Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (Tric^CKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, Tric^CKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
Sjogren's Syndrome/complications* ; Animals ; Xerostomia/etiology* ; Mice ; Mice, Inbred NOD ; MARVEL Domain Containing 2 Protein/metabolism* ; Humans ; Mice, Knockout ; Disease Models, Animal ; Interferon-gamma ; Salivary Glands/metabolism* ; Tight Junctions/metabolism* ; MicroRNAs/metabolism* ; Female

Exosomes are extracellular vesicles that facilitate cellular communication by transmitting biomolecules and altering the biochemical characteristics of receptor cells. Mesenchymal stem cell-derived exosomes(MSC-Exos)are lipid bilayer vesicles secreted by mesenchymal stem cells(MSCs). These exosomes have similar functions to MSCs and contain bioactive substances such as proteins, lipids, and nucleic acids. MSC-Exos play a vital role in intercellular communication and are involved in essential physiological processes including immune regulation, tissue damage repair, and angiogenesis promotion. Consequently, they have gained significant attention in research, particularly in the treatment of immune inflammatory diseases, ischemic diseases, and other related fields. This article provides an in-depth analysis of the potential treatment mechanisms for dry eye, focusing on the pathogenesis of the condition, including inflammatory reactions, nerve regeneration, and tissue repair. The objective is to establish a foundation for the application of MSC-Exos in the treatment of dry eye, thereby offering a valuable reference for the future clinical applications.

OBJECTIVE To study the role of phosphatidylinositol-3-kinase （PI3K） on sunitinib-induced myocardial systolic dysfunction. METHODS Using human-induced pluripotent stem cell-derived cardiomyocytes （hiPSC-CMS） as objects， the contractile force of cardiomyocytes was measured by CardioExcyte 96 system， and IC50 of sunitinib was calculated after hiPSC- CMS were treated with sunitinib at different concentrations [0 （control）， 0.5， 1， 3， 5， 10 μmol/L] for 24 hours. The effects of sunitinib （3.14 μmol/L） on the contractile frequency of cardiomyocytes， calcium transient amplitude and calcium transient recovery time course， mRNA expression of myocardial injury markers atrial natriuretic peptide （ANP）， brain natriuretic peptide （BNP） and β-myosin heavy chain （β-MHC） were detected. PI3K activator 3，4，5-triphosphate phos-phatidylinositol （PIP3， 1 μmol/L） and sunitinib were used to intervene in hiPSC-CMs jointly， so as to investigate the role of PI3K in the myocardial systolic dysfunction induced by sunitinib. RESULTS Sunitinib inhibited the contractile force of hiPSC-CMs in a concentration-dependent manner. IC50 of sunitinib was 3.14 μmol/L. After intervention with 3.14 μmol/L sunitinib， the contractile frequency of hiPSC-CMs and calcium transient amplitude were decreased significantly （P＜0.05 or P＜0.01）； the duration of calcium transient recovery was prolonged significantly （P＜0.05）， and mRNA expressions of ANP， BNP and β-MHC were significantly increased （P＜0.01）. After PI3K was activated with PIP3， the contractile force of hiPSC-CMs was increased significantly （P＜0.01）. CONCLUSIONS Activating PI3K activity is a potential molecular mechanism to improve myocardial toxicity induced by sunitinib.

Objective:To investigate the clinical value of fetal ultrasonography in the screening of congenital heart malformations in twins at 11-13 + 6 weeks of gestation. Methods:A retrospective cohort study method was used.Cases were collected from Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital (January 2012 to December 2016) and the Fourth Hospital of Shijiazhuang City (January 2014 to December 2018). The twins with singleton or twins with cardiac malformation were screened out as the cardiac malformation group, and the twins with normal delivery during the same period were selected as the control group. Ultrasound data such as the nuchal translucency (NT), crown-rump-length (CRL), chorionicity, conception method, NT discordance, CRL discordance, NT discordance ≥20% incidence rate between twins, and the CRL discordance ≥10% incidence rate between twins in the two groups at 11-13 + 6 weeks were compared and analyzed. Results:①There were 30 cases in the cardiac malformation group (including 27 twins with singleton cardiac malformation and 3 twins with twin cardiac malformation) and 1 906 cases in the control group. ②The incidence rates of NT value ≥95th percentile and NT value ≥99th percentile in one or two pregnancies were significantly higher in the cardiac malformation group than in the control group (20.00% vs 2.20%, P<0.001; 10.00% vs 0.63%, P=0.002), the area under the ROC curve (AUC) for cardiac malformation screening was 0.589 and 0.549, respectively; CRL discordance in cardiac malformation group was higher than that in control group ( P=0.018), the incidence of CRL discordance ≥10% in the cardiac malformation group was higher than that in the control group (26.67% vs 12.70%, P=0.024), the AUC of cardiac malformation screening was 0.570; there were no significant differences in the incidence of NT discordance, the incidence of NT discordance ≥20%, pregnancy pattern and chorionicity between the two groups (all P>0.05). ③Multivariate Logistic regression analysis was performed using the incidence rates of NT value ≥95% and NT value ≥99%, CRL discordance ≥10%, and NT discordance ≥20%. The incidences of fetal NT value ≥95% and NT value ≥99% were risk factors for cardiac malformation in twins ( OR=11.095, 105.778; 95% CI=4.311-28.558, 16.984-658.796). Conclusions:Ultrasound at 11-13 + 6 weeks of gestation showing thickened value of one or two fetuses, and the CRL discordance≥10%, indicates an increased risk of cardiac malformation in the twins; NT value ≥95% and NT value ≥99% is a risk factor for heart defects in twins.

Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6-CREB-SOD2-dependent pathway in IgG4-RS.
Cellular Senescence/genetics* ; Humans ; Immunoglobulin G/metabolism* ; Interleukin-13/pharmacology* ; Mitochondria/metabolism* ; Sialadenitis/metabolism*

Lung cancer is one of the most common malignancies with the highest incidence rate and mortality rate worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85%. Only 5% NSCLC patients are anaplastic lymphoma kinase (ALK) rearrangement positive NSCLC, but the prognosis of these patients is poor, and treatment is urgent. Ensartinib (X-396), a next-generation ALK tyrosine kinase inhibitor (ALK-TKI), has shown greater potency on inhibiting ALK activity and controlling brain metastases than crizotinib, which is indicated for the treatment of crizotinib-resistant, ALK-positive NSCLC patients. Several phase I to III clinical trials included both healthy volunteers and NSCLC patients have been conducted both in China and abroad. In this review, we briefly summarized the results of these trials, and preliminary efficacy, safety, pharmacology and pharmacokinetics/pharmacodynamics of ensartinib were discussed.

This paper introduced the design and application of the performance appraisal scheme for the interventional operation platform.The comparison of interventional operations before and after the means of performance management in place, presented the effective role of performance management in interventional operation platform, and analyzed the motivation effect of performance management on the enthusiasm of interventional operators.The authors recommend performance appraisal and incentive compensation mechanism to motivate the clinical use of the platform, and greater application of such a common platform, for perfection of surgery performance management.

Objective To analyze the effects of quality supervision and continuous improvement system on optimizing in-hospital diagnosis and treatment process in patients with acute ischemic stroke (AIS).Methods From September 2013 to May 2016,424 consecutive patients with AIS treated with intravenous thrombolysis and/or endovascular therapy in Changhai Hospital,the Second Military Medical University were enrolled retrospectively.They were analyzed according to the annual running process (the first year[from September 2013 to August 2014],the second year[from September 2014 to August 2015],and the third year[from September 2015 to May 2016]).The spend time and delay (DTN>60 min,DTP>90 min) rate of each treatment process in the first,second,and third year (time from door-to-imaging[DTI],door-to-needle[DTN],imaging-to-needle (ITN),door-to-groin puncture (DTP) and imaging-to-groin puncture (ITP) were compared.Taking the time periods (>median) of having significant differences of the spend time of the treatment processes as the dependent variables in the first,second,and third year,the influence of the years and treatment modalities on delay was observed.The difference of constituent ratio of the reasons for delay in intravenous thrombolysis and endovascular therapy (objective reasons/other reasons) in different years were analyzed.Results (1) DTIs were 23.0 (11.0,42.0) min,22.0 (10.1,39.0) min,and 13.0 (6.0,27.0) min,respectively,and DTNs were 50.0 (30.0,77.1) min,45.0 (30.0,70.2) min,and 36.0 (24.0,57.0) min,respectively in the first,second,and third year.The spending time was shortened year by year.There were significant differences among the different years (all P<0.01).The spending time of DTP had a tendency to be shortened,but there were significant differences among different years (P=0.06).There were no significant differences between the spending time of ITN and ITP (all P>0.05).(2) The DTN delay rates were 33.3% (40/120),20.7% (29/140),and 8.1% (9/111),respectively in the first,second,and third year.There were significant differences among the 3 years (x2=22.111,P<0.01).There were no significant differences among the DTP delay rates (P=0.08).(3) Multivariate Logistic regression analysis showed that taking the first years as a reference,the risk of DTI delay was reduced in the third year (OR,0.174,95%CI 0.101-0.298,P<0.01),the risks of DTN delay were reduced in the second and third year (OR,0.564,95%CI 0.338-0.941;OR,0.180,95%CI 0.101-0.320,all P<0.05).For simple intravenous thrombolysis,bridging therapy was a protective factor for the improvement of treatment efficiency in the DTI process (OR,0.530,95%CI 0.297-0.943,P=0.031).Compared with the bridging therapy,the direct endovascular therapy was a protective factor for DTP treatment (OR,0.427,95%CI 0.202-0.901,P=0.025).The remaining independent variables were not associated with the occurrence of DTN and DTP delay (all P>0.05).(4) During the three years,the delay of intravenous thrombolysis was mainly due to objective reasons.The constituent ratio of other reasons caused delay of intravenous thrombolysis was decreased year by year.There was no other reasons for delay in the third year).There was no significant difference in the constituent ratio of the delay reasons in endovascular treatment (x2=3.622,P=0.164).Conclusion Under the existing process and resource allocation,setting the DTN target time and implementing continuous quality improvement are conducive to the effective implementation of brain CT scan and continuous optimization of intravenous thrombolysis in the processes in AIS patients with the first diagnosis.

Objective To investigate the effect of dl-3n-Butylphthalide (NBP) on cardiac function and sympathetic remodeling in rats with myocardial infarction (MI).Methods Totally 50 male SD rats were randomly divided into 3 groups:Sham-operated (sham) group (n 10),myocardial infraction (MI) group (n=20) and MI with NBP group (n=20).A rat myocardial infarction model was established by ligating anterior descending branch of coronary artery.Rats in MI with NBP group were received the gavage treatment with NBP.Cardiac function was evaluated by hemodynamic detection at 7 day post-MI.Cardiac tissues were stained with hematoxylin and eosin as well as Masson trichrome.The distribution and density of growth associated protein-43-(GAP-43) and tyrosine hydroxytase-(TH) positive nerve at infarction border zone were detected by immunohistochemistry.The activation of nuclear factor-κB (NF-κB) signaling pathway was detected by western blot analysis.Results 8 rats died in MI group,in which 2 rats died within 24h.7 rats died in MI with NBP group,and in which 3 rats died within 24 h.The left ventricular end-diastolic pressure (LVEDP) and left ventricular end-systolic pressure (LVESP) were (7.81 ± 2.46) mmHg (1 mmHg=0.133 kPa) and (103.32±10.59) mmHg,(18.93±3.17) mmHg and (136.44±13.62) mmHg,(16.56±4.82) mmHg and (112.83±16.97) mmHg in sham group,MI group and MI with NBP group respectively.There were no significant differences in + dP/dt and-dP/dt between MI group and MI with NBP group (both P＞0.05).Compared with sham group,the collagen volume fraction at infarct border zone was increased in MI group (P＜0.05),but was reduced in MI with NBP group as compared to the MI group (P＜0.05).The densities of GAP-43-and TH-positive nerves at infarct border zone were increased in MI group as compared with sham group,and reduced in MI with NBP group as compared with MI group (both P＜0.05).NBP could reduced p IKBα protein expression and increase IKBα protein expression in rats with MI.Conclusions NBP may improve the sympathetic remodeling after MI via the inhibition of NF-κB signaling pathway.

Objective To evaluate the influence of inappropriate position deviation on radioactive iodine uptake (RAIU),effective half-life (Teff) and the corresponding dose variances in patients suffering from Graves hyperthyroidism.Methods RAIU was examined in 20 patients with Graves hyperthyroidism (7 males,13 females,average age (46.60 ±9.55) years) 2,4,6,and 24 h after intake of the radioiodine capsule.A scintillation probe was positioned at the center of the inferior edge of the thyroid cartilage 25 cm away for 2 min,which was defined as the standard manipulation (test 1).Then,the probe was moved either 5 cm backward (test 2) or 5 cm higher (test 3) compared with test 1.Variants of RAIU,Teff as well as dose calculations were acquired by different combinations (CⅠ-Ⅸ) of 4 h and 24 h-RAIU,according to the above 3 manipulations (C Ⅰ-Ⅲ:test 1 for RAIU4 h,test 1,2,3 for RAIU24 h respectively ; C Ⅳ-Ⅵ:test 2 for RAIU4h,test 1,2,3 for RAIU24h respectively; CⅦ-Ⅸ:test 3 for RAIU4h,test 1,2,3 for RAIU24h respectively).Paired t test was used to compare the statistical differences between C H-Ⅸ to C Ⅰ.Results RAIU24 h of test 2 (68.08％ ± 7.88％) and test 3 (62.18％ ± 7.45％) were significantly lower than that of test 1 (78.05％ ± 8.31％ ;t =12.15,14.37,respectively,both P ＜ 0.01).Teffs of C Ⅱ (4.42 ± 0.73) d,CⅢ(3.76 ±0.53) d,CⅤ(5.59 ±0.46) d,CⅥ(4.47 ±0.44) d,CⅧ(5.94 ±0.54) d and CⅨ (5.45 ±0.66) d were significantly different from that of C Ⅰ (5.04 ±0.56) d which was defined as standard (t:3.86-13.64,all P ＜0.01).Among the 180 131I dose values calculated by different Teff and RAIU values induced from C Ⅰ-Ⅸ combinations,74.4％ (119/160) were over-calculated while 9.4％ (15/160) were under-calculated.Taking one patient as an example,the changes of RAIU24 h (decreased up to 26.0％) and the percentage of Teff deviation(66.9％,ranged from-47.5％ to 19.4％)led to an over-calculated 131 I dosage by as high as 129.8％ compared with CⅠ.Conclusions Incorrect positioning in RAIU detection could result in various false RAIU,Teff and 131I dose calculations.Such deviations could possibly exert an impact on the patients' therapeutic outcomes,thus influencing the efficacy of the iodine therapy.Optimization of RAIU positioning is essential for clinical practice to guarantee radioiodine dose management.