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1.  Selection for Duration of Fertility and Mule Duck White Plumage Colour in a Synthetic Strain of Ducks (Anas platyrhynchos) 
A synthetic strain of ducks (Anas platyrhynchos) was developed by introducing genes for long duration of fertility to be used as mother of mule ducklings and a seven-generation selection experiment was conducted to increase the number of fertile eggs after a single artificial insemination (AI) with pooled Muscovy semen. Reciprocal crossbreeding between Brown Tsaiya LRI-2 (with long duration of fertility) and Pekin L-201 (with white plumage mule ducklings) ducks produced the G0. Then G1 were intercrossed to produce G2 and so on for the following generations. Each female duck was inseminated 3 times, at 26, 29, and 32 weeks of age. The eggs were collected for 14 days from day 2 after AI. Individual data regarding the number of incubated eggs (Ie), the number of fertile eggs at candling at day 7 of incubation (F), the total number of dead embryos (M), the maximum duration of fertility (Dm) and the number of hatched mule ducklings (H) with plumage colour were recorded. The selection criterion was the breeding values of the best linear unbiased prediction animal model for F. The results show high percentage of exhibited heterosis in G2 for traits to improve (19.1% for F and 12.9% for H); F with a value of 5.92 (vs 3.74 in the Pekin L-201) was improved in the G2. Heritabilities were found to be low for Ie (h2 = 0.07±0.03) and M (h2 = 0.07±0.01), moderately low for Dm (h2 = 0.13±0.02), of medium values for H (h2 = 0.20±0.03) and F (h2 = 0.23±0.03). High and favourable genetic correlations existed between F and Dm (rg = 0.93), between F and H (rg = 0.97) and between Dm and H (rg = 0.90). The selection experiment showed a positive trend for phenotypic values of F (6.38 fertile eggs in G10 of synthetic strain vs 5.59 eggs in G4, and 3.74 eggs in Pekin L-201), with correlated response for increasing H (5.73 ducklings in G10 vs 4.86 in G4, and 3.09 ducklings in Pekin L-201) and maximum duration of the fertile period without increasing the embryo mortality rate. The average predicted genetic response for F was 40% of genetic standard deviation per generation of selection. The mule ducklings’ feather colour also was improved. It was concluded that this study provided results for a better understanding of the genetics of the duration of fertility traits in the common female duck bred for mule and that the selection of a synthetic strain was effective method of improvement.
doi:10.5713/ajas.14.0740
PMCID: PMC4412989  PMID: 25715691
Duck; Duration of Fertilization; Fertility; Selection; Plumage Colour
2.  MiRNA-99a directly regulates AGO2 through translational repression in hepatocellular carcinoma 
Zhang, J | Jin, H | Liu, H | lv, S | Wang, B | Wang, R | Liu, H | Ding, M | Yang, Y | Li, L | Zhang, J | Fu, S | Xie, D | Wu, M | Zhou, W | Qian, Q
Oncogenesis  2014;3(4):e97-.
The regulation network consisting of microRNAs (miRNAs) and their target genes remains largely elusive in hepatocellular carcinoma (HCC), especially the reciprocal loop between specific miRNAs and the miRNA processing machinery. In this study, we found that miR-99a was remarkably decreased in 111 of 152 (73.03%) primary HCC tissues and low-level expression of miR-99a was correlated with low tumor differentiation (P=0.001), liver cirrhosis (P=0.015), poor tumor-free survival (P=0.004) and overall survival (P=0.006) for HCC patients. By restoration of miR-99a, the HCC growth could be considerably inhibited both in vitro and in vivo. Subsequently, Argonaute-2 (Ago2), a central component of RNA-induced silencing complex, was found to be directly regulated by miR-99a via translational repression. Overexpression of Ago2 could partly impair the inhibitory effect of miR-99a on HCC cells in vitro. Then, we demonstrated that Ago2 was upregulated in HCC tissues at both RNA and protein levels and the expression of AGO2 protein and miR-99a was negatively correlated within detected HCC tissues (r=−0.727, P=0.004). Interestingly, the tumorigenicity of Ago2-knockdown HCC cells was severely impaired (4/10 vs 10/10, P<0.05), and this was in contrast to the miR-99a-overexpressing HCC cells. Functionally, the increased AGO2 protein could specifically facilitate oncogenic miR-21 to repress its targeted gene phosphatase and tensin homolog (Pten) in HCC, whereas leave the regulatory capacity of let-7a on its targeted oncogenes almost unaltered. In summary, our study has revealed a novel pathway for the tumor suppressor miR-99a to control tumor growth in HCC, via its downstream signaling of AGO2/miR-21/PTEN. In addition, this study provides potential strategies for HCC therapy by reintroduction of miRNA suppressors.
doi:10.1038/oncsis.2014.11
PMCID: PMC4007193  PMID: 24732044
Hepatocellular carcinoma; miR-99a; AGO2; PTEN
3.  Ufmylation and FATylation Pathways are Down Regulated in Human Alcoholic and Non Alcoholic Steatohepatitis, and Mice Fed DDC, where Mallory-Denk Bodies (MDBs) Form 
We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly down regulated, both in DDC re-fed mice livers and patients’ livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was down regulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both up regulated as previously shown. An approximate 176- and 5-fold up regulation (respectively) of FAT10 were observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be down regulated both in patients’ livers and in the liver of DDC re-fed mice. Interestedly, the down regulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is down regulated. This was also shown in livers of DDC re-fed mice where MDBs had formed.
doi:10.1016/j.yexmp.2014.05.010
PMCID: PMC4127344  PMID: 24893112
Ubiquitin-like (Ubl) modifiers; Mallory-Denk bodies (MDBs); Ufm1; FAT10; transcript regulation
4.  Metadherin regulates proliferation and metastasis via actin cytoskeletal remodelling in non-small cell lung cancer 
Yao, Y | Gu, X | Liu, H | Wu, G | Yuan, D | Yang, X | Song, Y
British Journal of Cancer  2014;111(2):355-364.
Background:
Metaderin (MTDH) protein is a novel component part of tight junction complex. The aim of this study was to investigate the correlation between MTDH and prognosis of patients and to explore the role of MTDH on NSCLC development and metastasis.
Methods:
Relative mRNA expression was evaluated by quantitative real-time PCR, and protein expression was detected using immunohistochemistry staining. The role of MTDH in cancer cell proliferation, migration and invasion was studied by modulation of MTDH expression in NSCLC cell lines. These functions of MTDH were further confirmed in vivo.
Results:
In NSCLC, low MTDH protein expression was correlated with lymph node metastasis, TNM stage and decreased OS (P=0.001, 0.011 and 0.013, respectively). Overexpression of MTDH reduced anchorage-independent and -dependent growth through arresting cell cycle, inhibited migration and invasion in vitro and further suppressed tumorigenesis, tumour growth and metastasis in vivo. Knockdown of MTDH expression increased cell invasiveness. MTDH overexpression reversed pro-metastatic actin cytoskeleton remodelling and inhibited EMT, supporting that MTDH has a key role on cancer proliferation and metastasis.
Conclusions:
MTDH has an important role in NSCLC proliferation and metastasis and provides potential in predicting metastasis and prognosis for patients with NSCLC.
doi:10.1038/bjc.2014.267
PMCID: PMC4102939  PMID: 24918821
non-small cell lung cancer; metadherin; epithelial–mesenchymal transition; metastasis; proliferation
6.  High-Throughput Sequencing Identifies Novel and Conserved Cucumber (Cucumis sativus L.) microRNAs in Response to Cucumber Green Mottle Mosaic Virus Infection 
PLoS ONE  2015;10(6):e0129002.
Seedlings of Cucumis sativus L. (cv. 'Zhongnong 16') were artificially inoculated with Cucumber green mottle mosaic virus (CGMMV) at the three-true-leaf stage. Leaf and flower samples were collected at different time points post-inoculation (10, 30 and 50 d), and processed by high throughput sequencing analysis to identify candidate miRNA sequences. Bioinformatic analysis using screening criteria, and secondary structure prediction, indicated that 8 novel and 23 known miRNAs (including 15 miRNAs described for the first time in vivo) were produced by cucumber plants in response to CGMMV infection. Moreover, gene expression profiles (p-value <0.01) validated the expression of 3 of the novel miRNAs and 3 of the putative candidate miRNAs and identified a further 82 conserved miRNAs in CGMMV-infected cucumbers. Gene ontology (GO) analysis revealed that the predicted target genes of these 88 miRNAs, which were screened using the psRNATarget and miRanda algorithms, were involved in three functional categories: 2265 in molecular function, 1362 as cellular components and 276 in biological process. The subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the predicted target genes were frequently involved in metabolic processes (166 pathways) and genetic information processes (40 pathways) and to a lesser degree the biosynthesis of secondary metabolites (12 pathways). These results could provide useful clues to help elucidate host-pathogen interactions in CGMMV and cucumber, as well as for the screening of resistance genes.
doi:10.1371/journal.pone.0129002
PMCID: PMC4468104  PMID: 26076360
7.  Altered functional connectivity of the cingulate subregions in schizophrenia 
Wang, D | Zhou, Y | Zhuo, C | Qin, W | Zhu, J | Liu, H | Xu, L | Yu, C
Translational Psychiatry  2015;5(6):e575-.
Schizophrenia patients have shown altered resting-state functional connectivity (rsFC) of the cingulate cortex; however, it is unknown whether rsFCs of the cingulate subregions are differentially affected in this disorder. We aimed to clarify the issue by comparing rsFCs of each cingulate subregion between healthy controls and schizophrenia patients. A total of 102 healthy controls and 94 schizophrenia patients underwent resting-state functional magnetic resonance imaging with a sensitivity-encoded spiral-in imaging sequence to reduce susceptibility-induced signal loss and distortion. The cingulate cortex was divided into nine subregions, including the subgenual anterior cingulate cortex (ACC), areas 24 and 32 of the pregenual ACC, areas 24 and 32 of the anterior mid-cingulate cortex (aMCC), posterior MCC (pMCC), dorsal (dPCC) and ventral (vPCC) posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). The rsFCs of each cingulate subregion were compared between the two groups and the atrophy effect was considered. Results with and without global signal regression were reported. Most cingulate subregions exhibited decreased rsFCs in schizophrenia after global signal regression (GSR). Without GSR, only increased rsFC was found in schizophrenia, which primarily restricted to the aMCC, PCC and RSC. Some of these increased rsFCs were also significant after GSR. These findings suggest that GSR can greatly affect between-group differences in rsFCs and the consistently increased rsFCs may challenge the functional disconnection hypothesis of schizophrenia.
doi:10.1038/tp.2015.69
PMCID: PMC4490280  PMID: 26035059
8.  HPV-associated lung cancers: an international pooled analysis 
Carcinogenesis  2014;35(6):1267-1275.
Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South and Central America, followed by Asia, North America and Europe (adjusted prevalence rates = 22, 5, 4 and 3%, respectively). Higher HPV16 prevalence was noted in each geographic region compared with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12–0.90), whereas no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87–5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
doi:10.1093/carcin/bgu038
PMCID: PMC4043241  PMID: 24523449
9.  Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts 
Li, S | Li, L | Zhu, Y | Huang, C | Qin, Y | Liu, H | Ren-Heidenreich, L | Shi, B | Ren, H | Chu, X | Kang, J | Wang, W | Xu, J | Tang, K | Yang, H | Zheng, Y | He, J | Yu, G | Liang, N
British Journal of Cancer  2014;110(11):2812-2820.
Background:
Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study.
Methods:
Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis.
Results:
EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments.
Conclusions:
EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.
doi:10.1038/bjc.2014.210
PMCID: PMC4037826  PMID: 24743704
non-small cell lung cancer; somatic mutations; double and triple mutations; multiplex testing; liquid chip technology
10.  International Consensus On (ICON) Pediatric Asthma 
Allergy  2012;67(8):976-997.
Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference.
The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. In order to achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with health care professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent from chronic treatment. There is a trend towards considering phenotype specific treatment choices; however this goal has not yet been achieved.
doi:10.1111/j.1398-9995.2012.02865.x
PMCID: PMC4442800  PMID: 22702533
11.  Antioxidant and Hypoglycemic Activities of Exopolysaccharide by Submerged Culture of Inocutus Hispidus 
This work was to investigate the hypoglycemic and antioxidant activities of the exopolysaccharides produced in a stirred-tank bioreactor by Inocutus hispidus. The exopolysaccharides showed significant antioxidant activities, up to 70.7±2.5% inhibition of hydroxyl radicals, 50% inhibition of 2,2-diphenyl-1-picrylhydrazyl radicals, and a Trolox equivalent antioxidant capacity of 3.3 mM. The exopolysaccharide also showed notable hypoglycemic effects in streptozotocin-induced diabetic mice, reducing the plasma glucose, total cholesterol and triacylglycerol concentrations by 18.2±1.5, 20.9±0.8 and 14.4±0.4, respectively. The results demonstrated the potential of this EPS for human health protection against oxidative damage and hyperglycemia.
PMCID: PMC4502154  PMID: 26180285
Exopolysaccharides; Inocutus hispidus; fermentation; hypoglycemic effect; antioxidant
12.  ADAR1 deaminase contributes to scheduled skeletal myogenesis progression via stage-specific functions 
Cell Death and Differentiation  2014;21(5):707-719.
Adenosine deaminases acting on RNA 1 (ADAR1) catalyzes cellular RNA adenosine-to-inosine editing events on structured RNA molecules. In line with this critical role, ADAR1 exhibits ubiquitous expression and is essential for embryonic development. However, regulation and developmental significance of this RNA editor in a spatiotemporal context are largely elusive. Here we unveil a novel tissue-specific role of ADAR1 in skeletal myogenesis. ADAR1 expression displayed programmed alteration that is coordinated with differentiation cues, and mediated negatively by miRNA-1/206. Coincidently, ADAR1 exerts stage-dependent functions—suppression of apoptosis at the onset of differentiation and preservation of timely myotube formation through later phase. Furthermore, the post-transcriptional aspect of its myogenic role was illustrated by the spectrum of binding RNAs, as revealed by high-throughput approach, as well as by direct regulation of myogenesis-associated targets such as dynamin 1/2 (Dnm1/2) and annexin A4. Consequently, maintenance of target gene expression profiles likely contributes to a state of cytoskeleton and membrane dynamics that is amenable to myoblast morphogenesis. Collectively, these findings uncover a critical link of ADAR1 to myogenesis, and further highlight an epigenetic mechanism by which ADAR1 and miR-1/206 interplay to control scheduled myoblast–myotube transition.
doi:10.1038/cdd.2013.197
PMCID: PMC3978302  PMID: 24440912
ADAR1; dynamins; miRNA-1/206; myogenesis; RIP-Seq
13.  High CXC chemokine receptor 4 expression is an adverse prognostic factor in patients with clear-cell renal cell carcinoma 
An, H | Xu, L | Zhu, Y | Lv, T | Liu, W | Liu, Y | Liu, H | Chen, L | Xu, J | Lin, Z
British Journal of Cancer  2014;110(9):2261-2268.
Background:
Aberrant CXC chemokine receptor 4 (CXCR4) expressions in malignant tissues have been reported; however, its role in kidney cancer prognosis remains unknown. The aim of this study was to determine the prognostic value of CXCR4 expression in patients with clear-cell renal cell carcinoma (ccRCC).
Methods:
The study included 225 patients with ccRCC. The cohort was split into a training set (n=125) and a validation set (n=100). CXC chemokine receptor 4 expression was analysed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated.
Results:
CXCR4-staining intensity increased gradually accompanied with disease progression from TNM stages I to IV in 225 patients with ccRCC. Moreover, high CXCR4 expression indicated reduced overall survival (OS) in the training (P<0.001) and validation (P<0.001) sets, especially for patients with early-stage (TNM stage I+II) diseases. Furthermore, CXCR4 expression was identified as an independent prognostic factor for OS, and combining TNM stage with CXCR4 expression showed a better prognostic value for OS in both sets.
Conclusions:
High CXCR4 expression, an independent adverse prognostic factor, could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with ccRCC.
doi:10.1038/bjc.2014.179
PMCID: PMC4007240  PMID: 24714746
ccRCC; CXCR4; overall survival; nomogram; prognostic model
14.  Phase 2 Trial of Paclitaxel Polyglumex with Capecitabine for Metastatic Breast Cancer 
Background
Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability & efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.
Patients and Methods
This was a single stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression & overall survival. The main eligibility criteria were: age >18, no prior MBC chemotherapy, ECOG performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex 135 mg/m2 by intravenous infusion on day 1 + capecitabine 825 mg/m2 orally twice daily days 1 - 14, repeated on a 3-week cycle. Forty one (41) evaluable patients were required to test null hypothesis that complete and partial tumor response rate (CR + PR) was at most 40% against the alternative of at least 60%. Paclitaxel polyglumex + capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.
Results
48 patients were enrolled between April 2006 - April 2007; all patients were evaluable. The median cycles administered was 6. Eighteen (18) patients (38%; 95% CI: 24-53%) had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (15; 38%, 95% CI: 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI: 4.0-7.6 months). Six-month progression free survival was 42% (95% CI: 30-58%). Median dose level administered = 135 mg/m2 paclitaxel polyglumex, 825 mg/m2 capecitabine for cycles 1-7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neuro-sensory 4 (8%), skin reaction-hand/foot 4 (8%), dyspnea 2 (4%). Forrty-six% (22/47) of patients experienced a grade ≥3 toxicity and 8% (4/48) experienced a grade ≥4 toxicity. No alopecia was reported.
Conclusions
Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
doi:10.1097/COC.0b013e31826e0550
PMCID: PMC3593738  PMID: 23211220
15.  Leptin-mediated regulation of ICAM-1 is Rho/ROCK dependent and enhances gastric cancer cell migration 
Dong, Z | Fu, S | Xu, X | Yang, Y | Du, L | Li, W | Kan, S | Li, Z | Zhang, X | Wang, L | Li, J | Liu, H | Qu, X | Wang, C
British Journal of Cancer  2014;110(7):1801-1810.
Background:
Our previous study indicates that leptin enhances gastric cancer (GC) invasion. However, the exact effect of leptin on GC metastasis and its underlying mechanism remain unclear. Intercellular adhesion molecule-1 (ICAM-1), a major molecule in stabilising cell–cell and cell–extracellular matrix interactions, is overexpressed and has crucial roles in tumour metastasis.
Methods:
Here, we investigated leptin and ICAM-1 expression in GC tissues. Furthermore, we characterised the influence of leptin on ICAM-1 expression in GC cells and elucidated the underlying mechanism.
Results:
Leptin and ICAM-1 were overexpressed in GC tissues, and a strong positive correlation was observed. They were also related with clinical stage or lymph node metastasis. Furthermore, leptin induced GC cell (AGS and MKN-45) migration by upregulating ICAM-1, and knockdown of ICAM-1 by small interference RNA (siRNA) blocked this process. Cell surface ICAM-1, as well as soluble ICAM-1 (sICAM-1), was also enhanced by leptin. Moreover, leptin increased ICAM-1 expression through Rho/ROCK pathway, which was attenuated by pharmacological inhibition of Rho (C3 transferase) or its downstream effector kinase Rho-associated protein kinase (ROCK) (Y-27632).
Conclusions:
Our findings indicate that leptin enhances GC cell migration by increasing ICAM-1 through Rho/ROCK pathway, which might provide new insight into the significance of leptin in GC.
doi:10.1038/bjc.2014.70
PMCID: PMC3974087  PMID: 24548863
gastric cancer; leptin; ICAM-1; Rho/ROCK; migration
16.  Role of mitochondrial ATP-sensitive potassium channel-mediated PKC-ε in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats 
This study aimed to determine the role of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels and protein kinase C (PKC)-ε in the delayed protective effects of sevoflurane preconditioning using Langendorff isolated heart perfusion models. Fifty-four isolated perfused rat hearts were randomly divided into 6 groups (n=9). The rats were exposed for 60 min to 2.5% sevoflurane (the second window of protection group, SWOP group) or 33% oxygen inhalation (I/R group) 24 h before coronary occlusion. The control group (CON) and the sevoflurane group (SEVO) group were exposed to 33% oxygen and 2.5% sevoflurane for 60 min, respectively, without coronary occlusion. The mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) was given 30 min before sevoflurane preconditioning (5-HD+SWOP group). Cardiac function indices, infarct sizes, serum cardiac troponin I (cTnI) concentrations, and the expression levels of phosphorylated PKC-ε (p-PKC-ε) and caspase-8 were measured. Cardiac function was unchanged, p-PKC-ε expression was upregulated, caspase-8 expression was downregulated, cTnI concentrations were decreased, and the infarcts were significantly smaller (P<0.05) in the SWOP group compared with the I/R group. Cardiac function was worse, p-PKC-ε expression was downregulated, caspase-8 expression was upregulated, cTnI concentration was increased and infarcts were larger in the 5-HD+SWOP group (P<0.05) compared with the SWOP group. The results suggest that mitoKATP channels are involved in the myocardial protective effects of sevoflurane in preconditioning against I/R injury, by regulating PKC-ε phosphorylation before ischemia, and by downregulating caspase-8 during reperfusion.
doi:10.1590/1414-431X20143876
PMCID: PMC4470312  PMID: 25831209
Ischemia; Reperfusion; mitoKatp channel; Preconditioning; Protein kinase C
17.  The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells 
Oncogene  2013;33(33):4265-4272.
The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.
doi:10.1038/onc.2013.512
PMCID: PMC4351423  PMID: 24292675
deubiquitinase; ATXN3; phosphatase and tensin homolog; PTENP1; ceRNA; MJD
18.  Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease 
Tang, Y | Li, T | Li, J | Yang, J | Liu, H | Zhang, X J | Le, W
Cell Death and Differentiation  2013;21(3):369-380.
Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Here, we reported that histone H3K27me3 demethylase Jumonji domain containing 3 (Jmjd3) was essential for M2 microglia polarization. Suppression of Jmjd3 in N9 microglia inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, which led to extensive neuron death in vitro. We also observed that the suppression of Jmjd3 in the substantia nigra (SN) in vivo dramatically caused microglial overactivation and exacerbated dopamine (DA) neuron death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD. Moreover, we showed that the Jmjd3 level was lower in the midbrain of aged mice, which was accompanied by an elevated level of H3K27me3 and an increased ratio of M1 to M2 markers, suggesting that aging is an important factor in switching the microglia phenotypes. Overall, our studies indicate that Jmjd3 is able to enhance the polarization of M2 microglia by modifying histone H3K27me3, and therefore it has a pivotal role in the switch of microglia phenotypes that may contribute to the immune pathogenesis of PD.
doi:10.1038/cdd.2013.159
PMCID: PMC3921590  PMID: 24212761
Parkinson's disease; microglia polarization; histone H3K27me3 demethylase; Jmjd3; aging; neuron degeneration
19.  A prospective randomised controlled trial of laparoscopic vs open radical cystectomy for bladder cancer: perioperative and oncologic outcomes with 5-year follow-upT Lin et al 
Lin, T | Fan, X | Zhang, C | Xu, K | Liu, H | Zhang, J | Jiang, C | Huang, H | Han, J | Yao, Y | Xie, W | Dong, W | Bi, L | Huang, J
British Journal of Cancer  2014;110(4):842-849.
Background:
Laparoscopic radical cystectomy (LRC) is increasingly being used for muscle-invasive bladder cancer. However, high levels of clinical evidence comparing laparoscopic vs open radical cystectomy (ORC) are lacking.
Methods:
A prospective randomised controlled clinical trial comparing LRC vs ORC in patients undergoing radical cystectomy for bladder cancer. Thirty-five patients were eligible for final analysis in each group.
Results:
The median follow-up was 26 months (range, 4–59 months) for laparoscopic vs 32 months (range, 6–60 months) for ORC. Significant differences were noted in operative time, estimated blood loss (EBL), blood transfusion rate, analgesic requirement, and time to resumption of oral intake. No significant differences were noted in the length of hospital stay, complication rate, lymph node yield (14.1±6.3 for LRC and 15.2±5.9 for ORC), positive surgical margin rate, postoperative pathology, or recurrence rate (7 for LRC and 8 for ORC). The 5-year recurrence-free survival with laparoscopic vs ORC was 78.5% vs 70.9%, respectively (P=0.773). The overall survival with laparoscopic vs ORC was 73.8% vs 67.4%, respectively (P=0.511).
Conclusion:
Our study demonstrated that LRC is superior to ORC in perioperative outcomes, including EBL, blood transfusion rate, and analgesic requirement. We found no major difference in oncologic outcomes. The number of patients is too small to allow for a final conclusion.
doi:10.1038/bjc.2013.777
PMCID: PMC3929868  PMID: 24407192
bladder cancer; laparoscopic radical cystectomy; open radical cystectomy; orthotopic ileal neobladder; randomised controlled study
20.  β-Catenin and NF-κB co-activation triggered by TLR3 stimulation facilitates stem cell-like phenotypes in breast cancer 
Jia, D | Yang, W | Li, L | Liu, H | Tan, Y | Ooi, S | Chi, L | Filion, L G | Figeys, D | Wang, L
Cell Death and Differentiation  2014;22(2):298-310.
Cancer stem cells (CSCs) are responsible for tumor initiation and progression. Toll-like receptors (TLRs) are highly expressed in cancer cells and associated with poor prognosis. However, a linkage between CSCs and TLRs is unclear, and potential intervention strategies to prevent TLR stimulation-induced CSC formation and underlying mechanisms are lacking. Here, we demonstrate that stimulation of toll-like receptor 3 (TLR3) promotes breast cancer cells toward a CSC phenotype in vitro and in vivo. Importantly, conventional NF-κB signaling pathway is not exclusively responsible for TLR3 activation-enriched CSCs. Intriguingly, simultaneous activation of both β-catenin and NF-κB signaling pathways, but neither alone, is required for the enhanced CSC phenotypes. We have further identified a small molecule cardamonin that can concurrently inhibit β-catenin and NF-κB signals. Cardamonin is capable of effectively abolishing TLR3 activation-enhanced CSC phenotypes in vitro and successfully controlling TLR3 stimulation-induced tumor growth in human breast cancer xenografts. These findings may provide a foundation for developing new strategies to prevent the induction of CSCs during cancer therapies.
doi:10.1038/cdd.2014.145
PMCID: PMC4291491  PMID: 25257174
21.  Femtosecond all-optical synchronization of an X-ray free-electron laser 
Nature Communications  2015;6:5938.
Many advanced applications of X-ray free-electron lasers require pulse durations and time resolutions of only a few femtoseconds. To generate these pulses and to apply them in time-resolved experiments, synchronization techniques that can simultaneously lock all independent components, including all accelerator modules and all external optical lasers, to better than the delivered free-electron laser pulse duration, are needed. Here we achieve all-optical synchronization at the soft X-ray free-electron laser FLASH and demonstrate facility-wide timing to better than 30 fs r.m.s. for 90 fs X-ray photon pulses. Crucially, our analysis indicates that the performance of this optical synchronization is limited primarily by the free-electron laser pulse duration, and should naturally scale to the sub-10 femtosecond level with shorter X-ray pulses.
Few-femtosecond synchronization at free-electron lasers is key for nearly all experimental applications, stable operation and future light source development. Here, Schulz et al. demonstrate all-optical synchronization of the soft X-ray FEL FLASH to better than 30 fs and illustrate a pathway to sub-10 fs.
doi:10.1038/ncomms6938
PMCID: PMC4309427  PMID: 25600823
22.  Platelet P2Y12 receptors are involved in the haemostatic effect of notoginsenoside Ft1, a saponin isolated from Panax notoginseng 
Gao, B | Huang, L | Liu, H | Wu, H | Zhang, E | Yang, L | Wu, X | Wang, Z
British Journal of Pharmacology  2013;171(1):214-223.
BACKGROUND AND PURPOSE
Saponins isolated from Panax notoginseng (Burk.) F.H. Chen have been shown to relieve thrombogenesis and facilitate haemostasis. However, it is not known which saponin accounts for this haemostatic effect. Hence, in the present study we aimed to identify which saponins contribute to its haemostatic activity and to elucidate the possible underlying mechanisms.
EXPERIMENTAL APPROACH
Platelet aggregation was analysed using a platelet aggregometer. Prothrombin time, activated partial thromboplastin time and thrombin time were measured using a blood coagulation analyser, which was further corroborated with bleeding time and thrombotic assays. The interaction of notoginsenoside Ft1 with the platelet P2Y12 receptor was determined by molecular docking analysis, cytosolic Ca2+ and cAMP measurements, and phosphorylation of PI3K and Akt assays.
KEY RESULTS
Among the saponins examined, Ft1 was the most potent procoagulant and induced dose-dependent platelet aggregation. Ft1 reduced plasma coagulation indexes, decreased tail bleeding time and increased thrombogenesis. Moreover, it potentiated ADP-induced platelet aggregation and increased cytosolic Ca2+ accumulation, effects that were attenuated by clopidogrel. Molecular docking analysis suggested that Ft1 binds to platelet P2Y12 receptors. The increase in intracellular Ca2+ evoked by Ft1 in HEK293 cells overexpressing P2Y12 receptors could be blocked by ticagrelor. Ft1 also affected the production of cAMP and increased phosphorylation of PI3K and Akt downstream of P2Y12 signalling pathways.
CONCLUSION AND IMPLICATIONS
Ft1 enhanced platelet aggregation by activating a signalling network mediated through P2Y12 receptors. These novel findings may contribute to the effective utilization of this compound in the therapy of haematological disorders.
doi:10.1111/bph.12435
PMCID: PMC3874708  PMID: 24117220
Panax notoginseng; saponin; notoginsenoside Ft1; haemostasis; P2Y12 receptor
23.  Microwave-assisted Extraction of Alantolactone and Isoalantolactone from Inula helenium 
Microwave-assisted extraction was used for the extraction of alantolactone and isoalantolactone from Inula helenium. Effects of various experimental factors including ethanol concentration, particle size, microwave radiation time, the ratio of material to liquid and extraction temperature on yield of alantolactone and isoalantolactone were evaluated. The optimal extracting process of the alantolactone and isoalantolactone from the root of the Inula helenium was 1 g plant sample (sifted through 140 mesh) mixed with 15 ml of 80% ethanol solution, microwave radiation 120 s at 50°. Under these optimal conditions, the yield of alantolactone and isoalantolactone was 31.83±2.08 mg/g and 21.25±1.37 mg/g, respectively. Compared with heat reflux extraction, ultrasound-assisted extraction, microwave-assisted extraction was more efficient and timesaving for the extraction of alantolactone and isoalantolactone from Inula helenium.
PMCID: PMC4355875  PMID: 25767328
Inula helenium; microwave-assisted extraction; alantolactone; isoalantolactone
24.  A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes 
Bone marrow transplantation  2013;48(11):1437-1443.
Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m2/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity < 20% and blasts < 10%). Marrow cellularity (P < 0.0001) and blast% (P = 0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3–4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1–21), relapse was 29% (95% CI: 13–46) and OS was 71% (95% CI: 51–85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21–58) and 2 year OS was 31% (95% CI: 14–48). Disease at the nadir correlated with inferior OS after HCT (HR = 1.22 for each 10% marrow blasts, 95% CI: 1.02–1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P = 0.3) and OS (375 vs 195 days, P = 0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.
doi:10.1038/bmt.2013.79
PMCID: PMC4279870  PMID: 23771005
allo-SCT; relapsed leukemia; AML; bridge therapy; myelodysplastic syndrome
25.  IFN-γ induces aberrant CD49b+ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure 
Cell Death & Disease  2014;5(11):e1512-.
Interferon-γ (IFN-γ), a pleiotropic lymphokine, has important regulatory effects on many cell types. Although IFN-γ is essential for the initiation of uterine vascular modifications and maintenance of decidual integrity, IFN-γ administration can also cause pregnancy failure in many species. However, little is known about the effector mechanisms involved. In this study, using an IFN-γ-induced abortion mouse model, we reported that no Dolichos biflorus agglutinin lectin-positive uterine natural killer (uNK) cells were observed in the uteri from IFN-γ-induced abortion mice. By contrast, the percentage of CD3−CD49b+ NK cells in the uterus and blood from a foetal resorption group was significantly higher than that of the control group. Similarly, significantly upregulated expression of CD49b (a pan-NK cell marker), CX3CL1 and CX3CR1 (CX3CL1 receptor) was detected in the uteri of IFN-γ-induced abortion mice. Using isolated uterine stromal cells, we showed that upregulated expression of CX3CL1 by IFN-γ was dependent on a Janus family kinase 2-signal transducers and activators of transcription 1 (JAK2-STAT1) pathway. We further demonstrated the chemotactic activity of CX3CL1 in uterine stromal cell conditioned medium on primary splenic NK cells. Finally, we observed increased recruitment of CD49b+ NK cells into the endometrium after exogenous CX3CL1 administration. Collectively, our findings indicate that IFN-γ can significantly increase uterine CX3CL1 expression via activation of the JAK2-STAT1 pathway, thus inducing CD49b+ NK cell uterine homing, and eventually provoke foetal loss. Thus, we provide a new line of evidence correlating the deleterious effects of IFN-γ on pregnancy with the aberrant regulation of CX3CL1 and CD49b+ NK cells.
doi:10.1038/cddis.2014.470
PMCID: PMC4260728  PMID: 25375377

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