Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.
Mice ; Animals ; Humans ; Hepatitis, Autoimmune/pathology* ; Signal Transduction ; Disease Models, Animal ; Stem Cells

Posttranslational modifications(PTMs)of proteins,particularly acetylation,phosphory-lation,and ubiquitination,play critical roles in the host innate immune response.PTMs'dynamic changes and the crosstalk among them are complicated.To build a comprehensive dynamic net-work of inflammation-related proteins,we integrated data from the whole-cell proteome(WCP),acetylome,phosphoproteome,and ubiquitinome of human and mouse macrophages.Our datasets of acetylation,phosphorylation,and ubiquitination sites helped identify PTM crosstalk within and across proteins involved in the inflammatory response.Stimulation of macrophages by lipopolysac-charide(LPS)resulted in both degradative and non-degradative ubiquitination.Moreover,this study contributes to the interpretation of the roles of known inflammatory molecules and the dis-covery of novel inflammatory proteins.

Objective:To investigate the efficacy and safety of short-term transcatheter arterial chemoembolization （TACE）-radiofrequency ablation （RFA） sequential therapy for advanced hepatocellular carcinoma (HCC).Methods:The clinical data of 117 patients with advanced HCC enrolled in the Central Hospital of Lishui from March 2010 to January 2019 were retrospectively analyzed. All patients received TACE and RFA sequential therapy. The patients were divided into 2 groups including short interval group (interval≤7 d, 61 cases) and long interval group (interval>7 d, 56 cases) according to interval between TACE and RFA. The difference of response rate was analyzed by Wilcoxon test. Kaplan-Meier survival curve was used to calculate the overall survival (OS) time and progression free survival (PFS) time.The risk factors of TACE-RFA sequential therapy were tested using Cox multivariate analysis. The complications in the two groups were compared using χ 2 test. Results:The response rate in the short interval group (72.1%, 43/61) was significantly higher than that in the long interval group (41.1%，23/56) with significant difference ( Z=-2.50, P=0.01). The median PFS in the short interval group (14.9 months) was longer than that in the long interval group (9.1 months). The difference of PFS survival curve between the 2 groups was statistically significant (χ2 =5.90, P=0.01).The median OS in the short interval group (34.7 months) was longer than that in the long interval group (20.3 months). The difference of OS survival curve between the 2 groups was statistically significant (χ2 =6.60, P=0.01). Cox multivariate analysis showed that tumor size [hazard ratio (HR)=2.42, P<0.01], cirrhosis (HR=2.04, P<0.01), interval (HR=0.44, P<0.01), aspartate aminotransferase (HR=1.71, P=0.03) were the independent risk factors for advanced HCC.There were no significant differences in the complication incidence between the 2 groups ( P>0.05). Conclusion:Short-term interval TACE-RFA sequential therapy as a protective factor is efficient and safe for advanced HCC treatment.

Animals ; Cdc20 Proteins/metabolism* ; Cell Line ; Embryo, Mammalian/embryology* ; Embryonic Development ; Female ; Infertility, Female/metabolism* ; Mice ; Mutation ; Oocytes/metabolism*

Objective To investigate the morphological changes of the brainstem in patients with Alzheimer's disease (AD) and their relationship with hippocampal morphological changes.Methods Sixty AD patients (AD group) and sixty age-and gender-matched normal elderly (normal control group) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.The hippocampus and the brainstem of each subject were segmented and their normalized volumes were calculated.According to the hippocampal volume standard value (Z-score),AD patients were divided into two subgroups (hippocampal atrophy group (n=51) and hippocampal spared group (n=9)).A voxel-based morphology (VBM) study was also performed to investigate the morphological differences of the brainstem between the normal control group and the AD group,as well as between the AD subgroups.Results Compared with the normal control group,the brainstem volume in the AD group decreased significantly (16 741.31±1 739.11 vs 15 609.67±1 451.60,t=3.870,P=0.001).In AD subgroups,the volume of the brainstem in the hippocampal atrophy group was significantly smaller than that in the hippocampal spared group (16 556.30 ± 1 514.86 vs 15 442.62 ± 1 389.05,t=2.189,P=0.033).Pearson correlation analysis showed that Mini-Mental State Examination scores were positively correlated with the hippocampal and the brainstem volumes (r=0.590,P＜0.01;r=0.234,P＜0.05),and there was a positive correlation between the hippocampal and the brainstem volume changes in patients with AD (r=0.315,P=0.014).VBM results showed that both the bilateral midbrain and the bilateral pons in the AD group had significant atrophy compared with the normal control group (P＜0.05).In the AD subgroups,the bilateral midbrain and the left pons in the hippocampal atrophy group were significantly atrophied compared with the hippocampal spared group (P＜0.05).Conclusion The brainstem showed morphological changes in patients with AD,and the morphological changes of the brainstem in AD patients with different degrees of hippocampal atrophy were different,indicating the morphological changes of the hippocampus and the brainstem may have an interrelated relationship.

Objective To systematically evaluate the efficacy and safety of brachytherapy (BT) combined with external beam radiation therapy (EBRT) and EBRT alone for prostate cancer.Methods Databases including PubMed,Web of Science,Cochrane Library,CNKI,WanFang Data and VIP were searched from the inception to July 2018 to collect the clinical trials which comparatively analyzed the efficacy and safety between EBRT plus BT and EBRT alone for prostate cancer.According to the inclusion and exclusion criteria,data of the included studies were extracted and the methodological quality was evaluated.Then,a meta-analysis was performed using RevMan 5.3.Results Ten studies of 23 393 patients were included,in which 6 were randomized controlled trials (RCTs) and the other 4 were non-RCTs.The 3-year biochemical progression-free survival (b-PFS)[OR=2.03(95％CI:1.11 to 3.73),P=0.02] and the 5-year b-PFS of intermediate-risk patients[OR=2.27(95％CI:1.49 to 3.45),P＜0.01] in the EBRT+BT group were significantly higher compared with those in the EBRT group.The 3-and 5-year b-PFS,5-year overall survival and 5-year metastasis-free survival did not differ between two groups.in the incidence of ≥ grade 2 acute[OR=1.44(95％CI:1.11 to 1.38),P＜0.01] and chronic genitourinary adverse reactions [OR=3.06(95％CI:1.37 to 6.80),P＜0.01],≥ grade 3 acute[OR=1.75 (95％CI:1.14 to 2.69),P=0.01] and chronic genitourinary adverse reactions[OR=3.41(95％CI:2.42 to 4.82),P＜0.01] in the EBRT group were significantly lower than those in the EBRT+BT group.The incidence of gastrointestinal adverse reactions did not significantly differ between two groups.Conclusion Compared with EBRT alone,EBRT combined with BT can effectively improve the 3-and 5-year b-PFS,whereas increase the incidence of genitourinary adverse reactions for patients with intermediate-risk prostate cancer.

Objective To evaluate the feasibility, safety, and efficacy of Y-shaped jogged stent in patients with malignant hilar biliary obstruction. Methods During the period of January 2010 to June 2015,We retrospectively reviewed 98 cases of malignant hilar biliary obstruction who were received implantation of biliary tract stent. 17 consecutive patients who were treated with Y-shaped jogged stent were identified (group A) during January 2012 to June 2015. Group A was carefully matched according to patients' age, sex, type of tumor, stage, type of biliary obstruction, level of bilirubin at diagnosis, presence of metastasis and treatment, and 17 patients who were underwent unilateral stent placement alone with PTCD were chosen as control group (group B). Patients' baseline characteristics, stenting strategy, complications, stent patency time and survival rates were analyzed, and continuous variables of the two groups were compared using Student's t-test. Categorical variables were analyzed using the Fisher exact test. Results Y-shaped jogged stent implantation group and control groups were closely matched in terms of patients' age, sex, type of tumor, stage, type of biliary obstruction, level of bilirubin at diagnosis, presence of metastasis and treatment ( P>0.05). The bilirubin decreased rate in the two groups was 88.2%and 53.0%respectively (P<0.05). The median time of stent patency after stent implantation was(7.3 ± 1.0)months and(5.7 ± 0.9) months respectively (χ2=4.04,P=0.044), and the median survival time was(9.1 ± 1.5)months and(7.2 ± 1.1)months (χ2=4.60,P=0.032), with significant difference according to Kaplan-Meier analysis. There were no severe complications such as massive hemorrhage, perforation, biliary fistula and severe pancreatitis, which were associated with stent implantation. Conclusions The application of Y-shaped jogged stent is safe, feasible and effective in patients with malignant hilar biliary obstruction. It can relieve the clinical symptoms of biliary obstruction effectively with prolongation of stent patency time and survival rate significantly.

Objective To investigate the reasons and the methods of prevention and cure for serious complications of radiofrequency ablations in the treatments of hepatocellular carcinomas. Methods A total of 410 patients with BCLC at A or B stage of hepatocellular carcinomas in our hospital were enrolled between November 2014 and June 2009. These patients underwent a total of 504 times radiofrequency ablations for the treatments of liver lesions. This retrospective study analysed the reasons and the strategies of prevention and cure for the serious complications. Results In the patients with a total of 504 times radiofrequency ablations, 2 patients had massive hemorrhage caused by puncture injuries, 2 patients had the tumors which were close to the liver capsules and 1 patient had bile peritonitis caused by the injury of thermal ablation on the gallbladder. The maximum diameter of tumor was 5 cm. That tumor was close to the gallbladder. 2 patients had needle tract metastases caused by incompletely needle path ablations. 1 of the 2 patients had a tumor near the liver capsule, and the other patient had un-enough temperature for needle path ablation. Tumor outbreaks were happened in 2 patients. 1 of the 2 patients had a tumor which was located in the liver capsule and close to the portal vein. The other patient had a 12 cm diameter tumor with rich blood supplement. 2 patients had liver abscesses. 1 of the 2 patients had a tumor near the ascending colon, and the other patient had diabetes. 1 patient had colonic perforation caused by thermal ablation. The tumor in that patient was located in the right hepatic lobe segment and adjacent to the ascending colon. The incidence of serious complications was 1.98% (10/504). Conclusions The incidence of the serious complications of radiofrequency ablations for the treatments of hepatocellular carcinomas is relatively low. The main reasons for the serious complications were direct injuries caused by punctures, heat radiation injuries, tumors adjacent to large blood vessels, gallbladders and intestines, tumors with abundant blood supplement, needle paths fail to cross normal liver tissues, low scores of liver function, weak immune system and diabetes. The key points for avoiding and reducing the serious complications are preoperative evaluations of patients' basic situations, choices of appropriate puncture channels and control ranges of ablations when tumors are close to important blood vessels, intestines and gallbladders.

OBJECTIVETo evaluated the manganese (Mn), cobalt (Co) and molybdenum (Mo) levels in blood and urine among general population in China, and thereby to analyze their prevalent features.

METHODSFrom 2009 to 2010, a total of 18 120 subjects of general population aged 6-60 years were recruited from 24 districts in 8 provinces in eastern, central and western China mainland, by cluster random sampling method. The information about their living environment and health status were collected by questionnaire, and their blood and urine samples were also collected.Inductive coupled plasma mass spectrometry (ICP-MS) was applied to test the Mn, Co and Mo levels of blood and urine samples, and the Mn, Co, Mo distribution in blood and urine among groups of population in different ages and genders were then analyzed.

RESULTSAmong general population in China, the geometric mean (GM) of Mn concentration in blood was 8.98 µg/L. The Mn concentration in blood among males and females were separately 8.14 µg/L and 9.88 µg/L (Z = -18.84, P < 0.01). The GM of Mn concentration in urine was 0.63 µg/L. The Mn concentration in urine among males and females were separately 0.62 µg/L and 0.63 µg/L (Z = -0.67, P > 0.05). The geometric mean (GM) of Co concentration in blood was 0.194 µg/L. The Co concentration in blood among males and females were separately 0.166 µg/L and 0.225 µg/L (Z = -23.04, P < 0.01). The GM of Co concentration in urine was 0.282 µg/L. The Co concentration in urine among males and females were separately 0.260 µg/L and 0.307 µg/L (Z = -7.35, P < 0.01). The GM of Mo concentration in blood was 0.25 µg/L. The Mo concentration in blood among male and female group were separately 0.27 µg/L and 0.23 µg/L (Z = -5.03, P < 0.01). The GM of Mo concentration in urine was 27.7 µg/L. The Mo concentration in urine among males and females were 29.8 µg/L and 25.6 µg/L (Z = -6.31, P < 0.01), respectively.

CONCLUSIONThe Mn, Co and Mo levels in blood and urine varied by gender and area among general population in China, the study provided basic data evidence for the following Mn, Co and Mo biological monitoring studies in near future.

Adolescent ; Adult ; Child ; China ; epidemiology ; Cobalt ; Environmental Exposure ; Environmental Monitoring ; Female ; Humans ; Male ; Manganese ; Middle Aged ; Molybdenum