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Poly (ADP-ribose) polymerase (PARP) serves a key role in several neurological disorders, however, the specific role of PARP in delayed cerebral vasospasm (DCVS) following subarachnoid hemorrhage (SAH) remains unclear. The present study was conducted to clarify the possible mechanism of PARP in DCVS with the treatment of 3-aminobenzamide (3-AB), a PARP inhibitor. In the preliminary experiment, an internal carotid artery puncture SAH model, a cisterna magna double injection SAH model and prechiasmatic cistern single injection SAH model were compared with respect to mortality and neurobehavioral test results. The prechiasmatic cistern single injection SAH model was chosen to induce DCVS in the formal experiment. In the formal experiment, a total of 96 Sprague Dawley rats were randomly allocated into the sham group, the SAH group and the SAH+3-AB group and then each group was further subdivided into days 3, 5, 7 and 14 post-SAH subgroups (n=8 for each subgroup). The prechiasmatic cistern single injection SAH model was established to induce DCVS. Neurobehavioral testing and HE staining were conducted to evaluate the degree of cerebral vasospasm. PARP activity was assessed by ELISA and immunohistochemistry. An electrophoretic mobility shift assay was used to detect nuclear factor (NF)-κB DNA-binding activity. The expression of monocyte chemotactic protein 1 (MCP-1) and C-reactive protein (CRP) were measured by western blotting. Cerebral vasospasm occurred following SAH and became most severe on around day 7 post-SAH. NF-κB activity, PARP activity, the expression of MCP-1 and CRP exhibited a similar time course to cerebral vasospasm. Treatment with 3-AB alleviated the degree of cerebral vasospasm. NF-κB activity, PARP activity and the expression of MCP-1 and CRP were also suppressed by 3-AB treatment. In conclusion, PARP may serve an important role in regulating the inflammatory response and ultimately contribute to DCVS. Therefore 3-AB may be a potential therapeutic agent for DCVS.

Introduction 131I therapy is a choice for Graves’ hyperthyroidism. Several factors that affect the success of 131I treatment in Graves’ disease (GD) patients have been put forward. The aim of this retrospective study was to evaluate the factors influencing the success of 131I therapy and the occurrence of hypothyroidism after 131I therapy. Patients and methods We reviewed 325 GD patients, who were well documented out of 779 cases, treated with 131I in the First Affiliated Hospital of Xi’an Jiaotong University between 2010 and 2016. We collected the potential influencing factors, including demographic data (age, sex, family history), iodine intake state, antithyroid drugs (ATD) taking, thyroid texture, complications of hyperthyroidism, physical and laboratory examinations [thyroid weight, effective 131I half-life time (Teff), 24-h iodine uptake rate, tri-iodothyronine, thyroxine, free tri-iodothyronine (FT3), free thyroxine, thyroid-stimulating hormone, thyroglobulin antibody, thyroid microsome antibody, thyrotropin receptor antibody], and final administered dosages according to Quimby formula. The correlations between the prognosis of GD patients and these factors were analyzed by logistic regression analysis. Results Out of 325 patients, 247 (76.00%) were treated successfully with radioiodine. GD patients who were cured by 131I therapy were more likely to have smaller thyroid [odds ratio (OR)=0.988, 95% confidence interval (CI)=0.980–0.996, P=0.002], lower FT4 levels (OR=0.993, 95% CI=0.988–0.997, P=0.002), and shorter time of ATD withdrawal before 131I treatment (OR=0.985, 95% CI=0.975–0.996, P=0.002). Hypothyroidism occurred in 132 (41.00%) out of 325 patients. There was an increased risk of early hypothyroidism in patients with lower 24-h iodine uptake (OR=0.964, 95% CI=0.941–0.988, P=0.004), and treated with a lower total dose of iodine (OR=0.892, 95% CI=0.824–0.965, P=0.005) and a higher iodine dose per garm of thyroid tissue (OR=5.414E+14, 95% CI=45.495–6.444E+27, P=0.027). Conclusion Our results showed that 131I treatment was more successful in patients with lower weight of the thyroid, lower free thyroxine level, and shorter ATD taking period. Furthermore, early hypothyroidism after radioiodine treatment was more likely to occur in patients with lower 24-h iodine uptake, lower total dose of iodine, and higher iodine dose per garm of thyroid tissue.

Objective The aim of this study was to further elucidate the mechanisms of dual-phase technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) parathyroid imaging by exploring the association between early uptake results (EUR), delayed uptake results (DUR), and the retention index (RI) in dual-phase 99mTc-MIBI parathyroid imaging and P glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and glutathione S-transferase-π (GST-π) expression in hyperparathyroidism (HPT). Patients and methods Preoperative dual-phase (early and delayed) 99mTc-MIBI imaging was performed on 74 patients undergoing parathyroidectomy for HPT. EUR, DUR, and RI were calculated. P-gp, MRP1, and GST-π expressions were assessed using immunohistochemistry in resected tissue from HPT and control patients. The association between P-gp, MRP1, and GST-π expressions and EUR, DUR, and RI in HPT was evaluated. Results The positive rate of dual-phase 99mT c-MIBI imaging was 91.89% (68/74) and the false-negative rate was 8.11% (6/74). P-gp and GST-π expressions were higher in tissues resected from control compared with HPT patients (47.37 and 81.5%, P

To investigate the anticancer effects of curcumin-induced autophagy and its effects on the human lung adenocarcinoma A549 cell line, inverted phase contrast microscopy was used to observe alterations to the cytomorphology of cells. An MTT assay was used to measure cell viability. Autophagy was detected using acridine orange (AO) staining and 3-methyladenine (3-MA) was used as an autophagy-specific inhibitor. Dose- and time-dependent A549 cell viability inhibition was observed following curcumin treatment. A dose-dependent increase in the red fluorescent structures in A549 cells was identified following curcumin treatment for 48 h through AO staining. In addition, the activation of autophagy was determined through changes in the number of autophagic vesicles (AVs; fluorescent particles) infected with monodansylcadaverine (MDC). The fluorescence intensity and density of AVs in the curcumin-treated groups were higher at 48 h compared with the control group. Finally, the MTT assay demonstrated that the survival rates of the curcumin-treated cells were increased when pretreated with 3-MA for 3 h, indicating that the inhibitory effect of curcumin on A549 cells is reduced following the inhibition of autophagy. Furthermore, AO and MDC staining confirmed that 3-MA does inhibit the induction of autophagy. Thus, it was hypothesized that the induction of autophagy is partially involved in the reduction of cell viability observed following curcumin treatment. The anticancer effects of curcumin on A549 cells can be reduced using autophagy inhibitors. This suggests a possible cancer therapeutic application of curcumin through the activation of autophagy. These findings have improved the understanding of the mechanism underlying the anticancer property of curcumin.

Web service composition is a process to compose homogenous or heterogeneous services together in order to create value-added services. Many non-functional features including QoS and user preferences have been adopted to guide such a process. However, two issues are observed: (1) the expressiveness of user preference is subject to quantitative preferences without proper use of qualitative preferences; (2) a highly preferred composite service may not be trustworthy, or a highly trustworthy composite service may not be preferable. The existing studies concentrate on either user preference or service trust, and fail to provide a systematic solution to integrate both user preference and service trust together for service compositions. To address these issues, we combine both qualitative and quantitative preferences as well as service trust together in the process of service composition. We investigate the application of heuristic algorithms on multi-objective optimization for the service composition problem. A new hybrid nature inspired intelligent algorithm is also proposed and compared with other popular heuristic algorithms. We aim to obtain optimal web service compositions that can satisfy these (potentially conflicting) constraints as much as possible. Results demonstrate the efficiency and effectiveness of our approach in comparison with other counterparts.

With the increasing popularity of the service-oriented architecture and web service technologies, service composition has become widely adopted to create value-added services from existing ones. As more web services have been deployed on the Internet, it results in a large number of services providing identical functionalities while differing in their non-functional properties (NFPs). However, most of the existing techniques for NFP-aware service composition only consider quantitative NFPs. In this paper, we present a model that deals with both quantitative and qualitative NFPs. We develop two algorithms, where the first one combines global optimization with local selection and the second one leverages a genetic algorithm. We have conducted extensive experiments to evaluate the effectiveness of our model and algorithms.

The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokinetics, the determination of metabolic principles, and evaluation of treatment effect. The objective of the study was to investigate the pharmacokinetic characteristics of gene recombination angiogenesis inhibitor Kringle 5 in vivo. The SPECT/CT and specific 131I-Kringle 5 marked by Iodogen method were both applied to explore the pharmacokinetic characteristics of 131I-Kringle 5 in vivo, and to investigate the dynamic distributions of 131I-Kringle 5 in target organs. Labeling recombinant angiogenesis inhibitor Kringle 5 using 131I with longer half-life and imaging in vivo using SPECT instead of PET, could overcome the limitations of previous methods. When the doses of 131I-Kringle 5 were 10.0, 7.5 and 5.0 g/kg, respectively, the two-compartment open models can be determined within all the metabolic process in vivo. There were no significant differences in t1/2α, t1/2β, apparent volume of distribution and CL between those three levels. The ratio of AUC(0~∞) among three different groups of 10.0, 7.5 and 5.0 g/kg was 2.56:1.44:1.0, which was close to the ratio (2:1.5:1.0). It could be clear that in the range of 5.0–10.0 g/kg, Kringle 5 was characterized by the first-order pharmacokinetics. Approximately 30 min after 131I-Kringle 5 was injected, 131I-Kringle 5 could be observed to concentrate in the heart, kidneys, liver and other organs by means of planar imaging and tomography. After 1 h of being injected, more radionuclide retained in the bladder, but not in intestinal. It could be concluded that 131I-Kringle 5 is mainly excreted through the kidneys. About 2 h after the injection of 131I-Kringle 5, the radionuclide in the heart, kidneys, liver and other organs was gradually reduced, while more radionuclide was concentrated in the bladder. The radionuclide was completely metabolized within 24 h, and the distribution of radioactivity in rats was similar to normal levels. In our study, the specific marker 131I-Kringle 5 and SPECT/CT were successfully used to explore pharmacokinetic characteristics of Kringle 5 in rats. The study could provide a new evaluation platform of the specific, in vivo and real-time functional imaging and pharmacokinetics for the clinical application of 131I-Kringle 5.

Lung resident mesenchymal stem cells (LR-MSCs) contribute to the progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the molecular mechanism underlying LR-MSCs regulation upon transforming growth factor (TGF)-β1 stimulation. We induced fibrogenic differentiation of LR-MSCs isolated from mice by TGF-β1. Several stem cell markers were detected by flow cytometric analysis. Protein expression level was tested by Western blotting and mRNA level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, proliferation and apoptosis were measured. TGF-β1 promoted fibrogenic differentiation of LR-MSCs and upregulated β-catenin and p-glycogen synthase kinase-3β, suggesting the activation of Wnt signaling. MicroRNA (MiR)-124-3p was significantly upregulated in TGF-β1 treated LR-MSCs compared to untreated cells. Intriguingly, silence of miR-124 reversed the TGF-β1-induced changes in cell viability and proliferation, and also led to a decrease of cell apoptosis. Additionally, in miR-124 silenced cells, α-smooth muscle actin, collagen I and fibronectin were downregulated compared to control cells. We ultimately identified a new target of miR-124, AXIN1, which was repressed by miR-124. In conclusion, miR-124 regulates AXIN1 to activate Wnt signaling and therefore plays a crucial role in the TGF-β1-induced fibrogenic differentiation.

e21700 Background: Immune checkpoint inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have been new standard of care for non-small cell cancer patients. However, little is known about the difference in efficacy between these two types of drugs. In this study, we aimed to assess the differences between anti-PD-1 and anti-PD-L1 in NSCLC treatment through a systematic review and meta-analysis. Methods: We systematically searched PubMed, CENTRAL, and Embase from January, 2000 to November, 2019. We also reviewed abstracts and presentations from all major conference proceedings. All randomized controlled trials that compared anti-PD-1/anti-PD-L1 with standard treatment in NSCLC cancer patients were selected as candidates. Studies with anti-PD-1 and anti-PD-L1 were screened and paired upon the mirror principle. The primary outcome was the difference in overall survival (OS). As the main results, indirect comparison of anti-PD-1 and anti-PD-L1 were calculated for each mirror group and then pooled using a random-effects model. Results: 16 randomized controlled trials were included for the meta-analysis. Overall, anti-PD-1 exhibited superior OS (HR 0.80, 95% CI 0.68-0.95, P= .01) over anti-PD-L1. Subgroup analysis showed that anti-PD-1 exhibited superior OS over anti-PD-L1 ICIs in combination therapy (HR 0.67, 95% CI 0.54-0.82, P nd line therapy (HR 0.84, 95% CI 0.66-1.06) or 1st line therapy (HR 0.77, 95% CI 0.58-1.03). Conclusions: The results demonstrated that anti-PD-1 exhibited favorable survival outcomes compared to anti-PD-L1 in NSCLC treatment, which provides an important guide for clinicians.

Background: 24-h urine collection is regarded as the “gold standard” for monitoring sodium intake at the population level, but ensuring high quality urine samples is difficult to achieve. The Kawasaki, International Study of Sodium, Potassium, and Blood Pressure (INTERSALT) and Tanaka methods have been used to estimate 24-h urinary sodium excretion from spot urine samples in some countries, but few studies have been performed to compare and validate these methods in the Chinese population. Objective: To compare and validate the Kawasaki, INTERSALT and Tanaka formulas in predicting 24-h urinary sodium excretion using spot urine samples in 365 high-risk elder patients of strokefrom the rural areas of Shaanxi province. Methods: Data were collected from a sub-sample of theSalt Substitute and Stroke Study. 365 high-risk elder patients of stroke from the rural areas of Shaanxi province participated and their spot and 24-h urine specimens were collected. The concentrations of sodium, potassium and creatinine in spot and 24-h urine samples wereanalysed. Estimated 24-h sodium excretion was predicted from spot urine concentration using the Kawasaki, INTERSALT, and Tanaka formulas. Pearson correlation coefficients and agreement by Bland-Altman method were computed for estimated and measured 24-h urinary sodium excretion. Results: The average 24-h urinary sodium excretion was 162.0 mmol/day, which representing a salt intake of 9.5 g/day. Three predictive equations had low correlation with the measured 24-h sodium excretion (r = 0.38, p < 0.01; ICC = 0.38, p < 0.01 for the Kawasaki; r = 0.35, p < 0.01; ICC = 0.31, p < 0.01 for the INTERSALT; r = 0.37, p < 0.01; ICC = 0.34, p < 0.01 for the Tanaka). Significant biases between estimated and measured 24-h sodium excretion were observed (all p < 0.01 for three methods). Among the three methods, the Kawasaki method was the least biased compared with the other two methods (mean bias: 31.90, 95% Cl: 23.84, 39.97). Overestimation occurred when the Kawasaki and Tanaka methods were used while the INTERSALT method underestimated 24-h sodium excretion. Conclusion: The Kawasaki, INTERSALT and Tanaka methods for estimation of 24-h urinary sodium excretion from spot urine specimens were inadequate for the assessment of sodium intake at the population level in high-risk elder patients of stroke from the rural areas of Shaanxi province, although the Kawasaki method was the least biased compared with the other two methods.

Curcumin is known to exhibit anticancer effects on various cancers with selective cytotoxicity in tumor cells. In the present study, the effects of curcumin‑induced multiple PCDs on human non‑small cell lung cancer (NSCLC) cells and the potential molecular mechanisms of apoptosis and autophagy triggered by curcumin via the PI3K/Akt/mTOR signaling pathway were explored, further confirmed by co‑culture of curcumin with mTOR blocker rapamycin and PI3K/Akt inhibitor LY294002. The anti‑proliferation effect of different stimulus was measured by MTT assay. Apoptosis was detected by flow cytometry. Autophagy induction was detected by MDC labeling and western blotting of Beclin1, LC3, and p62 expression. The mRNA and protein expression levels of Akt and mTOR were assayed by real‑time fluorescence quantitative (qRT‑PCR) technique and western blotting. Our results showed that curcumin inhibited the viability of A549 cells time‑ and dose‑dependently. In addition, a dosage-dependent A549 cell apoptosis‑induction phenomena was observed by the curcumin intervention. Moreover, obvious autophagy was induced after curcumin‑treatment, characterized by the formation of fluorescent particles [autophagic vesicles (AVs)] and significant increase in ratio of LC3‑Ⅱ/LC3‑Ⅰ and Beclin1 as well as decreased p62 expression. Furthermore, the effect of curcumin on a substantial downregulation of phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was observed. It is worth noting that the inhibition of mTOR by rapamycin or of PI3K/Akt by LY294002 augmented curcumin‑induced apoptosis and autophagy, leading to significant inhibition of cell proliferation. From these findings, it can be speculated that curcumin potently inhibit the cell growth of NSCLC A549 cells through inducing both apoptosis and autophagy by inhibition of the PI3K/Akt/mTOR pathway. These results support the potential use of curcumin as a novel candidate in treatment of human lung cancer.

Correlation between the expression of STK33 and the pathology of lung cancer was investigated, to explore its effects on prognosis. Hundred and two lung cancer patients diagnosed by pathological examinations were randomly selected in Shanghai Jiao Tong University Affiliated Sixth People's Hospital from February, 2012 to February, 2017 to serve as observation group, and the tumor tissues were collected. At the same time, 19 patients with lung benign lesions were selected and lung tissues were also collected to serve as control group. RT-qPCR was used to detect the expression of STK33 mRNA in tissues. Expression levels of STK33 protein were detected and compared by SP immunohistochemistry staining and western blot analysis. Statistical analysis was performed to analyze the correlation between STK33 expression and the pathology and prognosis of lung cancer. Results of PCR showed that expression level of STK33 gene in control group was significantly lower than that in observation group (p

Elevated levels of KL-6 are reported in the serum and/or bronchoalveolar lavage fluid (BALF) of patients with interstitial lung disease (ILD) and are useful to estimate the severity and prognosis of the disease. However, whether the anti-KL-6 antibody could attenuate pulmonary fibrosis remains unclear.This study aims to investigate the therapeutic effects and mechanisms of anti-KL-6 antibody on bleomycin-induced pulmonary fibrosis.A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (5 mg/kg). Mouse received anti-KL-6 antibody (20 ug/day, once a day) from day 7 to 21 after bleomycin injection. The effects of anti-KL-6 antibody were evaluated by pathological examination, measuring hydroxyproline measurements in lung tissues, leukocyte counts in BALF and the expression of collagen type I and type III using qRT-PCR. The expression of profibrotic cytokine (transforming growth factor-β1, TGF-β1), antifibrotic cytokine (hepatocyte growth factor, HGF), and KL-6 in lung tissues were analyzed by ELISA. The apoptosis of epithelial cell was examined by TUNEL staining.Anti-KL-6 antibody significantly reduced the number of alveolar inflammatory leukocytes (total and differential counts) in BALF of mice with bleomycin-induced pulmonary fibrosis as well as the content of hydroxyproline in the lung tissues. Treatment with anti-KL-6 antibody downregulated the expression of collagen type I, TGF-β1 and KL-6, upregulated the expression of HGF and inhibited the apoptosis of epithelial cells.These findings indicated the anti-KL-6 antibody may potentially be developed as a useful inhibitor of pulmonary fibrosis.