Search

Ting Yang,1,2 Wen-Juan Wu,1 Li-Ming Tian,3 Deng-Feng Zhang,4 Xiao-Yan Yang,1 Jue Qi,1 Ying Tu,1 Li He1 1Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650023, People’s Republic of China; 2Department of Dermatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, 435000, People’s Republic of China; 3Department of Dermatology, First Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China; 4Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, People’s Republic of ChinaCorrespondence: Li HeDepartment of Dermatology, First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, 650023, People’s Republic of ChinaTel/Fax +86 0871-65317895Email lihe_4785@163.comObjective: Androgens acting through the androgen receptor play a crucial role in the pathogenesis of acne. This study aimed to identify whether two key genes (CYP21A2 and CYP19A1) involved in the synthesis and metabolism of androgens were associated with Pillsbury III-IV severe acne vulgaris.Methods: We carried out a standard questionnaire survey about acne and enlisted 600 Pillsbury III-IV severe acne vulgaris patients and 652 healthy controls of Han Chinese descent from Yunnan, China in the study. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot assay and analyzed for association with severe acne.Results: There was no significant difference in gender between the two groups (P = 0.085), and the age of the acne case group was significantly lower than that of the control group (P < 0.001). Our results revealed that only two SNPs, rs6474 (p.Arg102Lys) (P = 0.001) and rs6465 (P = 0.025) of the CYP21A2 gene were significantly associated with severe acne among the Han Chinese. When subjects were divided into males and females, significant associations were observed only in male patients with severe acne vulgaris for four variants: CYP21A2 rs6474 (p.Arg102Lys) (P = 0.002); CYP21A2 rs6465 (P = 0.012); CYP19A1 rs8023263 (P = 0.037); and CYP19A1 rs2470152 (P = 0.007). Haplotype analyses showed that the distribution of CYP21A2 haplotypes was significantly associated with male patients, while no association of CYP19A1 haplotypes was observed. The structure of the human CYP21A2 consists of two substrate binding sites and one substrate access channel.Conclusion: This study shed a light on a potentially important effect of CYP21A2 and CYP19A1 genes in severe acne vulgaris in the Han Chinese, especially for male patients. Future studies using independently verified datasets from a broader geographical spectrum will be valuable in identifying the causal and functional variants responsible for severe acne vulgaris within the CYP19A1 and CYP21A2 genes.Keywords: androgen receptor, severe acne, synthesis, metabolism, genetic risk

Purpose To assess the pharmacokinetic (PK) effect of proton pump inhibitors on the novel poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor fluzoparib, and observe the safety of its co-administration with omeprazole. Patients and methods Sixteen male healthy volunteers (HVs) were enrolled in a single-center, single-arm, open-label, fixed-sequence study. HVs took fluzoparib (100 mg, p.o.) after meal consumption on day-1, took omeprazole 40 mg (p.o.) under a fasting condition from day-5 to day-9, and took fluzoparib (100 mg, p.o.) after meal consumption on day-9. Blood samples were collected at predetermined timepoints for PK analyses. Safety was assessed via clinical laboratory tests. The study was registered with the Clinical Trials Registry on 30 September 2019 (NCT04108676). Results The peak plasma concentrations (Cmax) after fluzoparib administration was 2395.17 ± 418.27 ng/mL, the area under the curve (AUC) within 72 h (AUC0 − 72 h) was 26669.09 ± 7320.12 h·ng/mL, and AUC0−∞ was 26897.44 ± 7573.61 h·ng/mL. The Cmax after co-administration of fluzoparib and omeprazole was 2489.43 ± 423.72 ng·mL, AUC0 − 72 h was 30300.49 ± 8350.08 h·ng/mL, and AUC0−∞ was 30678.74 ± 8595.55 h·ng/mL. The geometric mean ratio of Cmax, AUC0 − 72 h and AUC0−∞ was 104.0% (90%CI: 94.8–114.0%), 113.6% (104.2–123.9%) and 104.1% (104.5–124.6%). The number of HVs with adverse reactions was identical (eight) for administration of fluzoparib and co-administration of fluzoparib and omeprazole. Conclusions The proton pump inhibitor omeprazole did not have a significant influence on the PK behavior of fluzoparib, and its safety profile was good upon co-administration with omeprazole. (NCT04108676, 30 September 2019)

The current study compared the safety, tolerability, and pharmacokinetics of the new compound pharmaceutical preparation tazarotene clindamycin cream, and 2 single pharmaceutical preparations, tazarotene cream and clindamycin phosphate gel. Twelve healthy volunteers were enrolled in this single-center, single-blind, 3-treatment, 3-period crossover, single-dose randomized study. An 800-cm2 area on volunteers' backs was evenly smeared with 1.6 g of the test preparation to form a film. Blood samples were collected at predetermined time points for pharmacokinetic analysis. Safety and tolerability were assessed via skin reaction evaluation and clinical laboratory tests. The incidences of skin reactions were 18.2% for tazarotene clindamycin cream, 25.0% for tazarotene cream, and 18.2% for clindamycin phosphate gel. There were no significant differences in safety or tolerability among the 3 groups. Erythema, desquamation, and pruritus occurred in 7 volunteers, but no burning or tingling occurred. All adverse events were mild and resolved spontaneously, and there were no severe adverse events. The respective maximum plasma concentrations of tazarotenic acid after local administration of tazarotene clindamycin cream and tazarotene cream were 11 ± 5 pg/mL and 18 ± 12 pg/mL, and the areas under the curve within 72 hours were 444 ± 341 pg · h/mL and 692 ± 462 pg · h/mL.

Purpose To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects. Methods This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC0–t, AUC0–∞ and Cmax in plasma. Results Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for flumatinib, Cmax, AUC0–t and AUC0–∞ were 281.65% (225.80–351.31%), 167.43% (143.92–194.79%), and 166.87% (143.47–194.09%); for M1, Cmax, AUC0–t, and AUC0–∞ were 188.59% (145.29–244.79), 163.94% (149.11–180.24%), and 164.48% (150.36–179.94%); for M3, Cmax, AUC0–t, and AUC0–∞ were 63.47% (54.02–74.57%), 85.23% (74.72–97.22%), and 96.73% (86.63–108.02%). Conclusion Among the subjects, oral administration of 400 mg of flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to flumatinib, therefore, fasting may be recommended. Clinical trial registration The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.

Aims Hetrombopag olamine is a novel small-molecule, nonpeptide thrombopoietin receptor agonist developed for immune thrombocytopenia treatment. This study aims to determine the safety and the effect of fasting duration after administration of hetrombopag on pharmacokinetics and pharmacodynamics in Chinese healthy subjects. Methods A randomized, open-label, single-dose, 3-period crossover, self-control trial was conducted. 15 eligible subjects were enrolled and received hetrombopag 7.5 mg at day 1 of each period followed by a standard meal 4 hours postdose (treatment A/fasting condition), or a high-calorie, high-fat meal 1 hour postdose (treatment B), or a high-calorie, high-fat meal 2 hours postdose (treatment C). The plasma concentrations of hetrombopag were determined by validated liquid chromatography-tandem mass spectrometry, platelet counts were quantified by blood test. Analysis was performed using a mixed model, including treatment, period as fixed effects and participant as a random effect. Results Compared with treatment A, peak concentration and area under concentration-time curve extrapolated to infinity decreased by 56 and 74.6%, and 44 and 61% in treatments B and C, respectively. The mean platelet number on day 6 increased by 15.8, 6.96 and 10.26%, respectively, in treatments A, B and C in comparison with baseline platelet level. No severe adverse events happened in any of the 3 treatments. Conclusion Hetrombopag was well tolerated in healthy male subjects under fasted/fed conditions. The shorter fasting duration resulted in lower hetrombopag exposure, corresponding to a lower level of platelet elevation. Therefore, we recommended oral administration of hetrombopag on an empty stomach (fasting condition) or at least 2 hours before a meal to achieve maximum bioavailability.

In recent years, online sentiment texts are generated by users in various domains and in different languages. Binary polarity classification (positive or negative) on business sentiment texts can help both companies and customers to evaluate products or services. Sometimes, the polarity of sentiment texts can be modified, making the polarity classification difficult. In sentiment analysis, such modification of polarity is termed as polarity shifting , which shifts the polarity of a sentiment clue (emotion, evaluation, etc.). It is well known that detection of polarity shifting can help improve sentiment analysis in texts. However, to detect polarity shifting in corpora is challenging: (1) polarity shifting is normally sparse in texts, making human annotation difficult; (2) corpora with dense polarity shifting are few; we may need polarity shifting patterns from various corpora. In this article, an approach is presented to extract polarity shifting patterns from any text corpus. For the first time, we proposed to select texts rich in polarity shifting by the idea of natural annotation , which is used to replace human annotation. With a sequence mining algorithm, the selected texts are used to generate polarity shifting pattern candidates, and then we rank them by C-value before human annotation. The approach is tested on different corpora and different languages. The results show that our approach can capture various types of polarity shifting patterns, and some patterns are unique to specific corpora. Therefore, for better performance, it is reasonable to construct polarity shifting patterns directly from the given corpus.

Purpose This is the first study to compare the pharmacokinetics of QL1101, a proposed bevacizumab biosimilar, with Avastin® sourced from Roche Diagnostics GmbH. Methods In this double-blind, single-dose, parallel-group study, healthy male subjects were randomized 1:1 to receive QL1101 or Avastin® 3 mg/kg intravenously. Pharmacokinetic assessments were conducted for 85 days, with additional safety and immunogenicity assessments until day 90. Primary study endpoints were area under the concentration–time curve (AUC) from time zero to infinity (AUC0–∞), AUC from time zero to the last quantifiable concentration (AUC0–last), and maximum serum concentration (Cmax). Pharmacokinetic equivalence was shown if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the C0–max, AUC0–last, and AUC0–∞ were within the predefined bioequivalence margin of 80–125.00%. Results A total of 82 subjects were randomized to the following groups: 42 to QL1101 and 40 to Avastin®. The 90% CIs of the GMRs of AUC0–∞, AUC0–last, and Cmax of QL1101 and Avastin® were (97.8%, 107.0%), (94.5%, 106.9%), and (94.1%, 107.3%), respectively, which were all within the bioequivalence margin. The incidence of adverse events was 90.5% and 95.0% in the QL1101 and Avastin® groups, respectively. Mean serum concentration–time profiles, secondary pharmacokinetic parameters, and safety and immunogenicity profiles were comparable across the two treatment groups. Conclusions The study demonstrated the pharmacokinetic equivalence of QL1101 to Avastin®. QL1101 (3 mg/kg, iv) is safe and tolerable in healthy Chinese subjects. These data support the further clinical evaluation of QL1101 as a bevacizumab biosimilar.

Background: Therapeutic plasma exchange (TPE) has been recommended by guidelines for the treatment of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) with severe kidney dysfunction. In recent years, some researchers have proposed that double-filtration plasmapheresis (DFPP) can also be used effectively in the treatment of these patients, but the difference between the 2 modalities of plasmapheresis is not clear. Methods: In this retrospective cohort study of AAV patients with serum creatinine ≥500 μmol/L from March 2013 to July 2018 who received TPE or DFPP treatment, we compared TPE and DFPP in terms of the changes of clinical parameters before and after plasmapheresis, the rates of adverse events during plasmapheresis, and kidney and patient survival during follow-up. Results: Forty-two AAV patients with kidney injury were included in this study. Twenty patients were treated with TPE and 22 patients were treated with DFPP. All patients were followed up for a median of 22 months. In each group, there were 10 deaths, and 6 patients developed end-stage kidney disease (ESKD). There were no significant differences between TPE and DFPP in terms of the changes of renal function or other laboratory results after treatment. During the plasmapheresis treatment, there was no significant difference in the rate of adverse events (p = 0.67). During the follow-up, there was no difference between the groups regarding the level of serum creatinine for patients with kidney recovery. The hazard ratio (HR) for TPE compared to DFPP for the outcome of ESKD was 0.92 (95% CI 0.45–1.9; p = 0.79) and the HR for death was 1.11 (95% CI 0.45–2.76; p = 0.82). Conclusion: There were no differences in short-term effectiveness, safety, or long-term outcomes between the 2 modalities of plasmapheresis. Our study suggests that DFPP may be a choice of plasmapheresis for AAV patients with severe kidney injury especially in countries and regions with limited blood resources.

Blood vessels in tumors often exhibit abnormal morphology and function, which promotes the growth, metastasis and resistance of tumors to conventional therapies. Therefore, vascular normalization is an emerging strategy to enhance the effectiveness of radiotherapy and chemotherapy when used in combination; however, there is a lack of evidence regarding the optimal schedule for the co-administration of anti-angiogenic and chemotherapeutic drugs. Scheduling treatment is important as the period for normalization is transient, also known as the 'time window'; however, no biomarker has been identified to detect this window. In the present study, recombinant human endostatin (rhES) was employed as an anti-angiogenic agent in xenograft tumor tissue in mice. Following rhES or control (saline) treatment, the density and integrity of tumor vessels were detected by immunofluorescence staining for cluster of differentiation 31 and α-smooth muscle actin; the level of hypoxia in tumor tissue was examined by immunohistochemistry with pimonidazole; the necrotic area was evaluated by hematoxylin and eosin staining; and the level of thrombospondin-1 (TSP-1) in plasma was tested by ELISA. The Cell Counting Kit-8 assay was also used to evaluate the effect of rhES on the proliferation of colon carcinoma SW620 cells. A 'time window' normalized vasculature was determined between day 4 and 6 following rhES treatment, and accompanied by a decrease in hypoxia in tumor tissue. Decreasing plasma TSP-1 levels were consistent with changes in vascular morphology and hypoxia, which exhibited features of normalization. In addition, rhES had no effect on the proliferation of SW620 cells, suggesting that the reduction in TSP-1 was associated with increased oxygen content during vascular normalization, rather than inhibited cell proliferation. In conclusion, TSP-1 may be a potential biomarker for predicting the normalization window of colon cancer vessels.

OBJECTIVE Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. METHODS Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. RESULTS A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. SIGNIFICANCE In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50-150 mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB.

Aims Type 2 diabetes mellitus (T2DM) is commonly complicated by renal impairment. Polyethylene glycol loxenatide (PEX168) is a novel long-acting glucagon-like peptide-1 receptor agonist for T2DM. PEX168 pharmacokinetics was studied to identify requirements for dose-modification in T2DM complicated by renal impairment. Methods This was a single-centre, open-labelled, parallel-group, single-dose, phase I clinical trial of patients with mild and moderate renal impairment, and with or without T2DM. Age-, sex- and body mass index-matched subjects with normal renal function, and with or without T2DM were recruited as controls. Subjects received a single abdominal subcutaneous injection of PEX168 200 μg. Pharmacokinetic samples were taken at 0, 24, 48, 72, 96, 120, 144, 216, 312, 480, 648 and 720 hours. Results Twenty-three patients were included in the pharmacokinetics analysis. Vz/F and CL/F were lower in the moderate impairment group than in the other groups. The mean t1/2 (163 hours) in the moderate impairment group was prolonged compared to the mild impairment (117 hours) and normal (121 hours) groups. AUC0-inf increased by 13 and 100.7% in patients with mild and moderate renal impairment, respectively. Most adverse events were mild gastrointestinal disorders, with only 1 serious adverse event observed. Conclusion A single dose of 200 μg of PEX168 was in general well tolerated in patients with renal impairment. The in vivo clearance rate of PEX168 in patients with moderate renal impairment is slower than in patients with mild renal impairment and normal renal function and dose adjustment might be required (ClinicalTrials.org #NCT02467790).

Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P

Abnormal expression of microRNAs is closely related to human diseases. Ultrasensitive detection of microRNAs with wide linear dynamic range is necessary as the concentrations of microRNAs distributed in biological samples usually range from fM to nM. Here, we constructed an ultrasensitive electrochemical sensor for microRNA-21 based on the integration of a dual signal amplification strategy of hybridization chain reaction (HCR) and enzyme-induced metallization (EIM) with anodic stripping voltammetry (ASV). MicroRNA-21 was captured by capture probe H1 (CP H1) modified magnetic nanobeads (MBs) and amplified by HCR. Multiple alkaline phosphatases (ALP) were coupled based on the specific reaction of biotin and streptavidin. A dual amplification strategy of HCR and EIM enhanced electrochemical signal by approximately 120-fold from the perspectives of target amplification and detection signal amplification, which decreased the detection limit of microRNA-21 to 0.12 fM. Compared to the reports previously reported, a wider linear dynamic range of 2.5 fM to 25 nM spanning 7 orders of magnitude was obtained. The method provides high sensitivity, specificity and a wider linear dynamic range, which shows a great potential in the early diagnosis of diseases.

Background Inhaled formulations are the first choices for treating asthma and chronic obstructive pulmonary disease (COPD), attracting the increasing investment and development in the pharmaceutical industry. Both the equivalence of local and systemic exposures need to be considered when assessing the equivalence of generic inhaled drugs, which has become a dilemma in the development of generic inhaled drugs. There is an urgent need for reliable methods such as physiologically-based pharmacokinetic (PBPK) model to assist in the development of inhaled drugs. Method To test the strategy that in silico simulation is an effective tool in developing inhaled products and further assessing their clinically feasibility, a long-acting beta2-adrenergic agonists indacaterol, which was referred as the first-line therapy for patient with COPD, was selected as a tool drug. The PBPK model was established and the predicted plasma concentration curve was obtained by inputting the physicochemical properties of indacaterol and adjusting model parameters. The accuracy of simulation was verified by an alignment with the actual data. The main factor affecting PK in vivo was investigated by parameter sensitivity analysis. The biological equivalent size of indacaterol was investigated by virtual bioequivalence analysis. Results The models of indacaterol after intravenous and oral administration were established and confirmed, and used as a background for PBPK model of inhaled administration. All those models showed favorable stability and applicability. Appropriate lung deposition was generated in the PBPK model, and the predicted plasma profile of indacaterol was consistent with the clinical actual observation values. Particle size is the most important factor affecting the PK of indacaterol in vivo. Furthermore, virtual bioequivalence simulation exhibited statistically comparable results between the particle size fluctuates in the range of 3.5–6.5 μm and baseline levels (D90 = 5 μm). Conclusions The PBPK model can simulate the pharmacokinetics and lung deposition of indacaterol, which will be a powerful tool to assist the development of inhaled drugs.

Background: Previously known as the anti-rejection drug, then famous for its efficacy on many mTOR-regulated diseases, sirolimus is now reported as the drug to reverse the process of many age-related diseases, rejuvenate immunity, and extend life span. However, its long-term safety profile for all-age groups is still a concern. Methods: Data were from two 10-year prospective cohort studies (ChiCTR-OOB-15006535，NCT031938), in which patients were diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. Indicators on growth, hematopoietic, liver and renal function, and blood lipid were all primary outcomes. GLM analysis and Chi-square test were used to reveal their changes between the baseline and five follow-up periods (< 6 months, 6 to < 12 months, 1 to < 2 years, 2 to < 4 years, and 4-to-10 years)). Four models with cross-validation were constructed for prediction. Descriptive adverse events and the change of regimens were also recorded (secondary outcomes). Findings: 1738 patients aging from 5 days to 69 years were included. The median follow-up period was 25 (12-43) months, and 380 patients were followed for more than four years. Z scores of height, weight, and BMI increased significantly throughout the follow-up (baseline versus 4-to-10-year follow-up: 0·24 vs 0·69, 0·25 vs 0·56, 0·14 vs 0·29). The dose of sirolimus was the only factor related to all the changes. No negative effects on hematopoietic, liver, and renal function were observed throughout the follow-up. On the contrary, the long-term use of sirolimus showed beneficial effects. The increase of blood lipids was mainly in the first six months. Stomatitis was the most common adverse event (920/1738, 52·9% ), and 48·5% of adult females were with menstrual disorders. The economic burden was the main reason for discontinuing therapy. Interpretation: For the first time, we observed the increase in height and weight brought by sirolimus. Also, the length of follow-up was associated with different safety profiles. Some beneficial effects were observed in a longer follow-up. Clinical Trial Registration Details: The pediatric patients in this study are from the "Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSIPT)" study (Chinese Clinical Trial Registration, http://www.chictr.org.cn, No. ChiCTR-OOB-15006535). The adult patients re from "A National Registry on Chinese Patients with Lymphangioleiomyomatosis" (ClinicalTrials.gov, No. NCT03193892). Funding Information: This work was supported by grants from the National Key Research and Development Program of China (No. 2016YFC1000707，No.2016YFC0901502) and the National Natural Science Foundation of China (No. 81471329). Declaration of Interests: The authors have no conflicts of interest relevant to this article to disclose. Ethics Approval Statement: The Ethics Committee of Chinese PLA General Hospital approved the pediatric study (No. S2013-028-01). The Ethics Committee of Peking Union Medical College Hospital (PUMCH) approved the adult study(JS-1323).

Introduction:Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects. Areas covered: We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics. Expert opinion: Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.

This study conducts a correlation exploration of CYP2C19 gene polymorphism and clopidogrel resistance in Han Chinese patients with cerebral infarction in Guizhou Region. A total of 270 Han Chinese patients with cerebral infarction, who were hospitalized in our hospital from January 2016 to January 2018, are selected. These patients were divided into 2 groups, clopidogrel resistance group (n = 60) and clopidogrel sensitive group (n = 210). According to the TEG results, the CYP2C19 gene polymorphism detection was carried out by using the PCR-RFLP method, while IL-6 level in the patient's blood was measured by using the ELISA method. The resistance group occupies 22.22%. The platelet inhibition ratio of the resistance group was 23 ± 7%, which was significantly lower than that of the sensitive group (65 ± 13%), and the difference was statistically significant (P

Umbilical hernias constitute some of the most common surgical diseases addressed by surgeons. Endoscopic techniques have become standard of care together with the conventional open techniques for the treatment of umbilical hernias. Several different approaches were described to achieve laparoscopic sublay repair. We prospectively collected and reviewed the medical records of 10 patients with umbilical hernias underwent total endoscopic sublay repair (TES) at our institution from November 2017 to November 2019. All operations were performed by a same surgical team. The demographics, intraoperative details, and postoperative complications were evaluated. All TES procedures were successfully performed without conversion to an open operation. No intraoperative morbidity was encountered. The average operative time was 109.5 minutes (range, 80–140 minutes). All the patients resumed an oral diet within 6 hours after the intervention. The mean time to ambulation was 7.5 hours (range, 4–14 hours), and mean postoperative hospital stay was 2.2 day (range, 1–4 days). One patient developed postoperative seroma. No wound complications, chronic pain, or recurrence were registered during the follow-up. Initial experiences with this technique show that the TES is a safe, and effective procedure for the treatment of umbilical hernias.

PURPOSE (R,R)-penehyclidine fumarate (R2PHF) is a highly selective muscarinic receptor antagonist used to suppress glandular secretions before general anesthesia or tracheal intubation and to treat organophosphorus poisoning. This is the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of R2PHF in healthy subjects. MATERIALS AND METHODS In this single-center, double-blind, randomized study, 23 subjects received escalation doses of R2PHF (0.0625 mg, 0.25 mg, 0.50 mg, and 1.0 mg), 4 received the parent drug penehyclidine hydrochloride (PHC, 1.0 mg) as a reference, and 4 received a placebo. The pharmacokinetic parameters of R2PHF were determined. Tolerability was assessed based on adverse events and clinical laboratory tests. RESULTS Single doses of 0.0625 mg, 0.25 mg, and 0.50 mg R2PHF were well-tolerated by healthy subjects. Delirium was set as the termination outcome and appeared in 1 case receiving 1.0 mg. For this reason, the escalation experiment was cut off. The mean half-life (T1/2) ranged from 30.57 to 32.27 hours. CONCLUSION R2PHF was safe and well-tolerated at doses ranging from 0.0625 to 0.50 mg. A single administration of 0.50 mg was determined to be the maximum tolerated dose of R2PHF. Further pharmacodynamics, safety, and efficacy testing is required to advance R2PHF to the next stage of clinical development and application.

Jie Huang,1,2,* Cheng-xiao Fu,1,2,* Xiao-yan Yang,1,2 Chan Cui,1,2 Shuang Yang,1,2 Yun Kuang,1,2 Cheng-xian Guo,1,2 Pei Hu,3 Qi Pei,2,4 Guo-ping Yang1,2 1Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Center for Clinical Drug Evaluation, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100032, People’s Republic of China; 4Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China *These authors contributed equally to this work Purpose: To determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects.Subjects and methods: Both the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests.Results: After every single dose, the time to the maximum concentration (Cmax) of roflumilast (Tmax) was 0.25–2.0 hours; thereafter, the concentration declined, with a mean half-life (t1/2) of 19.7–20.9 hours over the range of 0.25–0.50 mg. As for roflumilast N-oxide, the mean t1/2 was 23.2–26.2 hours. The area under curve from the beginning to 24 hours (AUC0–24 h), the AUC until infinity (AUCinf), and the Cmax of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial.Conclusion: Roflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its Cmax and AUC values was observed at doses ranging from 0.25 to 0.50 mg. Keywords: pharmacokinetics, roflumilast, roflumilast N-oxide, healthy volunteer, phosphodiesterase 4 inhibitor

To improve the ability of city agglomeration to resist emergency disruption, the model of a city agglomeration compound traffic network was constructed with a new perspective on investigating its vulnerability. First, on the basis of complex network theory, the city agglomeration compound traffic network structure was analyzed thoroughly and its model was established using the site mapping method. Then, facing the compound traffic network structure of urban agglomeration, both the different attack strategies and the measures of the vulnerability of a city agglomeration compound traffic network were proposed. Finally, taking Hohhot-Baotou-Erdos city agglomeration as an example of our empirical study, the city agglomeration road network and rail transit network were formed, and the topology characteristics and vulnerability of the compound traffic network were analyzed to identify critical sites and lines within the network. Results show that the construction of urban agglomeration compound traffic network can effectively reduce the vulnerability of a single-mode network. Moreover, strengthening the protection of the identified key sites and lines further increases the likelihood of reducing the vulnerability of urban complex transportation networks and the risks of traffic network paralysis caused by sudden disasters.

The radiation and the diffraction of linear waves by a rectangular structure with an opening at its bottom floating in oblique seas of finite depth are investigated. Analytical expressions for the radiated potentials and the diffracted potential are obtained by use of the method of separation of variables and the eigenfunction expansion method, with the unknown coefficients being determined by the boundary conditions and the matching requirement on the interface. The hydrodynamic coefficients and the wave excitation forces are verified using the symmetry properties of coupled hydrodynamic coefficients and one specific example investigated previously. By use of the present analytical-numerical solution, the influences of the angle of incidence, the width of the opening on the wave forces and the hydrodynamic coefficients are investigated. It is also found that in the oblique sea the external excitation frequency that can lead to the resonance of a rectangular tank depends on the wave direction and the wave number of the incident wave.

SummaryAim LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety, and tolerability profile. Methods Healthy subjects were randomised to receive LY3031207 (25, 75, and 275 mg), placebo, or celecoxib (400 mg) once daily for 28 days. The safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. Results The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. Conclusions This study emphasised the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers. Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30-300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel. Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

AIMS To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P < .05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ΔCmax0-4h and ΔAUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44-120.90 and 53.65-112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSION Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2-4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (ΔCmax0-4h and ΔAUC0-4h ). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR-IIR-17013918, ChiCTR-IIR-17011903). All subjects provided written informed consent before screening.

Background/aims Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Many studies have demonstrated that serum microRNAs have potential applications as non-invasive biomarkers for cancer diagnosis. The aim of the present study was to investigate the expression of serum miR-551b-3p in patients with GC and to explore its potential as a diagnostic biomarker in GC. Materials and methods The expression of miR-551b-3p was detected using quantitative reverse transcription polymerase chain reaction in preoperative serum samples of 50 patients with GC and 53 healthy individuals. An analysis was performed to determine the correlation between serum miR-551b-3p levels and clinicopathological characteristics of patients with GC. The receiver operating characteristic curve was generated, and the cut-off point of serum miR-551b-3p for the diagnosis of GC was selected. The clinical value of serum miR-551b-3p for GC was analyzed by a consistency test. Results The expression of serum miR-551b-3p was significantly lower in patients with GC than in healthy individuals (p=0.000). Low level was positively associated with tumor size (p=0.014), depth of invasion (p=0.001), and Tumor-Node-Metastasis stage (p=0.022). The area under the curve for serum miR-551b-3p distinguishing patients with GC from healthy individuals was 0.860 (95% CI: 0.787-0.933, p=0.000), with a specificity of 96.2% and a sensitivity of 70%. The kappa consistency test had a kappa value of 0.667 (p=0.000) in GC. Conclusion Serum miR-551b-3p may potentially serve as a diagnostic biomarker for GC.

Backgrounds: The diagnosis of pulmonary embolism (PE) still remains difficult in clinical practice. MicroRNAs (miRNAs) have been widely investigated as biomarkers for various diseases. However, the diagnostic biomarker value of miRNAs in the diagnosis of PE is unclear. Therefore, we conducted this meta-analysis to establish the diagnostic power of miRNAs for PE diagnosis. Methods: A systematic literature search in PubMed and Embase was conducted to identify relevant studies dated up to July 22, 2016. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from those included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall diagnostic power of miRNAs for PE diagnosis. Results: A total of three studies with five types of miRNAs covering 254 participants were included in our meta-analysis. The overall pooled results for sensitivity, specificity, PLR, NLR, and DOR of miRNAs for PE diagnosis were 0.83 [95% confidence intervals (CI): 0.67–0.92], 0.85 (95% CI: 0.72–0.92), 5.4 (95% CI: 2.7–10.9), 0.20 (95% CI: 0.10–0.44), and 26.00 (95% CI: 7.00–101.00), respectively. The area under the SROC curve was 0.90 (95% CI: 0.87–0.92). Even though heterogeneity was observed in the analysis of sensitivity, there was no evidence of publication bias. Conclusions: MiRNAs could serve as novel non-invasive diagnostic biomarkers of PE with a relatively high diagnostic power. More researches, however, are needed to explore the diagnostic as well as therapeutic values of miRNAs for PE.

Orthotropic membrane components and structures are widely used in building structures, instruments and meters, electronic engineering, space and aeronautics, etc., because of their light weights. However, the same lightweight combined with low stiffness make membranes prone to vibration under dynamic loads, and in some cases the vibration may lead to structural failure. Herein, the undamped nonlinear vibration response of pretension rectangular orthotropic membrane structures subjected to impact loading is studied by analytical and numerical methods. The analytical solution is obtained by solving the governing equations by the Bubnov-Galerkin method and the Lindstedt-Poincare perturbation method. Numerical analysis has also been carried out based on the same theoretical model. The analytical and numerical results have been compared and analyzed, and the influence of various model parameters on membrane vibration discussed. The results obtained herein provide some theoretical basis for the vibration control and dynamic design of orthotropic membrane components and structures.

Background: Polypharmacy and potentially inappropriate medications (PIMs) are prominent prescribing issues in elderly patients. This study was to investigate the different prevalence of PIM use in elderly inpatients between 65-79 years of age and 80 years or older, who were discharged from Geriatric Department in West China Hospital. Methods: A large-scale cohort of 1796 inpatients aged 65 years or over was recruited. Respectively, 618 patients were 65-79 years and 1178 patients were 80 years or older. Updated 2012 Beers Criteria by the American Geriatric Society was applied to assess the use of PIM among the investigated samples. Results: A review of the prescribed medications identified 686 patients aged 80 years or older consumed at least one PIM giving a rate of 58.2%. Conversely, 268 (43.4%) patients aged 65-79 years consumed at least one PIM (χ2 = 40.18, P < 0.001). Patients aged 80 years or older had higher hospitalization expenses, length of stay, co-morbidities, medical prescription, and mortality than patients aged 65-79 years (all with P < 0.001). Patients aged 80 years or older were prescribed with more benzodiazepines, drugs with strong anticholinergic properties, megestrol, antipsychotics, theophylline, and aspirin. In multiple regression analysis, PIM use was significantly associated with female gender, age, number of diagnostic disease, and number of prescribed medication. Conclusions: The finding from this study revealed that inpatients aged 80 years or older encountered more PIM use than those aged 65-79 years. Anticholinergic properties, megestrol, antipsychotics, theophylline, and aspirin are medications that often prescribed to inpatients aged 80 years or older. Doctors should carefully choose drugs for the elderly, especially the elderly aged 80 years or older.

To investigate the biological behavior and clinical characteristics of perivascular epithelioid cell tumor (PEComa). Eighteen PEComa patients admitted to Zhongshan Hospital and the Central Hospital of Xuhui District in China from January 2006 to October 2018 were included. All patients were diagnosed based on pathological findings and treated with surgical resection or medication. Among the 18 patients, 1 underwent lymph node biopsy for multiple enlarged lymph nodes and 17 underwent mass resection. The median disease-free survival was 22 months after the first resection and over 12 months following a second resection. Treatment with mechanistic target of rapamycin (mTOR) inhibitors was effective for patients with unresectable or metastatic lesions. The median progression-free survival was approximately 13 months. Surgery is the predominant treatment approach for PEComa and patients can benefit from multiple operations. mTOR inhibitors are considered for patients with multiple lesions or intolerance to surgery. Anti-angiogenetic drugs can be selected when mTOR inhibitors fail to control the illness.

Background Indacaterol is one of the long-acting beta2-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life. Objective The three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol. Methods Two BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 μg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of Cmax and AUC0-t fell within the limits of 0.8–1.25. Results Indacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean Cmax and AUC0-t was 109.9% (90% CI, 106.1–113.8%) and 104.8% (90% CI, 101.5–108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%–104.4%) for non-block subjects. No serious adverse events were reported. Conclusions The results showed that 150 μg indacaterol (+/− 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.

Identifying the factors that are correlated with and predictive of reduced quality of life (QOL) is essential to optimize the treatment of epilepsy and the management of comorbidities.We analyzed the independent associations between the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the demographic, clinical, psychiatric, and cognitive variables of 47 consecutive patients with temporal lobe epilepsy (TLE). Predictors of the correlated variables were analyzed by multiple linear regression analysis.The QOLIE-31 total score was positively correlated with occupational status and Mini-Mental State Examination (MMSE) scores (r = 0.290 and 0.295, respectively; P 0.05) and negatively correlated with the duration of seizures, adverse effects of antiepileptic drugs (AEDs), and the Pittsburgh Sleep Quality Inventory (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) scores (r = -0.357, 0.321, 0.328, -0.672, and -0.565, respectively; P 0.05; P 0.01 for the SAS and SDS). In the final multivariate regression model, anxiety, long durations of seizures, adverse effects of AEDs, and depression explained approximately 60.6% (adjusted RAnxiety, long durations of seizures, adverse effects of AEDs, and depression were significant predictors of QOL, and these variables had relatively high prediction capacities for the overall QOLIE-31 in the regression model. Comorbid anxiety is the most powerful negative determinant of the QOLIE-31.

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

The aim of this paper is to investigate the time-varying effect of stay cable of long-span cable-stayed bridges subject to vehicle load. The analysis has been carried out on the Su-Tong cable-stayed bridge in Jiangsu, China that has the second-longest span among the completed composite-deck cable-stayed bridges in the world currently. Probability models of vehicle load in each lane (fast lane, middle lane and slow lane) and cable stress under random vehicle load were developed based on the stochastic process theory. The results show the gross vehicle weight follows lognormal distribution or multi-peak distribution, and the time-interval of the vehicle follows a lognormal distribution. Then, the probability function of maximum cable stress was determined using up-crossing theory. Finally, the reliability of stay cable under random vehicle load was analysed. The reliability index ranges from 9.59 to 10.82 that satisfies the target reliability index of highway bridge structure of finished dead state.

Due to the increasing amount of opinion data on the internet, opinion mining has become a hot topic, in which extracting opinion targets is a key step. The state-of-the-art approaches only use direct dependency relation patterns to extract opinion targets and the indirect dependency relation patterns have not been used. In this paper, the dependency relations between opinion target and opinion word are defined, and direct and indirect dependency relation patterns are designed. Then, a bootstrapping approach is used to extract and evaluate both candidate patterns and opinion targets. The experimental results show that in formal text, the approach improves the performance compared with the state-of-the-art approaches for opinion target extraction.

Rationale: We report our experience with 2 patients diagnosed with grey zone lymphoma (GZL). The histopathological characteristics of lymphomatous tissues in these patients ranged between those of diffuse large B-cell lymphoma (DLBCL) and the classical Hodgkin lymphoma. Patient concerns: A 52-year-old female presented to the hospital with a history of lower abdominal pain of metastatic origin for 2 days. She was diagnosed with acute appendicitis and had undergone emergency surgery. A 17-year-old male was admitted to the hospital because of acute left upper abdomen pain. Diagnoses: Both patients are diagnosed of GZL primarily based on histopathology. Interventions: Both patients were treated with R-CODOX-M/R-IVAC regimen for 4 to 6 cycles. Outcomes: The short-term curative effect was complete response; no recurrence was observed as of 32-month follow-up. Lessons: R-CODOX-M/IVAC regimen exhibited relatively good curative effect. International Prognostic Index score and lactate dehydrogenase level may correlate with prognosis of these patients.

Lymphocytic neoplasm involving the heart is not common and usually presents with pericardial effusion or focal myocardial infiltration. Myocardial infarctions due to leukemic infiltration of the coronary arteries are rarely reported. We present the case of a 52-year-old Guatemalan man with a one-year history of untreated T-cell prolymphocytic leukemia. He was admitted to our hospital for chemotherapy and evaluation of a pulmonary cavitary lesion by wedge resection. During sedation, the patient experienced acute respiratory failure and hypovolemic shock, from which he could not be resuscitated. Autopsy revealed that leukemic cells extensively infiltrated the aorta, myocardium, and coronary arteries. The lumina of the 3 major coronary artery branches showed 70% to 95% stenosis, with multifocal remote myocardial infarctions. Tumor cells were also detected in the lungs and other organs. The acute cardiorespiratory insufficiency secondary to leukemia—particularly the extensive infiltration of the coronary arteries and myocardium, and the multiple myocardial infarctions—eventually resulted in cardiac death.

Component fingerprints are a recognized method used worldwide to evaluate the quality of traditional Chinese medicines (TCMs). To foster the strengths and circumvent the weaknesses of the fingerprint technique in TCM, spectrum-effect relationships would complementarily clarify the nature of pharmacodynamic effects in the practice of TCM. The application of the spectrum-effect relationship method is crucial for understanding and interpreting TCM development, especially in the view of the trends towards TCM modernization and standardization. The basic requirement for using this method is in-depth knowledge of the active material basis and mechanisms of action. It is a novel and effective approach to study TCMs and great progress has been made, but to make it more accurate for TCM research purposes, more efforts are needed. In this review, the authors summarize the current knowledge about the spectrum-effect relationship method, including the fingerprint methods, pharmacodynamics studies and the methods of establishing relationships between the fingerprints and pharmacodynamics. Some speculation regarding future perspectives for spectrum-effect relationship approaches in TCM modernization and standardization are also proposed.

The main cause of deterioration in reinforced concrete (RC) structures is related to reinforcing steel corrosion, therefore, the calculation of steel corrosion loss should be evaluated in detail. The corrosion initiation time and concrete cracking time are random variables due to the various uncertainties in reinforcement corrosion process. Thus, RC structural member at a specific observation time of design period may be in three different states, namely no corrosion, ongoing corrosion but no cover concrete cracking, concrete cover cracking. Accordingly, a probabilistic model for corrosion loss of steel cross-section was developed in three critical phases. For illustrative purpose, statistic analysis of the percentage of corrosion was conducted using Monte Carlo simulation for a simply supported RC flexural member, in which the occurrence probabilities of above three different states at an observation time were determined. The statistical results showed that percentage of corrosion can be described by a double-peak probability distribution; the occurrence probabilities of no corrosion and no concrete cracking decrease with time; the reliability of RC flexural element in marine environment significantly decreases with time due to reinforcement corrosion.

Ever since Pierre GuBaidan and his colleagues restored the Olympic Games at the end of the19th century, the modem Olympic Games have evolved for a. hundred years during which they experienced both hard and exciting moments. Although according to the history, the 1916's, 1940's and 1944's Olympic Games were cancelled because of the war, although frequently chaotic arose from the inside of the organization of the Olympic Games and some external pressure arose from outside of the organization, the modem Olympic Games are still regarded as one of the few successes which elaborate the internationalism. Starting from a humble, indefinite beginning, the Olympic Games gradually grow into a marvelous sporty event in the world; nowadays, not any other event can compare with it in the style, scale or in the complexity of the organization. Each past Olympic Games is an important opportunity for exchanging the ideas in science and cultural, and it also provides a giant stage to the hosting city, demonstrating the hosting city's history, culture as well as the resident's expectation to the audience of the world.

Process held in sports events and sports facilities is a key concept. Sports is the sports products production base, with the sports event organizing work unceasingly thorough, the focus gradually around the stadium and development, the resources utilization and allocation according to the layout and characteristics of venues need to. Large sports practice management experts gradually realized "venue" not only for the sport games is very important, for the whole event also played a decisive influence directly. Therefore, the stadium to run the risk of control theory research is very necessary.

The dissertation targets on the evolvement of the Olympic architectures together with the analysis of some concrete historical cases. The dissertation has been divided into two halves, which are logically related. The first half is organized as follows: first, the historically evolvement of the Olympic Games over the past 100 years was illustrated via 4 important phases. Then it concluded the characteristics on the space layout of the Olympic architectures. Finally the technical and economical influences on the Olympic architectures were analyzed in detail. Within the second half, for each of the four characteristic stages, detailed elaborations were launched to cover the unique characteristics of the Olympic architectures in each stage chronologically.

With the development of higher education, college sports architecture is no exception in the revolution. Due to many factors, such as economic, sports science and technology, the development of Europe and the United States and Japan and other countries of the sports building has been at the forefront of the world. At the same time as the Europe and the United States, Japan and other countries recognize in the mass sports, competitive sports and school sports are abundant, and established a relatively perfect sports club system, at the same time, many large-scale sports events and commercial events are held in Colleges and universities. These are vigorously promoting the construction of college sports architecture. Many college students in Europe and the United States, in the school the sports entertainment facilities in Colleges and universities are available as an important condition for the choice of schools, the quantity and quality of sports facilities has become one of the window to show the strength of the competition, promote the sports facilities in Colleges and universities to develop.

Three new humulane-type sesquiterpenes, antrodols A–C (1–3), were isolated from cultures of the fungus Antrodiella albocinnamomea. Their structures were elucidated on the basis of extensive spectroscopic analysis. Antrodols A–C (1–3) are first examples of humulane-type sesquiterpenes isolated from cultures of higher fungi, and antrodol A (1) was the first report of humulane-type sesquiterpene with a methyl rearranged at C-3. All compounds were evaluated in the enzyme inhibition assay against two protein-tyrosine phosphatases (PTPs): MEG2 and PTP1Bc. Electronic supplementary material The online version of this article (doi:10.1007/s13659-014-0032-4) contains supplementary material, which is available to authorized users.

According to the characteristics of mobile navigation based on PDA, the map scenes in the screens should be changed in real time, which needs to dynamically output map labels to adapt to these challenges. In this paper, based on angle bisector advanced algorithm is used for labeling dynamic on line water system and obtaining smooth location of line features as the location of labels. The results obtained in this paper can be applied to solve the problems of ambiguous expressions and/or invisibility of labels of line features, achieving the unity of the integrity and aesthetics of the automated output.