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1.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
doi:10.1093/ije/dyt078
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
2.  Establishment of using serum YKL-40 and SCCA in combination for the diagnosis of patients with esophageal squamous cell carcinoma 
BMC Cancer  2014;14:490.
Background
Elevated serum YKL-40 levels have been observed in various cancers. We evaluated the diagnostic performance of serum YKL-40 alone or in combination with the CEA, CYFRA21-1 and SCCA tumor markers for patients with esophageal squamous cell carcinoma (ESCC).
Methods
YKL-40 was detected in ESCC cell lines and tissues by real-time RT-PCR, Western blotting and ELISA. YKL-40 protein expression was determined in 20 ESCC tumor tissues using immunohistochemistry. Serum YKL-40 was measured by ELISA in 126 healthy donors, 59 patients with benign esophageal diseases and 150 patients with ESCC. Serum CEA, CYFRA21-1 and SCCA were determined by electrochemiluminescence.
Results
YKL-40 mRNA and protein were observed in ESCC cancer cell lines, tissues and cell culture media, respectively. YKL-40 expression was observed in 17 of 20 ESCC samples (85%). Serum YKL-40 concentration was significantly elevated in patients with ESCC (Range: 6.95-502.10 ng/ml) compared with patients with benign diseases (Range: 1.21-429.30 ng/ml; P = 0.038) and healthy controls (Range: 2.56-132.26 ng/ml; P < 0.001). ROC curves demonstrated that serum YKL-40 has a sensitivity of 72.70%, a specificity of 84.13% and an AUC of 0.874 for the diagnosis of ESCC, which was superior to CEA (Sen: 8.00%; Spe: 96.80%, AUC = 0.652), CYFRA21-1 (Sen: 40.00%; Spe: 92.06%, AUC = 0.746) and SCCA (Sen: 32.67%; Spe: 94.44%, AUC = 0.789). The YKL-40 and SCCA combination was better for diagnosing ESCC (Sen: 82.00%, Spe: 79.37%, PPV: 82.55 and NPV: 78.74; AUC = 0.917) than the YKL-40 and CEA combination (Sen: 74.00%, Spe: 83.20%, PPV: 84.09 and NPV: 72.73; AUC = 0.877), the YKL-40 and CYFRA21-1 combination (Sen: 82.00%, Spe: 77.78%, PPV: 81.46% and NPV: 78.40%; AUC = 0.897) or the CEA, CYFRA21-1 and SCCA combination (Sen: 56.67%, Spe: 84.80%, PPV: 81.73 and NPV: 61.99; AUC = 0.831). Associations between serum YKL-40 levels and the clinic characteristics of ESCC were not significant, with the exception of age (p = 0.001).
Conclusions
ESCC tumor cells and tissues express YKL-40. Serum YKL-40 may be a potential biomarker for ESCC. Serum YKL-40 in combination with SCCA significantly increases the sensitivity of detecting ESCC.
doi:10.1186/1471-2407-14-490
PMCID: PMC4094903  PMID: 25001061
YKL-40; Esophageal cancer; ESCC
3.  Progranulin-Derived Atsttrin Directly Binds to TNFRSF25 (DR3) and Inhibits TNF-Like Ligand 1A (TL1A) Activity 
PLoS ONE  2014;9(3):e92743.
Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.
doi:10.1371/journal.pone.0092743
PMCID: PMC3961393  PMID: 24651300
4.  Endosonography-Assisted Diagnosis and Therapy of Gastrointestinal Submucosal Tumors 
Endoscopic Ultrasound  2013;2(3):125-133.
Submucosal tumors (SMTs) are usually discovered fortuitously during routine endoscopy, including various non-neoplastic and neoplastic conditions. Endoscopic ultrasound (EUS) is considered to be the best imaging procedure to characterize SMTs and to determine the need for further treatment. In this review, the following issues will be addressed: The role of EUS in diagnosis for SMTs, tissue diagnosis for SMTs and the influence of EUS on endoscopic resection techniques for SMTs.
doi:10.7178/eus.06.003
PMCID: PMC4062264  PMID: 24949380
Endoscopic ultrasound; submucosal tumor; gastrointestinal; diagnosis; therapy
5.  Aggregation of Whey Protein Hydrolysate Using Alcalase 2.4 L 
PLoS ONE  2014;9(10):e109439.
Here, we describe peptide aggregation, which is also known as enzymatic protein resynthesis. Whey protein hydrolysate (WPH) is the starting material for assembling peptides. Analyses of the involved amino acids, intrinsic fluorescence, fluorescence phase diagram, secondary structure, turbidity, and surface hydrophobicity were performed to investigate the reaction process. The aggregation mechanism consists of two parts: 1) formation and 2) aggregation of the building blocks that form the ordered secondary β-sheet structure. Constructing the building blocks requires at least one intermediate state, which is formed after 0.5 hours. Non-synergistic changes in the secondary and tertiary structures then allow the intermediate state to emerge.
doi:10.1371/journal.pone.0109439
PMCID: PMC4188594  PMID: 25290460
6.  miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6 
Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-κB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop.
doi:10.1038/emm.2014.63
PMCID: PMC4221693  PMID: 25277211
7.  EUS assisted transmural cholecystogastrostomy fistula creation as a bridge for endoscopic internal gallbladder therapy using a novel fully covered metal stent 
BMC Gastroenterology  2014;14(1):164.
Background
Laparoscopic cholecystectomy (LC) has become the “gold standard” for treating symptomatic gallstones. Innovative methods, such as a scarless therapeutic procedure through a natural orifice are being introduced, and include transgastric or transcolonic endoscopic cholecystectomy. However, before clinical implementation, instruments still need modification, and a more convenient treatment is still needed. The aim of this study was to evaluate the feasibility of endoscopic internal gallbladder therapy such as cholecystolithotomy in an animal survival model.
Methods
Four pigs underwent endoscopic-ultrasound (EUS)-guided cholecystogastrostomy and the placement of a novel covered mental stent. Four weeks later the stents were removed and an endoscope was advanced into the gallbladder via the fistula, and cholecystolithotomy was performed. Two weeks later the pigs were sacrificed, and the healing of the fistulas was assessed.
Results
EUS-guided cholecystogastrostomy with mental stent deployment was successfully performed in all the animals. Four weeks after the procedure, the fistulas had formed and all the stents were removed. Endoscopic cholecystolithotomy was performed through each fistula. All the animals survived until they were sacrificed 2 weeks later. The fistulas were found to be completely healed.
Conclusions
This study reports the first endoscopic transmural cholecystolithotomy after placement of a novel mental stent in an animal survival model.
doi:10.1186/1471-230X-14-164
PMCID: PMC4189557  PMID: 25249425
Endoscopic-ultrasound; Cholecystectomy; Mental stent
8.  Grape seed pro-anthocyanidins ameliorates radiation-induced lung injury 
Radiation-induced lung injury (RILI) is a potentially fatal and dose-limiting complication of thoracic radiotherapy. This study was to investigate the protective effects of grape seed pro-anthocyanidins (GSPs), an efficient antioxidant and anti-carcinogenic agent, on RILI. In our study, it was demonstrated that acute and late RILI was ameliorated after GSPs treatment possibly through suppressing TGF-β1/Smad3/Snail signalling pathway and modulating the levels of cytokines (interferon-γ, IL-4 and IL-13) derived from Th1/Th2 cells. In addition, a sustained high level of PGE2 was also maintained by GSPs treatment to limited fibroblast functions. As shown by electron spin resonance spectrometry, GSPs could scavenge hydroxyl radical (•OH) in a dose-dependent manner, which might account for the mitigation of lipid peroxidation and consequent apoptosis of lung cells. In vitro, GSPs radiosensitized lung cancer cell A549 while mitigating radiation injury on normal alveolar epithelial cell RLE-6TN. In conclusion, the results showed that GSPs protects mice from RILI through scavenging free radicals and modulating RILI-associated cytokines, suggesting GSPs as a novel protective agent in RILI.
doi:10.1111/jcmm.12276
PMCID: PMC4124012  PMID: 24758615
radiation-induced lung injury; grape seed pro-anthocyanidins; reactive oxygen species; epithelial–mesenchymal transition
9.  Using Surgical Microscope for Sclera Buckling and Transscleral Cryopexy: An Alternative Procedure of Treatment for Rhegmatogenous Retinal Detachment 
BioMed Research International  2014;2014:364961.
Purpose. To observe the long-term effectiveness of scleral buckling and transscleral cryopexy conducted under a surgical microscope in the treatment of uncomplicated rhegmatogenous retinal detachment. Methods. This was a retrospective analysis in a total of 227 consecutive patients (244 eyes) with uncomplicated rhegmatogenous retinal detachment (proliferative vitreoretinopathy ≤ C2). All patients underwent scleral buckling and transscleral cryopexy under a surgical microscope without using a binocular indirect ophthalmoscope or a contact lens. Results. After initial surgery, complete retinal reattachment was achieved in 226 eyes (92.6%), and retinal redetachment developed in 18 eyes (7.4%). The causes of retinal redetachment included presence of new breaks in eight eyes (44%), failure to completely seal the breaks in five eyes (28%), missed retinal breaks in four eyes (22%), and iatrogenic retinal breaks in one eye (6%). Scleral buckling surgery was performed again in 12 eyes (66%). Four eyes (22%) developed proliferative vitreoretinopathy and then were treated by vitrectomy. The sealing of retinal breaks and complete retinal reattachment were achieved in 241 eyes (98.8%). Conclusion. Probably because of clear visualization of retinal breaks and being controllable under a surgical microscope, the microsurgery of scleral buckling and transscleral cryopexy for uncomplicated retinal detachment exhibits advisable effectiveness.
doi:10.1155/2014/364961
PMCID: PMC3984779  PMID: 24790997
10.  High-Density Lipoprotein Cholesterol Is a Favorable Prognostic Factor and Negatively Correlated with C-Reactive Protein Level in Non-Small Cell Lung Carcinoma 
PLoS ONE  2014;9(3):e91080.
Background
Although the alterations of lipid profile in lung cancer have been documented, the prognostic value of serum HDL-C level and its correlation with inflammation in NSCLC remain unknown.
Subjects and Methods
Levels of preoperative serum lipid concentrations (including HDL-C, LDL-C, TC, and TG) and the inflammatory biomarker C-reactive protein level (CRP) were retrospectively analyzed in 228 patients with NSCLC and in 300 healthy controls. The serum lipid levels in these two populations were compared. Univariate and multivariate cox hazards analyses were performed to investigate the prognostic value of serum lipid levels in NSCLC. The correlation between CRP and lipid profile were also analyzed.
Results
Compared with those in normal controls, the serum HDL-C, LDL-C, and TC levels were statistically decreased and the TG levels were significantly increased in 228 NSCLC patients. The patients with decreased levels of HDL-C had significantly lower 5-year survival rates than those with normal HDL-C, not only in the whole NSCLC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other lipid components were not independent prognostic factors for NSCLC. Of the lipid components, a lower HDL-C level was observed more often in patients with a high CRP level than in those with a normal CRP level. Spearman’s rank correlation analysis revealed that the HDL-C level presented a negative correlation with the CRP level (r = −0.360, p<0.001).
Conclusions
A decreased level of preoperative HDL-C was found to be associated with poor survival in patients with NSCLC. Serum HDL-C level may be a clinical prognosis factor for NSCLC patients. In addition, a negative correlation was present between the levels of HDL-C and CRP, the well-known inflammation biomarker.
doi:10.1371/journal.pone.0091080
PMCID: PMC3953329  PMID: 24625581
11.  G-protein-coupled receptor participates in 20-hydroxyecdysone signaling on the plasma membrane 
Background
Animal steroid hormones are conventionally known to initiate signaling via a genomic pathway by binding to the nuclear receptors. The mechanism by which 20E initiates signaling via a nongenomic pathway is unclear.
Results
We illustrate that 20E triggered the nongenomic pathway through a plasma membrane G-protein-coupled receptor (named ErGPCR) in the lepidopteran insect Helicoverpa armigera. The transcript of ErGPCR was increased at the larval molting stage and metamorphic molting stage by 20E regulation. Knockdown of ErGPCR via RNA interference in vivo blocked larval–pupal transition and suppressed 20E-induced gene expression. ErGPCR overexpression in the H. armigera epidermal cell line increased the 20E-induced gene expression. Through ErGPCR, 20E modulated Calponin nuclear translocation and phosphorylation, and induced a rapid increase in cytosolic Ca2+ levels. The inhibitors of T-type voltage-gated calcium channels and canonical transient receptor potential calcium channels repressed the 20E-induced Ca2+ increase. Truncation of the N-terminal extracellular region of ErGPCR inhibited its localization on the plasma membrane and 20E-induced gene expression. ErGPCR was not detected to bind with the steroid hormone analog [3H]Pon A.
Conclusion
These results suggest that ErGPCR participates in 20E signaling on the plasma membrane.
doi:10.1186/1478-811X-12-9
PMCID: PMC3937218  PMID: 24507557
Steroid hormones; G-protein-coupled receptors; Protein phosphorylation; Calcium influx; Signal transduction
12.  Targeting GRP75 Improves HSP90 Inhibitor Efficacy by Enhancing p53-Mediated Apoptosis in Hepatocellular Carcinoma 
PLoS ONE  2014;9(1):e85766.
Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.
doi:10.1371/journal.pone.0085766
PMCID: PMC3894982  PMID: 24465691
13.  A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors 
Purpose
Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations.
Experimental design
The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients.
Results
Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median Tmax was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC0-24hr was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in ≥40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease.
Conclusions
Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously.
doi:10.1186/1756-8722-6-48
PMCID: PMC3716995  PMID: 23829943
MTOR inhibitor; Phase I study; Pharmacokinetic analysis; Adverse event
14.  CpG-Oligodeoxynucleotide Treatment Protects against Ionizing Radiation-Induced Intestine Injury 
PLoS ONE  2013;8(6):e66586.
Background
the bone marrow and the intestine are the major sites of ionizing radiation (IR)-induced injury. Our previous study demonstrated that CpG-oligodeoxynucleotide (ODN) treatment mitigated IR-induced bone marrow injury, but its effect on the intestine is not known. In this study, we sought to determine if CpG-ODN have protective effect on IR-induced intestine injury, and if so, to determine the mechanism of its effect.
Methods and Findings
Mice were treated with CpG-ODN after IR. The body weight and survival were daily monitored for 30 days consecutively after exposure. The number of surviving intestinal crypt was assessed by the microcolony survival assay. The number and the distribution of proliferating cell in crypt were evaluated by TUNEL assay and BrdU assay. The expression of Bcl-2, Bax and caspase-3 in crypt were analyzed by Immunohistochemistry assay. The findings showed that the treatment for irradiated mice with CpG-ODN diminished body weight loss, improved 30 days survival, enhanced intestinal crypts survival and maintained proliferating cell population and regeneration in crypt. The reason might involve that CpG-ODN up-regulated the expression of Bcl-2 protein and down-regulated the expression of Bax protein and caspase-3 protein.
Conclusion
CpG-ODN was effective in protection of IR-induced intestine injury by enhancing intestinal crypts survival and maintaining proliferating cell population and regeneration in crypt. The mechanism might be that CpG-ODN inhibits proliferating cell apoptosis through regulating the expression of apoptosis-related protein, such as Bax, Bcl-2 and caspase-3.
doi:10.1371/journal.pone.0066586
PMCID: PMC3689777  PMID: 23805241
15.  From Recurrent Syncope to Sudden Cardiac Death: Clinical Characteristics in a Chinese Patient Carrying a Plakophilin-2 Gene Mutation 
Case Reports in Cardiology  2013;2013:246891.
We report a case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) which illustrates the natural progression of disease in the absence of availability of an implanted cardiac defibrillator (ICD). Electrocardiograms and cardiac imaging show the progress of ARVC and these clinical milestones of disease are presented herein.
doi:10.1155/2013/246891
PMCID: PMC4007784  PMID: 24826278
16.  A comparative study of the safety and efficacy effect of 5-fluorouracil or mitomycin C mounted biological delivery membranes in a rabbit model of glaucoma filtration surgery 
Purpose
To investigate the potential usage of biological delivery membranes containing mitomycin C (MMC) or 5-fluorouracil (5-FU) in the construction of glaucoma-filtering blebs, and to evaluate their safety and efficacy.
Methods
Chitosan was selected as the biological membrane carrier to prepare sustained-released membranes. Twelve micrograms of 5-FU or MMC was covalently conjugated onto the membranes by solvent volatilization. Rabbits underwent glaucoma filtration surgery and were randomly allocated into one of the four treatment regimens: glaucoma filtration operation with no implantation of chitosan membrane group (as control), drug-free chitosan membrane implantation group (blank/placebo group), membrane containing 5-FU treatment group (5-FU group), and membrane containing MMC treatment group (MMC group). Each group consisted of 12 rabbits. Intraocular pressure (IOP) was measured and evaluated over a 28-day period follow-up preoperatively, then after surgery on days 1, 3, 5, 7, 14, 21, and 28 by Tono-Pen. The aqueous humor was analyzed in each experimental and control groups at days 4, 6, 8, 10, 12, 14, 16, and 20 after operation. Bleb survival and anterior segment were examined with a slit lamp microscope and photographed simultaneously. Two rabbits from each group were killed on day 28 and eight eye samples obtained for histopathological study. Corneas and lenses were examined by transmission and scanning electron microscopy.
Results
Both 5-FU and MMC significantly prolonged bleb survival compared with control groups. The filtering bleb’s survival period was significantly more prolonged in the MMC and 5-FU groups (maintained 14 days) than the other two groups (maintained 7 days). Significantly lower IOP was observed within the control, blank, and 5-FU groups after surgery on day 14 compared with that before operation, with F-values of 6.567, 11.426, and 13.467, respectively (P < 0.01). The most significant lower IOP was recorded in the MMC group on day 28 postoperation (F-value 26.866, P < 0.01). No obvious abnormalities were found in cornea or anterior lens capsule 28 days after surgery.
Conclusion
The study provided evidence that 5-FU and MMC biological delivery membranes could significantly improve the outcome of filtering procedures, the survival of the bleb, and maintenance of lower IOP. MMC membrane is superior to 5-FU, with regard to the more effective reduction of IOP. The results indicated a safe and effective treatment strategy in glaucoma surgery.
doi:10.2147/OPTH.S34200
PMCID: PMC3616693  PMID: 23576864
chitosan; biological delivery; mitomycin C (MMC); 5-fluorouracil (5-FU); glaucoma
17.  Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain 
EMBO Molecular Medicine  2013;5(3):384-396.
Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.
doi:10.1002/emmm.201201623
PMCID: PMC3598079  PMID: 23495140
cancer stem-like cell; IL-1β; metastasis; notch; reactive astrocytes
18.  Mitochondria-Dependent Apoptosis of Con A-Activated T Lymphocytes Induced by Asiatic Acid for Preventing Murine Fulminant Hepatitis 
PLoS ONE  2012;7(9):e46018.
Selectively facilitating apoptosis of activated T cells is essential for the clearance of pathogenic injurious cells and subsequent efficient resolution of inflammation. However, few chemicals have been reported to trigger apoptosis of activated T cells for the treatment of hepatitis without affecting quiescent T cells. In the present study, we found that asiatic acid, a natural triterpenoid, selectively triggered apoptosis of concanavalin A (Con A)-activated T cells in a mitochondria-dependent manner indicated by the disruption of the mitochondrial transmembrane potential, release of cytochrome c from mitochondria to cytosol, caspases activation, and cleavage of PARP. In addition, asiatic acid also induced the cleavage of caspase 8 and Bid and augmented Fas expression in Con A-activated T cells. However, following activation of T cells from MRLlpr/lpr mice with mutation of Fas demonstrated a similar susceptibility to asiatic acid-induced apoptosis compared with normal T cells, suggesting that Fas-mediated death-receptor apoptotic pathway does not mainly contribute to asiatic acid-induced cell death. Furthermore, asiatic acid significantly alleviated Con A-induced T cell-dependent fulminant hepatitis in mice, as assessed by reduced serum transaminases, pro-inflammatory cytokines, and pathologic parameters. Consistent with the in vitro results, asiatic acid also induced apoptosis of activated CD4+ T cells in vivo. Taken together, our results demonstrated that the ability of asiatic acid to induce apoptosis of activated T cells and its potential use in the treatment of T-cell-mediated inflammatory diseases.
doi:10.1371/journal.pone.0046018
PMCID: PMC3454338  PMID: 23029367
19.  Treatment of Pancreatic Abscess with Endoscopic Ultrasound-guided Placement of a Covered Metal Stent Following Failed Balloon Dilation and Endoscopic Necrosectomy 
Endoscopic Ultrasound  2012;1(2):110-113.
For the management of pancreatic abscess, endoscopic ultrasound (EUS)-guided puncture and drainage has become recognized as a safer and more effective alternative to surgery. Typically, a double-pigtail plastic stent is placed for drainage. When an abscess is complicated by infected necrosis, endoscopic evacuation is essential. However, endoscopic evacuation carries a high risk of hemorrhage and needs to be performed daily to be effective. We describe EUS-guided endoscopic evacuation and placement of a fully covered metal stent following two failed evacuations. Patient recovery time was excellent, and no complications occurred.
doi:10.7178/eus.02.010
PMCID: PMC4062208  PMID: 24949347
pancreatic abscess; endoscopic ultrasound; metal stent; balloon dilation; endoscopic necrosectomy
20.  Rupture of a duodenal stromal tumor during EUS-FNA: A case report 
Endoscopic Ultrasound  2012;1(1):53-55.
doi:10.7178/eus.01.009
PMCID: PMC4062198  PMID: 24949336
21.  NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling 
Cancer cell  2010;17(6):560-573.
SUMMARY
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-cancer effects through cyclooxygenase-2 (COX-2)-dependent and -independent mechanisms. Here we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-α (RXRα). We identified an N-terminally-truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.
doi:10.1016/j.ccr.2010.04.023
PMCID: PMC2907921  PMID: 20541701
22.  PHF8 Mediates Histone H4 Lysine 20 Demethylation Events Involved in Cell Cycle Progression 
Nature  2010;466(7305):508-512.
While reversible histone modifications are linked to an ever-expanding range of biological functions1–5, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me1, and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of the first H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.
doi:10.1038/nature09272
PMCID: PMC3059551  PMID: 20622854
23.  Acidic Saline-Induced Primary and Secondary Mechanical Hyperalgesia in Mice 
Most of our knowledge about chronic musculoskeletal pain is based on cutaneous pain models. To test the hypothesis that animals develop chronic muscular hyperalgesia following intramuscular acidic saline injections, primary hyperalgesia within the gastrocnemius muscle was analyzed and compared to secondary cutaneous hyperalgesia in the hind paw that develops following intramuscular acid saline injection. Two acidic saline (pH 4.0) injections were administrated into the gastrocnemius of female CF-1 mice. The results indicate that mice developed a robust hypersensitivity bilaterally in primary (gastrocnemius muscle) and secondary (cutaneous hind paw) sites that lasted up to 2 weeks. In addition, primary hyperalgesia correlated well with levels of Fos expression. Fos expression patterns in the spinal cord were different for primary and secondary site stimulation. Hind paw palpation stimulated ipsilateral Fos expression in the superficial spinal laminae at L4/L5 levels, and bilaterally in deep laminae at L2-L5 spinal levels. In contrast, gastrocnemius compression stimulated widespread Fos expression in all regions of the ipsilateral dorsal horn within L2-L6 spinal segments. These findings indicate that acidic saline injection induces primary hyperalgesia in muscle and that the patterns of Fos expression in response to primary versus secondary stimulation are strikingly different.
doi:10.1016/j.jpain.2009.04.014
PMCID: PMC2787877  PMID: 19592308
Fos; spinal cord; muscle pain; acidic saline; mice; cutaneous pain
24.  Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus 
BMC Microbiology  2007;7:99.
Background
Community acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) increasingly causes disease worldwide. USA300 has emerged as the predominant clone causing superficial and invasive infections in children and adults in the USA. Epidemiological studies suggest that USA300 is more virulent than other CA-MRSA. The genetic determinants that render virulence and dominance to USA300 remain unclear.
Results
We sequenced the genomes of two pediatric USA300 isolates: one CA-MRSA and one CA-methicillin susceptible (MSSA), isolated at Texas Children's Hospital in Houston. DNA sequencing was performed by Sanger dideoxy whole genome shotgun (WGS) and 454 Life Sciences pyrosequencing strategies. The sequence of the USA300 MRSA strain was rigorously annotated. In USA300-MRSA 2658 chromosomal open reading frames were predicted and 3.1 and 27 kilobase (kb) plasmids were identified. USA300-MSSA contained a 20 kb plasmid with some homology to the 27 kb plasmid found in USA300-MRSA. Two regions found in US300-MRSA were absent in USA300-MSSA. One of these carried the arginine deiminase operon that appears to have been acquired from S. epidermidis. The USA300 sequence was aligned with other sequenced S. aureus genomes and regions unique to USA300 MRSA were identified.
Conclusion
USA300-MRSA is highly similar to other MRSA strains based on whole genome alignments and gene content, indicating that the differences in pathogenesis are due to subtle changes rather than to large-scale acquisition of virulence factor genes. The USA300 Houston isolate differs from another sequenced USA300 strain isolate, derived from a patient in San Francisco, in plasmid content and a number of sequence polymorphisms. Such differences will provide new insights into the evolution of pathogens.
doi:10.1186/1471-2180-7-99
PMCID: PMC2222628  PMID: 17986343
25.  Paradoxical DNA Repair and Peroxide Resistance Gene Conservation in Bacillus pumilus SAFR-032 
PLoS ONE  2007;2(9):e928.
Background
Bacillus spores are notoriously resistant to unfavorable conditions such as UV radiation, γ-radiation, H2O2, desiccation, chemical disinfection, or starvation. Bacillus pumilus SAFR-032 survives standard decontamination procedures of the Jet Propulsion Lab spacecraft assembly facility, and both spores and vegetative cells of this strain exhibit elevated resistance to UV radiation and H2O2 compared to other Bacillus species.
Principal Findings
The genome of B. pumilus SAFR-032 was sequenced and annotated. Lists of genes relevant to DNA repair and the oxidative stress response were generated and compared to B. subtilis and B. licheniformis. Differences in conservation of genes, gene order, and protein sequences are highlighted because they potentially explain the extreme resistance phenotype of B. pumilus. The B. pumilus genome includes genes not found in B. subtilis or B. licheniformis and conserved genes with sequence divergence, but paradoxically lacks several genes that function in UV or H2O2 resistance in other Bacillus species.
Significance
This study identifies several candidate genes for further research into UV and H2O2 resistance. These findings will help explain the resistance of B. pumilus and are applicable to understanding sterilization survival strategies of microbes.
doi:10.1371/journal.pone.0000928
PMCID: PMC1976550  PMID: 17895969

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