocarcinoma is a poor prognostic factor in advanced gastric cancer after curative resection.
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