IGSF8 is an innate immune checkpoint and cancer immunotherapy target.

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.

E3 ubiquitin ligase mind bomb 1 overexpression reduces apoptosis and inflammation of cardiac microvascular endothelial cells in coronary microvascular dysfunction.

BACKGROUND: The apoptosis and inflammation in cardiac microvascular endothelial cells (CMECs) promote the development of coronary microvascular dysfunction (CMD). The present study aimed to explore the role of E3 ubiquitin ligase mind bomb 1 (MIB1) in the apoptosis and inflammation in CMECs during CMD. METHODS: In vivo, CMD in rats was induced by sodium laurate injection. In vitro, rat primary CMECs were stimulated by homocysteine (Hcy). The apoptosis of CMECs was measured using flow cytometry. The inflammation of CMECs was evaluated by the level of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). The interplay between MIB1 and mitogen-activated protein kinase kinase kinase 5 (map3k5, also called ASK1) was measured using Co-immunoprecipitation. RESULTS: MIB1 expression was decreased and ASK1 expression was increased in the heart tissues of CMD rats and Hcy-treated CMECs. MIB1 overexpression decreased fibrinogen-like protein 2 (FGL2) secretion, inflammation, and apoptosis induced by Hcy in CMECs. Meanwhile, MIB1 overexpression decreased the protein levels of ASK1 and p38, while not affected ASK1 mRNA levels. The following mechanism experiments revealed that MIB1 downregulated ASK1 expression by increasing its ubiquitination. ASK1 overexpression reversed the inhibitory effect of MIB1 on FGL2 secretion, apoptosis, inflammation, and p38 activation in Hcy-treated CMECs. In CMD rats, MIB1 overexpression partly retarded CMD progression, manifesting as increased coronary capillary density and decreased microthrombi formation. CONCLUSION: MIB1 overexpression relieved apoptosis and inflammation of CMECs during CMD by targeting the ASK1/p38 pathway.

Effectiveness of a Cloud-Based Telepathology System in China: Large-Sample Observational Study.

BACKGROUND: Whole-slide imaging allows the entire slide to be viewed in a manner that simulates microscopy; therefore, it is widely used in telepathology. However, managing the large digital files needed for whole-slide imaging is difficult. To solve this problem, we set up the Chinese National Cloud-Based Telepathology System (CNCTPS). CNCTPS has been running for more than 4 years and has accumulated a large amount of data. OBJECTIVE: The main purpose of this study was to comprehensively evaluate the effectiveness of the CNCTPS based on a large sample. The evaluation indicators included service volume, turnaround time, diagnosis accuracy, and economic benefits. METHODS: Details of 23,167 cases submitted to the CNCTPS from January 2016 to December 2019 were collected to analyze the service volume, turnaround time, and economic benefits. A total of 564 patients who visited the First Affiliated Hospital of Zhengzhou University and obtained final diagnoses were followed up to analyze the diagnostic accuracy of the CNCTPS. RESULTS: From 2016 to 2019, the service volume of the CNCTPS increased from 2335 to 9240, and the number of participating hospitals increased from 60 to 74. Consultation requests from county-level hospitals accounted for 86.57% (20,287/23,167). A total of 17,495 of 23,167 cases (75.52%) were confirmed, including 12,088 benign lesions, 5217 malignant lesions, and 190 borderline lesions. Of the cases, 3.85% (893/23,167) failed to be diagnosed for reasons such as poor slice quality and incomplete sampling. The median turnaround time was 16.93 hours and was shortened yearly (between 2018 and 2019: adjusted P=.01; other groups: adjusted P<.001); 82.88% cases were diagnosed in 48 hours. There was a discrepancy between the diagnosis and final diagnosis for 11 cases, including 4 false-positive cases and 7 false-negative cases. The sensitivity and specificity were 97.66% and 98.49%, respectively. The diagnostic accuracy of the system was 98.05%, with no statistical difference from the final diagnosis in the hospital (P=.55). By using this system, a total of US $300,000 was saved for patients every year. CONCLUSIONS: The novel cloud-based telepathology system has the potential to relieve the shortage of pathologists in primary hospitals. It can also simultaneously reduce medical costs for patients in China. It should, therefore, be further promoted to enhance the efficiency, quantity, and quality of telepathology diagnoses.

Greenhouse gas emissions reduction in different economic sectors: Mitigation measures, health co-benefits, knowledge gaps, and policy implications.

To date, greenhouse gas (GHG) emissions, mitigation strategies and the accompanying health co-benefits in different economic sectors have not been fully investigated. The purpose of this paper is to review comprehensively the evidence on GHG mitigation measures and the related health co-benefits, identify knowledge gaps, and provide recommendations to promote further development and implementation of climate change response policies. Evidence on GHG emissions, abatement measures and related health co-benefits has been observed at regional, national and global levels, involving both low- and high-income societies. GHG mitigation actions have mainly been taken in five sectors: energy generation, transport, food and agriculture, household and industry, consistent with the main sources of GHG emissions. GHGs and air pollutants to a large extent stem from the same sources and are inseparable in terms of their atmospheric evolution and effects on ecosystem; thus, GHG reductions are usually, although not always, estimated to have cost effective co-benefits for public health. Some integrated mitigation strategies involving multiple sectors, which tend to create greater health benefits. The pros and cons of different mitigation measures, issues with existing knowledge, priorities for research, and potential policy implications were also discussed. Findings from this study can play a role not only in motivating large GHG emitters to make decisive changes in GHG emissions, but also in facilitating cooperation at international, national and regional levels, to promote GHG mitigation policies that protect public health from climate change and air pollution simultaneously.

Public health co-benefits of greenhouse gas emissions reduction: A systematic review.

BACKGROUND AND OBJECTIVES: Public health co-benefits from curbing climate change can make greenhouse gas (GHG) mitigation strategies more attractive and increase their implementation. The purpose of this systematic review is to summarize the evidence of these health co-benefits to improve our understanding of the mitigation measures involved, potential mechanisms, and relevant uncertainties. METHODS: A comprehensive search for peer-reviewed studies published in English was conducted using the primary electronic databases. Reference lists from these articles were reviewed and manual searches were performed to supplement relevant studies. The identified records were screened based on inclusion criteria. We extracted data from the final retrieved papers using a pre-designed data extraction form and a quality assessment was conducted. The studies were heterogeneities, so meta-analysis was not possible and instead evidence was synthesized using narrative summaries. RESULTS: Thirty-six studies were identified. We identified GHG mitigation strategies in five domains - energy generation, transportation, food and agriculture, households, and industry and economy - which usually, although not always, bring co-benefits for public health. These health gains are likely to be multiplied by comprehensive measures that include more than one sectors. CONCLUSIONS: GHG mitigation strategies can bring about substantial and possibly cost-effective public health co-benefits. These findings are highly relevant to policy makers and other stakeholders since they point to the compounding value of taking concerted action against climate change and air pollution.

Perceptions of Health Co-Benefits in Relation to Greenhouse Gas Emission Reductions: A Survey among Urban Residents in Three Chinese Cities.

Limited information is available on the perceptions of stakeholders concerning the health co-benefits of greenhouse gas (GHG) emission reductions. The purpose of this study was to investigate the perceptions of urban residents on the health co-benefits involving GHG abatement and related influencing factors in three cities in China. Beijing, Ningbo and Guangzhou were selected for this survey. Participants were recruited from randomly chosen committees, following quotas for gender and age in proportion to the respective population shares. Chi-square or Fisher's exact tests were employed to examine the associations between socio-demographic variables and individuals' perceptions of the health co-benefits related to GHG mitigation. Unconditional logistic regression analysis was performed to investigate the influencing factors of respondents' awareness about the health co-benefits. A total of 1159 participants were included in the final analysis, of which 15.9% reported that they were familiar with the health co-benefits of GHG emission reductions. Those who were younger, more educated, with higher family income, and with registered urban residence, were more likely to be aware of health co-benefits. Age, attitudes toward air pollution and governmental efforts to improve air quality, suffering from respiratory diseases, and following low carbon lifestyles are significant predictors of respondents' perceptions on the health co-benefits. These findings may not only provide information to policy-makers to develop and implement public welcome policies of GHG mitigation, but also help to bridge the gap between GHG mitigation measures and public engagement as well as willingness to change health-related behaviors.

Haze, public health and mitigation measures in China: A review of the current evidence for further policy response.

With rapid economic development, China has been plagued by choking air pollution in recent years, and the frequent occurrence of haze episodes has caused widespread public concern. The purpose of this study is to describe the sources and formation of haze, summarize the mitigation measures in force, review the relationship between haze pollution and public health, and to discuss the challenges, potential research directions and policy options. Haze pollution has both natural and man-made causes, though it is anthropogenic sources that are the major contributors. Accumulation of air pollutants, secondary formation of aerosols, stagnant meteorological conditions, and trans-boundary transportation of pollutants are the principal causes driving the formation and evolution of haze. In China, haze includes gaseous pollutants and fine particles, of which PM2.5 is the dominant component. Short and long-term exposure to haze pollution are associated with a range of negative health outcomes, including respiratory diseases, cardiovascular and cerebrovascular diseases, mental health problems, lung cancer and premature death. China has paid increasing attention to the improvement of air quality, and has introduced action plans and policies to tackle pollution, but many interventions have only temporary effects. There may be fierce resistance from industry groups and some government agencies, and often it is challenging to enforce relevant control measures and laws. We discuss the potential policy options for prevention, the need for wider public dialogue and the implications for scientific research.

Effect of the calcium sensing receptor on rat bone marrow-derived mesenchymal stem cell proliferation through the ERK1/2 pathway.

Migration and proliferation of bone marrowderived mesenchymal stem cells (BMSCs) is critical to treatment of ischemic injury. The calcium sensing receptor (CaSR) has an important role in maintaining systemic calcium homeostasis, which is related to cell proliferation, apoptosis and paracrine signaling. We hypothesize that CaSR may enhance BMSC proliferation. Rat BMSCs were incubated with various calcium concentrations for 48 h in vitro to activate CaSR. To investigate potential mechanisms responsible for growth enhancement by calcium, the rat BMSC cell cycle progression was analyzed by fluorescence-activated cell sorting (FACS), and induction of apoptosis confirmed by cytofluorimetric analysis using propidium iodide and Annexin V-FITC double staining. Since the mitogen-activated protein kinase (MAPK) signaling pathway was one of the most significantly affected by CaSR, MAPK activation was measured by western blotting. Calcium exposure significantly enhanced rat BMSCs proliferation, as well as the proportion of the population in S phase, in a dose-dependent manner, effects which were abolished by NPS2390 (a CaSR antagonist) and U0126 (a MEK1/2 inhibitor). These results demonstrate that CaSR is involved in rat BMSC proliferation, as seen by an increased proliferation index, decreased apoptosis, and ERK1/2 activation, and provide important insight into the cellular and molecular mechanisms by which CaSR affects cell proliferation. A CaSR agonist may prove useful to enhance BMSC survival during transplantation.