Exogenous Iron Induces Mitochondrial Lipid Peroxidation, Lipofuscin Accumulation, and Ferroptosis in H9c2 Cardiomyocytes.

Lipid peroxidation plays an important role in various pathologies and aging, at least partially mediated by ferroptosis. The role of mitochondrial lipid peroxidation during ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate at submillimolar doses induces production of reactive oxygen species (ROS) and lipid peroxidation in mitochondria that precede ferroptosis in H9c2 cardiomyocytes. The mitochondria-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of ROS in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis. SkQ1 and methylene blue also prevented accumulation of lipofuscin observed after 24 h incubation of cardiomyocytes with ferric ammonium citrate. Using isolated cardiac mitochondria as an in vitro ferroptosis model, it was shown that rotenone (complex I inhibitor) in the presence of ferrous iron stimulates lipid peroxidation and lipofuscin accumulation. Our data indicate that ROS generated in complex I stimulate mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis induced by exogenous iron.

CircIQGAP1 regulates RCAN1 and RCAN2 through the mechanism of ceRNA and promotes the growth of malignant glioma.

Circular RNA (circRNA) is one of non-coding RNA with specific circular structure, which has been found to be involved in regulating a series of malignant biological behaviors in many malignant tumors. In this study, based on the IDH1 molecular typing of gliomas, we identified a significant downregulation of circRNA (circIQGAP1) expression in IDH1 mutant gliomas by high-throughput sequencing. In 79 tissue samples, we confirmed that circIQGAP1 expression was significantly downregulated in IDH1 mutant gliomas, and that low circIQGAP1 expression was positively associated with better prognosis. Knockdown of circIQGAP1 in glioma cell lines inhibited glioma cell malignancy and conversely overexpression of circIQGAP1 promoted glioma malignancy. circIQGAP1 regulated glioma cell migration, proliferation, invasion and apoptosis through miR-1256/RCAN1/Bax/Bcl-2/Caspase3 and miR-622/RCAN2/Bax/Bcl-2/Caspase3 axes. These results suggest that circIQGAP1 plays an important role in glioma development, promotes tumor growth, and is a potential therapeutic target for glioma.

Mechanism of Flemiphilippinin D Regulating Inflammatory Response in CIA Rats Through TLR2/MyD88/NF-κB Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of Flemiphilippinin D on collagen-induced arthritis （CIA） in rats and explore its mechanism. MethodForty rats were randomly divided into normal group， CIA group， methotrexate （MTX） group （1.35 mg·kg-1）， low-dose Flemiphilippinin D group （1.5 mg·kg-1）， and high-dose Flemiphilippinin D group （3.0 mg·kg-1）， with eight rats in each group. Except for the normal group， the CIA model was induced by type Ⅱ collagen. Each group was given corresponding liquid medicine or normal saline， once a week in the MTX group， and once a day in the Flemiphilippinin D groups for a total of 28 days. The arthritis score and joint swelling degree of rats were experimentally recorded. Pathological changes in the ankle joint of rats were observed by hematoxylin-eosin （HE） staining. Serum levels of inflammatory cytokines interleukin （IL）-1β， IL-6， IL-8， and tumor necrosis factor （TNF）-α were detected by enzyme-linked immunoabsorbent assay （ELISA）， and the mRNA expression of Toll-like receptor 2 （TLR2）， myeloid differentiation factor 88 （MyD88）， and nuclear transcription factor-κB （NF-κB） p65 were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and the protein expressions of TLR2， MyD88， and NF-κB p65 were detected by Western blot. ResultCompared with the normal group， the ankle joint of the CIA group was significantly swollen， and the clinical score of arthritis and the degree of joint swelling were significantly increased （P<0.01）. The ankle joint tissue structure was significantly damaged， and the levels of inflammatory factors IL-1β， IL-6， IL-8， and TNF-α in serum were significantly increased （P<0.01）. The mRNA levels and protein levels of TLR2， MyD88， and NF-κB p65 were significantly increased（P<0.01）. Compared with the CIA group， arthritis clinical score and joint swelling of rats in each administration group were significantly reduced （P<0.05， P<0.01）， and the pathological changes in the ankle joint were significantly improved. The contents of serum IL-1β， IL-6， IL-8， and TNF-α were significantly decreased （P<0.05， P<0.01）. The mRNA levels and protein levels of TLR2， MyD88， and NF-κB p65 in the ankle joint were significantly decreased （P<0.05， P<0.01）. ConclusionTo a certain extent， Flemiphilippinin D can reduce the expression of inflammatory factors in rheumatoid arthritis rats and play a good therapeutic effect. It works perhaps by inhibiting the activation of the TLR2/MyD88/NF-κB signaling pathway and thus shows an anti-inflammatory effect.

The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma.

Background: Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied. Methods: Several glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic. Results: Two subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed. Conclusion: The current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.

Effects of Tangtong formula on the expression of PI3K, Akt and mTOR in sciatic nerve of diabetic peripheral neuropathy rats / 国际中医中药杂志

Objective:To observe the effect of Tangtong formula on the expression of autophagy pathway proteins PI3K, Akt and mTOR in sciatic nerve of DPN rats, and to explore its mechanism. Methods:There were 60 male SD rats, 15 of which were randomly selected as the normal group, and the other rats were used to establish DPN model with STZ + ischemia-reperfusion method. Then they were divided into model group, Tangtong formula low-dose group and Tangtong formula high-dose group, with 15 rats in each group with random number table method. 36.67 g/kg Tangtong formula was administered by gavage in the high-dose group and 18.33 g/kg Tangtong formula was administered by gavage in the low-dose group, once a day. After 8 weeks of continuous gavage, the conduction velocity of sciatic nerve was detected. The mRNA and protein expression levels of PI3K, Akt and mTOR were detected by PCR and Western blot. The structure of sciatic nerve fibers was observed by HE staining. Results:Compared with the model group, the motor nerve conduction velocity, sensory nerve conduction velocity, muscle compound action potential and sensory nerve action potential in the low-dose Tangtong formula group and high-dose Tangtong formula group were increased ( P<0.05). The expression of PI3K mRNA(6.05±0.18, 3.36±0.29 vs. 11.57±1.93), Akt mRNA(1.26±0.13, 0.64±0.04 vs. 1.86±0.06), mTOR mRNA(1.82±0.11, 0.92±0.06 vs. 2.68±0.18) of sciatic nerve in rats of the low-dose and high-dose group were increased ( P<0.05). The expression of PI3K(0.40±0.00, 0.19±0.02 vs. 0.61±0.03), Akt(0.64±0.02, 0.45±0.01 vs. 0.83±0.02), mTOR(0.17±0.01, 0.09±0.00 vs. 0.34±0.01)of sciatic nerve in rats of the low-dose and high-dose group were increased ( P<0.05). The model group's nerve fibers were loose and swollen, myelin sheath became thin, and the axis Atresia, the neuromorphology of the low-dose and high-dose group tended to be normal, and the morphology of myelin sheath and axon were better. Conclusions:Tangtong formula could improve the conduction velocity and potential amplitude of sciatic nerve in DPN rats, reduce nerve injury and demyelinating changes, improve axon morphology and protect nerve fiber structure. Its mechanism might be related to activating PI3K/Akt/mTOR signal pathway and inhibiting excessive autophagy.

Luteoloside protects the vascular endothelium against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway / 中国天然药物

Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine. Its primary therapies include clearing heat and detoxification, activating blood circulation, and removing blood stasis. Lonicera japonica flos (LJF) has long been known as an excellent antipyretic and antidote. Luteoloside (Lut) is one of the main components of LJF and exhibits antioxidant, anti-inflammatory, and cytoprotective properties. However, the protection of Lut against iron overload injury and its underlying mechanisms remain unclear. Therefore, HUVECs were exposed to 50 μmol·L-1 iron dextran for 48 h to establish an iron overload damage model and the effects of Lut were assessed. Our results showed that 20 μmol·L-1 Lut not only increased cell viability and weakened LDH activity, but also significantly up-regulated DDAHⅡ expression and activity, increased p-eNOS/eNOS ratio and NO content, and reduced ADMA content in HUVECs exposed to iron overload. Furthermore, Lut significantly attenuated intracellular/mitochondrial ROS generation, improved SOD, CAT, and GSH-Px activities, reduced MDA content, maintained MMP, inhibited mPTP opening, prevented cyt c from mitochondria released into cytoplasm, reduced cleaved-caspase3 expression, and ultimately decreased cell apoptosis induced by iron overload. The effects of Lut were similar to those of L-arginine (an ADMA competitive substrate), cyclosporin A (a mPTP blocker agent), and edaravone (a free radical scavenger) as positive controls. However, addition of pAD/DDAH II-shRNA adenovirus reversed the above beneficial effects of Lut. In conclusion, Lut can protect HUVECs against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway. The mitochondria are the target organelles of Lut's protective effects.

Effects of prolonged sevoflurane exposure on metabolomics of prefrontal cortex in aged mice / 中国临床药理学与治疗学

AIM: To explore the effects of prolonged sevoflurane exposure on prefrontal cortical metabolites in aged mice using a metabolomics approach. METHODS: Ten 18-month-old male C57BL/J6 mice were divided into a sevoflurane group (Sev group) and a control group (Con group) by the random number table method, with five mice in each group. Mice in the sevoflurane group were anesthetized with 3% sevoflurane and 60% oxygen for 6 h. Mice in the control group were given 60% oxygen under the same conditions for 6 h. All mice were executed immediately after the end of anesthesia or oxygenation, and fresh prefrontal cortex was taken for LC-MS/MS analysis. The data obtained were processed and analyzed using OSV2.1 software (AB SCIEX). RESULTS: Compared with the control group, the content of glutathione, arginine, coenzyme A, 1-methyl-histi-dine, L-arginino-succinate and 2-isopropylmalic acid was reduced in the prefrontal cortex of aged mice in the sevoflurane group, while the content of mesaconic acid was increased. A total of 29 metabolic pathways were involved in the differential metabolites, with significant enrichment in nine pathways including arginine biosynthesis. CONCLUSION: Significant changes in metabolites such as glutathione, arginine, and coenzyme A occurred in the prefrontal cortex of aged mice exposed to prolonged sevoflurane. The changes in these products may affect the amino acid metabolic pathway and the gluconeogenic pathway.

Reopening International Borders without Quarantine: Contact Tracing Integrated Policy against COVID-19

With the COVID-19 vaccination widely implemented in most countries, propelled by the need to revive the tourism economy, there is a growing prospect for relieving the social distancing regulation and reopening borders in tourism-oriented countries and regions. The need incentivizes stakeholders to develop border control strategies that fully evaluate health risks if mandatory quarantines are lifted. In this study, we have employed a computational approach to investigate the contact tracing integrated policy in different border reopening scenarios in Hong Kong, China. Built on a modified SEIR epidemic model with a 30% vaccination coverage, the results suggest that scenarios with digital contact tracing and quick isolation intervention can reduce the infectious population by 92.11% compared to those without contact tracing. By further restricting the inbound population with a 10,000 daily quota and applying moderate-to-strong community non-pharmacological interventions (NPIs), the average daily confirmed cases in the forecast period of 60 days can be well controlled at around 9 per day (95% CI: 7-12). Two main policy recommendations are drawn from the study. First, digital contact tracing would be an effective countermeasure for reducing local virus spread, especially when it is applied along with a moderate level of vaccination coverage. Second, implementing a daily quota on inbound travelers and restrictive community NPIs would further keep the local infection under control. This study offers scientific evidence and prospective guidance for developing and instituting plans to lift mandatory border control policies in preparing for the global economic recovery.

FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.

Genetic analysis of a Chinese pedigree affected with congenital split-hand/foot malformation / 中华医学遗传学杂志

OBJECTIVE@#To analyze the molecular genetics of a Chinese pedigree with congenital hand foot cleft.@*METHODS@#Single nucleotide polymorphism microarray (SNP array) was used to analyze the whole genome copy number variation.@*RESULTS@#SNP array analysis showed that there was a 433 kb repeat in 10q24.31-10q24.32 region, which contained LBX1, BTRC, POLL, OPCD and FBXW4 genes.@*CONCLUSION@#Microduplication of chromosome 10q24.31-10q24.32 may be the cause of congenital hand foot cleft in this pedigree.

Tetramethylpyrazine attenuates doxorubicin induced cardiotoxicity through 14-3-3γ/Bcl-2 / 中国临床药理学与治疗学

AIM: To investigate the effect of tetramethylpyrazine (TMP) on doxorubicin (Dox) induced cardiotoxicity and the role of 14-3-3γ/Bcl-2 protein expression. METHODS: Primary cultured cardiomyocytes were randomly divided into Control group, Dox group, Dox+TMP group and Dox+TMP+pAD/14-3-3γ-shRNA group. After 48 hours, the cell viability was detected by MST, the activity of LDH in culture medium, the activities of Caspase-3, SOD, GSH-Px and the content of MDA were detected; the expression of 14-3-3γ and mitochondrial Bcl-2 was detected by Western blot; ROS generation, mitochondrial membrane potential and mPTP opening were detected by flow cytometry; apoptosis was detected by TUNEL method. RESULTS: After Dox exposed for 48 hours, the viability of cardiomyocytes decreased significantly, the activity of LDH in culture medium increased, the activities of SOD and GSH-Px decreased, the content of MDA increased, ROS generation increased; the mitochondrial membrane potential decreased, mPTP continued to open, caspase-3 activity and apoptosis increased. TMP pretreatment significantly upregulated the expression of 14-3-3γ and mitochondrial Bcl-2, and reversed the above changes simultaneously; pAD/14-3-3γ-shRNA not only downregulated the expression of 14-3-3γ, but also decreased the expression of Bcl-2 in mitochondria. CONCLUSION: TMP pretreatment upregulates the expression of 14-3-3γ and mitochondrial Bcl-2, inhibits oxidative stress, maintains mitochondrial function and reduces Dox induced apoptosis.

Risk factors of thyroid nodule in diabetic patients and the correlation with Traditional Chinese Medicine constitution / 国际中医中药杂志

Objective:To explore the risk factors of thyroid nodules in diabetic patients and its correlation with Traditional Chinese Medicine (TCM) constitution.Methods:A Total of 213 cases of diabetic patients in Guang’anmen Hospital and Tangshan Hospital from January 2019 to August 2020 were choosen to do the questionnaire, with containly symptom and constitution. The patients were divided into diabetes with thyroid nodules group and diabetes without thyroid nodules group according to whether thyroid nodules were combined. We compared the clinical data characteristics of 2 groups, and used multi-factor logistic regression model to analyze the risk factors of diabetic patients with thyroid nodules and their correlation with TCM constitutions. Results:Diabetes patients aged from 50-80 years old [ OR=2.949, 95% CI (1.266-6.714)], females [ OR=3.736, 95% CI (1.823-1.541)], diabetes duration≥15 years [ OR=1.558, 95% CI (1.623-1.585)], elevated HbA1c [ OR=5.862, 95% CI (1.418-23.629)], elevated VLDL [ OR=2.851, 95% CI (1.597-6.824)], frequent insomnia [ OR=1.970, 95% CI (1.315-3.395)], Qi stagnation [ OR=4.357, 95% CI (2.634-8.377)], blood stasis [ OR=4.420, 95% CI (1.874-15.258)] are more likely to suffer from thyroid nodules ( P<0.05). Conclusion:Diabetic patients aged from 50-80 years old, females, diabetes duration≥15 years, elevated HbA1c, family history of thyroid nodules, frequent insomnia, and mood swings are more likely to develop thyroid nodules; qi stagnation and blood stasis are dangerous constitutions for diabetic patients with thyroid nodules.

Application effect of timing theory in alcohol abstinence intervention for patients with alcoholic liver disease / 中国实用护理杂志

Objective:To explore the effect of alcohol abstinence intervention based on timing theory on patients with alcoholic liver disease.Methods:A total of 106 patients with alcoholic liver disease hospitalized in the Department of liver disease of Taian Medical District, 960th Hospital of Chinese PLA from July 2018 to June 2019 were selected by convenience sampling method and divided into observation group and control group by random digits table method, 53 cases in each group. The control group received routine nursing, and through the improvement of patients' cognition and support system, implemented short abstinence intervention during hospitalization; the observation group received abstinence intervention based on timing theory on the basis of the control group intervention. At 1 month and 6 months after discharge, the differences of rehydration rate, alcohol dependence and physical and mental status between the two groups were compared.Results:Finally, 49 cases in the control group completed the study, and 51 cases in the observation group completed the study. The rehydration rates of the observation group were 21.57%(11/51) and 15.69%(8/51) respectively at 1 month and 6 months after discharge, while those of the control group were 40.82%(20/49) and 36.73%(18/49) respectively at 1 month and 6 months after discharge. The difference was statistically significant ( χ2 values were 4.328, 5.754, P<0.05). The alcohol dependence scores were 0(2,3), 0(1,2) in the observation group and 2(0,3), 3(1,4) in the control group at 1 month and 6 months after discharge, and the difference was statistically significant ( Z values were -6.719, -7.345, P<0.01). There was no significant difference in the score of Symptom Checklist-90(SCL-90) before intervention and 1 month after discharge between the two groups ( P>0.05). Six months after discharge, the score of SCL-90 was 8.26 ± 1.37 in the observation group and 10.11 ± 1.68 in the control group, and the difference was statistically significant( t value was 6.046, P<0.01). Conclusions:The application of timing theory in alcohol abstinence of patients with alcoholic liver disease can significantly reduce the relapse rate and the degree of alcohol dependence of patients with alcoholic liver disease, improve the physical and mental state of patients.

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer.

BACKGROUND: Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC). METHODS: Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson's or Spearman's chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls. RESULTS: We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR- MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II-IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037). CONCLUSION: Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.

Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways.

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (TExh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a TExh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The TExh phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes MYC and fibroblast growth factor 11 (FGF11). Downregulation of MYC and FGF11 induces TExh differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of FGF11 and MFN1. In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.

An Aberration Detection-Based Approach for Sentinel Syndromic Surveillance of COVID-19 and Other Novel Influenza-Like Illnesses

Coronavirus Disease 2019 (COVID-19) has emerged as a significant global concern, triggering harsh public health restrictions in a successful bid to curb its exponential growth. As discussion shifts towards relaxation of these restrictions, there is significant concern of second-wave resurgence. The key to managing these outbreaks is early detection and intervention, and yet there is significant lag time associated with usage of laboratory confirmed cases for surveillance purposes. To address this, syndromic surveillance can be considered to provide a timelier alternative for first-line screening. Existing syndromic surveillance solutions are however typically focused around a known disease and have limited capability to distinguish between outbreaks of individual diseases sharing similar syndromes. This poses a challenge for surveillance of COVID-19 as its active periods are tend to overlap temporally with other influenza-like illnesses. In this study we explore performing sentinel syndromic surveillance for COVID-19 and other influenza-like illnesses using a deep learning-based approach. Our methods are based on aberration detection utilizing autoencoders that leverages symptom prevalence distributions to distinguish outbreaks of two ongoing diseases that share similar syndromes, even if they occur concurrently. We first demonstrate that this approach works for detection of outbreaks of influenza, which has known temporal boundaries. We then demonstrate that the autoencoder can be trained to not alert on known and well-managed influenza-like illnesses such as the common cold and influenza. Finally, we applied our approach to 2019-2020 data in the context of a COVID-19 syndromic surveillance task to demonstrate how implementation of such a system could have provided early warning of an outbreak of a novel influenza-like illness that did not match the symptom prevalence profile of influenza and other known influenza-like illnesses.

The impact of goggle-associated harms to health and working status of nurses during management of COVID-19

BackgroundTo investigate the impact of goggles on their health and clinical practice during management of patients with COVID-19. Methods231 nurse practitioners were enrolled who worked in isolation region in designated hospitals to admit patients with COVID-19 in China. Demographic data, goggle-associated symptoms and underlying reasons, incidence of medical errors or exposures, the effects of fog in goggles on practice were all collected. Data were stratified and analyzed by age or working experience. Risk factors of goggle-associated medical errors were analyzed by multivariable logistical regression analysis. FindingsGoggle-associated symptoms and foggy goggles widely presented in nurses. The most common symptoms were headache, skin pressure injury and dizziness. Headache, vomit and nausea were significantly fewer reported in nurses with longer working experience while rash occurred higher in this group. The underlying reasons included tightness of goggles, unsuitable design and uncomfortable materials. The working status of nurses with more working experience was less impacted by goggles. 11.3% nurses occurred medical exposures in clinical practice while 19.5% nurses made medical errors on patients. The risk factors for medical errors were time interval before adapting to goggle-associated discomforts, adjusting goggles and headache. InterpretationGoggle-associated symptoms and fog can highly impact the working status and contribute to medical errors during management of COVID-19. Increased the experience with working in PPE through adequate training and psychological education may benefit for relieving some symptoms and improving working status. Improvement of goggle design during productive process was strongly suggested to reduce incidence of discomforts and medical errors.

Sphingosine 1 phosphate receptor-1 (S1P1) promotes tumor-associated regulatory T cell expansion: leading to poor survival in bladder cancer.

Regulatory T cells (Tregs) represent an important contributor to cancer immune escape, but the molecular mechanism responsible for Treg expansion in tumors is heterogeneous and unclear. Here, we investigated the role of S1P1, a receptor of the bioactive lipid sphingosine 1-phosphate (S1P), in regulating the crosstalk between tumor cells and tumor-associated Tregs in bladder cancer (BC). We found that the frequency of CD4+Foxp3+ Tregs was increased in circulating and tumor-infiltrating lymphocytes from BC patients. S1P1 expression was upregulated in BC tissues compared with tumor-adjacent tissues and was positively correlated with the density of tumor-infiltrated Foxp3+ Tregs. Both S1P1 and Treg predicted poor overall survival in BC patients. The in vitro data paralleled the in vivo data and suggested that the activation or overexpression of S1P1 in BC cells promoted the generation of BC-induced (i)Tregs from CD4+CD25-cells, and the generation of these cells was reversed by treatment with anti-IL-10 or anti-TGF-ß. Moreover, S1P1 promoted Treg migration mediated by BC cells. Mechanistically, S1P1 activated the TGF-ß signaling pathway, leading to the secretion of TGF-ß and IL-10 from BC cells. In total, our findings suggest that S1P1 induces tumor-derived Treg expansion in a cell-specific manner and serves as a potent prognostic biomarker and therapeutic target in BC.

Epidemiology of allergic rhinitis in children in grassland of Inner mongolia / 中华耳鼻咽喉头颈外科杂志

Objective@#To investigate the self-reported prevalence, clinical characteristics, complications of allergic rhinitis (AR) and the sensitization of outdoor air pollen allergens in children in the Inner mongolia grassland region.@*Methods@#A multistage, stratified and random clustered sampling with a face-to-face interview survey study in children from 0 to 17 years old was performed together with 10 common allergen skin prick tests (SPT) and measurements of the daily pollen count in 6 regions in the Inner mongolia grassland region from May to August of 2015. SAS 9.4 software was used for data analysis.@*Results@#A total of 2 443 subjects completed the study. The self-reported prevalence of AR was 26.6%. The prevalence of boys was higher than that of girls (28.8% vs 24.3%, χ2=6.157, P<0.05). Subjects from urban areas showed higher prevalence than rural areas (34.7% vs 18.8%, χ2=79.107, P<0.05). There was significant regional difference in the prevalence of AR among the six areas investigated (χ2=221.416, P<0.05). The main clinical symptoms of AR were sneezing (88.2%) and nasal congestion (78.6%). Among combined diseases, asthma accounted for 16.5% (107/650), rhinoconjunctivitis accounted for 47.9% (311/650). The peak season of AR was April and July, with the top SPT positive allergens of Artemisia species and chenopodium in this area.@*Conclusions@#The prevalence AR in children in the Inner mongolia grassland region is extremely high. Sneezing is the main clinical symptom. Rhinoconjunctivitis is the most common combined disease. High summer and autumn pollen exposure is the main cause of AR.