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1.  Genome-wide Association Study (GWAS) of mesocotyl elongation based on re-sequencing approach in rice 
BMC Plant Biology  2015;15:218.
Mechanized dry seeded rice can save both labour and water resources. Rice seedling establishment is sensitive to sowing depth while mesocotyl elongation facilitates the emergence of deeply sown seeds.
A set of 270 rice accessions, including 170 from the mini-core collection of Chinese rice germplasm (C Collection) and 100 varieties used in a breeding program for drought resistance (D Collection), was screened for mesocotyl lengths of seedlings grown in water (MLw) in darkness and in 5 cm sand culture (MLs). Twenty six accessions (10.53 %) have MLw longer than 1.0 cm. Eleven accessions had the highest mesocotyl lengths, i.e. 1.4 – 5.05 cm of MLw and 3.0 – 6.4 cm in 10 cm sand culture, including 7 upland landraces or varieties. The genotypic data of 1,019,883 SNPs were developed by re-sequencing of those accessions. A whole-genome SNP array (Rice SNP50) was used to genotype 24 accessions as a validation panel, giving 98.41 % of consistent SNPs with the re-sequencing data in average. GWAS based on compressed mixed linear model was conducted using GAPIT. Based on a threshold of -log(P) ≥8.0, 13 loci were associated to MLw on rice chromosome 1, 3, 4, 5, 6 and 9, respectively. Three associated loci, on chromosome 3, 6, and 10, were detected for MLs. A set of 99 associated SNPs for MLw, based on a compromised threshold (−log(P) ≥7.0), located in intergenic regions or different positions of 36 annotated genes, including one cullin and one growth regulating factor gene.
Higher proportion and extension of elongated mesocotyls were observed in the mini-core collection of rice germplasm and upland rice landraces or varieties, possibly causing the correlation between mesocotyl elongation and drought resistance. GWAS found 13 loci for mesocotyl length measured in dark germination that confirmed the previously reported co-location of two QTLs across populations and experiments. Associated SNPs hit 36 annotated genes including function-matching candidates like cullin and GRF. The germplasm with elongated mesocotyl, especially upland landraces or varieties, and the associated SNPs could be useful in further studies and breeding of mechanized dry seeded rice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0608-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4566844  PMID: 26362270
2.  A stewardship intervention program for safe medication management and use of antidiabetic drugs 
Clinical Interventions in Aging  2015;10:1201-1212.
Diabetes patients are complex due to considerations of polypharmacy, multimorbidities, medication adherence, dietary habits, health literacy, socioeconomic status, and cultural factors. Meanwhile, insulin and oral hypoglycemic agents are high-alert medications. Therefore it is necessary to require a multidisciplinary team’s integrated endeavors to enhance safe medication management and use of antidiabetic drugs.
A 5-year stewardship intervention program, including organizational measures and quality improvement activities in storage, prescription, dispensing, administration, and monitoring, was performed in the Second Affiliated Hospital of Zhejiang University, People’s Republic of China, a 3,200-bed hospital with 3.5 million outpatient visits annually.
The Second Affiliated Hospital of Zhejiang University has obtained a 100% implementation rate of standard storage of antidiabetic drugs in the Pharmacy and wards since August 2012. A zero occurrence of dispensing errors related to highly “look-alike” and “sound-alike” NovoMix 30® (biphasic insulin aspart) and NovoRapid® (insulin aspart) has been achieved since October 2011. Insulin injection accuracy among ward nurses significantly increased from 82% (first quarter 2011) to 96% (fourth quarter 2011) (P<0.05). The number of medication administration errors related to insulin continuously decreased from 20 (2011) to six (2014). The occurrence rate of hypoglycemia in non–endocrinology ward diabetes inpatients during 2011–2013 was significantly less than that in 2010 (5.03%–5.53% versus 8.27%) (P<0.01). Percentage of correct management of hypoglycemia by nurses increased from 41.5% (April 2014) to 67.2% (August 2014) (P<0.01). The percentage of outpatient diabetes patients receiving standard insulin injection education increased from 80% (April 2012) to 95.2% (October 2012) (P<0.05). Insulin injection techniques among diabetes outpatients who started to receive insulin were better than indicated in data from two questionnaire surveys in the literature, including the percentage checking injection sites prior to injection (85.6%), priming before injection (98.1%), rotation of injecting sites (98.1%), remixing before use (94.5%), keeping the pen needle under the skin for >10 seconds (99.4%), and using the pen needle only once (88.7%). On-site inspection indicated of great improvement in the percentage of drug-related problems in the antidiabetes regimen between the first and second quarter of 2014 (1.08% versus 0.28%) (P<0.05).
Quality improvements in safe medication management and use of antidiabetic drugs can be achieved by multidisciplinary collaboration among pharmacists, nurses, physicians, and information engineers.
PMCID: PMC4516029
diabetes nursing specialists; injection technique; insulin; medication errors; oral hypoglycemic agents; pharmacy; quality improvements
3.  Score model for predicting acute-on-chronic liver failure risk in chronic hepatitis B 
AIM: To establish a clinical scoring model to predict risk of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients.
METHODS: This was a retrospective study of 1457 patients hospitalized for CHB between October 2008 and October 2013 at the Beijing Ditan Hospital, Capital Medical University, China. The patients were divided into two groups: severe acute exacerbation (SAE) group (n = 382) and non-SAE group (n = 1075). The SAE group was classified as the high-risk group based on the higher incidence of ACLF in this group than in the non-SAE group (13.6% vs 0.4%). Two-thirds of SAE patients were randomly assigned to risk-model derivation and the other one-third to model validation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. Model discrimination and calibration were assessed using area under the receiver operating characteristic curve and the Hosmer-Lemeshow test.
RESULTS: The risk prediction scoring model included the following four factors: age ≥ 40 years, total bilirubin ≥ 171 μmol/L, prothrombin activity 40%-60%, and hepatitis B virus DNA > 107 copies/mL. The sum risk score ranged from 0 to 7; 0-3 identified patients with lower risk of ACLF, whereas 4-7 identified patients with higher risk. The Kaplan-Meier analysis showed the cumulative risk for ACLF and ACLF-related death in the two risk groups (0-3 and 4-7 scores) of the primary cohort over 56 d, and log-rank test revealed a significant difference (2.0% vs 33.8% and 0.8% vs 9.4%, respectively; both P < 0.0001). In the derivation and validation data sets, the model had good discrimination (C index = 0.857, 95% confidence interval: 0.800-0.913 and C index = 0.889, 95% confidence interval: 0.820-0.957, respectively) and calibration demonstrated by the Hosmer-Lemeshow test (χ2 = 4.516, P = 0.808 and χ2 = 1.959, P = 0.923, respectively).
CONCLUSION: Using the scoring model, clinicians can easily identify patients (total score ≥ 4) at high risk of ACLF and ACLF-related death early during SAE.
PMCID: PMC4507107  PMID: 26217089
Acute-on-chronic liver failure; Chronic hepatitis B; Prediction model; Risk score; Severe acute exacerbation
4.  Modified Leukocyte Filter Removes Tumor Cells from the Salvaged Blood 
PLoS ONE  2015;10(6):e0130864.
Intraoperative blood salvage, an effective blood conservation strategy, has not been applied in onco-surgery, because of potential malignant cell contamination. In this study we tested effectiveness of a modified leukocyte depletion filter (M-LDF) for removal of tumor cells.
Materials and Methods
The effects of M-LDF and regular LDF on removal of cells (HepG2 cell line) were compared. The safety of M-LDF was tested with blood (collected and washed during onco-surgery), the salvaged blood mixed with tumor cells from the solid tumor of the same patient, or mixed with HepG2 cells (n=30 in each protocol). Cancer cells were identified by flow cytometry, culture and bioassay with and without filtration.
M-LDF removed 5-log of HepG2 and nucleated cells, which was much higher than regular LDF, and cells were destroyed when they passed through M-LDF. Cytokeratin-positive cells in all samples were removed by M-LDF. Invasive growth adherent cells were found in most of unfiltered samples and 67% of the inoculated nude mice developed tumors in LDF-treated sample. Neither adherent cells nor nude mice developed tumors were found in M-LDF-treated samples.
Discussion and Conclusion
Since M-LDF can effectively remove and destroy cancer cells in the salvaged blood, it has great potential for clinical application.
PMCID: PMC4476620  PMID: 26098626
5.  Collective rehabilitation training conductive to improve psychotherapy of college students with anxiety disorder 
Objective: Study the auxiliary therapeutic effect of psychological counseling treatment after collective rehabilitation training of the patients with anxiety disorder. Methods: 38 college students with anxiety disorder are randomly divided into an experiment group and a control group, each of which consists of 19 students. The experiment group only receives psychological counseling treatment; the control group, based on psychological counseling treatment, receives the collective rehabilitation training, that is, the joint therapy. Results: before the treatment, the inter-group difference of the general data about the patients in 2 groups shows no statistically significance, P > 0.05, which is comparable; after 8 weeks’ treatment, HAMA and SAS scores of the patients in 2 groups are significantly improved compared with those before treatment, P < 0.05; meanwhile, the improvement effect of the experiment group is better than that of the control group P < 0.05. After 3 months’ follow-up, it is found that the recurrence rate of the experiment group is obviously lower than that of the control group P < 0.05. Conclusion: the joint treatment, consisting of psychological counseling and collective rehabilitation training, exercises synergetic effect on the college students who are anxiety disorder patients and its curative effect is obviously superior to the single psychological counseling and its recurrence rate is low.
PMCID: PMC4538143  PMID: 26309681
Psychological counseling; rehabilitation training; joint; anxiety disorder; curative effect
6.  Irradiation Can Selectively Kill Tumor Cells while Preserving Erythrocyte Viability in a Co-Culture System 
PLoS ONE  2015;10(5):e0127181.
An understanding of how to safely apply intraoperative blood salvage (IBS) in cancer surgery has not yet been obtained. Here, we investigated the optimal dose of 137Cs gamma-ray irradiation for killing human hepatocarcinoma (HepG2), gastrocarcinoma (SGC7901), and colonic carcinoma (SW620) tumor cells while preserving co-cultured erythrocytes obtained from 14 healthy adult volunteers. HepG2, SGC7901, or SW620 cells were mixed into the aliquots of erythrocytes. After the mixed cells were treated with 137Cs gamma-ray irradiation (30, 50, and 100 Gy), tumor cells and erythrocytes were separated by density gradient centrifugation in Percoll with a density of 1.063 g/ml. The viability, clonogenicity, DNA synthesis, tumorigenicity, and apoptosis of the tumor cells were determined by MTT assay, plate colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, subcutaneous xenograft implantation into immunocompromised mice, and annexin V/7-AAD staining, respectively. The ATP concentration, 2,3-DPG level, free Hb concentration, osmotic fragility, membrane phosphatidylserine externalization, blood gas variables, reactive oxygen species levels, and superoxide dismutase levels in erythrocytes were analyzed. We found that 137Cs gamma-ray irradiation at 50 Gy effectively inhibited the viability, proliferation, and tumorigenicity of HepG2, SGC7901, and SW620 cells without markedly damaging the oxygen-carrying ability or membrane integrity or increasing the oxidative stress of erythrocytes in vitro. These results demonstrated that 50 Gy irradiation in a standard 137Cs blood irradiator might be a safe and effective method of inactivating HepG2, SGC7901, and SW620 cells mixed with erythrocytes, which might help to safely allow IBS in cancer surgery.
PMCID: PMC4446348  PMID: 26018651
7.  Severe Henoch-Schönlein purpura with infliximab for ulcerative colitis 
Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn’s disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schönlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX.
PMCID: PMC4438047  PMID: 26019477
Henoch-Schönlein purpura; Infliximab; Vasculitis; Subcutaneous ecchymosis; Ulcerative colitis
8.  Primary hepatic angiosarcoma: A report of two cases and literature review 
Primary hepatic angiosarcoma (PHA) is a rare malignancy that carries a poor prognosis. Of 1500 patients who underwent hepatectomy for primary hepatic tumors between 1994 and 2013 at our center, two patients were pathologically diagnosed with PHA. Clinical characteristics, treatment modalities, and outcomes of the two patients were collected and analyzed. Both patients underwent hepatectomy and had a postoperative survival time of 8 and 16 mo, respectively. A search of PubMed yielded eight references reporting 35 cases of PHA published between 2004 and 2013. On the basis of the presented cases and review of the literature, we endorse complete surgical resection as the mainstay definitive treatment of PHA, with adjuvant postoperative chemotherapy potentially improving survival. Palliative chemotherapy is an option in advanced hepatic angiosarcoma.
PMCID: PMC4438048  PMID: 26019478
Diagnosis; Hemangiosarcoma; Therapy; Surgery; Liver
9.  Restin suppressed epithelial-mesenchymal transition and tumor metastasis in breast cancer cells through upregulating mir-200a/b expression via association with p73 
Molecular Cancer  2015;14:102.
Restin belongs to MAGE superfamily and is known as MAGE H1. Restin was firstly cloned from HL-60 cells treated with all-trans retinoic acid (ATRA). Previous studies showed a pro-apoptotic role of Restin in several cell lines. However, little information is available on its expression patterns and functions in vivo. Our study was performed to detect if Restin plays a role in breast cancer cells in vitro and in vivo.
Methods and results
Real-time PCR and western blot were conducted to detect Restin expression in multiple breast cancer cell lines and Restin level was negatively related with cell motility. Restin overexpression and knockdown stable cell lines were established by transducing lentivirus into MCF-7 and MDA-MB-231 cells. Cell morphology, wound closure assay, transwell migration and invasion assays were performed to detect if Restin inhibited EMT. Our data showed that Restin overexpressed cells exhibited classical epithelial cell morphology, and Restin overexpression resulted in activation of epithelial markers and suppression of mesenchymal markers, and inhibition of cell migration and invasion. Tumor xenograft model was used to characterize the biological functions of Restin in vivo. We found that Restin overexpression led to reduced lung metastasis. Real-time PCR, western blot, luciferase assay and ChIP assay were performed to identify the potential targets of Restin and the underlying molecular mechanisms. Among several master regulators of EMT, only ZEB1/2 levels were dramatically inhibited by Restin. Unexpectedly, Restin indirectly regulated ZEB1/2 expression at post-transcriptional level. We further identified mir-200a/b, well-characterized mediators controlling ZEB1/2 expression, were transcriptionally activated by Restin and the regulation was dependent on the p53 binding site in mir-200b/a/429 promoter. Further mechanical studies demonstrated Restin interacted with p73, one of p53 family members, which contributed to Restin-mediated activation of mir-200a/b and suppression of ZEB1/2.
Taken together, our results suggest that Restin inhibits EMT and tumor metastasis by controlling the expression of the tumor metastasis suppressor mir-200a/b via association with p73. Our findings not only establish a mechanistic link between Restin, EMT and tumor metastasis, but also provide strong evidence supporting the notion that MAGE Group II proteins may exert a tumor suppressive effect in vivo.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0370-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4429374  PMID: 25972084
Restin; EMT; Tumor metastasis; mir-200a/b; p73; Breast cancer; MAGE superfamily
10.  Cisplatin combined with hyperthermia kills HepG2 cells in intraoperative blood salvage but preserves the function of erythrocytes*  
The safe use of intraoperative blood salvage (IBS) in cancer surgery remains controversial. Here, we investigated the killing effect of cisplatin combined with hyperthermia on human hepatocarcinoma (HepG2) cells and erythrocytes from IBS in vitro. HepG2 cells were mixed with concentrated erythrocytes and pretreated with cisplatin (50, 100, and 200 μg/ml) alone at 37 °C for 60 min and cisplatin (25, 50, 100, and 200 μg/ml) combined with hyperthermia at 42 °C for 60 min. After pretreatment, the cell viability, colony formation and DNA metabolism in HepG2 and the Na+-K+-ATPase activity, 2,3-diphosphoglycerate (2,3-DPG) concentration, free hemoglobin (Hb) level, osmotic fragility, membrane phosphatidylserine externalization, and blood gas variables in erythrocytes were determined. Pretreatment with cisplatin (50, 100, and 200 μg/ml) combined with hyperthermia (42 °C) for 60 min significantly decreased HepG2 cell viability, and completely inhibited colony formation and DNA metabolism when the HepG2 cell concentration was 5×104 ml−1 in the erythrocyte (P<0.01). Erythrocytic Na+-K+-ATPase activity, 2,3-DPG level, phosphatidylserine externalization, and extra-erythrocytic free Hb were significantly altered by hyperthermia plus high concentrations of cisplatin (100 and 200 μg/ml) (P<0.05), but not by hyperthermia plus 50 μg/ml cisplatin (P>0.05). In conclusion, pretreatment with cisplatin (50 μg/ml) combined with hyperthermia (42 °C) for 60 min effectively eliminated HepG2 cells from IBS but did not significantly affect erythrocytes in vitro.
PMCID: PMC4432992  PMID: 25990057
Erythrocytes; HepG2 cells; Intraoperative blood salvage; Cisplatin; Hyperthermia
11.  Characterization of Differentially Expressed Genes Involved in Pathways Associated with Gastric Cancer 
PLoS ONE  2015;10(4):e0125013.
To explore the patterns of gene expression in gastric cancer, a total of 26 paired gastric cancer and noncancerous tissues from patients were enrolled for gene expression microarray analyses. Limma methods were applied to analyze the data, and genes were considered to be significantly differentially expressed if the False Discovery Rate (FDR) value was < 0.01, P-value was <0.01 and the fold change (FC) was >2. Subsequently, Gene Ontology (GO) categories were used to analyze the main functions of the differentially expressed genes. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we found pathways significantly associated with the differential genes. Gene-Act network and co-expression network were built respectively based on the relationships among the genes, proteins and compounds in the database. 2371 mRNAs and 350 lncRNAs considered as significantly differentially expressed genes were selected for the further analysis. The GO categories, pathway analyses and the Gene-Act network showed a consistent result that up-regulated genes were responsible for tumorigenesis, migration, angiogenesis and microenvironment formation, while down-regulated genes were involved in metabolism. These results of this study provide some novel findings on coding RNAs, lncRNAs, pathways and the co-expression network in gastric cancer which will be useful to guide further investigation and target therapy for this disease.
PMCID: PMC4415781  PMID: 25928635
12.  Tissue-specific patterns of gene expression in the epithelium and stroma of normal colon in healthy individuals in an aspirin intervention trial 
BMC Medical Genetics  2015;16:18.
Regular aspirin use reduces colon adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of colon neoplasia.
In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and colon prostaglandin E2 (PGE2) levels.
No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p <0.001). Transcripts differentially expressed between epithelium and stroma (N = 4916, P <0.01, false discovery rate <0.001), included a high proportion of genes involved in cell signaling, cellular movement, and cancer. Genes preferentially expressed in epithelium were involved in drug and xenobiotic metabolism, fatty acid and lipid metabolism, apoptosis signaling, and ion transport. Genes preferentially expressed in stroma included those involved in inflammation, cellular adhesion, and extracellular matrix production. Wnt-Tcf4 pathway genes were expressed in both epithelium and stroma but differed by subcellular location.
These results suggest that, in healthy individuals, subtle effects of aspirin on gene expression in normal colon tissue are likely overwhelmed by inter-individual variability in microarray analyses. Differential expression of critical genes between colonic epithelium and stroma suggest that these tissue types need to be considered separately.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-015-0161-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4422425  PMID: 25927723
Gene expression; Colon stroma; Colon epithelium; Microarray; Colon biopsy; UGT1A6; Aspirin
13.  Notch pathway regulates female germ cell meiosis progression and early oogenesis events in fetal mouse 
Cell Cycle  2014;13(5):782-791.
A critical process of early oogenesis is the entry of mitotic oogonia into meiosis, a cell cycle switch regulated by a complex gene regulatory network. Although Notch pathway is involved in numerous important aspects of oogenesis in invertebrate species, whether it plays roles in early oogenesis events in mammals is unknown. Therefore, the rationale of the present study was to investigate the roles of Notch signaling in crucial processes of early oogenesis, such as meiosis entry and early oocyte growth. Notch receptors and ligands were localized in mouse embryonic female gonads and 2 Notch inhibitors, namely DAPT and L-685,458, were used to attenuate its signaling in an in vitro culture system of ovarian tissues from 12.5 days post coitum (dpc) fetus. The results demonstrated that the expression of Stra8, a master gene for germ cell meiosis, and its stimulation by retinoic acid (RA) were reduced after suppression of Notch signaling, and the other meiotic genes, Dazl, Dmc1, and Rec8, were abolished or markedly decreased. Furthermore, RNAi of Notch1 also markedly inhibited the expression of Stra8 and SCP3 in cultured female germ cells. The increased methylation status of CpG islands within the Stra8 promoter of the oocytes was observed in the presence of DAPT, indicating that Notch signaling is probably necessary for maintaining the epigenetic state of this gene in a way suitable for RA stimulation. Furthermore, in the presence of Notch inhibitors, progression of oocytes through meiosis I was markedly delayed. At later culture periods, the rate of oocyte growth was decreased, which impaired subsequent primordial follicle assembly in cultured ovarian tissues. Taken together, these results suggested new roles of the Notch signaling pathway in female germ cell meiosis progression and early oogenesis events in mammals.
PMCID: PMC3979914  PMID: 24398584
mouse; oogenesis; meiosis; Stra8; notch
14.  HER2 expression status in diverse cancers: review of results from 37,992 patients 
Cancer Metastasis Reviews  2015;34(1):157-164.
Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/− amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.
Electronic supplementary material
The online version of this article (doi:10.1007/s10555-015-9552-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4368842  PMID: 25712293
HER2 overexpression; Cancer; IHC; FISH; HER2 amplification
15.  Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma 
Molecular Cancer  2015;14(1):10.
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.
Methods and results
We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in a 3-D tumor/endothelial co-culture system, we found that alcohol enhanced the migration/invasion of HepG2 cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1 and NF-κB was observed in HCC tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis.
This study suggested that chronic moderate alcohol consumption may promote the progression and metastasis of HCC; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation.
PMCID: PMC4320626  PMID: 25622857
Alcohol; Angiogenesis; Human hepatocellular cancer; Metastasis; Reactive oxygen species
16.  Effects of a native parasitic plant on an exotic invader decrease with increasing host age 
AoB Plants  2015;7:plv031.
Infection by parasitic plants has been considered as an effective method for controlling invasive plants because the parasites partially or completely absorb water, nutrients, and carbohydrates from their host plants, suppressing the vitality of the host. Our study verified that younger and smaller Bidens pilosa plants suffer from higher levels of damage and are less likely to recover from infection by the parasitic plant Cuscuta australis than relatively older and larger plants, suggesting that Cuscuta australis is only a viable biocontrol agent for younger Bidens pilosa plants.
Understanding changes in the interactions between parasitic plants and their hosts in relation to ontogenetic changes in the hosts is crucial for successful use of parasitic plants as biological controls. We investigated growth, photosynthesis and chemical defences in different-aged Bidens pilosa plants in response to infection by Cuscuta australis. We were particularly interested in whether plant responses to parasite infection change with changes in the host plant age. Compared with the non-infected B. pilosa, parasite infection reduced total host biomass and net photosynthetic rates, but these deleterious effects decreased with increasing host age. Parasite infection reduced the concentrations of total phenolics, total flavonoids and saponins in the younger B. pilosa but not in the older B. pilosa. Compared with the relatively older and larger plants, younger and smaller plants suffered from more severe damage and are likely less to recover from the infection, suggesting that C. australis is only a viable biocontrol agent for younger B. pilosa plants.
PMCID: PMC4417202  PMID: 25838325
Defence; deleterious effect; growth; invasive plant; parasitic plant
17.  Efficacy of capecitabine-based combination therapy and single-agent capecitabine maintenance therapy in patients with metastatic breast cancer 
The purpose of this study was to observe the efficacy and toxicities of capecitabine-based chemotherapy and capecitabine monotherapy as maintenance therapy in the treatment of metastatic breast cancer (MBC).
Patients and methods
A total of 98 MBC patients were treated with capecitabine combined with vinorelbine (NX).
The median number of treatment was 6 cycles (1-7 cycles). There were two cases of complete remission (CR), 58 partial remission, 27 stable disease (SD), 11 progression disease. The overall response rate (ORR) (CR + PR) was 61.2%. The clinical benefit rate (CBR) was 75.5%. Fifty of effective patients received with capecitabine monotherapy as maintenance therapy. The ORR (CR + PR) was 4%. The CBR was 48%. The median progression-free survival (PFS) was 12 months. In maintenance therapy or not, the median post metastasis survival rate (MSR) was 63 and 28 months, respectively. In the combination therapy group, the major grade 3/4 toxicities included hand-foot syndrome (3.1%), skin pigmentation (2.0%), diarrhoea and abdominal distension (5.1%), stomatitis (1.0%), and leukopenia (20.4%).
Capecitabine-based combination therapy and single-agent capecitabine maintenance therapy were well tolerated and effective to MBC.
PMCID: PMC4279202  PMID: 25561767
Metastatic breast cancer (MBC); capecitabine; maintenance therapy
18.  SOX1 down-regulates β-catenin and reverses malignant phenotype in nasopharyngeal carcinoma 
Molecular Cancer  2014;13:257.
Aberrant activation of the Wnt/β-catenin signaling pathway is an important factor in the development of nasopharyngeal carcinoma (NPC). Previous studies have demonstrated that the developmental gene sex-determining region Y (SRY)-box 1 (SOX1) inhibits cervical and liver tumorigenesis by interfering with the Wnt/β-catenin signaling pathway. However, the role of SOX1 in NPC remains unclear. This study investigates the function of SOX1 in NPC pathogenesis.
Down-regulation of SOX1 was detected in NPC cell lines and tissues. Besides, quantitative methylation-specific polymerase chain reaction revealed that SOX1 promoter was hypermethylated in NPC cell lines. Ectopic expression of SOX1 in NPC cells suppressed colony formation, proliferation and migration in vitro and impaired tumor growth in nude mice. Restoration of SOX1 expression significantly reduced epithelial-mesenchymal transition, enhanced cell differentiation and induced cellular senescence. Conversely, transient knockdown of SOX1 by siRNA in these cells partially restored cell proliferation and colony formation. Notably, SOX1 was found to physically interact with β-catenin and reduce its expression independent of proteasomal activity, leading to inhibition of Wnt/β-catenin signaling and decreased expression of downstream target genes.
SOX1 decreases the expression of β-catenin in a proteasome-independent manner and reverses the malignant phenotype in NPC cells.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-257) contains supplementary material, which is available to authorized users.
PMCID: PMC4326525  PMID: 25427424
SOX1; β-catenin; Methylation; Differentiation; NPC
19.  CEACAM6 Promotes Gastric Cancer Invasion and Metastasis by Inducing Epithelial-Mesenchymal Transition via PI3K/AKT Signaling Pathway 
PLoS ONE  2014;9(11):e112908.
Overexpressed CEACAM6 in tumor tissues plays important roles in invasion, metastasis and anoikis resistance in a variety of human cancers. We recently reported that CEACAM6 expression is upregulated in Gastric cancer (GC) tissues and promoted GC metastasis. Here, we report that CEACAM6 promotes peritoneal metastases in vivo and is negatively correlated with E-cadherin expression in GC tissues. Overexpressed CEACAM6 induced epithelial-mesenchymal transition (EMT) in GC, as measured by increases in the EMT markers N-cadherin, Vimentin and Slug while E-cadherin expression was decreased in CEACAM6-overexpressing GC cells; opposing results were observed in CEACAM6-silenced cells. Furthermore, E-cadherin expression was negatively correlated with depth of tumor invasion, lymph node metastasis and TNM stage in GC tissues. Additionally, CEACAM6 elevated matrix metalloproteinase-9 (MMP-9) activity in GC, and anti-MMP-9 antibody could reverse the increasing invasion and migration induced by CEACAM6. CEACAM6 also increased the levels of phosphorylated AKT, which is involved in the progression of a variety of human tumors. We further observed that LY294002, a PI3K inhibitor, could reverse CEACAM6-induced EMT via mesenchymal-epithelial transition. These findings suggest that CEACAM6 enhances invasion and metastasis in GC by promoting EMT via the PI3K/AKT signaling pathway.
PMCID: PMC4232574  PMID: 25398131
20.  Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling 
Asian Journal of Andrology  2014;16(6):817-823.
Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.
PMCID: PMC4236322  PMID: 24994782
androgen receptor; keratin 33B; penis; testosterone
21.  Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9 
Oncotarget  2014;5(21):10584-10595.
Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment.
PMCID: PMC4279395  PMID: 25301736
Androgen receptor; AKT; MMP9; Gastric cancer
22.  PI3K/AKT Pathway Involvement in the Osteogenic Effects of Osteoclast Culture Supernatants on Preosteoblast Cells 
Tissue Engineering. Part A  2013;19(19-20):2226-2232.
This study aimed to investigate the ability of osteoclasts during bone resorption activities to regulate the differentiation and calcification of osteoblast precursor cells. The bone resorption model was established using in vitro cortical bone slices and mouse RAW264.7 cells, which were differentiated into osteoclasts by stimulation with the receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Tartrate-resistant acid phosphatase (TRAP) staining, reverse transcriptase–polymerase chain reaction (RT-PCR), and scanning electron microscopy (SEM) were used to detect osteoclast differentiation. The osteoblast precursor cell line MC3T3-E1 was cultured with the bone resorption supernatant (BRS). Involvement of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in osteogenesis was evaluated by Western blotting, RT-PCR, and ELISA analysis of markers of the early (runt-related transcription factor-2 and alkaline phosphatase) and late (osteocalcin [OCN]) stages of osteogenesis, and Alizarin Red S staining of matrix mineralization. TRAP staining, RT-PCR, and SEM analysis demonstrated the successful establishment of the bone resorption model. Osteoclast BRS effectively increased the differentiation and calcification of MC3T3-E1 cells. Western blot analysis indicated that the BRS enhanced AKT and p-AKT expression levels in MC3T3-E1 cells. Following AKT2 knockdown and treatment with the PI3K/AKT pathway inhibitor LY294002, the expression of OCN in MC3T3-E1 cells was decreased (p<0.05), as was the calcification area (p<0.05). The data obtained in this study indicated that the osteoclast bone resorption medium promoted the differentiation and calcification of MC3T3-E1 cells and that the PI3K/AKT pathway played a role in this process.
PMCID: PMC3761438  PMID: 23617625
23.  Essential roles for GSK-3s and GSK-3 primed substrates in neurotrophin-induced and hippocampal axon growth 
Neuron  2006;52(6):981-996.
Glycogen synthase kinase-3β (GSK-3β) is thought to mediate morphological responses to a variety of extracellular signals. Surprisingly we found no gross morphological deficits in nervous system development in GSK-3β null mice. We therefore designed an shRNA that targeted both GSK-3 isoforms. Strong knockdown of both GSK-3α and β markedly reduced axon growth in dissociated cultures and slice preparations. We then assessed the role of different GSK-3 substrates in regulating axon morphology. Elimination of activity towards primed substrates only using the GSK-3 R96A mutant was associated with a defect in axon polarity (axon branching) compared to an overall reduction in axon growth induced by a kinase dead mutant. Consistent with this finding, moderate reduction of GSK-3 activity by pharmacological inhibitors induced axon branching and was associated primarily with effects on primed substrates. Our results suggest that GSK-3 is a downstream convergent point for many axon growth regulatory pathways and that differential regulation of primed versus all GSK-3 substrates is associated with a specific morphological outcome.
PMCID: PMC4167845  PMID: 17178402
GSK-3; axon; neurotrophin; hippocampal neurons; MAP1B; APC; CRMP2
24.  Aberrant neuronal synaptic connectivity in CA1 area of the hippocampus from pilocarpine-induced epileptic rats observed by fluorogold 
In this study, we observed synaptic connectivity among neurons in CA1 region of pilocarpine-induced chronic seizures in rats. Twenty healthy male Sprague-Dawley rats were divided randomly into an epilepsy group (n = 10) and a control group (n = 10). Approximately 60 days after status epilepticus (SE) , Fluorogold (FG) was injected into the CA1 area of the hippocampus in vivo. Somatostatin (SS) expression was observed using immunofluorescence. The distribution of FG-positive and FG/SS double-labeled neurons was observed using a confocal microscope. FG-labeled pyramidal cells could be seen remotely from the FG-injected site in the CA1 area and in the subiculum in the experimental group. FG/SS double-labeled interneurons were distributed remotely from the FG-injected site in the CA1 area in the epileptic rats. These changes suggest aberrant neuronal connectivity in CA1 region, which may lead to the formation of aberrant excitatory and inhibitory circuitry, and may play an important role in the generation or compensation for temporal lobe epilepsy.
PMCID: PMC4211776  PMID: 25356126
Temporal lobe epilepsy (TLE); fluorogold (FG); somatostatin (SS); neuronal connectivity; circuit rearrangement; interneuron; lithium chloride; pilocarpin
25.  Gold nanoparticle transfer through photothermal effects in a metamaterial absorber by nanosecond laser 
Scientific Reports  2014;4:6080.
A non-complicated, controllable method of metallic nanoparticle fabrication at low operating light power is proposed. The method is based on laser-induced forward transfer, using a metamaterial absorber as the donor to significantly enhance the photothermal effect and reduce the operating light fluence to 35 mJ/cm2, which is much lower than that in previous works. A large number of metallic nanoparticles can be transferred by one shot of focused nanosecond laser pulses. Transferred nanoparticles exhibit good size uniformity and the sizes are controllable. The optical properties of transferred particles are characterized by dark-field spectroscopy and the experimental results agree with the simulation results.
PMCID: PMC4143792  PMID: 25156404

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