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.

Objective : The purpose of this study was to clarify the regulatory effect and mechanism of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) on human periodontal ligament stem cell (hPDLSC) proliferation and osteogenic differentiation under inflammatory environment and to provide a new target for the treatment of periodontitis. Methods: SHP2 was knocked down in hPDLSCs, and the transfection efficiency of SHP2 was detected by RT-qPCR and Western blot. An in vitro inflammatory environment was created using tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The effect of SHP2 knockdown on hPDLSC viability under normal and inflammatory conditions was detected by CCK-8, and the osteogenic capacity of hPDLSCs under normal and inflammatory conditions was detected by ALP staining, ALP activity, ARS staining, RT-qPCR and Western blot. The mechanism by which SHP2 knockdown affected the MAPK pathway and its downstream NF-κB pathway under inflammatory conditions was assessed by Western blot. Results: Green fluorescence was observed after transfection for 72 h, and the titer of SHP2 shRNA recombinant lentivirus was 2.9×108 TU/mL. SHP2 expression was significantly downregulated in lentivirus-transfected cells, as demonstrated by Western blot and RT-qPCR (P<0.001). SHP2 knockdown inhibited hPDLSC proliferation to a certain extent and increased the expression of early osteogenic markers under normal conditions, including increased ALP activity and increased ALP and COL-1 expression (P<0.05). However, SHP2 knockdown exerted no effect on mineralized nodule formation. In the TNF-α- and IL-1β-induced inflammatory environment, SHP2 knockdown exerted no effect on hPDLSC proliferation (P>0.05). Osteogenic markers were upregulated (P<0.05), and mineralized nodules were significantly increased (P<0.05) after SHP2 knockdown. Western blot analysis showed that p65 phosphorylation and IκB-α degradation were reduced in SHP2-knockdown hPDLSCs in the inflammatory environment. Moreover, SHP2 knockdown significantly inhibited the expression of p-p38 and p-JNK MAPK, which represent pathways upstream of the NF-κB pathway (P<0.05). Conclusion SHP2 knockdown did not affect cell viability but promoted the osteogenic potential of hPDLSCs by inhibiting the MAPK/NF-κB-mediated signaling pathway under inflammatory environment.

Objective: To explore the incidence and risk factors of cardiovascular events in hematological neoplasms patients treated with anthracyclines in the real world. Methods: A total of 408 patients with lymphoma and leukemia, who were treated with anthracyclines during hospitalization in the First Affiliated Hospital of Dalian Medical University from January 1, 2018 to July 31, 2021, were included in this retrospective study. Patients were divided into cardiovascular event group (n=74) and non-cardiovascular event group (n=334). The primary endpoint was cardiovascular events (arrhythmia, heart failure, acute myocardial infarction etc.) after anthracyclines therapy. The secondary endpoint was all-cause mortality, cardiovascular-cause death, discontinued chemotherapy due to cardiovascular events. Multivariate regression analysis was used to investigate the risk factors of cardiovascular events. Kaplan-Meier was performed to calculate the incidence of all-cause mortality. Results: The mean age was (55.6±14.9) years, and there were 227 male patients (55.6%) in this cohort. The median follow-up time was 45 months. During follow-up, cardiovascular adverse events occurred in 74 patients (18.1%), including 45 heart failure (38 were heart failure with preserved ejection fraction), 30 arrhythmia, 4 acute myocardial infarction and 2 myocarditis/pericarditis. Multivariate regression analysis showed age (OR=1.024, 95%CI 1.003-1.045, P=0.027) and history of hypertension over 10 years (OR=2.328, 95%CI 1.055-5.134, P=0.036) were independent risk factors for the cardiovascular events. Kaplan-Meier survival curve showed mortality was significantly higher in cardiovascular event group than in non-cardiovascular event group (47.3% vs. 26.6%, P=0.001). In the cardiovascular event group, chemotherapy was discontinued in 9 cases (12.2%) due to cardiovascular events and cardiovascular death occurred in 7 cases (9.5%). Conclusions: Although heart failure is the main cardiovascular event in lymphoma and leukemia patients post anthracyclines therapy, other cardiovascular events especially arrhythmias are also common. The presence of cardiovascular events is associated with higher risk of all-cause mortality in these patients. Age and long-term hypertension are independent risk factors for cardiovascular events in lymphoma and leukemia patients after anthracyclines treatment.
Humans ; Male ; Adult ; Middle Aged ; Aged ; Child ; Anthracyclines/adverse effects* ; Retrospective Studies ; Risk Factors ; Heart Failure/drug therapy* ; Myocardial Infarction/complications* ; Hematologic Neoplasms/complications* ; Arrhythmias, Cardiac/complications* ; Leukemia/complications* ; Hypertension/complications*

OBJECTIVETo isolate platelet-rich plasma(PRP) from the white slurry(WS), a depleted fraction of the clinical blood supply, so as to provide an easier method to harvest PRP for related studies and clinical use.

METHODSThe protocols preparing PRP from whole blood and WS were compared. The morphological characteristics of the different PRPs were observed under transmission electron microscope; the expression of the platelet markers CD41a and CD42b were detected by the flow cytometry. Moreover, the ingredients of the PRPs were measured by using cytoanalyzer. for detecting the physiological function of the PRP, the harvested PRP were added to MSC culture and the cell proliferation was detected by using CCK-8 method.

RESULTSa large amount of PRP from WS was easier harvested. the WS-derived PRP shared similar morphological characteristics and ingredients as compared with whole blood-derived PRP. Importantly, the WS-derived PRP exhibited a higher expression of CD41a and CD42b than that of traditional PRP, which indicate that the WS is a promising reservoir for PRP.

CONCLUSIONThe WS can be used to prepare PRP, and the novel PRP share similar biological characteristics as traditional PRP prepared from whole blood. The present study provides an easier and economical method to harvest PRP and this findings may be helpful for PRP related studies.

Objective To explore clinical effect of metacentric particles with bisoprolol fumarate pesos on the elderly patients with heart failure with ventricular arrhythmia treatment.Methods In August 2013 to April 2016, 102 cases of elderly patients in our hospital heart failure with ventricular arrhythmia were selected as research object, according to touch the ball method, they were divided into control group and experimental group, each group of 51 cases, control group was given bisoprolol fumarate pesos, on this basis, the experimental group was combined use of metacentric particles.Two groups of clinical curative effect were compared .Results The experimental group and control group rate of sinus heart rate to maintain statistical comparison of the experimental group was higher than control group ,the difference was statistically significant(P<0.05),group total effective rate was significantly higher than the control group ( P <0.05 ) , the incidence of adverse reactions were significantly lower than the control group (P<0.05),the control group and experimental group heart rate compared before treatment, there was no statistically significant difference, but after treatment, the experimental group was lower than the control group, the differe nce was statistically significant (P <0.05). Conclusion Metacentric particles with bisoprolol fumarate pesos for elderly patients with heart failure with ventricular arrhythmia in clinical curative effect is distinct, high safety.

Objective:To compare the long-term prognosis of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with ostial/shaft lesions of unprotected left main coronary artery (ULMCA).Methods:A total of 259 patients with isolated ostial/midshaft lesions of ULMCA who received PCI or CABG in our hospital from 2003-01 to 2009-07 were enrolled.The patients were divided into 2 groups:PCI group,n=149 patients who received drug-eluting stents (DES) implantation and CABG group,n=110.The end points were all cause death,myocardial infarction (MI) and major adverse cardiac and cerebrovascular events (MACCE) which included cardiac death,non-fetal MI,stroke,repeated revascularization and the composite events death.Results:The median follow-up period was 7.1 years (inter quartile range 5.3-8.2 years) in all patients.Before multivariate adjusting,the following parameters were similar between PCI group and CABG group:all cause death (12.7％ vs 29.7％),P=-0.096;non-fatal MI (14.8％ vs 8.5％),P=0.844;stroke (9.3％ vs 6.3％),P=0.904;repeated revascularization (26.8％ vs 19.0％),P=0.234;composite events of cardiac death/stroke/MI (18.9％ vs 20.3％),P=0.224 and MACCE occurrence (37.5％ vs 34.2％),P=0.946.With adjusted variations,the trend was similar to pre-adjustment.Conclusion:During the maximum 8.2 years follow-up period,PCI and CABG had the similar efficacy and safety in patients with ostial/shaft lesions of ULMCA.

Objective To explore the immune mechanism of negative results of immune tests of schistosomiasis japonica pa?tients. Methods Totally 142 schistosomiasis patients(positive stool examinations)of Poyang Lake region were tested by ELI?SA method,and the ROC curve was applied to determine the high and low response of the patients. The levels of cellular immu?nity and cytokines of high and low responders were compared. Results Totally eight schistosomiasis patients were found as low responders. Besides SWAP?IgA(t= -1.588,P > 0.1),the levels of isotype antibodies were significantly lower in the low re?sponders compared with those in the high responders(t = -14.517 to -2.866,all P < 0.05). In the low responders,the propor?tion of CD3+T was increased;and the proportions of CD4+T,CD8+T,CD4+CD25+Treg,and the ratio of CD4+/CD8+ were all de?creased,but all of them were not significant(t = -1.72 to 0.974,all P > 0.05)compared with those in the high responders. The differences of IFN?γ and IL?10 between the high and low responders were both not significant(t= -2.426 to 0.216,all P >0.05). Conclusions There is a significant difference between the high and low responders only in the levels of isotype antibod?ies. One of the reasons of low response in the immune tests is the much lower antibody level after the antigen?antibody compound is completely formulated.

Clinical breakpoints are used in phaseⅡorⅢclinical trials to categorize microorganisms if susceptibility to new tested antibacterial agents that means the patient infected by the pathogen will be enrolled the study or not.The role of this consensus is to define procedure and required data to setting breakpoints and how to revaluate it in clinical trials.

Objective To evaluate the safety and tolerance of single oral dose of soxifloxacin hydrochloride in Chinese healthy subjects.Methods Seventy-two eligible subjects were randomized into 7 escalation dose groups.Eight subjects in 50 mg group were randomized to receive either study drug or placebo in the ratio of 3 to 1;each ten subjects in 100 mg, 200 mg and 300 mg group received study drug to placebo was 4∶1, respectively.Twelve subjects in 400mg and 600mg group, the ratio of study drug to placebo was 2∶1 , and ten subjects in 800 mg group was 3∶2, respectively.Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, electrocardiography and electroen-cephalogram. Results A total of 72 subjects finished study. One subject in 400 mg group had bruise on the left ankle with creatine kinase elevated, considered not related to study drug, the other one in 600 mg group complained mild dizziness and two subjects in 800 mg group complained mild nausea.All of these symptoms were assessed as related to study drug.Conclusion Soxifloxacin hydrochloride was safe and well tolerated after single oral administration at dose range of 50 to 800 mg.

Objective To predict the possible dosing regimen for the clinical study of pazufloxacin.Methods Based on the pharmacokinetic parameters of pazufloxacin, its protein binding rates and bacterium sus-ceptible data, the probability of target attainment( PTA) was calculated at different pharmacokinetic/pharmacodynamic ( PK/PD ) target values through Monte Carol simulation and was compared with the values of reference drug levofoxacin.Results The results showed the PTAs of daily dose of 1000 mg pazufloxacin to similar pathogens was comparable with that of daily dose of 750 mg of levofloxacin.Conclusion Based on the simulated data, 500 mg bid of pazufloxacin was recommended for the further clinical studies.