Cold Air Plasma Inhibiting Tumor-Like Biological Behavior of Rheumatoid Arthritis Fibroblast-Like Synovial Cells via G2/M Cell Cycle Arrest.

Background: Rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) have become the core effector cells for the progression of rheumatoid arthritis due to their "tumor-like cell" characteristics, such as being able to break free from growth restrictions caused by contact inhibition, promoting angiogenesis, invading surrounding tissues, and leading to uncontrolled synovial growth. In recent years, cold air plasma (CAP) has been widely recognized for its clear anticancer effect. Inspired by this, this study investigated the inhibitory effect of CAP on the tumor-like biological behavior of RA-FLS through in vitro experiments. Methods: Treatment of RA-FLS with CAP at different time doses (0s, 30s, 60s, 120s). 5-ethynyl-2'-deoxyuridine (EdU) proliferation assay was used to determine the cell viability. Analysis of cell migration and invasion was performed by wound-healing assay, transwell assay and immunofluorescent staining for f-actin, respectively. Flow cytometry technique was used for analysis of cell cycle and determination of reactive oxygen species (ROS). Hoechst staining was used for analysis of cell apoptosis. Protein expression was analyzed by Western blot analysis. Results: Molecular and cellular level mechanisms have revealed that CAP blocks RA-FLS in the G2/M phase by increasing intracellular reactive oxygen species (ROS), leading to increased apoptosis and significantly reduced migration and invasion ability of RA-FLS. Conclusion: Overall, CAP has significant anti proliferative, migratory, and invasive effects on RA-FLS. This study reveals a new targeted treatment strategy for RA.

Circulating secretoneurin level reflects angiographic coronary collateralization in stable angina patients with chronic total occlusion.

OBJECTIVE: To investigate the association between circulating secretoneurin (SN) and angiographic coronary collateralization in stable angina patients with chronic coronary total occlusion (CTO). METHODS: SN concentrations in serum were measured in 641 stable angina patients with CTO by radioimmunoassay. The status of coronary collaterals from the contra-lateral vessel was visually estimated using the Rentrop grading system, and was categorized into poor (grade 0 or 1) or good (grade 2 or 3) collateralization. RESULTS: Serum SN levels were significantly higher in patients with good coronary collaterals compared to those with poor collaterals (175.23 ± 52.09 pmol/L vs. 143.29 ± 42.01 pmol/L, P < 0.001). Serum SN increased stepwise across Rentrop score 0 to 3 (P < 0.001), and increasing SN tertiles were associated with higher proportion of good coronary collateralization (OR, 1.907; 95% CI, 1.558 ~ 2.335, P < 0.001). After adjustment for confounding variables, serum SN (per tertile) remained an independent factor for predicting good coronary collaterals (OR, 1.870; 95% CI, 1.515 ~ 2.309; P < 0.001). Moreover, the diagnostic value of serum SN (per tertile) was consistent after stratifying patients based on gender, age, body mass index, hypertension, diabetes, history of smoking, severity of coronary artery disease and kidney function (OR: 1.511 ~ 2.680, P interaction ≥ 0.327). CONCLUSION: Elevated circulating SN reflects good angiographic coronary collaterals in stable angina patients with CTO. The findings may provide insight into decision-making for these patients.

The impact of dynamic traffic and wind conditions on green infrastructure performance to improve local air quality.

Road traffic represents the dominant source of air pollution in urban street canyons. Local wind conditions greatly impacts the dispersion of these pollutants, yet street trees complicate ventilation in such settings. This case study adopts a novel modelling framework to account for dynamic traffic and wind conditions to identify the optimal street tree configuration that prevents a deterioration in air quality. Measurement data from a shallow to moderately deep street canyon (average 0.5 H/W aspect ratio and four lanes of 1-way traffic) in Dublin, Ireland was used for model calibration. The computational fluid dynamics (CFD) models were used to examine scenarios of dynamic traffic flows within each traffic lane with respect to its impact on local PM2.5 concentrations on adjacent footpaths, segmenting air quality monitoring results based on different wind conditions for model calibration. The monitoring campaign identified higher PM2.5 concentrations on the leeward (north) footpath, with average differences of 14.1 % (2.15 µg/m3) for early evening peaks. The modelling results demonstrated how street trees negatively impacted air quality on the windward footpath in parallel wind conditions regardless of leaf area density (LAD) or tree spacing, with mixed results observed on the leeward footpath in varying traffic flows and wind speeds. Perpendicular wind direction models and high wind speed exacerbated poor air quality on the windward footpath for all tree spacing models, while improving the air quality on the leeward footpath. The findings advise against planting high-LAD trees in this type of street, with a minimum of 20 m spacing for low-LAD trees to balance reducing local air pollution and ventilation capacity in the street. This study highlights the complexities of those in key decision-marking roles and demonstrates the need to adopt a transparent framework to ensure adequate modelling evidence can inform tree planting in city streets.

Early growth response factor 1 upregulates pro-fibrotic genes through activation of TGF-ß1/Smad pathway via transcriptional regulation of PAR1 in high-glucose treated HK-2 cells.

Tubulointerstitial fibrosis (TIF) makes a key role in diabetic kidney disease (DKD). In this study, we revealed that the expressions of Egr1 and protease-activated receptor 1 (PAR1) were increased in renal tissues of DKD rats. In vitro experiments demonstrated that both Egr1 overexpression and high glucose (HG) condition could promote the expressions of PAR1, fibronectin (FN) and collagen I (COL I). Furthermore, HG stimulation enhanced the binding capacity of Egr1 to PAR1 promoter. Both HG condition and Egr1 upregulation could increase, and thrombin inhibitor did not affect activity of TGF-ß1/Smad pathway via PAR1. Collectively, Egr1 is involved in TIF of DKD partly through activating TGF-ß1/Smad pathway via transcriptional regulation of PAR1 in HG treated HK-2 cells.

The Beneficial Effects of a Multispecies Probiotic Supplement on Glycaemic Control and Metabolic Profile in Adults with Type 1 Diabetes: A Randomised, Double-Blinded, Placebo-Controlled Pilot-Study.

Objective: In this pilot-study, the effects of a multispecies probiotic supplement on glycaemic control and metabolic parameters in adults with type 1 diabetes (T1DM) were explored. Material and Methods: A total of 50 T1DM patients were enrolled and randomly placed into a group receiving capsules containing multi-probiotic strains (Bifidobacterium longum, Lactobacterium bulagricumi, Streptococcus thermophilus) and insulin (probiotics group, n = 27) or a group receiving a placebo and insulin (placebo group, n = 23). All patients underwent continuous glucose monitoring at baseline and 12 weeks after intervention. The primary outcomes were determined by comparing factors such as changes in fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) between the groups. Results: Probiotic supplementation significantly reduced FBG (-1.0 ± 4.7 vs 1.8 ± 4.7 mmol/L, p = 0.048), 30 min postprandial glucose (-0.5 ± 4.6 vs 1.9 ± 3.3 mmol/L, p = 0.0495), and low-density lipoprotein cholesterol (-0.07 ± 0.45 vs 0.32 ± 0.78 mmol/L, p = 0.0413), compared with the placebo. Although not statistically significant, probiotic supplementation also lowered HbA1c levels by 0.49% (-5.33 mmol/mol, p = 0.310). Besides, no significant difference was observed in the continuous glucose monitoring (CGM) parameters between the two groups. Further subgroup analysis revealed a significant reduction in mean sensor glucose (MSG; -0.75 (-2.11, 0.48) mmol/L vs 1.51 (-0.37, 2.74) mmol/L, p = 0.010) and time above range (TAR; -5.47 (-20.1, 3.04)% vs 18.9 (-1.11, 35.6)%, p = 0.006), as well as an greater improvement in the time in range (TIR; 9.32 (-4.84, 16.6)% vs -19.9 (-31.4, 0.69)%, p = 0.005) in male patients than female patients in the probiotics group. Conclusion: Multispecies probiotics exerted beneficial effects on fasting and postprandial glucose and lipid profiles in adult T1DM patients, especially for male patients and those with higher baseline FBG levels.

A combination of FDM, EWM, and GRA to measure performance in higher vocational college: An empirical case from China.

Given the problems of unclear division of evaluation factors, inadequate utilization of objective data and unreasonable distribution of weight in college performance measurement, this study extracts relevant indicators and quantitative data from the survey report of administrational institutions, and constructs a comprehensive performance measurement model based on the integration of fuzzy Delphi method (FDM), Entropy weight method (EWM), and grey relational analysis (GRA). The study seeks to identify differences in measurement analysis by comparing the weights, the performance and the rankings of the alternatives about higher vocational colleges in Zhejiang province. Finally, the results show the following: (1) by FDM, 33 indicators about colleges' performance are selected to form the evaluation system of the college's performance, (2) the indicators' weights are obtained through EWM and GRA, and a nonparametric test shows that there is no significant difference between the two types of weights, (3) the grey relational degrees of the alternatives are obtained and ranked on the basis of comprehensive evaluation model. By nonparametric test, there is a significant difference between the two types of relational degrees. On the contrary, no significant difference is found in the ranking of relational degrees, (4) based on the analysis results, this study further compares the performance of alternatives in different forms. There are significant differences between the performance of public colleges and private colleges, while no significant differences are observed between the performance of vocational colleges in Hangzhou and non-Hangzhou. Given the reliability and validity of the model, the comprehensive measurement model provides a relatively objective reference for college governance and administrational institutions, and also becomes an effective tool of colleges' evaluation to assist and improve the management practice in educational institutions.

Purinergic signaling in thyroid disease.

It is known that thyroid hormones play pivotal roles in a wide variety of pathological and physiological events. Thyroid diseases, mainly including hyperthyroidism, hypothyroidism, and thyroid cancer, are highly prevalent worldwide health problems and frequently associated with severe clinical manifestations. However, etiology of hyperthyroidism, hypothyroidism, and thyroid cancer is not fully understood. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. It has been established that purinergic signaling modulates pathways in a wide range of physiopathological conditions including hypertension, diabetes, hepatic diseases, psychiatric and neurodegeneration, rheumatic immune diseases, and cancer. More recently, the purinergic system is found to exist in thyroid gland and play an important role in the pathophysiology of thyroid diseases. Therefore, throughout this review, we focus on elaborating the changes in purinergic receptors, extracellular enzymes, and extracellular nucleotides and adenosine in hyperthyroidism, hypothyroidism, and thyroid cancer. Profound understanding of the relationship between the purinergic signaling with thyroid diseases provides a promising research area for insights into the molecular basis of thyroid diseases and also develops new and exciting insights into the treatment of thyroid diseases, especially thyroid cancer.

SerpinG1: A Novel Biomarker Associated With Poor Coronary Collateral in Patients With Stable Coronary Disease and Chronic Total Occlusion.

Background This study aimed to explore predictive biomarkers of coronary collateralization in patients with chronic total occlusion. Methods and Results By using a microarray expression profiling program downloaded from the Gene Expression Omnibus database, weighted gene coexpression network analysis was constructed to analyze the relationship between potential modules and coronary collateralization and screen out the hub genes. Then, the hub gene was identified and validated in an independent cohort of patients (including 299 patients with good arteriogenic responders and 223 patients with poor arteriogenic responders). Weighted gene coexpression network analysis showed that SERPING1 in the light-cyan module was the only gene that was highly correlated with both the gene module and the clinical traits. Serum levels of serpinG1 were significantly higher in patients with bad arteriogenic responders than in patients with good arteriogenic responders (472.53±197.16 versus 314.80±208.92 µg/mL; P<0.001) and were negatively associated with the Rentrop score (Spearman r=-0.50; P<0.001). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.77 (95% CI, 0.72-0.81; P<0.001) for serum serpinG1 in prediction of bad arteriogenic responders. After adjusting for traditional cardiovascular risk factors, serum serpinG1 levels (per SD) remained an independent risk factor for bad arteriogenic responders (odds ratio, 2.20 [95% CI, 1.76-2.74]; P<0.001). Conclusions Our findings illustrate that SERPING1 screened by weighted gene coexpression network analysis was associated with poor collateralization in patients with chronic total occlusion.

Serum apolipoprotein A-IV levels are associated with flow-mediated dilation in patients with type 2 diabetes mellitus.

BACKGROUND: Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow-mediated dilation (FMD) and serum apoA-IV level in type 2 diabetes mellitus (T2DM) patients.  METHODS: A total of 84 T2DM patients with chest discomfort were enrolled in this study. Their baseline characteristics and clinical parameters were documented. Endothelial function of the participants was evaluated by examining FMD of brachial artery. The severity of coronary atherosclerosis was determined by quantitative coronary angiography. Serum apoA-IV levels were measured by ELISA. RESULTS: These diabetic patients were dichotomized into low FMD (n = 42) and high FMD (n = 42) groups. Serum apoA-IV levels were significantly higher in high FMD group than in low FMD group (29.96 ± 13.17 vs 17.69 ± 9.16 mg/dL, P < 0.001). Moreover, the patients were also categorized into three apoA-IV tertile groups. FMD was significantly different across three apoA-IV tertiles (P < 0.001). Serum apoA-IV levels were positively correlated to FMD (r = 0.469, P < 0.001). Logistic regression analysis was performed to determine risk factors for low FMD. apoA-IV levels together with the risk factor hsCRP remained significantly to be independent determinants of low FMD (P < 0.01). Linear regression analysis was performed, and apoA-IV levels together with total-to-HDL cholesterol ratio were independently correlated with FMD (P < 0.01). CONCLUSIONS: Serum apoA-IV levels are associated with FMD, suggesting that apoA-IV protects endothelial function in patients with T2DM.

Learning Curve Analysis of Microvascular Hepatic Artery Anastomosis for Pediatric Living Donor Liver Transplantation: Initial Experience at A Single Institution.

Background: The incidence of hepatic artery thrombosis in pediatric living donor liver transplantation (LDLT) is significantly higher than that in adults, and is closely related to the surgeon's experience with hepatic artery anastomosis. However, there are few studies on the learning curve of hepatic artery anastomosis among surgeons. Methods: We collected data related to 75 patients who underwent pediatric LDLT and hepatic artery anastomosis independently by the same surgeon. Cumulative sum method (CUSUM) was used to analyse the duration of hepatic artery anastomosis and determine the cut-off value. Patients were divided into two phases according to CUSUM. We analysed the intraoperative and postoperative data and survival outcomes of the included patients. Results: Total anastomosis duration decreased with an increased number of completed procedures, and the average duration was 42.4 ± 2.20 min. A cut-off value and two phases were identified: 1-43 cases and 44-75 cases. Intraoperative blood loss was significantly lower in phase 2 than in phase 1. The immediate functional changes of total bilirubin (TBIL) and direct bilirubin (DBIL) were significantly also lower in phase 2 than in phase 1. Other functional outcomes, postoperative complications, and the long-term survival rate were not significantly different between the two phases. Conclusions: Technical competence in pediatric LDLT hepatic artery anastomosis may be achieved after completing 43 cases. It is a safe procedure with a surgical loupe that can be systematized and adopted by pediatric surgeons with sufficient experience via a relatively long learning curve.

Short term outcomes of extremely low birth weight infants from a multicenter cohort study in Guangdong of China.

With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008-2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

High serum levels of N-epsilon-carboxymethyllysine are associated with poor coronary collateralization in type 2 diabetic patients with chronic total occlusion of coronary artery.

BACKGROUND: The formation of advanced glycation end-products (AGEs) is a crucial risk factor for the pathogenesis of cardiovascular diseases in diabetes. We investigated whether N-epsilon-carboxymethyllysine (CML), a major form of AGEs in vivo, was associated with poor coronary collateral vessel (CCV) formation in patients with type 2 diabetes mellitus (T2DM) and chronic total occlusion (CTO) of coronary artery. METHODS: This study consisted of 242 T2DM patients with coronary angiographically documented CTO. Blood samples were obtained and demographic/clinical characteristics were documented. The coronary collateralization of these patients was defined according to Rentrop or Werner classification. Serum CML levels were evaluated using ELISA assay. Receiver operating characteristic curve and multivariable regression analysis were performed. RESULTS: 242 patients were categorized into poor CCV group or good CCV group (107 vs. 135 by the Rentrop classification or 193 vs. 49 by the Werner classification, respectively). Serum CML levels were significantly higher in poor CCV group than in good CCV group (110.0 ± 83.35 vs. 62.95 ± 58.83 ng/ml by the Rentrop classification and 94.75 ± 78.29 ng/ml vs. 40.37 ± 28.69 ng/ml by Werner classification, both P < 0.001). Moreover, these CML levels were also significantly different across the Rentrop and Werner classification subgroups (P < 0.001). In multivariable logistic regression, CML levels (P < 0.001) remained independent determinants of poor CCV according to the Rentrop or Werner classification after adjustment of traditional risk factors. CONCLUSIONS: This study suggests that higher serum CML level is associated with poor collateralization in T2DM patients with CTO.

Experimental research on surface acoustic wave microfluidic atomization for drug delivery.

This paper demonstrates that surface acoustic wave (SAW) atomization can produce suitable aerosol concentration and size distribution for efficient inhaled lung drug delivery and is a potential atomization device for asthma treatment. Using the SAW device, we present comprehensive experimental results exploring the complexity of the acoustic atomization process and the influence of input power, device frequency, and liquid flow rate on aerosol size distribution. It is hoped that these studies will explain the mechanism of SAW atomization aerosol generation and how they can be controlled. The insights from the high-speed flow visualization studies reveal that it is possible by setting the input power above 4.17 W, thus allowing atomization to occur from a relatively thin film, forming dense, monodisperse aerosols. Moreover, we found that the aerosol droplet size can be effectively changed by adjusting the input power and liquid flow rate to change the film conditions. In this work, we proposed a method to realize drug atomization by a microfluidic channel. A SU-8 flow channel was prepared on the surface of a piezoelectric substrate by photolithography technology. Combined with the silicon dioxide coating process and PDMS process closed microfluidic channel was prepared, and continuous drug atomization was provided to improve the deposition efficiency of drug atomization by microfluidic.

The association of grandparental co-residence and dietary knowledge with excess body weight among children aged 7-15 years in China.

OBJECTIVES: To investigate the impact of grandparent's co-residence and dietary knowledge on the overweight and obesity risk among school-age children in China. METHODS: Data of 790 children aged 7-15 years were retrieved from the China Health and Nutrition Survey (CHNS). Co-residential status was evaluated using household and individual ID. Dietary knowledge was assessed using 17 dietary statements, which was scored by participants. Three principal factors were extracted by factor analysis. Logistic regression analysis was applied to examine the influence of grandparent's co-residence and dietary knowledge on the weight status of the child. RESULTS: The overweight and obesity incidence of the children increased significantly when they co-reside with two grandparents (OR=1.447, 95CI: 1.001-2.090, p=0.049). Mother's dietary knowledge regarding to protein-related food choices (PT) scored higher was associated with the increased risk (OR=1.270, 95CI: 1.059-1.523, p=0.010). For grandmother's dietary knowledge, the higher score in balanced food consumption (BF) was associated with the decreased overweight and obesity risk (OR=0.456, 95CI: 0.294-0.706, p<0.001). Grandfather's dietary knowledge in BF showed the similar result (OR=0.454, 95CI: 0.271-0.759, p=0.003). CONCLUSIONS: Living with two grandparents is associated with higher overweight and obesity risk, but grandparents with an adequate knowledge in the balanced food consumption may decrease the risk.

Clinical treatment outcomes and their changes in extremely preterm twins: a multicenter retrospective study in Guangdong Province, China. / è¶ æœªæˆç†ŸåŒèƒŽå„¿ä¸´åºŠæ•‘æ²»ç»“å±€åŠå˜åŒ–åˆ†æžï¼šä¸€é¡¹å¹¿ä¸œçœå¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.

Nutraceuticals use and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a complicated metabolic disease and has become one of the significant medical problems worldwide. Researchers aim to provide fine-tuned treatment for T2DM with minimal exposed side effects. Nutraceuticals are compounds or materials and emerging evidence suggests that the use of nutraceuticals has recently been recognized as a promising option for the prevention and management of T2DM, such as probiotics and prebiotics, Vitamin D, n-3 long-chain polyunsaturated fatty acids, and Plant-derived nutraceuticals. This review attempts to show the most popular nutraceuticals and review their effects and possible mechanisms in the prevention or glycemic control of T2DM.

GPCR-mediated EGFR transactivation ameliorates skin toxicities induced by afatinib.

Many G-protein-coupled receptor (GPCR) agonists have been studied for transactivating epidermal growth factor receptor (EGFR) signaling through extracellular or intracellular pathways. Accumulated evidence has confirmed that GPCR transactivation participates in various diseases. However, the clinical application of GPCR transactivation has not been explored, and more translational studies are needed to develop therapies to target GPCR-mediated EGFR transactivation. In cancer patients treated with EGFR inhibitors (EGFRi), especially afatinib, a unique acneiform rash is frequently developed. In this study, we first established the connection between GPCR transactivation and EGFRi-induced skin disease. We examined the ability of three different GPCR agonists to reverse signaling inhibition and ameliorate rash induced by EGFRi. The activation of different agonists follows unique time and kinase patterns. Rats treated with EGFRi show a similar skin phenotype, with rash occurring in the clinic; correspondingly, treatment with GPCR agonists reduced keratinocyte apoptosis, growth retardation and infiltration of inflammatory cytokines by transactivation. This phenomenon demonstrates that EGFR inhibition in keratinocytes regulates key factors associated with rash. Our findings indicate that maintaining EGFR signaling by GPCR agonists might provide a possible therapy for EGFR inhibitor-induced skin toxicities. Our study provides the first example of the translational application of GPCR transactivation in treating diseases.

A Nonlinear Relationship Between Serum 25-Hydroxyvitamin D and Urine Albumin to Creatinine Ratio in Type 2 Diabetes: A Cross-Sectional Study in China.

BACKGROUND: Diabetic kidney disease often presents as increased urine albumin to creatinine ratio (UACR). 25-hydroxyvitamin D (25(OH)D) is considered as the best indicator of vitamin D status. Previous studies have shown that 25(OH)D is related to the UACR. However, evidence concerning the connection between 25(OH)D and UACR is still limited in the Chinese population. MATERIALS AND METHODS: A total of 549 participants with type 2 diabetes were enrolled in the study from Shenzhen People's Hospital, China. The participants were grouped by the tertiles of 25(OH)D level. The association between 25(OH)D and UACR was examined by multiple linear regression. A generalized additive model (GAM) was used to verify a non-linear relationship. We conducted a subgroup analysis to evaluate the robustness of the results. RESULTS: After adjusting for relevant variables, 25(OH)D was negatively correlated with UACR (ß = -8.7, 95% CI (-12.0, -5.4)). A non-linear relationship was discovered between 25(OH)D and UACR, and the 25(OH)D threshold was 67. The effect sizes and confidence intervals on the left and right sides of the inflection point were -13.9 (-18.2, -9.6) and 8.9 (-1.1, 18.9), respectively. Subgroup analysis showed a stronger correlation could be detected in males. The same trend also could be found in patients older than 70 years old, those with using ACEI/ARB, with history of hypertension, with SBP ≥140 mmHg and eGFR <60 mL/min/1.73m2. CONCLUSION: The relationship between 25(OH)D and UACR is non-linear. 25(OH)D was negatively related to UACR when 25(OH)D is less than 67 nmol/L.

Klotho protects against diabetic kidney disease via AMPK- and ERK-mediated autophagy.

BACKGROUND: Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and results in serious public health problems. Although a great number of studies have been performed to elucidate the mechanisms of this disease, these mechanisms remain largely unknown. METHODS: Cell and animal models were first constructed using human renal proximal tubule cells stimulated by high glucose (HG) and mice induced by streptozotocin (STZ). After Klotho overexpression, Klotho expression was assessed by RT-PCR and western blot, immunofluorescence; autophagy and AMPK/ERK proteins were confirmed using western blot or immunohistochemical assay; the autophagosomes were observed by transmission electron microscope; the pathological structure, fibrosis, polysaccharides and glycogen of kidney were evaluated by H&E staining, Masson staining and PAS staining. RESULTS: We first confirmed that Klotho expression and autophagic activity were reduced in DM mice and HG-induced human renal proximal tubule cells. Besides, overexpression of Klotho could significantly enhance autophagy and AMPK and ERK1/2 activities in vivo and in vitro, which also could be abolished by selective AMPK inhibitor and ERK activator. Moreover, we proved that Klotho could inhibit hyperglycemia-induced renal tubular damage. CONCLUSION: In summary, our results proved that Klotho improved renal tubular cell autophagy via the AMPK and ERK pathways and played a role in renal protection. These findings provide new insight into the mechanism of Klotho and autophagy in DKD.

Study Protocol: Design and Implementation of the Pediatric Liver Transplantation Biobank.

Background: Early treatment of neonatal biliary atresia (BA) and other end-stage liver diseases can delay or prevent the necessity of liver transplantation (LT). The establishment of a standardized clinical pediatric liver transplantation (PLT) biobank is the prerequisite for scientific research, which helps to provide a qualified sample resource platform for research. Methods: Following standardized procedures to establish biobanks, the operational processes and quality control system were formulated. Liver tissue, blood, and stool samples undergoing LT were regularly collected, managed, and stored. Systematic management was conducted in collected specimens and corresponding clinical information. Results: Since implementation in August 2018, we have enrolled 49 unique subjects (0-18 years of age); the biobank contains nearly 3000 biospecimen aliquots. The most common LT diagnosis is BA (61.23%). Conclusion: The establishment of this biobank is a valuable resource that incorporates detailed clinical and biological information. It will help accelerate the pace of PLT discovery research. ClinicalTrials.gov ID: NCT04477967.