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1.  The association between expressions of Ras and CD68 in the angiogenesis of breast cancers 
Cancer Cell International  2015;15(1):17.
Objective
Angiogenesis is a critical step of breast cancer metastasis. Oncogenic Ras promotes the remodeling of cancer microenviroment. Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population emerging in the microenviroment and facilitating the angiogenesis and metastasis. In the present study, we tried to investigate the relationship between the expression of Ras and infiltration of TAM, both of which could further promote angiogenesis.
Methods
Expressions of Ras, CD68 and CD34 were assessed by immunohistochemistry. The infiltration of macrophages was evaluated by counting the number of CD68+ cells. Vessel endothelial cells were defined as CD34+ cells. Angiogenesis vascularity was defined by microvessel density (MVD) assay through counting the number of vessels per field counted in the area of highest vascular density. The Kaplan–Meier survival analysis was used to estimate the overall survival (OS). Macrophages were derived from monocytes in the presence of macrophage colony-stimulating-factor (MCSF). Breast cancer cells were treated with macrophage-conditioned medium (MCM) and tested the expressions of K-, H- and N-Ras by using realtime-PCR.
Results
Ras positive status was correlated with ER, PR and Her-2 positivity, larger tumour size and lymph node metastasis, as well as higher TNM stages. A higher number of CD68+ cells was correlated with larger tumour size, higher TNM stages and Her-2 positivity. Both Ras positivity and infiltration of CD68+ macrophages correlated with poor OS. The number of CD68+ cells was positively correlated with the expression of Ras. Treatment with MCM did not up-regulate but repressed the expression of Ras. Both up-regulation of Ras and infiltration of TAMs correlated with increased MVD.
Conclusion
Expression of Ras and infiltration of TAM were positively correlated, and both participated in angiogenesis. Elevated Ras could be responsible for the infiltration of TAM.
doi:10.1186/s12935-015-0169-1
PMCID: PMC4326448
Breast cancer; Ras; TAM; CD34; Angiogenesis
2.  Expression of Autophagy and UPR genes in the Developing Brain during Ethanol-Sensitive and Resistant Periods 
Metabolic brain disease  2013;28(4):10.1007/s11011-013-9430-2.
Fetal alcohol spectrum disorders (FASD) results from ethanol exposure to the developing fetus and is the leading cause of mental retardation. FASD is associated with a broad range of neurobehavioral deficits which may be mediated by ethanol-induced neurodegeneration in the developing brain. An immature brain is more susceptible to ethanol neurotoxicity. We hypothesize that the enhanced sensitivity of the immature brain to ethanol is due to a limited capacity to alleviate cellular stress. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that subcutaneous injection of ethanol induced a wide-spread neuroapoptosis in postnatal day 4 (PD4) C57BL/6 mice, but had little effect on the brain of PD12 mice. We analyzed the expression profile of genes regulating apoptosis, and the pathways of ER stress response (also known as unfolded protein response, UPR) and autophagy during these ethanol-sensitive and resistant periods (PD4 versus PD12) using PCR microarray. The expression of pro-apoptotic genes, such as caspase-3, was much higher on PD4 than PD12; in contrast, the expression of genes that regulate UPR and autophagy, such as atf6, atg4, atg9, atg10, beclin1, bnip3, cebpb, ctsb, ctsd, ctss, grp78, ire1α, lamp, lc3 perk, pik3c3, and sqstm1 was significantly higher on PD12 than PD4. These results suggest that the vulnerability of the immature brain to ethanol could result from high expression of pro-apoptotic proteins and a deficiency in the stress responsive system, such as UPR and autophagy.
doi:10.1007/s11011-013-9430-2
PMCID: PMC3809151  PMID: 23979425
alcohol; brain development; fetal alcohol syndrome; gene expression; neurodegeneration
3.  P21-Activated Kinase 7 Mediates Cisplatin-Resistance of Esophageal Squamous Carcinoma Cells with Aurora-A Overexpression 
PLoS ONE  2014;9(12):e113989.
Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality.
doi:10.1371/journal.pone.0113989
PMCID: PMC4250179  PMID: 25436453
4.  Transcriptome Profiling Identifies Differentially Expressed Genes in Huoyan Goose Ovaries between the Laying Period and Ceased Period 
PLoS ONE  2014;9(11):e113211.
The Huoyan goose is famous for its high egg-laying performance and is listed as a nationally protected domestic animal by the Chinese government. To elucidate the key regulatory genes involved in Huoyan goose egg laying, RNA from ovarian tissue during the ceased and laying periods was sequenced using the Illumina HiSeq 2000 sequencing platform. More than 12 million reads were produced in ceased and laying libraries that included 11,896,423 and 12,534,799 clean reads, respectively. More than 20% of the reads were matched to the reference genome, and 23% of the reads were matched to reference genes. Genes with a false discovery rate (FDR) ≤0.001 and log2ratio ≧1 or ≤−1 were characterized as differentially expressed, and 344 up-regulated and 344 down-regulated genes were classified into functional categories. Twelve genes that are mainly involved in pathways for reproduction regulation, such as steroid hormone biosynthesis, GnRH signaling pathways, oocyte meiosis, progesterone-mediated oocyte maturation, steroid biosynthesis, calcium signaling pathways, and G-protein coupled receptor signaling pathway were selected for validation by a quantitative real-time polymerase chain reaction (qRT-PCR) analysis, the qRT-PCR results are consistent with the general expression patterns of those genes from the Illumina sequencing. These data provide comprehensive gene expression information at the transcriptional level that might increase our understanding of the Huoyan goose's reproductive biology.
doi:10.1371/journal.pone.0113211
PMCID: PMC4242529  PMID: 25419838
5.  Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway 
Oncology Letters  2014;9(2):837-844.
Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERβ in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.
doi:10.3892/ol.2014.2711
PMCID: PMC4301527  PMID: 25624908
pancreactic cancer; cantharidin; protein phosphatase 2A; tamoxifen; protein kinase C
6.  Genetic Diversity Analysis Reveals that Geographical Environment Plays a More Important Role than Rice Cultivar in Villosiclava virens Population Selection 
Rice false smut caused by Villosiclava virens is an economically important disease of grains worldwide. The genetic diversity of 153 isolates from six fields located in Wuhan (WH), Yichang Wangjia (YCW), Yichang Yaohe (YCY), Huanggang (HG), Yangxin (YX), and Jingzhou (JZ) in Hubei province of China were phylogenetically analyzed to evaluate the influence of environments and rice cultivars on the V. virens populations. Isolates (43) from Wuhan were from two rice cultivars, Wanxian 98 and Huajing 952, while most of the other isolates from fields YCW, YCY, HG, YX, and JZ originated from different rice cultivars with different genetic backgrounds. Genetic diversity of isolates was analyzed using random amplified polymorphic DNA (RAPD) and single-nucleotide polymorphisms (SNP). The isolates from the same cultivars in Wuhan tended to group together, indicating that the cultivars had an important impact on the fungal population. The 110 isolates from individual fields tended to cluster according to geographical origin. The values of Nei's gene diversity (H) and Shannon's information index (I) showed that the genetic diversity among isolates was higher between than within geographical populations. Furthermore, mean genetic distance between groups (0.006) was higher than mean genetic distance within groups (0.0048) according to MEGA 5.2. The pairwise population fixation index (FST) values also showed significant genetic differentiation between most populations. Higher genetic similarity of isolates from individual fields but different rice cultivars suggested that the geographical factor played a more important role in the selection of V. virens isolates than rice cultivars. This information could be used to improve the management strategy for rice false smut by adjusting the cultivation measures, such as controlling fertilizer, water, and planting density, in the rice field to change the microenvironment.
doi:10.1128/AEM.03936-13
PMCID: PMC3993286  PMID: 24584249
7.  Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury 
BioMed Research International  2014;2014:634281.
Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by d-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.
doi:10.1155/2014/634281
PMCID: PMC4228720  PMID: 25544942
8.  Intramuscular Administration of a Synthetic CpG-Oligodeoxynucleotide Modulates Functional Responses of Neutrophils of Neonatal Foals 
PLoS ONE  2014;9(10):e109865.
Neutrophils play an important role in protecting against infection. Foals have age-dependent deficiencies in neutrophil function that may contribute to their predisposition to infection. Thus, we investigated the ability of a CpG-ODN formulated with Emulsigen to modulate functional responses of neutrophils in neonatal foals. Eighteen foals were randomly assigned to receive either a CpG-ODN with Emulsigen (N = 9) or saline intramuscularly at ages 1 and 7 days. At ages 1, 3, 9, 14, and 28, blood was collected and neutrophils were isolated from each foal. Neutrophils were assessed for basal and Rhodococcus equi-stimulated mRNA expression of the cytokines interferon-γ (IFN-γ), interleukin (IL)-4, IL-6, and IL-8 using real-time PCR, degranulation by quantifying the amount of β-D glucuronidase activity, and reactive oxygen species (ROS) generation using flow cytometry. In vivo administration of the CpG-ODN formulation on days 1 and 7 resulted in significantly (P<0.05) increased IFN-γ mRNA expression by foal neutrophils on days 3, 9, and 14. Degranulation was significantly (P<0.05) lower for foals in the CpG-ODN-treated group than the control group at days 3 and 14, but not at other days. No effect of treatment on ROS generation was detected. These results indicate that CpG-ODN administration to foals might improve innate and adaptive immune responses that could protect foals against infectious diseases and possibly improve responses to vaccination.
doi:10.1371/journal.pone.0109865
PMCID: PMC4198146  PMID: 25333660
9.  Association of Serum MicroRNA Expression in Hepatocellular Carcinomas Treated with Transarterial Chemoembolization and Patient Survival 
PLoS ONE  2014;9(10):e109347.
Background and Aim
Hepatocellular carcinoma (HCC) is one of the most deadly tumors. Transarterial chemoembolization (TACE) is effective for unresectable HCC. In recent years, miRNAs have been proposed as novel diagnostic and prognostic tools for HCC. This study aimed to identify whether microRNAs (miRNAs) can serve as biomarkers to reliably predict outcome before HCC patients are treated with TACE.
Methods
Eleven miRNAs (miR-, miR-19a, miR-101-3p, miR-199a-5p, miR-200a, miR-21, miR-214, miR-221, miR-222, miR-223 and miR-, -5p) were quantified by quantitative real-time PCR (qRT-PCR) in 136 HCC patients’ serum before they received TACE therapy. Univariate and multivariate analysis were used to identify the prognostic value of clinical parameters and miRNAs. Area under the receiver operating characteristic curve (AUC) was used to evaluate the prediction potency.
Results
The levels of some miRNAs were dramatically associated with clinicopathologic features regarding Child-Puge class, AFP, tumor size and satellite nodules. Univariate analysis revealed that miR-200a, miR-21, miR-122 and miR-224-5p were significantly associated with patients’ survival. Multivariate analysis demonstrated that AFP, satellite nodules and miR-200a were the independent prognostic factors associated with survival in this cohort (p = 0.000, 0.001, 0.000, respectively). The probability of the prognostic accuracy of miR-200a was 81.64% (74.47% specificity and 88.76% sensitivity), which was higher than the classifier established by combination of AFP and satellite nodules (76.87% probability, 70.21% specificity and 69.66% sensitivity). Furthermore, the combination of AFP, satellite nodules and miR-200a demonstrated as a classifier for HCC prognosis, yielding a ROC curve area of 88.19% (93.62% specificity and 68.54% sensitivity).
Conclusions
Our study indicated that serum miR-200a may prognosticate disease outcome in HCC patients with TACE therapy. Therefore, miR-200a can potentially guide individualized treatment for HCC patients with a high risk of TACE treatment failures.
doi:10.1371/journal.pone.0109347
PMCID: PMC4183700  PMID: 25275448
10.  Using immunoproteomics to identify tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis 
Autoimmunity reviews  2013;12(12):1123-1128.
Since intracellular proteins involved in carcinogenesis have been shown to provoke autoantibody responses, autoantibodies can be used as probes in immunoproteomics to isolate, identify, and characterize potential tumor-associated antigens (TAAs). Once a TAA is identified, several approaches will be used to comprehensively characterize and validate the identified TAA/anti-TAA systems that are potential biomarkers in certain types of cancer. Our ultimate goal is to establish rigorous criteria for designation of an autoantibody to a TAA as a cancer biomarker, examine candidate TAAs for sensitivity and specificity of anti-TAA antibody response, and further develop customized TAA arrays that can be used to enhance anti-TAA antibody detection in cancer. This review will mainly focus on the recent advances in our studies using immunoproteomic approach to identify and characterize TAAs as biomarkers in cancer.
doi:10.1016/j.autrev.2013.06.015
PMCID: PMC3789855  PMID: 23806562
autoantibody; tumor-associated antigen; immunoproteomics; immunodiagnosis; cancer
11.  Self-Reported Prior Lung Diseases as Risk Factors for Non-small Cell Lung Cancer in Mexican Americans 
This study was conducted to assess the association between prior history of respiratory disease and lung cancer among Mexican Americans using data from a multi-racial/ethnic lung cancer case–control study. Cases (n = 204) were patients with previously untreated lung cancer. Healthy control participants (n = 325) were recruited from a large physician group practice. Demographics, cigarette use, and history of respiratory disease were collected. Multivariable logistic regression models were used to estimate relative risk. Prior history of COPD (OR = 2.0; 95 % CI 1.2–3.3) and pneumonia (OR = 2.2; 95 % CI 1.3–3.6) were associated with an increased risk of lung cancer. These findings illustrate that prior COPD and pneumonia are associated with an increased risk of lung cancer among Mexican Americans. To our knowledge, this is one of largest case–control analyses assessing the role of respiratory disease and lung cancer risk specifically among Mexican-Americans.
doi:10.1007/s10903-012-9690-7
PMCID: PMC3919532  PMID: 22847640
Lung diseases; Mexican Americans; Case–control studies; Epidemiology; Lung cancer
12.  Bone marrow osteoma of the tibia: A case report 
Oncology Letters  2014;8(6):2776-2778.
In this study, an unusual case of osteoma is presented, whereby a bone marrow osteoma was identified in the tibia. No previous cases of bone marrow osteoma have been reported. In this case, an eight-year-old male presented with discontinuous discomfort in the right distal calf for six months. Radiological examination and computed tomography revealed a radiopaque lesion within the affected bone. A technetium-99m bone scan revealed focally increased uptake in the same region. Together, these observations prior to surgery indicated that the patient may suffer from bone disease. Subsequently, a surgical excision was performed and the biopsy specimen was identified as bone marrow osteoma. Following surgery, the symptoms were eradicated and the prognosis was positive during the 24-month follow-up period. Bone marrow osteoma should be considered when a patient suffers from discontinuous and unexplained limb discomfort.
doi:10.3892/ol.2014.2564
PMCID: PMC4214461  PMID: 25364463
osteoma; tibia; excision; lesion
13.  Age-Group-Specific Associations between the Severity of Obstructive Sleep Apnea and Relevant Risk Factors in Male and Female Patients 
PLoS ONE  2014;9(9):e107380.
Aim
To seek accurate and credible correlation manner between gender, age, and obesity; and the severity of obstructive sleep apnea (OSA) in large-scale population.
Methods
Totals of 1,975 male and 378 female OSA patients were sequentially recruited. Centralized covariant tendencies between age, body mass index (BMI), and waist hip ratio (WHR); and OSA severity, were explored in a gender-specific manner via multiple statistical analyses. The accuracies of observed correlations were further evaluated by adaptive multiple linear regression.
Results
All of age, BMI, WHR, smoking, drinking, and OSA severity differed between males and females. BMI and WHR were positively and (approximately) linearly associated with OSA severity in both males and females. Restricted cubic spline analysis was more effective than was the Pearson correlation approach in correlating age with AHI, and provided age crossover points allowing further piecewise linear modeling for both males and females. Multiple linear regression showed that increasing age was associated with OSA exacerbation in males aged ≤40 years and in females aged 45–53 years. BMI, WHR, and diabetes were independently associated with OSA severity in males with age-group-specific pattern. In females, only BMI was associated with OSA severity at all ages.
Conclusions
In male patients, BMI and WHR are prominent risk factors for OSA exacerbation. Age and diabetes are associated with OSA severity in males of particular ages. In females, BMI is also a prominent risk factor for severe OSA, and OSA severity increased with age in the range 45–53 years.
doi:10.1371/journal.pone.0107380
PMCID: PMC4161416  PMID: 25211035
14.  Functional expression of chloride channels and their roles in the cell cycle and cell proliferation in highly differentiated nasopharyngeal carcinoma cells 
Physiological Reports  2014;2(9):e12137.
Abstract
We previously demonstrated that the growth of the poorly differentiated nasopharyngeal carcinoma cells (CNE‐2Z) was more dependent on the activities of volume‐activated chloride channels than that of the normal nasopharyngeal epithelial cells (NP69‐SV40T). However, the activities and roles of such volume‐activated chloride channels in highly differentiated nasopharyngeal carcinoma cells (CNE‐1) are not clarified. In this study, it was found that a volume‐activated chloride current and a regulatory volume decrease (RVD) were induced by 47% hypotonic challenges. The current density and the capacity of RVD in the highly differentiated CNE‐1 cells were lower than those in the poorly differentiated CNE‐2Z cells, and higher than those in the normal cells (NP69‐SV40T). The chloride channel blockers, 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) and tamoxifen inhibited the current and RVD. Depletion of intracellular Cl− abolished the RVD. The chloride channel blockers reversibly inhibited cell proliferation in a concentration‐ and time‐dependent manner, and arrested cells at the G0/G1 phases, but did not change cell viability. The sensitivity of the three cell lines to the chloride channel blockers was different, with the highest in poorly differentiated cells (CNE‐2Z) and the lowest in the normal cells (NP69‐SV40T). ClC‐3 proteins were expressed in the three cells and distributed inside the cells as well as on the cell membrane. In conclusion, the highly differentiated nasopharyngeal carcinoma CNE‐1 cells functionally expressed the volume‐activated chloride channels, which may play important roles in controlling cell proliferation through modulating the cell cycle, and may be associated with cell differentiation. Chloride channels may be a potential target of anticancer therapy.
In this paper, we demonstrated that the volume‐activated chloride channels were involved in regulating CNE‐1 cells proliferation and cell cycle progress. Thus, volume‐activated chloride channels may be a potential target of anticancer therapy.
doi:10.14814/phy2.12137
PMCID: PMC4270222  PMID: 25214521
Cell cycle; cell proliferation; chloride channels; nasopharyngeal carcinoma; regulatory volume decrease
15.  Comparison of Attitudes Regarding Preimplantation Genetic Diagnosis Among Patients with Hereditary Cancer Syndromes 
Familial cancer  2014;13(2):291-299.
Introduction
Preimplantation Genetic Diagnosis (PGD) allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. This study investigated awareness and acceptance of PGD among patients with hereditary cancer syndromes.
Methods
Questionnaires were mailed to 984 adults with hereditary breast and ovarian cancer, Lynch syndrome, familial adenomatous polyposis, or multiple endocrine neoplasia type 1 or 2. Associations between clinical, demographic, and psychosocial factors and awareness and acceptance of PGD were examined.
Results
Of 370 respondents (38% return rate), 28% felt their syndrome impacted family planning, 24% were aware of PGD, 72% felt that PGD should be offered, 43% would consider using PGD, and 29% were uncertain. Family experience and syndrome-specific characteristics, such as disease severity, quality of life and availability of medical interventions as well as gender, family planning stage, and religiosity impact perceptions of the acceptability of PGD, though a high level of uncertainty exists.
Conclusion
Hereditary cancer patients' opinions about the acceptability of PGD are similar to those of genetics and ethical experts. Patients should be told about PGD given that most had not heard of PGD, but feel that PGD should be offered.
doi:10.1007/s10689-013-9685-0
PMCID: PMC4159051  PMID: 24072553
Preimplantation genetic diagnosis; hereditary cancer syndromes; hereditary breast and ovarian cancer; Lynch syndrome; familial adenomatous polyposis; multiple endocrine neoplasia
16.  Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer 
BMC Cancer  2014;14(1):650.
Background
P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. PAK1 overexpression is associated with poor prognosis in some tumor types, including breast cancer, gastric cancer, and colorectal cancer. However, the expression and clinical relevance of PAK1 expression in human pancreatic cancer remains unknown.
Methods
The present study investigated the clinical and prognostic significance of PAK1 expression in pancreatic carcinoma. We examined and scored the expression of PAK1 by immunohistochemistry in 72 primary pancreatic carcinoma samples and 20 liver metastatic samples. The relationships between PAK1 and clinicopathological parameters and prognosis in primary and metastatic pancreatic cancer were analyzed.
Results
Among the total 92 cases, primary pancreatic cancer samples had a significantly higher rate (38/72, 52.8%) of high PAK1 expression than liver metastatic samples (5/20, 25.0%) (P = 0.028). Among the 72 primary pancreatic cancer patients, high PAK1 expression was associated with younger age (P = 0.038) and moderately or well differentiated tumor (P = 0.007). Moreover, a positive relationship was found between high PAK1 expression and overall survival (OS) (P < 0.005). Patients with high PAK1 expression had a better OS than those with low PAK1 expression. Univariate and multivariate analysis by Cox regression including PAK1 and other prognostic pathological markers demonstrated high PAK1 immunostaining as a prognostic factor for survival in pancreatic cancer patients (P < 0.005).
Conclusions
We report for the first time that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer. Reduced expression of PAK1 correlates with poor histological differentiation in pancreatic cancer.
doi:10.1186/1471-2407-14-650
PMCID: PMC4242600  PMID: 25182632
P21-activated protein kinase 1 (PAK1); Pancreatic cancer; Immunohistochemistry; Prognosis
17.  Predicting drug responsiveness in human cancers using genetically engineered mice 
Purpose
To use genetically engineered mouse models (GEMMs) and orthotopic syngeneic murine transplants (OSTs) to develop gene-expression based predictors of response to anti-cancer drugs in human tumors. These mouse models offer advantages including precise genetics and an intact microenvironment/immune system.
Experimental Design
We examined the efficacy of four chemotherapeutic or targeted anti-cancer drugs, alone and in combination, using mouse models representing three distinct breast cancer subtypes: Basal-like (C3(1)-T-antigen GEMM), Luminal B (MMTV-Neu GEMM), and Claudin-low (T11/TP53−/− OST). We expression-profiled tumors to develop signatures that corresponded to treatment and response, then tested their predictive potential using human patient data.
Results
Although a single agent exhibited exceptional efficacy (i.e. lapatinib in the Neu-driven model), generally single-agent activity was modest, while some combination therapies were more active and life-prolonging. Through analysis of RNA expression in this large set of chemotherapy-treated murine tumors, we identified a pair of gene expression signatures that predicted pathological complete response to neoadjuvant anthracycline/taxane therapy in human patients with breast cancer.
Conclusions
These results show that murine-derived gene signatures can predict response even after accounting for common clinical variables and other predictive genomic signatures, suggesting that mice can be used to identify new biomarkers for human cancer patients.
doi:10.1158/1078-0432.CCR-13-0522
PMCID: PMC3778918  PMID: 23780888
18.  TolC Promotes ExPEC Biofilm Formation and Curli Production in Response to Medium Osmolarity 
BioMed Research International  2014;2014:574274.
While a high osmolarity medium activates Cpx signaling and causes CpxR to repress csgD expression, and efflux protein TolC protein plays an important role in biofilm formation in Escherichia coli, whether TolC also responds to an osmolarity change to regulate biofilm formation in extraintestinal pathogenic E. coli (ExPEC) remains unknown. In this study, we constructed ΔtolC mutant and complement ExPEC strains to investigate the role of TolC in the retention of biofilm formation and curli production capability under different osmotic conditions. The ΔtolC mutant showed significantly decreased biofilm formation and lost the ability to produce curli fimbriae compared to its parent ExPEC strain PPECC42 when cultured in M9 medium or 1/2 M9 medium of increased osmolarity with NaCl or sucrose at 28°C. However, biofilm formation and curli production levels were restored to wild-type levels in the ΔtolC mutant in 1/2 M9 medium. We propose for the first time that TolC protein is able to form biofilm even under high osmotic stress. Our findings reveal an interplay between the role of TolC in ExPEC biofilm formation and the osmolarity of the surrounding environment, thus providing guidance for the development of a treatment for ExPEC biofilm formation.
doi:10.1155/2014/574274
PMCID: PMC4163439  PMID: 25243151
19.  Molecular cloning and expression analysis of the Synaptotagmin-1 gene in the hypothalamus and pituitary of Huoyan goose during different stages of the egg-laying cycle 
Background
Synaptotagmin-1 (Syt1) is an abundant, evolutionarily conserved integral membrane protein that plays essential roles in neurotransmitter release and hormone secretion. Neurotransmitters secreted by hypothalamic neurons can alter GnRH (gonadotropin-releasing hormones) neuronal activity by binding to and activating specific membrane receptors in pituitary cells and, in turn, control the release of gonadotropin hormones from the pituitary gland. To reveal the influence of Syt1 on the process of goose egg-laying, we cloned and characterized the cDNA of goose Syt1 originating from hypothalamus and pituitary tissues of Huoyan goose and investigated the mRNA expression profiles during different stages of the egg-laying cycle.
Methods
Hypothalamus and pituitary tissues were obtained from 36 Huoyan geese in the pre-laying period, early laying period, peak-laying period, and ceased period. The cDNA sequences of goose Syt1 were cloned and characterized from Huoyan goose tissues using 5’-RACE and 3’-RACE methods. Multiple alignments and phylogenetic analyses of the deduced Syt1 amino acid sequence were conducted using bioinformatics tools. The expression profiles of the Syt1 mRNA in the hypothalamus and pituitary during pre-laying, early laying, peak-laying and ceased period were examined using real-time PCR (qRT-PCR).
Results
The cDNA of Syt1 consisted of a 274 bp 5’ UTR, a 1266 bp open reading frame (ORF) encoding 421 amino acids, and a 519 bp 3’ UTR. The deduced amino acid sequence of goose Syt1 is highly conserved with the sequence from other species, especially with birds (more than 98%), and contains two protein kinase C2 conserved regions (C2 domain) from amino acids residue 157 to 259 and 288 to 402. The results of qRT-PCR demonstrated that the expression of Syt1 mRNA increased from the pre-laying period to the peak-laying period, reached its peak in the peak-laying period, and then decreased in the ceased period.
Conclusions
To the best of our knowledge, this study is the first to obtain full-length cDNA sequences of the goose Syt1 gene, and the results of Syt1 mRNA expression profiling in the hypothalamus and pituitary tissues suggested that Syt1 may play an important role in regulating the secretion of hormones relevant to the reproduction and egg-laying of female geese.
doi:10.1186/1477-7827-12-83
PMCID: PMC4147189  PMID: 25146222
Huoyan goose; Syt1; Hypothalamus; Pituitary; cDNA; RACE; Real time RT-PCR
20.  Circulating miR-19a and miR-205 in Serum May Predict the Sensitivity of Luminal A Subtype of Breast Cancer Patients to Neoadjuvant Chemotherapy with Epirubicin Plus Paclitaxel 
PLoS ONE  2014;9(8):e104870.
Background
The luminal A subtype of breast cancer has a good prognosis and is sensitive to endocrine therapy but is less sensitive to chemotherapy. It is necessary to identify biomarkers to predict chemosensitivity and avoid over-treatment. We hypothesized that miRNAs in the serum might be associated with chemosensitivity.
Methods
Sixty-eight breast cancer patients received neoadjuvant chemotherapy with epirubicin plus paclitaxel. The serum of the patients was collected before chemotherapy and stored at −80°C. The samples were classified into two groups in term of the chemosensitivity. We identified the differential expression patterns of miRNAs between the chemotherapy sensitive and resistant groups using microRNA profiling. Four miRNAs that were differentially expressed between the two groups were further validated in another 56 samples. We created a model fitting formula and a receiver operating characteristics (ROC) curve using logistic regression analysis to evaluate the prediction potency.
Results
We identified 8 miRNAs differentially expressed between the two groups: 6 miRNAs were up-regulated, and 2 miRNAs were down-regulated in the resistant group compared with the sensitive group. The expression of miR-19a and miR-205 were determined to have significant differences between the two groups (P<0.05). A predictive model of these two miRNAs was created by the logistic regression analysis. The probability of this model was 89.71%. Based on the ROC curve, the specificity was 75.00%, and the sensitivity was 81.25%.
Conclusions
The combination of miR-19a and miR-205 in the serum may predict the chemosensitivity of luminal A subtype of breast cancer to epirubicin plus paclitaxel neoadjuvant chemotherapy.
doi:10.1371/journal.pone.0104870
PMCID: PMC4138038  PMID: 25137071
21.  Breast carcinoma with choriocarcinomatous features: a case report and review of the literature 
Background
Breast carcinoma with choriocarcinomatous features (BCCF) is a rare variant of breast cancer, characterized by high expression of human chorionic gonadotropin (HCG) in cancer cells such as multinucleated syncytiotrophoblast-like giant cells. The first case of BCCF was reported in 1981 by Saigo and Rosen. Only one case of BCCF was reported to show no component of breast ductal carcinoma, and only partially cancer cells, such as multinucleated syncytiotrophoblast-like giant cells, expressed HCG in all previous BCCF cases. Here, we report the first BCCF case without any component of breast ductal carcinoma in which HCG was found to express in all cancer cells.
Case presentation
A 32-year-old female patient presented with a small lump in her left breast 3 years prior. The mass was clinically suspected to be breast infiltrating ductal carcinoma based on breast excisional biopsy and magnetic resonance imaging findings. Due to rupture and bleeding of the left kidney, the left kidney excisional biopsy was performed. After a retrospective analysis of the initial excised breast cancer and breast cancer metastatic to the kidney, the cancer cells were positive for HCG by immunohistochemistry, and multinucleated or mononucleated giant cells resembled syncytiotrophoblastic and cytotrophoblastic cells which could be seen in a background of poor differentiated breast carcinoma and extensive necrosis and hemorrhage in the lesion. Thus, a final diagnosis of BCCF and BCCF metastatic to the kidney was made. After combination of surgical resection (the affected left breast and left kidney wereremoved) and consecutive chemotherapy consisting of docetaxel, epirubicin, cisplatin, lobaplatin, and capecitabine, the patient achieved favorable therapeutic efficacy (the HCG level returned to normal values, the metastatic lesions in the lungs disappeared, and the survival was 37 months). Capecitabine was very efficient and highly recommended due to its superior efficacy in reducing the HCG level and eliminating the metastatic lesions in the lungs.
Conclusions
This is the first report of a rare case of BCCF without any component of breast ductal carcinoma, featured by high expression of HCG in all cancer cells. Combination of surgery and chemotherapy (especially capecitabine) achieved a favorable therapeutic efficacy.
doi:10.1186/1477-7819-12-239
PMCID: PMC4121303  PMID: 25073898
Breast cancer; Breast carcinoma with choriocarcinomatous features; Breast infiltrating ductal carcinoma; Chemotherapy, Human chorionic gonadotropin
22.  Overexpression of HCC1/CAPERα may play a role in lung cancer carcinogenesis 
HCC1/CAPERα is considered to be a novel human tumor-associated antigen, and the tumor-specific immunity of HCC1/CAPERα has been reported in several types of cancer. However, there was very limited evidence indicating its function in tumorigenesis. In the present study, to elucidate the roles and underlying molecular mechanism of HCC1/CAPERα in lung cancer, we examined the expression of HCC1/CAPERα in human non-small cell lung cancer (NSCLC) cell line and NSCLC tissue microarray (TMA). Immunohistochemistry with TMA was performed to detect HCC1/CAPERα expression in NSCLC and adjacent lung tissues. NSCLC cell line constitutively transfected by pcDNA3.1-HCC1/CAPERα, and empty pcDNA3.1 vector were used. These cells were analyzed by Western blot, MTT, immunofluorescence, wound healing assay, and transwell assays. It was found that HCC1/CAPERα was mainly localized in the nucleus of the lung cancer cells and overexpression of HCC1/CAPERα may promote lung cancer cells proliferation and increase cells migration. The frequency of HCC1/CAPERα expression in NSCLC tissues was significantly higher than that in adjacent and normal tissues (P<0.01). Our data suggest that overexpression of HCC1/CAPERα may increase the proliferation and migration of NSCLC cells, and HCC1/CAPERα could be a promising biomarker for lung cancer.
doi:10.1007/s13277-014-1819-y
PMCID: PMC4110178  PMID: 24643682
Lung cancer; HCC1/CAPERα; Biomarker; Overexpression; Carcinogenesis
23.  Experimental infection of duck origin virulent Newcastle disease virus strain in ducks 
BMC Veterinary Research  2014;10:164.
Background
Newcastle disease (ND) caused by virulent Newcastle disease virus (NDV) is an acute, highly contagious and fatal viral disease affecting most species of birds. Ducks are generally considered to be natural reservoirs or carriers of NDV while being resistant to NDV strains, even those most virulent for chickens; however, natural ND cases in ducks have been gradually increasing in recent years. In the present study, ducks of different breeds and ages were experimentally infected with duck origin virulent NDV strain duck/Jiangsu/JSD0812/2008 (JSD0812) by various routes to investigate the pathogenicity of NDV in ducks.
Results
Six breeds (mallard, Gaoyou, Shaoxing, Jinding, Shanma, and Pekin ducks) were infected intramuscularly (IM) with JSD0812 strain at the dose of 5 × 108 ELD50. Susceptibility to NDV infection among breeds varied, per morbidity and mortality. Mallard ducks were the most susceptible, and Pekin ducks the most resistant. Fifteen-, 30-, 45-, 60-, and 110-day-old Gaoyou ducks were infected with JSD0812 strain at the dose of 5 × 108 ELD50 either IM or intranasally (IN) and intraocularly (IO), and their disease development, viral shedding, and virus tissue distribution were determined. The susceptibility of ducks to NDV infection decreased with age. Most deaths occurred in 15- and 30-day-old ducklings infected IM. Ducks infected IN and IO sometimes exhibited clinical signs, but seldom died. Clinical signs were primarily neurologic. Infected ducks could excrete infectious virus from the pharynx and/or cloaca for a short period, which varied with bird age or inoculation route; the longest period was about 7 days. The rate of virus isolation in tissues from infected ducks was generally low, even in those from dead birds, and it appeared to be unrelated to bird age and infection route.
Conclusions
The results confirmed that some of the naturally occurring NDV virulent strains can cause the disease in ducks, and that ducks play an important role in the epidemiology of ND. The prevention of NDV spread in ducks should receive more attention and research in terms of preventing the occurrence and prevalence of ND.
doi:10.1186/1746-6148-10-164
PMCID: PMC4105097  PMID: 25030425
Newcastle disease virus; Duck; Breed; Age; Susceptibility; Pathogenesis; Virus shedding
24.  RANKING GENE-DRUG RELATIONSHIPS IN BIOMEDICAL LITERATURE USING LATENT DIRICHLET ALLOCATION 
Drug responses vary greatly among individuals due to human genetic variations, which is known as pharmacogenomics (PGx). Much of the PGx knowledge has been embedded in biomedical literature and there is a growing interest to develop text mining approaches to extract such knowledge. In this paper, we present a study to rank candidate gene-drug relations using Latent Dirichlet Allocation (LDA) model. Our approach consists of three steps: 1) recognize gene and drug entities in MEDLINE abstracts; 2) extract candidate gene-drug pairs based on different levels of co-occurrence, including abstract level, sentence level, and phrase level; and 3) rank candidate gene-drug pairs using multiple different methods including term frequency, Chi-square test, Mutual Information (MI), a reported Kullback-Leibler (KL) distance based on topics derived from LDA (LDA-KL), and a newly defined probabilistic KL distance based on LDA (LDA-PKL). We systematically evaluated these methods by using a gold standard data set of gene-drug relations derived from PharmGKB. Our results showed that the proposed LDA-PKL method achieved better Mean Average Precision (MAP) than any other methods, suggesting its promising uses for ranking and detecting PGx relations.
PMCID: PMC4095990  PMID: 22174297
Gene-drug Relation; Latent Dirichlet Allocation; Ranking; Pharmacogenomics
25.  A cancer-related protein 14-3-3ζ is a potential tumor-associated antigen in immunodiagnosis of hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Serum alpha-fetoprotein (AFP) is the conventional biomarker currently used in clinical diagnosis of this malignancy. However, AFP is not reliable for early diagnosis, and especially the sensitivity and specificity of AFP in HCC diagnosis are not optimal. Early detection of HCC is an important issue because of the very poor prognosis and usually no more than 6 months survival after diagnosis. Therefore, there is a need for the development of more sensitive and specific methods that can supplement AFP in the early detection of this cancer. In this study, autoantibody responses to 14-3-3ζ in HCC were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot, and indirect immunofluorescence assay. Immunohistochemistry (IHC) with tissue array slides was also performed to analyze protein expression of 14-3-3ζ in HCC and control tissues. The prevalence of autoantibodies against 14-3-3ζ was 16.7 % (28/168) in HCC, which was significantly higher than that in liver cirrhosis (LC), chronic hepatitis (CH), and normal human sera (NHS) (P<0.01). The average titer of autoantibodies against 14-3-3ζ in HCC sera was higher compared to that in LC, CH, and NHS (P<0.01). In the further study, anti-14-3-3ζ antibodies have been detected in the sera from several HCC patients with serial bleeding samples. A stronger reactive band with 14-3-3ζ in western blot can be seen in sera at 9 months before the clinical diagnosis of HCC. Our preliminary data indicate that anti-14-3-3ζ autoantibodies may be potential biomarkers for early-stage HCC screening and diagnosis.
doi:10.1007/s13277-013-1555-8
PMCID: PMC4096569  PMID: 24390614
Hepatocellular carcinoma (HCC); 14-3-3ζ; Tumor-associated antigens (TAAs); Immunodiagnosis

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