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Background and Aim: Obesity is association with elevated risks of erosive esophagitis (EE), and metabolic abnormalities play crucial roles in its development. The aim of the study was to assess the association between metabolic obesity phenotypes and the risk of EE., Methods: This retrospective study enrolled 11,599 subjects who had undergone upper gastrointestinal endoscopy at the First Affiliated Hospital of Dalian Medical University from January 1, 2008, to December 31, 2023. The enrolled individuals were grouped into four cohorts based on their metabolic health and obesity profiles, namely, metabolically healthy non-obesity (MHNO; n=2134, 18.4%), metabolically healthy obesity (MHO; n=1736, 15.0%), metabolically unhealthy non-obesity (MUNO; n=4290, 37.0%), and metabolically unhealthy obesity (MUO; n=3439, 29.6%). The relationships of the different phenotypes of metabolic obesity with the risks of developing EE in the different sexes and age groups were investigated by multivariate logistic regression analysis., Results: The MUNO, MHO, and MUO cohorts exhibited elevated risks of developing EE than the MHNO cohort. The confounding factors were adjusted for, and the findings revealed that the MUO cohort exhibited the greatest risk of EE, with odds ratios (ORs) of 5.473 (95% CI: 4.181-7.165) and 7.566 (95% CI: 5.718-10.010) for males and females, respectively. The frequency of occurrence of EE increased following an increase in proportion of metabolic risk factors. Subgroup analyses showed that the individuals under and over 60 years of age in the MHO, MUNO, and MUO cohorts exhibited elevated risks of developing EE. Further analysis suggested that obesity has a stronger influence on the risks of developing EE compared to metabolic disorders., Conclusion: Metabolic disorders and obesity are both related with an elevated risk of EE, in which obesity has a potentially stronger influence. Clinical interventions should target both obesity and metabolic disorders to reduce EE risk., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 He et al.)

This study aims to enhance the effectiveness of high resolution manometry (HRM) and pH-impedance monitoring metrics in distinguishing between gastro-esophageal reflux disease (GERD) and non-GERD. A retrospective propensity score matching (PSM) study was conducted on 643 patients with GERD symptoms. PSM matched 134 GERD patients with 134 non-GERD controls. Body mass index (BMI), intra-esophageal pressure (IEP) and intra-gastric pressure (IGP) were significantly higher in the GERD group compared to the non-GERD group. BMI was correlated with IEP and IGP positively. IGP was positively correlated with esophagogastric (EGJ) pressure (EGJ-P) in participants with EGJ type 1 and 2, but not in participants with EGJ type 3. BMI was correlated with distal MNBI negatively. Logistic regression showed BMI as an independent risk factor for GERD. Receiver operating characteristic curve (ROC) and decision curve analysis (DCA) showed that BMI adjusted EGJ contractile integral (EGJ-CI) and BMI adjusted MNBI were superior to the corresponding original ones in predicting GERD susceptibility. According to the findings, BMI and IGP are the main factors contributing to the development of GERD. BMI affects IEP through the adaptive response of EGJ-P to IGP. Incorporating BMI into the calculations of EGJ-CI and MNBI can improve their ability in predicting GERD susceptibility., (© 2024. The Author(s).)

New daily persistent headache (NDPH) is a kind of persistent headache that patients can identify the exact date of the sudden onset.It is one of the rare primary headaches difficult to be cured and may lead to disability,seriously affecting the daily life and work.The exact pathogenesis of NDPH remains unclear,which makes the treatment difficult.Here we report a case of refractory NDPH treated by intravenous injection of esketamine at a sub-anesthetic dose.

The efficacy and safety of different Chinese patent medicines in the treatment of coronary heart disease complicated with heart failure were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for coronary heart disease complicated with heart failure was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to July 5, 2023. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool, and a network Meta-analysis was performed in Stata 16.0. Finally, a total of 82 RCTs were included, involving 9 298 patients and 11 Chinese patent medicines. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of improving the clinical response rate, the top three interventions were Qishen Yiqi Dripping Pills + conventional western medicine, Zhenyuan Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(2) In terms of increasing left ventricular ejection fraction(LVEF), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Compound Danshen Dripping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(3) In terms of reducing left ventricular end-diastolic diameter(LVEDD), the top three interventions were Shexiang Tongxin Dripping Pills + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(4) In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Qi-shen Yiqi Dripping Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(5) In terms of reducing hyper-sensitive C-reactive protein(hs-CRP), the top three interventions were Naoxintong Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(6) In terms of increasing the distance of the six-minute walking trail(6MWT), the top three interventions were Zhen-yuan Capsules + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Qishen Yiqi Dripping Pills + conventional western medicine. The results showed that Chinese patent medicines combined with conventional western medicine can effectively improve the clinical response rate, LVEF, and 6MWT and reduce LVEDD, NT-proBNP, and hs-CRP. However, due to the overall low quality of the articles included and the few articles of some Chinese patent medicines, direct comparison between diffe-rent Chinese patent medicines remains to be carried out and the results need to be further verified.

This study reviewed the current status of the use of outcome indicators in randomized controlled trial(RCT) on traditional Chinese medicine(TCM) treatment of microvascular angina(MVA) and analyzed the existing problems and possible solutions, aiming to provide a basis for the design of high-quality RCT and the establishment of core outcome sets for MVA. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries were searched for the RCT on TCM treatment of MVA according to pre-defined criteria. The Cochrane's risk of bias assessment tool was used to evaluate the methodological quality of the included RCT and the use of outcome indicators was summarized. A total of 69 RCTs were included, from which 100 outcome indicators were extracted, with the frequency of 430. The extracted outcome indicators belonged to 8 domains: response rate, symptoms and signs, physical and chemical examinations, TCM efficacy, safety, quality of life, economic evaluation, and long-term prognosis. The indicators of physical and chemical examinations were the most(70 indicators with the frequency of 211), followed by those of response rate(7 indicators with the frequency of 73) and symptoms and signs(7 indicators with the frequency of 54). The outcome indicators with higher frequency were adverse reactions, angina attack frequency, clinical efficacy, endothelin-1, total duration of treadmill exercise, and hypersensitive C-reactive protein. The RCT on TCM treatment of MVA had the following problems: irregular reporting of adverse reactions, diverse indicators with low frequency, lack of attention to the application of endpoint indicators, insufficient use of TCM differentiation and efficacy indicators, non-standard evaluation criteria and failure to reflect the basic characteristics of TCM. A unified MVA syndrome differentiation standard should be established, on the basis of which an MVA treatment efficacy evaluation system and core outcome indicator set that highlights the characteristics of TCM with patient-reported outcomes as the starting point should be established to improve the clinical research and research value.

Objectives: Proximal interruption of the pulmonary artery (PIPA) has various clinical manifestations. This review focused on and summarized the clinical and radiological features of PIPA, based on relevant literature studies., Methods: The study included a total of 25 PIPA cases in the Guangzhou Women and Children's Medical Center between January 2015 and December 2021. Conventional chest photographs and chest computed tomography angiography (CCTA) of patients with PIPA were analyzed and summarized., Results: The radiological results showed that 17 cases were right-sided and 8 cases were left-sided PIPA. Additionally, the percentage of pulmonary hypoplasia on the affected side was 44%, 36% for pulmonary hypertension, 28% for the mosaic sign, 20% for subpleural cystic lucency shadow, 20% for subpleural serrated shadow, 20% for collateral vessel thickening, 16% for subpleural band-like parenchyma, 12% for pneumonia, and 56% for patent ductus arteriosus., Conclusion: The clinical manifestations of PIPA are non-specific. Awareness of this anomaly, based on radiological manifestations, particularly those observed on CCTA images, is important for ruling out alternative diagnoses and implementing appropriate management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Zhang, Cao, Zhou, Wang, Wu and Zhang.)

A field experiment was conducted to study the effects of different organic material amendments on soil respiration in a flue-cured tobacco field. Five treatments were set up:no fertilizer (NF), chemical fertilizer (NPK), chemical fertilizer+ryegrass (NPKG), chemical fertilizer+wheat straw (NPKS), and chemical fertilizer+tobacco straw biochar (NPKB). The results showed that:① Compared with that under NPK, NPKG and NPKS decreased the temperature sensitivity ( Q 10 ) of total soil respiration and heterotrophic respiration, whereas NPKB increased the Q 10 of heterotrophic respiration. The two-factor fitting model of soil respiration and soil hydrothermal factors accounted for 50%-80% of the variation in soil respiration. ② The addition of organic materials significantly increased the content of soil soluble organic carbon (DOC) and root dry matter. Soil heterotrophic respiration( R h ) was significantly positively correlated with DOC content, and soil autotrophic respiration( R a ) was significantly parabolically correlated with root biomass, with an R 2 of 0.327-0.634. ③ Soil respiration increased first and then decreased during the tobacco growth period. Compared with that under the NF treatment, the NPK treatment significantly promoted soil respiration and its components. Compared with those of the NPK treatment, R s rates were significantly increased by 20.08%, 10.32%, and 9.88% under the NPKG, NPKS, and NPKB treatments, respectively; R h rate increased by 24.21%, 16.51%, and 11.68% respectively, and R a rate was increased by 15.12% in the NPKG treatment. In summary, straw returning and biochar addition significantly increased R h by increasing soil DOC, thereby promoting R s . Incorporation of ryegrass not only increased the R h but also increased R a by promoting the growth and development of roots and therefore the R s .

Background: Application of Treprostinil (TRE) in the patients with single ventricle (SV) physiology is very limited, and the optimal dose for children has not been determined. In this study, we aimed to analyze plasma samples to assess the attainment of clinically therapeutic concentrations of TRE and its efficacy and safety in the treatment of pediatric functional SV pulmonary arterial hypertension (FSV-PAH).., Methods: Pediatric patients with FSV-PAH were recruited in this study. IV TRE at an initial rate of 5 ng/kg/min was administered through the femoral vein with an increase in rate to 10 ng/kg/min every 30 minuntil the aiming dose of 80 ng/kg/min had been reached. The drug was gradually discontinued after 12 h of treatment at a stable dose. The mean postoperative pulmonary artery pressure (mPAP), pulmonary-to-systemic arterial pressure ratio (Pp/Ps), and the ratio between arterial oxygen partial pressure and inhaled oxygen concentration (PaO 2 /FiO 2 ) were used to evaluate the efficacy of TRE treatment. A multiple linear regression model was used to explore the relevant factors associated with TRE blood concentration., Results: A total of eight patients were enrolled in the investigation, with an age range of 2.5-9.9 years. The median stable dose of TRE was 70 ng/kg/min with a range of 55-75 ng/kg/min. The median subliminal dose was 55 ng/kg/min with a range of 25-75 ng/kg/min. A linear relationship was established between the TRE dose and the plasma concentration. TRE blood concentrations were associated with dose and patient height. After TRE treatment, mPAP, Pp/Ps, and PaO 2 /FiO 2 were significantly improved (P<0.05)., Conclusions: A linear relationship was found between the blood concentration of TRE and its dose. IV TRE was an effective therapy without serious side effects in pediatric patients with FSV-PAH., Trial Registration: ClinicalTrials.gov Identifier: NCT02865733., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-3188). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Objective: This study aimed to summarize the magnetic resonance imaging (MRI) and computed tomography (CT) features of the central nervous system (CNS) in children with Hoyeraal-Hreidarsson syndrome., Methods: The imaging and clinical data of four children diagnosed with Hoyeraal-Hreidarsson syndrome by clinical and laboratory tests in the Guangzhou Women and Children's Medical Center were gathered and analyzed retrospectively. The clinical manifestations and CNS imaging features of Hoyeraal-Hreidarsson syndrome were summarized based on our results and a literature review., Results: Our results showed that delayed development, skin pigmentation, nail/toenail dystrophy, thrombocytopenia, and anemia are the most observed clinical presentations of Hoyeraal-Hreidarsson syndrome. Important findings on CNS imaging showed that all patients had cerebellar hypoplasia, delayed myelination, hydrocephalus, brain atrophy, and calcification. The gene mutations in all cases were consistent with those of dyskeratosis congenita, including TINF2 mutations in three cases and DKC1 mutations in one case., Conclusion: Hoyeraal-Hreidarsson syndrome is a severe variant of dyskeratosis congenita. Both DKC1 and TINF2 mutations can lead to the phenotypes of Hoyeraal-Hreidarsson syndrome. In our study, CNS imaging revealed that cerebellar hypoplasia has an important diagnostic value for Hoyeraal-Hreidarsson syndrome while delayed myelination, calcification of the parenchyma, brain atrophy, and hydrocephalus are also important findings on CNS imaging. Combining imaging features with clinical and laboratory indicators can assist the diagnosis of Hoyeraal-Hreidarsson syndrome., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART)., Methods: From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People's Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (10 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group., Results: From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P = 0.006) and CD8 level (β = 322.47, P = 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course., Conclusions: This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted. REGISTRATION INFO:: www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).

Single ventricle (SV) physiology is associated with growth retardation in children. The nutritional status of pediatric patients with SV undergoing a bidirectional Glenn (BDG) procedure vitally affects the feasibility of the next operation stages. To explore the nutritional status and to identify specific anthropometric parameters relevant to short-term surgical outcomes in children with SV after the BDG procedure, this study included 151 patients who underwent the BDG procedure. Anthropometric assessments and Infant and Child Feeding Index (ICFI) scores were used to evaluate nutritional status. There was a significant statistical correlation between ICFI and malnutrition in both the height-for-age Z-score (HAZ) and weight-for-age Z-score (WAZ) groups (P < 0.05). The clinical data, including ventilation time, nosocomial infection presence, pressure injury presence, peritoneal dialysis status, and total intensive care unit days, after BDG surgery were significantly different among the HAZ groups (P < 0.05), while nosocomial infection was different among the WAZ groups (P < 0.05). Children after BDG procedure had a high incidence of malnutrition, in addition to disease factors, the type and frequency of dietary intake were also important factors leading to worse clinical outcomes during hospitalization. Therefore, it is vital to maintain an optimal nutritional status in infants with SV who are undergoing a series of surgical procedures.

Background: Intracranial infections with Corynebacterium striatum (C. striatum) have been described sporadically in the literature over the last two decades. However, C. striatum meningitis combined with multiple abscesses has not been published before., Case Presentation: In this report, we describe the clinical and imaging findings in a 54-year-old woman with meningitis caused by C. striatum and combined with suspected brain and lung abscesses. This patient who underwent multiple fractures and a recent cut presented with headache and paraphasia. C. striatum was isolated in cerebrospinal fluid and supposedly transmitted from the skin purulent wound through blood. The patient was treated with intravenous vancomycin and had a transient improvement, but died finally. Multiple abscesses, especially in the brain, could be a reason to explain her conditions were deteriorating rapidly., Conclusions: Note that C. striatum can cause life-threatening infections. Early identification and diagnosis, early administration of antibiotics to which the bacterium is susceptible, and treatment of complications will be beneficial in patients with C. striatum-related infection.

To identify and verify the active ingredients from Astragalus membranaceus on hypertensive cardiac remodeling based on network pharmacology and heart RNA-sequencing data. The monomers of A. membranaceus and their intervention target database were established by using network pharmacology. The genes associated to cardiac remodeling were then screened by analyzing cardiac RNA-sequencing data. An overlap between genes related to cardiac remodeling and targets of ingredients form A. membranaceus was collected to obtain monomers with protective effect on hypertensive cardiac remodeling. Angiotensin Ⅱ(AngⅡ)-induced mouse cardiac remodeling model was used to validate the protective effect of active ingredients from A. membranaceus on hypertensive cardiac remodeling. Finally, a total of 81 monomers and 1 197 targets were enrolled in our database. Mouse RNA-sequencing data showed that 983 genes were significantly up-regulated and 465 genes were down-regulation in myocardial tissues of the cardiac remodeling mice as compared with blank group mice, respectively. Ninety-two genes were found via overlapping between genes related to cardiac remodeling and targets, involving 59 monomers from A. membranaceus. Further research found that vanillic acid(VA) could intervene 27 genes associated with hypertensive cardiac remodeling, ranking top 1. Meanwhile, VA could significantly inhibit AngⅡ-induced increase in ratio of heart weight to body weight and heart weight to tibial length, ANP and BNP mRNA levels in myocardial tissues, myocardial tissue damage, cardiac fibrosis level and cardiac hypertrophy level in vivo. Those results showed that network pharmacology screen-based VA has protective effect on AngⅡ-induced cardiac remodeling.

Background: The congenital stationary night blindness (CSNB) affects the patients' dim light vision or dark adaption by impairing the normal function of retina. It is a clinically and genetically heterogeneous disorder and can be inherited in an X-linked, autosomal dominant or autosomal recessive pattern. Several genetic alterations to the genes involved in visual signal transduction of photoreceptors and/or bipolar cells underlie its pathogenesis., Methods: In this study, we used Sanger sequencing and next-generation sequencing (NGS)-based gene panel screening to investigate a family of three patients with CSNB inherited in an apparent autosomal dominant pattern. We expected to find out the disease-causing gene defects carried by this family., Results: We found that the patients in this family did not carry the RHO, GNAT1, or PDE6B mutation, but carried compound heterozygotes mutations of GRM6. Three deleterious GRM6 variants, p.Arg621Ter, p.Gly51Val, and p.Gly464Arg, were found to be co-segregating with the disease, causing a pseudodominant inheritance of GRM6-related autosomal recessive complete CSNB., Conclusion: This study presents a rare case of autosomal recessive CSNB (arCSNB) pseudodominant inheritance, which potentially leads us to expand our gene candidate list in future genetic testing for apparent dominant pedigrees. The discovery of the two novel likely pathogenic variants p.Gly51Val and p.Gly464Arg could broaden our knowledge about the genetics of CSNB and provide insights into the structure and function of the GRM6 protein., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent cancer types in the world. The ubiquitin specific protease 7 (USP7), a kind of deubiquitylating enzyme, has been reported to play multifaceted roles in different tumor types. EZH2 has been found to be highly expressed in various malignantcells and high expression of EZH2 is closely related to tumor growth infiltration, lymph node involvement, clinical stage, and poor prognosis. The aim of this study was to investigate the expression and function of USP7 and EZH2 in LSCC., Case Presentation: Immunohistochemical staining and histochemical staining were performed to explore the expression of USP7 and EZH2 in both LSCC tissues and adjacent normal laryngeal tissues. Chi-square test, univariate analysis, and multivariate analysis were conducted to statistically evaluate the clinical significance of USP7 and EZH2., Conclusions: USP7and EZH2 affects LSCC evolution; USP7 and EZH2 were upregulated in LSCC tissues, which can serve as independent prognostic predictors, and potential therapeutic targets for LSCC., Competing Interests: None., (IJCEP Copyright © 2019.)

High-fat diet (HFD) is known to promote atherosclerosis which accelerates the development of atherosclerotic cardiovascular diseases. Vascular dysfunction characterized by inflammation and lipid accumulation is common in atherosclerosis caused by HFD. The specific effects of HFD on blood vessels and the underlying mechanisms need to be further clarified. Toll-like receptor 4 (TLR4) is a key contributing factor in atherosclerosis and TLR4 deficiency protects vascular smooth muscle cells against inflammatory responses and lipid accumulation in vitro. However, the physiological significance of TLR4 signaling in HFD-induced changes is unknown. In this study, we observed that HFD feeding increased body weight, circulating inflammatory cytokines and lipid accumulation in the aorta of wild-type mice but apart from increasing body weight, did not affect the TLR4 knockout mice. TLR4 expression increased significantly in the arterial walls after receiving HFD treatment, while that of the co-localizing PPARγ and ABCG1 markedly decreased. TLR4 deficiency reversed the HFD-induced attenuation of PPARγ and ABCG1. In conclusion, TLR4 mediates HFD induced increase in body weight, inflammation and aortic lipid accumulation through, at least partly, the PPARγ/ABCG1 signaling pathway. Therefore, interfering with TLR4 signaling is a viable therapeutic option in diet induced atherosclerosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pancreatic cancer is one of the most lethal types of cancer; owing to low early detection rates and high metastasis rates, it is associated with an extremely poor prognosis. Therefore, a better understanding of the molecular mechanisms that underlie its metastasis and the identification of potential prognostic biomarkers are urgently required. Although high expression levels of asparaginyl endopeptidase (AEP) have been detected in various types of solid tumor, the expression and functions of AEP in pancreatic carcinomas have yet to be determined. The present study aimed to examine the putative functions of AEP in pancreatic carcinoma. Immunohistochemical analysis revealed that AEP was highly expressed in pancreatic cancer tissues compared with adjacent normal tissues. Patients with high AEP expression exhibited a significantly shorter overall survival time. Results from multivariate Cox regression analysis revealed that AEP was an independent prognostic factor for overall survival. Gain- and loss-of-function experiments demonstrated that knockdown of AEP expression significantly reduced the invasive ability of pancreatic cancer cells, whereas overexpression of AEP increased the invasive ability. In addition, AEP was detected in exosomes that were derived from cultured pancreatic ductal adenocarcinoma cells (PDACs) and in the serum from patients with PDAC. The Matrigel-Transwell invasion assay revealed that exosomes enriched with AEP were able to enhance the invasive ability of PDAC cells, whereas exosomes lacking AEP decreased the invasive ability. Furthermore, results from the present study suggested that AEP may be crucial for activation of the phosphoinositide 3-kinase/RAC‑α serine/threonine-protein kinase signaling pathway in PDAC cells. The present study data indicated that high AEP expression may be important for pancreatic carcinoma progression in an exosome-dependent manner, and that AEP may be an independent indicator of poor prognosis in patients with PDAC and may be a novel prognostic biomarker or therapeutic target in pancreatic carcinoma.

In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-NK in patients with stage IV non- small cell lung cancer (NSCLC) as a reference for understanding the relevance of any changes to the efficacy of NK cells therapy. The patients were given one to three courses of immunotherapy. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 31 patients with stage IV NSCLC at 1day before and 7 and 30d after NK cells therapy using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). Throughout the research, fever was the most common reaction (34.6%). The number of CTCs was 18.11±5.813, 15.13±5.984 and 10.32±5.623, respectively, and this decreased significantly over time. ΔCt values for the CTC-related genes CEA, MAGE-3 and CK18 increased significantly after NK cells infusion. The expression of CEA, CK18 and MAGE-3 decreased significantly with time after NK. CTC was a useful biomarker for evaluating the efficacy of NK cells therapy on stage IV NSCLC., (Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

In this study, the safety and clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) were evaluated. From July 2016 to March 2017, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n = 30) and (2) the cryoablation combined with allogenic NK cell group (n = 30). The changes in immune function, quality of life, and clinical response were evaluated. We found that allogenic NK cells combined with cryosurgical treatment for advanced NSCLC have a synergistic effect, which not only enhancing the immune function of patients, improving the quality of life, and significantly increasing the response rate (RR) and disease control rate (DCR) compared to cryoablation group. This study is the first clinical trial of allogenic NK cells combined with cryosurgery for the treatment of advanced NSCLC and preliminaily its safety and efficacy.

An alginate lyase producing bacterial strain, Cobetia sp. WG-007, was isolated and identified from rotting seaweed. The alginate lyase, Aly-W02, was purified by procedures of ultrafiltration, Q-Sepharose Fast Flow, Phenyl Sepharose 6 Fast Flow, and Superdex-G100 with specific activity of 21,285.5 U/mg. Aly-W02 had an apparent molecular mass of 35 kDa. It exhibited maximum activity at 45 °C in 50 mM sodium phosphate buffer (pH 8.5). This alginate lyase was stable in the pH range of 6.0-8.5. Among the tested metal ions, the addition of K + , Na + , and Mg 2+ ions can enhance the enzyme activities, while Ba 2+ , Ni + , Cu 2+ , Mn 2+ , Zn 2+ , Ag + , and ethylenediaminetetraacetic acid decreased the activities. It displayed high salt-tolerant ability; 0.8 M NaCl or 1.5 M KCl significantly enhanced the enzyme activity. Furthermore, Aly-W02 mainly released disaccharide, trisaccharide, and tetrasaccharid from alginate. It showed potential in producing low molecular weight alginate oligosaccharides., (© 2016 International Union of Biochemistry and Molecular Biology, Inc.)

Objectives: To investigate the characteristics of differentiation of lung side population cells (LSP cells) in vitro ., Methods: CD45 - /CD31 + LSP cells sorted by flow cytometry were taken from mouse lung tissues and cultured for 14 d. The cultured LSP cells were observed with colony formation assay and flow cytometry in vitro . The mRNA expressions of ATP-binding cassette transporter G2 ( ABCG2 ), smooth muscle actin ( SMA ) and α-smooth muscle tropomyosin ( α-SMT ) in both freshly isolated LSP cells and cultured LSP cells were examined. The expressions of ABCG2 and stem cell antigen 1 (Sca1) in LSP cells were detected using immunofluorescence. RT-PCR tests were performed to detect the expressions of ABCG2, SMA and α-SMT in LSP cells., Results: The isolated CD45 - /CD31 + lung side population cells expressed ABCG2, SMA and Sca1, but not α-SMT . A large number of LSP in aggregated state were observed after 14 d of culture. Before induction of differentiation, the CD45 - /CD31 + LSP cells expressed ABCG2 and SMA , but not α-SMT. After induction of differentiation, the CD45 - /CD31 + lung side population cells expressed α-SMT and SMA , but not ABCG2 ., Conclusions: CD45 - /CD31 + LSP cells might be progenitor cells of vascular smooth muscle cells, possessing the characteristics of stem cell differentiations.

The phenotypic modulation of contractile vascular smooth muscle cell (VSMC) is widely accepted as the pivotal process in the arterial remodeling induced by hypertension. This study aimed to investigate the potential role of transient receptor potential vanilloid type 1 (TRPV1) on regulating VSMC plasticity and intracranial arteriole remodeling in hypertension. Spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats and TRPV1 -/- mice on a C57BL/6J background were used. By microscopic observation of the histopathological sections of vessels from hypertensive SHR and age-matched normotensive WKY control rats, we found that hypertension induced arterial remodeling. Decreased α-smooth muscle actin (α-SMA) and SM22α while increased osteopontin (OPN) were observed in aorta and VSMCs derived from SHR compared with those in WKY, and VSMCs derived from SHR upregulated inflammatory factors. TRPV1 activation by capsaicin significantly increased expression of α-SMA and SM22α, reduced expression of OPN, retarded proliferative and migratory capacities and inhibited inflammatory status in VSMCs from SHR, which was counteracted by TRPV1 antagonist 5'-iodoresiniferatoxin (iRTX) combined with capsaicin. TRPV1 activation by capsaicin ameliorated intracranial arteriole remodeling in SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive mice. However, the attenuation of arteriole remodeling by capsaicin was not observed in TRPV1 -/- mice. Furthermore, TRPV1 activation significantly decreased the activity of PI3K and phosphorylation level of Akt in SHR-derived VSMCs. Taken together, we provide evidence that TRPV1 activation by capsaicin attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation during hypertension, which may be at least partly attributed to the suppression PI3K/Akt signaling pathway. These findings highlight the prospect of TRPV1 in prevention and treatment of hypertension.

Background and Objectives: Patients with previous gastrectomy have an increased incidence of gallstones and gallbladder morbidity requiring surgery. We investigated the possible risk factors that contribute to severe gallbladder disease in patients with previous gastrectomy and the role of laparoscopic cholecystectomy (LC) in the treatment of these patients., Methods: In this retrospective study, we reviewed a database of patients who underwent LC in our hospital during the period January 1, 2010, through May 1, 2015., Results: The average operation time in patients with previous gastrectomy was longer ( P < .05), but the operation times of patients with a long interval (>5 years) between gastrectomy and LC showed no statistical difference from those of patients without a history of gastrectomy ( P > .05). The conversion rate did not differ between the 2 groups ( P > .05), but in patients with previous gastrectomy, the conversion rate was significantly reduced after we adopted a comprehensive preoperative evaluation procedure ( P < .05). The frequency of cholecystitis attacks, rate of combination with gallbladder polyps, and rate of combination with pancreatitis were higher and gallstone formation time shorter, in the patients with malignant tumor, those undergoing Billroth II gastroenterostomy or esophagojejunostomy, and those with accompanying diabetes mellitus or hypercholesterolemia ( P < .05)., Conclusion: LC plays an important role in the treatment of benign gallbladder diseases in patients with a history of gastrectomy, and a comprehensive preoperative evaluation and accomplished surgical technique are necessary for successful outcomes. Previously identified clinical features may represent a risk factor for severe cholecystic morbidity in these patients.

The formation of fat-laden foam cells, contributing to the fatty streaks of the plaques of atheroma, is the critical early process in atherosclerosis. The previous study demonstrated that vascular smooth muscle cells (VSMCs) contain a much larger burden of the excess cholesterol in comparison with monocyte-derived macrophages in human coronary atherosclerosis, as the main origin of foam cells. It is noteworthy that VSMC-derived foam cells are deposited in subintima but not media, where VSMCs normally deposit in. Therefore, migration from media to intima is an indispensable step for a VSMC to accrue neutral lipids and form foam cell. Whether this migration occurs paralleled with or prior to the formation of foam cell is still unclear. Herein, the present study was designed to test the VSMC migratory capability in the process of foam cell formation induced by oxidized low-density lipoprotein (oxLDL). In conclusion, we provide evidence that oxLDL induces the VSMC-derived foam cells formation with increased migration ability and MMP-9 expression, which were partly attributed to the impaired SIRT1 and enhanced nuclear factor-kappa B (NF-κB) activity. As activation of transient receptor potential vanilloid type 1 (TRPV1) has been reported to have anti-atherosclerotic effects, we investigated its role in oxLDL-treated VSMC migration. It is found that activating TRPV1 by capsaicin inhibits VSMC foam cell formation and the accompanied migration through rescuing the SIRT1 and suppressing NF-κB signaling. The present study provides evidence that SIRT1 may be a promising intervention target of atherosclerosis, and raises the prospect of TRPV1 in prevention and treatment of atherosclerosis.

Background: Fragile histidine triad (FHIT), fibronectin (FN), and phosphatase and tensin homology deleted on chromosome ten (PTEN) are widely reported as having abnormal expression in malignant tumors. The role of FHIT, fibronectin, PTEN expression in patients with hepatocellular carcinoma (HCC) has not been characterized. Our study aims to investigate the expression of FHIT, fibronectin, and PTEN in human HCC and their relationship with clinicopathological features and prognosis of HCC., Methods: Immunohistochemistry was used to detect expression of FHIT, FN, and PTEN in tumor tissues from 138 HCC patients. The correlation between their expression and clinicopathological features and prognosis were analyzed., Results: FHIT, fibronectin, and PTEN proteins have different expressions between HCC and adjacent nontumor tissue (χ2 = 5.968, 7.380, 4.962; p < 0.05), which are expressed differently in the groups of different tumor stage, grade, tumor size, tumor number, lymph node metastasis, HBV infection, and cirrhosis in the background of nontumor sections (p < 0.05). In the FHIT and fibronectin positive expression group, the cumulative survival times were shorter than those in the negative expression groups (χ2 = 4.443, 9.867; p < 0.05), and in the PTEN positive expression group the cumulative survival times were longer than in the negative expression group (χ2 = 4.199; p < 0.05)., Conclusions: FHIT, fibronectin, and PTEN were abnormally expressed in HCC cells, which have stimulative or suppressive effects on HCC carcinogenesis and progression. FHIT and fibronectin can be used as negative makers for prognosis and PTEN as a positive one.

Some epidemiological studies have evaluated the association between interleukin (IL)-18 promoter polymorphisms and the risk of ischemic stroke (IS), but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between IL-18 promoter 137G/C and 607C/A polymorphisms and the risk of IS in the Chinese population. Related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to November 1, 2014 were systematically searched, also the reference lists of identified articles were manually searched. Information was extracted to calculate for the allelic, genotypic, dominant and recessive models using the pooled odds ratios (ORs) along with 95% confidence intervals (CIs). Evidence of significant association between 607C/A polymorphism and risk of IS was found in four genetic models based on the overall population. However, no significant association between 137G/C polymorphism and risk of IS was found in four genetic models. In summary, the present study suggests that IL-18 gene promoter 607A polymorphism is a protective factor for IS in the Chinese population, while 137C polymorphism has weaker or no protective properties. Still, a larger number of studies with large scale and sufficient original information are required to further confirm our findings.

Increasing evidence showed that abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are common event in the pathophysiology of many vascular diseases, including atherosclerosis and restenosis after angioplasty. Among the underlying mechanisms, oxidative stress is one of the principal contributors to the proliferation and migration of VSMCs. Oxidative stress occurs as a result of persistent production of reactive oxygen species (ROS). Recently, the protective effects of peroxisome proliferator-activated receptor γ (PPARγ) against oxidative stress/ROS in other cell types provide new insights to inhibit the suggests that PPARγ may regulate VSMCs function. However, it remains unclear whether activation of PPARγ can attenuate oxidative stress and further inhibit VSMC proliferation and migration. In this study, we therefore investigated the effect of PPARγ on inhibiting VSMC oxidative stress and the capability of proliferation and migration, and the potential role of mitochondrial uncoupling protein 2 (UCP2) in oxidative stress. It was found that platelet derived growth factor-BB (PDGF-BB) induced VSMC proliferation and migration as well as ROS production; PPARγ inhibited PDGF-BB-induced VSMC proliferation, migration and oxidative stress; PPARγ activation upregulated UCP2 expression in VSMCs; PPARγ inhibited PDGF-BB-induced ROS in VSMCs by upregulating UCP2 expression; PPARγ ameliorated injury-induced oxidative stress and intimal hyperplasia (IH) in UCP2-dependent manner. In conclusion, our study provides evidence that activation of PPARγ can attenuate ROS and VSMC proliferation and migration by upregulating UCP2 expression, and thus inhibit IH following carotid injury. These findings suggest PPARγ may represent a prospective target for the prevention and treatment of IH-associated vascular diseases.

Despite advancements in diagnosis and treatment of cardiovascular diseases (CVDs), the morbidity and mortality of CVDs are still rising. Atherosclerosis is a chronic inflammatory disease contributing to multiple CVDs. Considering the complexity and severity of atherosclerosis, it is apparent that exploring the mechanisms of atherosclerotic formation and seeking new therapies for patients with atherosclerosis are required to overcome the heavy burden of CVDs on the quality and length of life of the global population. Vascular smooth muscle cells (VSMCs) play a dominant role in functional and structural changes of the arterial walls in response to atherogenic factors. Therefore, improvement of VSMC functions will slow down the development of atherosclerosis to a large extent. Given its protective performances on regulation of cholesterol metabolism and inflammatory responses, SIRT1 has long been known as an anti-atherosclerosis factor. In this review, we focus on the effects of SIRT1 on VSMC functions and thereby the development of atherosclerosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

Objective: To compare the application of MRI and CT imageological examination in diagnosis of middle-aged patients with multiple cerebral infarction., Methods: 218 cases of patients with multiple cerebral infarction were selected for CT and MRI examinations, and the clinical value of CT and MRI examinations in diagnosis and imaging of middle-aged patients with multiple cerebral infarction was compared and analyzed., Results: For the 218 cases of patients, the total detection rate of CT examination was 56.88% and that of MRI examination was 95.87%, indicating a statistically significant difference (x (2)=6.795, P=0.008). For the 85 patients in the group of less than 24 h, the detection rate of CT examination was 37.65% and that of MRI examination was 94.12%, and the comparative analysis between two groups suggested a statistically significant difference (x (2)=6.357, P=0.006); for the 70 cases in the group of 24~72 h, the detection rate of CT examination was 48.57%, and that of MRI examination was 97.14%, suggesting a statistically significant difference (x (2)=5.315, P=0.026); for the 63 cases in the group of greater than 72 h, the detection rate of CT and MRI examinations showed no statistically significant difference (P>0.05). This showed that the cerebral infarction detection rate of MRI examination was significantly higher than that of CT examination in the group of less than 24 h and the group of 24~72 h, while the difference in the cerebral infarction detection rate was not significant in the group of greater than 72 h. The number of lesions detected by MRI examination was significantly higher than that by CT examination (P<0.01); the capability of MRI examination to detect small lesions of cerebral infarction was significantly stronger than that of CT examination (P<0.05)., Conclusion: MRI has significant advantages in diagnosis of middle-aged patients with multiple cerebral infarction when compared to CT.

Objective: To investigate the clinical efficacy of CT-guided percutaneous chemical ablation in treatment of pelvic hypovascular metastasis., Methods: Based on a retrospective analysis of the clinical data of 78 patients with pelvic hypovascular metastasis, CT-guided percutaneous chemical ablation was used to directly puncture lesions. The emulsion consisting of ultra-liquid iodized oil, anhydrous ethanol and oxaliplatin in the proportion of 1:2:2 was slowly injected to the lesions, which should be filled to the greatest extent. The postoperative follow-up lasted for 2~51 months., Results: After surgery, 23 of these 78 cases were reported with merely residual fibrous cords or calcified shadow or complete recovery, and the lesion volume was reduced by ≥ 50% in 55 cases compared to that before surgery, indicating a total effective rate of 100% (78/78). The tumor size after treatment was significantly reduced compared to that before treatment [(4.5 ± 1.9) cm(2) vs (20.6 ± 10.1) cm(2)], and the difference was statistically significant (P = 0.018). Of 34 patients suffering from pain in perineum, buttocks and/or legs and limited mobility of the lower extremities, eliminated pain were reported in 13 cases and relieved symptoms in 21 cases. No intraoperative and postoperative complications were observed., Conclusion: In treatment of pelvic hypovascular metastasis, CT-guided percutaneous chemical ablation proves to be minimally invasive, effective and worthy of clinical promotion.

Several epidemiologic studies have evaluated the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and stroke, but the results were inconsistent. The present meta-analysis was performed to investigate the relationship between K469E polymorphism and stroke in the Chinese population. A comprehensive search for related studies from the electronic databases of PubMed, Embase, Web of Science, CBMdisc and CNKI as well as a manual search of the references of identified articles was performed. Data were extracted to calculate for allelic, additive, dominant and recessive models using pooled odds ratios (ORs) along with 95% confidence intervals (CIs) by Review Manager 5.0 and Stata 11.0. Different effect models, subgroup analysis, sensitivity analysis, publication bias and power calculations were used to improve the comprehensive analysis. Finally, a total of 12 studies containing 1593 cases and 1555 controls were included in the final meta-analysis. No evidence of significant association between ICAM-1 gene K469E polymorphism and stroke was found in all four models (allelic model: OR = 1.07, 95%CI = 0.78-1.47; additive model: OR = 1.21, 95% CI = 0.67-2.16 (EE vs. KK); OR = 1.04, 95%CI = 0.75-1.45 (EK vs. KK); dominant model: OR = 1.07, 95% CI = 0.73-1.56; and recessive model: OR = 1.18, 95% CI = 0.77-1.83, respectively) based on the overall population, as well as subgroup analysis and sensitivity analysis. In conclusion, the present meta-analysis showed no evidence of significant association between ICAM-1 gene K469E polymorphism and stroke in the Chinese population. Nonetheless, this conclusion should be interpreted cautiously due to the low statistical power and considerable heterogeneity. Therefore, larger sample-size studies with homogeneous cases and well-matched controls are needed to further address this correlation.

The transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated cation channel of the TRP subfamily, can be activated by multiple stimuli, including capsaicin. Currently, cumulative studies have demonstrated an interesting link between TRPV1 and cardiovascular diseases, including hypertension. Additionally, the protective effect of TRPV1 against hypertension and its related disorders has been proved to be partly involved with the improved action of vascular smooth muscle cells (VSMCs). This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Natural killer (NK) cells are a key component of the innate immune system and play pivotal roles as inflammatory regulators and in tumor surveillance. Human aspartyl β-hydroxylase (HAAH) is a plasma membrane and endoplasmic reticulum protein with hydroxylation activity, which is over-expressed in many malignant neoplasms and can be detected from the sera of tumor patients. HAAH is involved in regulating tumor cell infiltration and metastasis. Escaping from immune surveillance may help tumor cell infiltration and metastasis. However, the effects of HAAH on tumor immune surveillance have not yet been investigated carefully. The present study investigated the potential use of HAAH as an immune regulator of human NK cells. We assessed the effects of recombinant HAAH (r-HAAH) on primary human NK cell morphology, viability, cytotoxicity, apoptosis, receptors expression and cytokine/cytolytic proteins production. Our results demonstrated that r-HAAH negatively affects NK cell activity in a time and dose-dependent manner. It noticeably reduces the viability of the NK cells by increasing apoptosis and necrosis via caspase signaling pathways. Moreover, r-HAAH reduces the NK cell cytotoxicity by inhibiting surface expression of NKG2D, NKp44 and IFN-γ secretion. These findings suggest that one of the ways by which HAAH actively promotes tumor formation and proliferation is by inhibiting NK cell-surveillance activity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and cerebrovascular disease, but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between C677T polymorphism and cerebrovascular disease in Chinese population. Systematically searching for related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to 20 September 2013 and manual searching of the reference lists of identified articles was performed. Information was extracted to calculate for the additive, dominant, and recessive models using the pooled odds ratios (ORs) along with 95 % confidence intervals (CIs), using Review Manager 5.0, STATA 11.0 and SPSS 17. Logistic regression, fixed or random effects model, subgroup analysis, sensitivity analysis, meta-regression analysis and publication bias were conducted to improve the comprehensive analysis. A total of 68 case-control studies containing 7,990 cases and 6,941 controls were included in the final meta-analysis. Evidence of significant association between C677T polymorphism and risk of cerebrovascular disease was found in all three genetic models (additive model OR 1.472, 95 % CI 1.368-1.585, P L < 0.001 (CT vs. CC); OR 1.819, 95 % CI 1.666-1.985, P L < 0.001 (TT vs. CC); dominant model OR 1.77, 95 % CI 1.57-1.98, p < 0.00001; and recessive model OR 1.54, 95 % CI 1.39-1.71, p < 0.00001, respectively) based on the overall population. In addition, the results were verified by the subgroup analysis and sensitivity analysis. The present meta-analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of cerebrovascular disease. TT genotype may act as an independent risk factor for cerebrovascular disease in Chinese population.

Epidemiological studies have evaluated the association between Toll-like receptor 4 (TLR4) gene Asp299Gly (rs4986790) polymorphism and the risk of ischemic cerebrovascular disease, but the results are inconsistent. In an effort to clarify earlier inconclusive results, a meta-analysis was performed. We searched the PubMed, Web of Science, Embase, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, CNKI, CBMdisc, Chinese Clinical Trial Registry and Google Scholar until up to 20 July 2013. Additionally, hand searching of the references of identified articles was performed. Original observational studies investigating the association between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk were included. All statistical analyses were performed using Stata 11.0. The search strategy identified 1038 potentially relevant articles, seven of which were included in the final meta-analysis, covering a total of 1767 cases and 2785 controls. Overall, no significant association was found between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk (for G allele versus A allele: OR = 0.95, 95% CI = 0.75-1.21, p = 0.69; for G/G+A/G versus A/A: OR = 0.96, 95% CI = 0.75-1.22, p = 0.73). In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. In summary, the present meta-analysis indicates that TLR4 gene Asp299Gly polymorphism is not associated with increased ischemic cerebrovascular disease risk.

Polysaccharides are believed to be strong immunostimulants that can promote the proliferation and activity of T cells, B cells, macrophages and natural killer (NK) cells. This study aimed to investigate the effects of five polysaccharides (Grifola frondosa polysaccharide (GFP), lentinan (LNT), G. lucidum polysaccharide (GLP), Lycium barbarum polysaccharide (LBP) and yeast glucan (YG)) on primary human NK cells under normal or simulated microgravity (SMG) conditions. Our results demonstrated that polysaccharides markedly promoted the cytotoxicity of NK cells by enhancing IFN-γ and perforin secretion and increasing the expression of the activating receptor NKp30 under normal conditions. Meanwhile polysaccharides can enhance NK cell function under SMG conditions by restoring the expression of the activating receptor NKG2D and reducing the early apoptosis and late apoptosis/necrosis. Moreover, the antibody neutralization test showed that CR3 may be the critical receptor involved in polysaccharides induced NK cells activation. These findings indicated that polysaccharides may be used as immune regulators to promote the health of the public and astronauts during space missions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Numerous epidemiological studies have evaluated the associations between ATP-binding cassette transporter 1 (ABCA1) R219K (rs2230806) and M883I (rs4149313) polymorphisms and atherosclerosis (AS), but results remain controversial. The purpose of the present study is to investigate whether these two polymorphisms facilitate the susceptibility to AS using a meta-analysis., Methods: PubMed, Embase, Web of Science, Medline, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI, Google Scholar and Baidu Library were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0., Results: Forty-seven articles involving 58 studies were included in the final meta-analysis. For the ABCA1 R219K polymorphism, 42 studies involving 12,551 AS cases and 19,548 controls were combined showing significant association between this variant and AS risk (for K allele vs. R allele: OR = 0.77, 95% CI = 0.71-0.84, P<0.01; for K/K vs. R/R: OR = 0.60, 95% CI = 0.51-0.71, P<0.01; for K/K vs. R/K+R/R: OR = 0.69, 95% CI = 0.60-0.80, P<0.01; for K/K+R/K vs. R/R: OR = 0.74, 95% CI = 0.66-0.83, P<0.01). For the ABCA1 M883I polymorphism, 16 studies involving 4,224 AS cases and 3,462 controls were combined. There was also significant association between the variant and AS risk (for I allele vs. M allele: OR = 0.85, 95% CI = 0.77-0.95, P<0.01)., Conclusions: The present meta-analysis suggested that the ABCA1 R219K and M883I polymorphisms were associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

Background: The association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and adult stroke remains controversial. The present article was designed to clarify this relationship through pooled analysis of the numerous epidemiological studies focusing on this association., Methods: We comprehensively searched all published papers in electronic database including PubMed, Embase, Web of Science, Chinese Biomedical Literature on disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) up to 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for allelic (C allele vs. A allele), additive (CC vs. AA), dominant (CC+AC vs. AA), and recessive (CC vs. AA+AC) models were calculated. Subgroup and sensitivity analyses were performed to detect the heterogeneity and examine the reliability of results, respectively. Begg's funnel plots and Egger's regression test were used to assess the potential publication bias., Results: A total of fifteen studies containing 2,361 cases and 2,653 controls were included in the final meta-analysis. The combined results of overall analysis showed that there was significant association between MTHFR gene A1298C polymorphism and adult stroke (allelic model: OR=1.36, 95% CI=1.11-1.67; additive model: OR=1.88, 95% CI=1.12-3.18; dominant model: OR=1.33, 95% CI=1.08-1.65 and recessive model: OR=1.77, 95% CI=1.07-2.94, respectively). On subgroup analysis by ethnicity of study population, significant association was shown in meta-analysis based on Asian population (allelic model: OR=1.40, 95% CI=1.19-1.65; additive model: OR=2.58, 95% CI=1.34-4.96; dominant model: OR=1.44, 95% CI=1.20-1.73 and recessive model: OR=2.12, 95% CI=1.20-3.76, respectively), but not in Caucasian population (allelic model: OR=1.30, 95% CI=0.93-1.82; additive model: OR=1.65, 95% CI=0.81-3.33; dominant model: OR=1.17, 95% CI=0.86-1.61 and recessive model: OR=1.70, 95% CI=0.83-3.50, respectively). In addition, the heterogeneity was effectively removed or decreased by limiting the included studies with population of Asian ethnicity. Furthermore, the corresponding pooled ORs were not materially changed in all genetic models of meta-analysis after limiting the included studies with population-based controls. However, except the recessive model, publication bias presented in the allelic, additive, dominant models identified by the Begg's funnel plots and Egger's regression test., Conclusions: In conclusion, the overall analysis suggests that MTHFR gene A1298C polymorphism plays an important role in the development of adult stroke. Genotype CC of MTHFR-1298A/C could increase the risk of stroke and may act as a predictor for clinical evaluation, especially in the Asian population. More studies with large-scale and different ethnicities are required to further confirm our findings., (© 2014 S. Karger AG, Basel.)

Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene -174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene -174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene -174G>C polymorphism and AS risk (for C allele vs. G allele: OR=1.02, 95% CI=0.94-1.11, p=0.64; for C/C vs. G/G: OR=1.01, 95% CI=0.85-1.21, p=0.88; for C/C vs. C/G+G/G: OR=0.97, 95% CI=0.84-1.12, p=0.68; for C/C+C/G vs. G/G: OR=1.07, 95% CI=0.97-1.17, p=0.18). In the subgroup analyses, significant associations were found between the IL-6 gene -174G>C polymorphism and AS in non-Caucasian group (for CC+CG vs. GG: OR=1.22, 95% CI=1.06-1.41, p=0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR =0.75, 95% CI=0.61-0.93, p=0.008; for C/C vs. G/G: OR=0.56, 95% CI=0.38-0.81, p=0.002; for C/C vs. C/G+G/G: OR=0.60, 95% CI=0.45-0.79, p=0.0004) and population-based group (for C allele vs. G allele: OR=1.09, 95% CI=1.00-1.18, p=0.04; for CC+CG vs. GG: OR=1.15, 95% CI=1.04-1.27, p=0.005). In summary, the present meta-analysis suggests that the IL-6 gene -174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution., (© 2013 Elsevier B.V. All rights reserved.)

Objective: To investigate the risk factors of postsurgical gastroparesis syndrome (PGS) after subtotal gastrectomy in gastric cancer and the impact of PGS on prognosis., Methods: Clinical data of 422 patients who underwent subtotal gastrectomy for gastric cancer in the Central Hospital of Huzhou Sity from January 2004 to May 2010 were analyzed retrospectively. Risk factors of PGS were indentified and the recurrence-free survival was compared between the patients with and without PGS., Results: PGS occurred in 42 patients (9.5%). Univariate analysis showed that: age over 65, combination of anxiety disorder, low-albuminemia in perioperative period, pyloric obstruction in preoperative period, high serume glucose level (≥ 11.2 mmol/L) in postoperative period, Billroth II (gastroenterostomy, operation time over 4 hours, using patient-controlled analgesia, or intravenous fluid over 3500 ml/d (all P<0.05) were prone to develop PGS. These might be potential clinical risk factors associated to PGS. Correlation analysis showed the number of clinical risk factors was positively correlated with the incidence of PGS (r=0.967, P<0.05). A total of 215 cases (50.9%) were followed up for 3-60 months. The mean recurrence-free survival time of patients with PGS was 26.1 months, which was shorter than that of those without PGS (33.4 months, P=0.029)., Conclusions: Gastric cancer patients with the clinical risk factors mentioned above are prone to develop PGS after subtotal gastrectomy. PGS is associated with poor prognosis.

Objective: To investigate the distribution and hot spots of literatures on headache by bibliometric analysis in order to provide reference for further study., Methods: Literatures that contained headache or migraine in text words published in 2011 in PubMed databases (www.ncbi.nlm.nih.gov/Pubmed) were searched. Journals, countries and subjects were bibliometrically analysed., Results: There were 3683 papers involved to headache published in PubMed in 2011, of which 1527 papers were on headache research. The number of papers on headache research published by USA was the most followed by Italy and Germany (USA 23.25%, Italy 10.74%, Germany 5.83%). The mainly studied subjects were therapy (29.60%), pathophysiology (18.66%) and etiology (16.31%). 14.86% papers published in Cephalalgia, which is one of the most important journals, reported negative results., Conclusion: The emphasis of headache research was on migraine. Therapy, pathophysiology and etiology were the hot spot. Literatures with negative result attracted authors to give the more attention.

A comb ethyl cellulose-g-sodium polyacrylate (EC-g-SPA) was synthesized by atom transfer radical polymerization. The amphiphilic properties of the EC-g-SPA were determined by surface tension measurements. The interactions between EC-g-SPA and the cationic surfactant dodecyl-trimethylammonium bromide (C12TAB) were investigated by surface tension, turbidity, dynamic light scattering and transmission electron microscopy (TEM). The results revealed that the critical aggregate concentration (CAC) of the complexes was 0.8mM. When the C12TAB concentration was lower than the CAC, the hydrodynamic diameter (Dh) of the complexes decreased as the surfactant concentration was increased. As the C12TAB concentration was increased above the CAC, the Dh initially increased slightly, followed by a sharp decrease. The changes in the sizes and shapes of the aggregates were studied by TEM. The interactions between two species and the structure of the EC-g-SPA/C12TAB complexes were also discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To explore the surgical treatment of hypopharyngeal and cervical esophageal cancers and the ways of reconstruction after hypopharyngo-oesphagectomy, and to evaluate their efficacy., Methods: Twenty five patients with cancer of the laryngopharynx and cervical esophagus treated in our department between 1995 and 2007 were included in this study. Their clinical data were restrspectively analyzed. Among them, 17 cases had the tumor originated from the pyriform sinus, 3 of the posterior pharyngeal wall and 5 of the postcricoid region. Acording to the 2002 UICC criteria, all the tumors were stage T4, including 9 patients with cN0, 11 with cN1, and 5 with cN2 disease. The pharyngoesophageal defect reconstruction methods were as following: pharyngogastric anastomosis in 7 patients, free jejunal transplantion in 4, laryngotracheal flap in 8, and pectoralis major musculocutaneous flap in 6 patients. All patients were treated with modified and/or selective neck dissection. Among them, 8 cases received pre-operation radiotherapy, 17 received post-operative auxiliary radiotherapy., Results: There was no operation death case in this group. All patients were followed up for 3 to 5 years. Three patients died in the first year. According to Kaplan-Meier analysis, the 1-year survival rate was 88.0%, 3-year survival rate was 48.0%, and 5-year survival rate was 28.0%., Conclusions: The use of primary repair of the defects of laryngopharynx and cervical esophagus expands the operative indication for cancers of the laryngopharynx and cervical esophagus, improves the survival rate and life quality of the patients. Regarding the repair method of choice, site of the tumor and size of the defect are the most important factors regarding choice of reconstruction method, while the patients' age and general condiction should also be considered to minimize the complications as more as possible.

Aim: To obtain sufficient numbers of pure and activated human primary NK cells for potential clinical application., Methods: PBMC based ex vivo expansion of natural killer cells was set up. The expansion was initiated by co-culture of PBMC and stimulator cells (irradiate genetic modified K562 cells) in RPMI1640 medium with 1 000 U/mL IL-2. Genetic modified K562 cells 'K562D3' were prepared by expressing IL-15, 4-1BBL and IL-18 on K562 cell membrane., Results: An average of 500 fold expansion of CD56(+)CD3(-) cells was observed after 3 weeks of co-culture. The NK cells population could reach 93% after expansion, comparing with 7% before expansion. The expanded NK cells lysed 95% of K562 targets in a 5:1 effector to target ratio. IL-15/4-1BBL bound K562 stimulatory cells could expand same fold NK cells as K562D3, but the cytotoxicity of NK cells expanded by 'K562D3' was 10% higher., Conclusion: The described method is a simple and efficient way for the expansion of human NK cells.

Human metallothionein-3 (hMT3), also named as human neuronal growth inhibitory factor (hGIF), can inhibit the outgrowth of embryonic cortical neurons in the presence of brain extracts. In order to systematically study the structure-property-reactivity-function relationship of hGIF, our laboratory designed a series of mutants and studied their structure, property, reactivity and functions by a series of chemical and biological tools including UV spectroscopy, CD spectroscopy, NMR, chemical reaction and primary neuronal culture assays. In summary, we concluded that the bioactivity of hGIF was regulated by multiple factors, including the (6)CPCP(9) motif, an additional threonine insert at sequence position 5, domain-domain interactions, the structure and stability of the metal-thiolate cluster and the linker. Our studies provide more and more evidences which revealed that the bioactivity of hGIF is mainly related to the essential metal release and its characteristic conformation.

Human metallothionein-3 (hMT3), also named human neuronal growth inhibitory factor (hGIF), is attractive due to its distinct neuronal growth inhibitory activity, which is not shown by other human MT isoforms. It has been reported that the neuronal growth inhibitory activity arises from the N-terminal beta-domain rather than its C-terminal alpha-domain. However, previous bioassay results have shown that the single beta-domain is less effective at inhibiting the neuron growth than that in intact hMT3 on a molar basis, which suggests that the alpha-domain is indispensable to the neuronal growth inhibitory activity of hMT3. In order to confirm this assumption, we constructed two domain-hybrid mutants, the beta(MT3)-beta(MT3) mutant and the beta(MT3)-alpha(MT1) mutant, and investigated their structural and metal binding properties by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, etc. The results showed that stability of the Cd(3)S(9) cluster of the beta(MT3)-beta(MT3) mutant decreased significantly while the Cd(3)S(9) cluster of the beta(MT3)-alpha(MT1) mutant had a similar stability and solvent accessibility to that of hMT3. Interestingly, the bioassay results showed that the neuronal growth inhibitory activity of the beta(MT3)-beta(MT3) mutant decreased significantly, while the beta(MT3)-alpha(MT1) mutant showed similar inhibitory activity to hMT3. Based on these results, we conclude that the alpha-domain is indispensable and plays an important role in modulating the stability of the metal cluster in the beta-domain by domain-domain interactions, thus influencing the bioactivity of hMT3.

The beta-domain of metallothionein-3 (MT3) has been reported to be crucial to the neuron growth inhibitory bioactivity. Little detailed three-dimensional structural information is available to present a reliable basis for elucidation on structure-property-function relationships of this unique protein by experimental techniques. So, molecular dynamics simulation is adopted to study the structure of beta-domain of MT3. In this article, a 3D structural model of beta-domain of MT3 was generated. The molecular simulations provide detailed protein structural information of MT3. As compared with MT2, we found a characteristic conformation formed in the fragment (residue 1-13) at the N-terminus of MT3 owing to the constraint induced by 5TCPCP9, in which Pro7 and Pro9 residues are on the same side of the protein, both facing outward and the two 5-member rings of prolines are arranged almost in parallel, while Thr5 is on the opposite side. Thr5 in MT3 is also found to make the first four residues relatively far from the fragment (residue 23-26) as compared with MT2. The simulated structure of beta-domain of MT3 is looser than that of MT2. The higher energy of MT3 than that of MT2 calculated supports these conclusions. Simulation on the four isomer arising from the cis- or trans-configuration of 6CPCP9 show that the trans-/trans-isomer is energetic favorable. The partially unfolding structure of beta-domain of MT3 is also simulated and the results show the influence of 6CPCP9 sequence on the correct folding of this domain. The correlations between the bioactivity of MT3 and the simulated structure as well as the folding of beta-domain of MT3 are discussed based on our simulation and previous results., (2007 Wiley-Liss, Inc.)

Human metallothionein-3 (hMT3), first isolated and identified as a neuronal growth inhibitory factor (GIF), is a metalloprotein expressed predominantly in brain. However, until now, the exact mechanism of the bioactivity of hMT3 is still unknown. In order to study the influence of acid-base catalysis on S-nitrosylation of hMT3, we constructed the E23K mutant of hMT3. During the course of bioassay, we found out unexpectedly that mutation at E23 of hMT3 eliminates the neuronal growth inhibitory activity completely. To the best of our knowledge, it is the first report that other residues, besides the TCPCP motif, in the beta-domain can alter the bioactivity of hMT3. In order to figure out the causes for the loss of bioactivity of the E23K mutant, the biochemical properties were characterized by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, and SNOC reaction. All data demonstrated that stability of the metal-thiolate cluster and overall structure of the E23K mutant were not altered too much. However, the reaction of the E23K mutant with SNOC exhibited biphasic kinetics and the mutant protein released zinc ions much faster than hMT3 in the initial step, while hMT3 exhibited single kinetic process. The 2D [1H-15N] HSQC was also employed to characterize structural changes during the reaction of hMT3 with varying mounts of nitric oxide. It was shown that the resonance of Glu23 disappeared at a molar ratio of NO to protein of 4. Based on these results, we suggest that mutation at Glu23 may alter the NO metabolism and/or affect zinc homeostasis in brain, thus altering the neuronal growth inhibitory activity.

GIF, a member of the metallothionein (MT) family (assigned as MT3), is a neuron growth inhibitory factor that inhibits neuron outgrowth in Alzheimer's disease. The conserved Thr5 is one of the main differences between GIF and other members in the MT family. However, natural sheep GIF has an unusual Ala5, casting doubt on the role of common Thr5. We constructed a series of human GIF mutants at site 5, and characterized their biochemical properties by UV spectroscopy, circular dichroism spectroscopy, EDTA reaction, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) reaction, and pH titration. Their inhibitory activity toward neuron survival and neurite extension was also examined. Interestingly, the T5A mutant exhibited distinct metal thiolate activity in the EDTA and DTNB reactions, and also lost its bioactivity. Meanwhile, the T5S mutant had similar biochemical properties and biological activity as wild-type human GIF, indicating the hydroxyl group on the Thr5 was critical to the bioactivity of human GIF. We suggest the hydroxyl group in human GIF may help stabilize the biologically active conformation. On the other hand, lack of the hydroxyl group in sheep GIF may be partially compensated by its abnormal structure.