Association between spot urinary sodium-to-potassium ratio and blood pressure among Chinese adults aged 18-69 years: the SMASH study.

Background: Excessive sodium and low potassium intake are involved in the development of hypertension. Growing evidence showed that the sodium-to-potassium ratio (Na/K) was significantly associated with blood pressure (BP). However, studies on the dose-response relationship of spot urinary Na/K ratio with hypertension and BP in the general population are scarce, especially in the Chinese population. Materials and methods: Data from the post-intervention survey of the Shandong Ministry of Health Action on Salt and Hypertension (SMASH) project was analyzed. Associations between Na/K molar ratio and hypertension prevalence and between Na/K molar ratio and BP indices were analyzed using multivariable logistic and linear regression, respectively, followed by subgroup analysis and interaction analysis. The restricted cubic spline model was used to explore the dose-response relationship. Informed by existing literature, we adjusted for potential confounding factors, including temperature and renal function, to assess the association and dose-response relationship. Results: There was a non-linear positive association between Na/K and hypertension (OR:1.09, 95%CI: 1.08-1.11) and a linear positive association between Na/K and systolic BP, diastolic BP, and mean arterial pressure (ß 0.53, 95%CI: 0.45-0.60; ß 0.36, 95%CI: 0.31-0.41; and ß 0.42, 95%CI: 0.36-0.47, respectively). The association was stronger in individuals with hypertension, female patients, those in the 50-59-year age group, and those who were obese. Environmental temperatures had little impact on associations. Conclusion: Our findings provide further evidence that the spot urinary Na/K ratio is a simple, useful, and convenient indicator for monitoring salt reduction and potassium increase, which could be used in clinical and public health practices.

Superoxide Photoproduction from Wetland Plant-Derived Dissolved Organic Matter: Implications for Biogeochemical Impacts of Plant Invasion.

Although the impacts of exotic wetland plant invasions on native biodiversity, landscape features, and carbon-nitrogen cycles are well appreciated, biogeochemical consequences posed by ecological competition, such as the heterogeneity of dissolved organic matter (DOM) from plant detritus and its impact on the formation of reactive oxygen species, are poorly understood. Thus, this study delves into O2•- photogeneration potential of DOM derived from three different parts (stem, leaf, and panicle) of invasive Spartina alterniflora (SA) and native Phragmites australis (PA). It is found that DOM from the leaves of SA and the panicles of PA has a superior ability to produce O2•-. With more stable aromatic structures and a higher proportion of sulfur-containing organic compounds, SA-derived DOM generally yields more O2•- than that derived from PA. UVA exposure enhances the leaching of diverse DOM molecules from plant detritus. Based on the reported monitoring data and our findings, the invasion of SA is estimated to approximately double the concentration of O2•- in the surrounding water bodies. This study can help to predict the underlying biogeochemical impacts from the perspective of aquatic photochemistry in future scenarios of plant invasion, seawater intrusion, wetland degradation, and elevated solar UV radiation.

The Relationship between Low-Sodium Salt Intake and Both Blood Pressure Level and Hypertension in Chinese Residents.

Compared to common salt, low-sodium salt can reduce blood pressure to varying degrees. However, the exact dosage relationship remains unclear. We aimed to investigate the dose-response relationships between low-sodium salt intake and systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as the risk of hypertension, and to determine the optimal range for low-sodium salt intake. We investigated the basic characteristics and dietary profile of 350 individuals who consumed low-sodium salt. The samples were divided into three groups according to the 33.3rd and 66.6th percentiles of low-sodium salt intake in condiments (Q1: <4.72 g/d, Q2: ≥4.72 g/d, and <6.88 g/d, and Q3: ≥6.88 g/d). The restricted cubic spline results indicated that low-sodium salt intake decreased linearly with SBP and DBP, while low-sodium intake demonstrated a non-linear, L-shaped relationship with the risk of hypertension, with a safe range of 5.81 g to 7.66 g. The multiple linear regression analysis revealed that compared with group Q1, the DBP in group Q2 decreased by 2.843 mmHg (95%CI: -5.552, -0.133), and the SBP in group Q3 decreased by 4.997 mmHg (95%CI: -9.136, -0.858). Exploratory subgroup analyses indicated that low-sodium salt intake had a significant impact on reducing SBP in males, DBP in females, SBP in rural populations, and DBP in urban populations. The intake of low-sodium salt adheres to the principle of moderation, with 5.81-7.66 g potentially serving as a pivotal threshold.

Effect Modification of Heat-Related Mortality Risk by Air Pollutants in Shandong, China.

Although studies have reported the modification effect of air pollutants on heat-related health risk, little is known on the modification effect among various particulate matter with different particle size on mortality. We aimed to investigate whether the associations of hot temperatures with daily mortality were modified by different air pollutant levels in Shandong Province, China. Daily data of air pollutants, meteorological factors, and mortality of 1,822 subdistricts in Shandong province from 2013 to 2018 were collected. We used a time-stratified case-crossover model with an interaction term between the cross-basis term for ambient temperature and the linear function of particulate matter ≤1 µm (PM1), PM2.5, nitrogen dioxide (NO2), and ozone to obtain heat-mortality associations during the hot season. Results showed that the cumulative odds ratio of extreme heat on mortality over 0 to 10 days was 3.66 (95% CI: 3.10-4.31). The mortality risk during hot seasons was stronger at high air pollutant levels. The modification effect of particulate matters on heat-related mortality decreased by its aerodynamic diameter. Females and older adults over 75 years were more vulnerable to the modification effect of air pollutants, and significant differences were detected in the association between temperatures and mortality stratified by PM1 and PM2.5. Higher heat-related mortality risks were observed at high NO2 levels, especially for cardiorespiratory disease. The findings suggest that more consideration should be given to the combined effect of very fine particles and NO2 with ambient heat when developing healthcare strategies, and women and older adults should be given priority in health-related settings.

Development of a c-MET x CD137 bispecific antibody for targeted immune agonism in cancer immunotherapy.

BACKGROUND: Targeting the costimulatory receptor CD137 has shown promise as a therapeutic approach for cancer immunotherapy, resulting in anti-tumor efficacy demonstrated in clinical trials. However, the initial CD137 agonistic antibodies, urelumab and utomilumab, faced challenges in clinical trials due to the liver toxicity or lack of efficacy, respectively. Concurrently, c-MET has been identified as a highly expressed tumor-associated antigen (TAA) in various solid and soft tumors. METHODS: In this study, we aimed to develop a bispecific antibody (BsAb) that targets both c-MET and CD137, optimizing the BsAb format and CD137 binder for efficient delivery of the CD137 agonist to the tumor microenvironment (TME). We employed a monovalent c-MET motif and a trimeric CD137 Variable Heavy domain of Heavy chain (VHH) for the BsAb design. RESULTS: Our results demonstrate that the c-MET x CD137 BsAb provides co-stimulation to T cells through cross-linking by c-MET-expressing tumor cells. Functional immune assays confirmed the enhanced efficacy and potency of the c-MET x CD137 BsAb, as indicated by activation of CD137 signaling, target cell killing, and cytokine release in various tumor cell lines. Furthermore, the combination of c-MET x CD137 BsAb with Pembrolizumab showed a dose-dependent enhancement of target-induced T cell cytokine release. CONCLUSION: Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies.

Phosphate-mediated degradation of organic pollutants in water with peroxymonosulfate revisited: Radical or non-radical oxidation?

Whilst it is generally recognized that phosphate enables to promote the removal of some organic pollutants with peroxymonosulfate (PMS) oxidation, however, there is an ongoing debate as to whether free radicals are involved. By integrating different methodologies, here we provide new insights into the reaction mechanism of the binary mixture of phosphates (i.e., NaH2PO4, Na2HPO3, and NaH2PO2) with peroxymonosulfate (PMS) or hydrogen peroxide (H2O2). Enhanced degradation of organic pollutants and observation of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) adducts (i.e. DMPOOH and 5,5-dimethyl-2-oxopyrroline-1-oxyl (DMPOX)) with electron paramagnetic resonance (EPR) in most phosphates/PMS system seemly support a radical-dominant mechanism. However, fluorescence probe experiments confirm that no significant amount of hydroxyl radicals (•OH) are produced in such reaction systems. PMS in the phosphate solutions (without any organics) remains relatively stable, but is only consumed while organic substrates are present, which is distinct from a typical radical-dominant Co2+/PMS system where PMS is continuously decomposed. Through density functional theory (DFT) calculation, the energy barriers of the phosphates/PMS reaction processes are greatly decreased when non-radical mechanism dominates. Complementary evidence suggests that the reactive intermediates of PMS-phosphate complex, rather than the free radicals, are capable of oxidizing electron-rich substrates such as DMPO and organic pollutants. Taking the case of phosphate/PMS system as an example, this study demonstrates the necessity of acquisition of lines of evidence for resolving paradoxes in identifying EPR adducts.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

Association of Resting Heart Rate with the Risk of Stroke in Men.

Background: A resting heart rate may be correlated with an increased risk of stroke. Therefore, we explored the independent and joint influences of heart rate and body mass index on the incidence of stroke and its sub-types in a Chinese rural population. Methods: Cox proportional hazard models were adopted for measuring the influence exerted by heart rate on stroke in the Tongxiang China Kadoorie Biobank prospective cohort analyses, in which 23,132 men and 32,872 women were included. Incident stroke refers to '24-hour acute focal disorder, considered to result from ischemia or intracranial hemorrhage'. Results: Over a 6.9 year mean follow up period, 986 men and 925 women developed stroke, representing an incidence of 6.35 and 4.00 per 1,000 person-years. In contrast to men with heart rate < 69 beats/minute, men at heart rate ≥ 90 beats/minute could more probably develop stroke and ischemic stroke with representing hazard ratio [95% confidence interval (CI)] 1.29 (1.05 - 1.58), and 1.35 (1.06 - 1.71). An adjusted hazard ratio of 1.37 (95% CI = 1.06 - 1.74) and 1.46 (95% CI = 1.08 - 1.96) were respectively identified for stroke and ischemic stroke in non-overweight/obese male patients with heart rate ≥ 90 beats/minute. Joint analyses also favored the results. Unfortunately, non-significant results were found in women. Conclusion: Higher resting heart rate acts as an independent predictor of any stroke and ischemic stroke risk in adult Chinese male but not in female. This relationship was particularly evident among nonoverweight/obese male participants.

Association of 24-h urinary sodium excretion with microalbuminuria in a Chinese population.

To assess the relationship of sodium, potassium and the ratio of sodium to potassium (Na/K) with albuminuria, a cross-sectional study was carried out in China in 2017. Sodium, potassium and albumin excretions were examined in a 24-h (h) urine sample collected from 1486 participants. Microalbuminuria was defined as 24-h urinary albumin excretion between 30 and 300 mg/24 h. The participants had an average age of 46.2 ± 14.1 years old, and 48.9% were men. The proportion of patients with microalbuminuria was 9.0%. As illustrated by the adjusted generalized linear mixed model, sodium concentration increased significantly with the increase in 24-h urinary albumin (ß = 1.16, 95% confidence interval (CI) 0.38-1.93; P = 0.003). Multivariable-adjusted logistic regression analyses demonstrated that the odds ratio (OR) of microalbuminuria increased with the quartiles of sodium [OR = 2.20, 95% CI 1.26-3.84 (the maximum quartile vs. the minimum quartile), Pfor trend = 0.006]. Potassium and the Na/K ratio did not have any association with outcome indicators. A high amount of sodium intake was potentially correlated with early renal function impairment.

Fast and Accurate Illumination Estimation Using LDR Panoramic Images for Realistic Rendering.

A high dynamic range (HDR) image is commonly used to reveal stereo illumination, which is crucial for generating high-quality realistic rendering effects. Compared to the high-cost HDR imaging technique, low dynamic range (LDR) imaging provides a low-cost alternative and is preferable for interactive graphics applications. However, the limited LDR pixel bit depth significantly bothers accurate illumination estimation using LDR images. The conflict between the realism and promptness of illumination estimation for realistic rendering is yet to be resolved. In this paper, an efficient method that accurately infers illuminations of real-world scenes using LDR panoramic images is proposed. It estimates multiple lighting parameters, including locations, types and intensities of light sources. In our approach, a new algorithm that extracts illuminant characteristics during the exposure attenuation process is developed to locate light sources and outline their boundaries. To better predict realistic illuminations, a new deep learning model is designed to efficiently parse complex LDR panoramas and classify detected light sources. Finally, realistic illumination intensities are calculated by recovering the inverse camera response function and extending the dynamic range of pixel values based on previously estimated parameters of light sources. The reconstructed radiance map can be used to compute high-quality image-based lighting of virtual models. Experimental results demonstrate that the proposed method is capable of efficiently and accurately computing comprehensive illuminations using LDR images. Our method can be used to produce better realistic rendering results than existing approaches.

Application of persulfate-based oxidation processes to address diverse sustainability challenges: A critical review.

Over the past years, persulfate (PS) is widely applied due to their high versatility and efficacy in decontamination and sterilization. While treatment of organic chemicals, remediation of soil and groundwater, sludge treatment, disinfection on pathogen microorganisms have been covered by most published reviews, there are no comprehensive and specific reviews on its application to address diverse sustainability challenges, including solid waste treatment, resources recovery and regeneration of ecomaterials. PS applications mainly rely on direct oxidation by PS itself or the reactive sulfate radical (SO4•-) or hydroxyl radical (•OH) from the activation of peroxodisulfate (PDS, S2O82-) or peroxymonosulfate (PMS, HSO5-) in SO4•--based advanced oxidation processes (SO4•--AOPs). From a broader perspective of environmental cleanup and sustainability, this review summarizes the various applications of PS except pollutant decontamination and elaborates the possible reaction mechanisms. Additionally, the differences between PS treatment and conventional technologies are highlighted. Challenges, research needs and future prospect are thus discussed to promote the development of the applications of PS-based oxidation processes in niche environmental fields. In all, this review is a call to pay more attention to the possibilities of PS application in practical resource reutilization and environmental protection except widely reported pollutant degradation.

The Impact of a Family Doctor Contract Service on Outcomes for Type 2 Diabetes Patients in Zhejiang Province.

This study evaluated the effect of family doctor contract service on the health management in Chinese type 2 diabetes mellitus (T2DM) patients over a 24-month period. According to whether patients signing contracts with family doctors or not, the contracting status was divided into contracted and noncontracted. The analysis of covariance was used to examine changes in weight, body mass index, waist circumference, systolic blood pressure, fasting plasma glucose, and lipid parameters between the two groups. The hazard ratios for incident diabetes-related complications were calculated using a Cox proportional hazard model. Of the 2310 patients, 1155 were contracted. The contracted patients displayed the improved fasting blood glucose control and lower low-density lipoprotein cholesterol level than the noncontracted group. Patients signed up with family doctors had a lower risk of diabetes-related complications than those who did not. The data suggested that family doctor contract service might help to achieve better T2DM control.

An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.

DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFß/PD-L1 Targeted Cancer Immunotherapy.

Radiotherapy is the most widely used cancer treatment and improvements in its efficacy and safety are highly sought-after. Peposertib (also known as M3814), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses the repair of radiation-induced DNA double-strand breaks (DSB) and regresses human xenograft tumors in preclinical models. Irradiated cancer cells devoid of p53 activity are especially sensitive to the DNA-PK inhibitor, as they lose a key cell-cycle checkpoint circuit and enter mitosis with unrepaired DSBs, leading to catastrophic consequences. Here, we show that inhibiting the repair of DSBs induced by ionizing radiation with peposertib offers a powerful new way for improving radiotherapy by simultaneously enhancing cancer cell killing and response to a bifunctional TGFß "trap"/anti-PD-L1 cancer immunotherapy. By promoting chromosome misalignment and missegregation in p53-deficient cancer cells with unrepaired DSBs, DNA-PK inhibitor accelerated micronuclei formation, a key generator of cytosolic DNA and activator of cGAS/STING-dependent inflammatory signaling as it elevated PD-L1 expression in irradiated cancer cells. Triple combination of radiation, peposertib, and bintrafusp alfa, a fusion protein simultaneously inhibiting the profibrotic TGFß and immunosuppressive PD-L1 pathways was superior to dual combinations and suggested a novel approach to more efficacious radioimmunotherapy of cancer. IMPLICATIONS: Selective inhibition of DNA-PK in irradiated cancer cells enhances inflammatory signaling and activity of dual TGFß/PD-L1 targeted therapy and may offer a more efficacious combination option for the treatment of locally advanced solid tumors.

NHS-IL12 and bintrafusp alfa combination therapy enhances antitumor activity in preclinical cancer models.

Combinatorial immunotherapy approaches are emerging as viable cancer therapeutic strategies for improving patient responses and outcomes. This study investigated whether two such immunotherapies, with complementary mechanisms of action, could enhance antitumor activity in murine tumor models. The immunocytokine NHS-IL12, and surrogate NHS-muIL12, are designed to deliver IL-12 and muIL-12, respectively, to the tumor microenvironment (TME) to activate NK cells and CD8+ T cells and increase their cytotoxic functions. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domains of the TGF-ß receptor II to function as a TGF-ß "trap" fused to a human IgG1 antibody blocking PD-L1. With this dual-targeting strategy, BA enhances efficacy over that of monotherapies in preclinical studies. In this study, NHS-muIL12 and BA combination therapy enhanced antitumor activity, prolonged survival, and induced tumor-specific antitumor immunity. This combination therapy increased tumor-specific CD8+ T cells and induced immune profiles, consistent with the activation of both adaptive and innate immune systems. In addition, BA reduced lung metastasis in the 4T1 model. Collectively, these findings could support clinical trials designed to investigate NHS-IL12 and BA combination therapy for patients with advanced solid tumors.

Simultaneous targeting of TGF-ß/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor ß (TGF-ß). We report that a bifunctional fusion protein that simultaneously inhibits TGF-ß and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-ß trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.

Near-Null Magnetic Field Suppresses Fruit Growth in Arabidopsis.

We previously found that a near-null magnetic field affected reproductive growth in Arabidopsis under white light. To test whether the effect of a near-null magnetic field on fruit growth of Arabidopsis is related to cryptochrome, we grew wild-type Arabidopsis and cryptochrome double mutant, cry1/cry2, in a near-null magnetic field under blue light. We found that fruit growth of wild-type Arabidopsis instead of the cry1/cry2 mutant was suppressed by the near-null magnetic field. Furthermore, gibberellin (GA) levels of GA4 , GA9 , GA34 , and GA51 in fruits of wild-type plants in the near-null magnetic fields were significantly lower than local geomagnetic field controls. However, in cry1/cry2 mutants, levels of the four detected GAs in fruits in the near-null magnetic fields did not differ significantly from controls. Expressions of GA20-oxidase (GA20ox) genes (GA20ox1 and GA20ox2) and GA3-oxidase (GA3ox) genes (GA3ox1 and GA3ox3) in fruits of wild-type plants rather than cry1/cry2 mutants were downregulated by the near-null magnetic field. In contrast, expressions of GA2-oxidase (GA2ox) genes and GA signaling genes were not affected by the near-null magnetic field. These results indicate that suppression of fruit growth by the near-null magnetic field is mediated by cryptochrome and that GAs are involved in the regulation of fruit growth by the near-null magnetic field. © 2021 Bioelectromagnetics Society.

MicroRNA-139-5p inhibits vascular endothelial cell viability and serves as a diagnostic biomarker in acute myocardial infarction patients.

BACKGROUND: Acute myocardial infarction (AMI) is a cardiovascular disease with high morbidity and mortality, and microRNA-139-5p (miR-139-5p) has been reported to be closely related with myocardial viability. This study aimed to investigate the effects of miR-139-5p on vascular endothelial cells, detect miR-139-5p expression in AMI patients and evaluate its diagnostic value. METHODS: A dual-luciferase reporter assay was utilized to confirm the interaction of miR-139-5p with vascular endothelial growth factor receptor-1 (VEGFR-1). Quantitative real-time PCR was used to detect the levels of miR-139-5p and VEGFR-1 in serum and cells. The viability of human umbilical vein endothelial cells (HUVECs) was measured using a cell counting kit-8 assay. The correlation between miR-139-5p and VEGFR-1 was analyzed by Pearson correlation analysis. The diagnostic value of miR-139-5p, cardiac troponin I (cTnI) and creatine kinase isoenzymes (CK-MB) was identified by receiver operating characteristic analysis. RESULTS: miR-139-5p suppressed cell viability by directly targeting VEGFR-1 in HUVECs. Increased miR-139-5p and decreased VEGFR-1 levels were found in AMI patients and hypoxia-treated HUVECs, and miR-139-5p and VEGFR-1 were shown to be negatively correlated. The diagnostic value of miR-139-5p for AMI screening was high, and the combination of cTnI, CK-MB and miR-139-5p had the highest diagnostic accuracy. miR-139-5p inhibited cell viability by inhibiting VEGFR-1 in hypoxia-treated HUVECs. CONCLUSION: miR-139-5p inhibits endothelial cell viability of AMI by inhibiting VEGFR-1, and increased miR-139-5p expression in AMI patients has high diagnostic value for AMI screening, indicating that miR-139-5p may serve as a diagnostic biomarker and molecular therapeutic target for AMI.

Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress.

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

Comprehensive Pan-Cancer Analysis Confirmed That ATG5 Promoted the Maintenance of Tumor Metabolism and the Occurrence of Tumor Immune Escape.

BACKGROUND: Autophagy related protein 5 (ATG5) is an important autophagosome formation related protein, and its involvement in the biological process of autophagy has been shown to correlate with tumor metabolic patterns and the formation of tumor heterogeneity. However, the role of ATG5 in tumor metabolism and tumor immunity remains unclear. METHOD: In order to explore this problem, this study was designed to reveal the role of ATG5 in tumor metabolism and tumor immunity through pan-cancer analysis of multi-database. GTEx database, CCLE database, and TCGA database were used to describe the expression, prognosis, immune microenvironment, immune new antigen, immune checkpoint, TMB, and microsatellite instability of ATG5 in 33 types of tumors. A series of bioinformatics tools and methods were used for quantitative analysis and panoramic description, such as to Estimate, Scanneo and GSEA. RESULT: The differential analysis results of multiple databases showed that ATG5 was ubiquitously highly expressed in pan-cancer, especially in solid tumors. Survival analysis revealed that ATG5 was universally associated with the prognosis of pan-cancer, and high ATG5 expression was significantly associated with poor patient prognosis in most cases. Further, the expression level of ATG5 was confirmed to be associated with tumor immune infiltration and tumor microenvironment, especially in BRCA, KIRC, and LIHC. In addition to this, ATG5 expression was confirmed to correlate with these clinically significant phenotypes, in conjunction with immune neoantigens and immune checkpoint gene expression profiles in pan-cancer. In addition to TMB and microsatellite instability in pan-cancer, we confirmed that ATG5 expression affects the expression of DNA repair genes and methyltransferases in pan-cancer, and found through gene set enrichment analysis that ATG5 is involved in the regulation of numerous signaling pathways involved in cancer metabolism and cancer immunity. CONCLUSIONS: ATG5 participated in the formation of autophagosomal membrane important molecule LC3-II outside, and played an important role in tumor metabolism and tumor immunity. The comprehensive pan-cancer analysis not only revealed the potential of ATG5 in tumor-targeted therapy but also suggested ATG5 as a promising tumor predictive biomarker in most solid tumors.