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1.  Colon Cancer-Specific Antigen-2 May Be Used as a Detecting and Prognostic Marker in Colorectal Cancer: A Preliminary Observation 
PLoS ONE  2014;9(4):e94252.
Background
A specific and sensitive serum marker for colorectal cancer (CRC) detection and surveillance is central to effective treatment. It was preliminarily reported that some nuclear matrix proteins may be served as a specific blood based marker for colon cancer. The objective of this study is to evaluate the value of serum CCSA-2 detection in diagnosis, prognostic estimation and surveillance for CRC.
Method
Serum CCSA-2 protein was measured in 181 various patient populations and 20 healthy donors before surgery. For 106 CRC patients, it was also measured on day 7 after surgery. Among them, 49 CRC patients' CCSA-2 protein were measured during the follow-up period according to NCCN Guideline.
Results
The serum CCSA-2 concentration in CRC patients was significantly higher than which in other patients and healthy individuals. Serum CCSA-2, at the cut-off point of 64.10 ng/mL, had a sensitivity of 98.10% and a specificity of 97.90% in separating CRC populations from all other individuals. The CCSA-2 assay was significantly more sensitive than CEA and CA19-9 assay in CRC detection. After surgery, the serum CCSA-2 level of CRC patients declined significantly, but it rebounded to a high level when recurrences occurred. The pre-operative serum CCSA-2 level in patients who had a relapse within the follow-up period was significantly higher than which in patients without relapse.
Conclusions
Serum CCSA-2 not only may be a potential biomarker using in screening and surveillance of CRC, but also may be an independent prognostic marker for CRC patients. Further clinical trials need to be performed in a larger population of patients to ulteriorly confirm these results.
doi:10.1371/journal.pone.0094252
PMCID: PMC3978011  PMID: 24710115
2.  Wave-packet rectification in nonlinear electronic systems: A tunable Aharonov-Bohm diode 
Scientific Reports  2014;4:4566.
Rectification of electron wave-packets propagating along a quasi-one dimensional chain is commonly achieved via the simultaneous action of nonlinearity and longitudinal asymmetry, both confined to a limited portion of the chain termed wave diode. However, it is conceivable that, in the presence of an external magnetic field, spatial asymmetry perpendicular to the direction of propagation suffices to ensure rectification. This is the case of a nonlinear ring-shaped lattice with different upper and lower halves (diode), which is attached to two elastic chains (leads). The resulting device is mirror symmetric with respect to the ring vertical axis, but mirror asymmetric with respect to the chain direction. Wave propagation along the two diode paths can be modeled for simplicity by a discrete Schrödinger equation with cubic nonlinearities. Numerical simulations demonstrate that, thanks to the Aharonov-Bohm effect, such a diode can be operated by tuning the magnetic flux across the ring.
doi:10.1038/srep04566
PMCID: PMC3972507
3.  Prediction of Nodal Involvement in Primary Rectal Carcinoma without Invasion to Pelvic Structures: Accuracy of Preoperative CT, MR, and DWIBS Assessments Relative to Histopathologic Findings 
PLoS ONE  2014;9(4):e92779.
Objective
To investigate the accuracy of preoperative computed tomography (CT), magnetic resonance (MR) imaging and diffusion-weighted imaging with background body signal suppression (DWIBS) in the prediction of nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures.
Methods and Materials
Fifty-two subjects with primary rectal cancer were preoperatively assessed by CT and MRI at 1.5 T with a phased-array coil. Preoperative lymph node staging with imaging modalities (CT, MRI, and DWIBS) were compared with the final histological findings.
Results
The accuracy of CT, MRI, and DWIBS were 57.7%, 63.5%, and 40.4%. The accuracy of DWIBS with higher sensitivity and negative predictive value for evaluating primary rectal cancer patients was lower than that of CT and MRI. Nodal staging agreement between imaging and pathology was fairly strong for CT and MRI (Kappa value = 0.331 and 0.348, P<0.01) but was relatively weaker for DWIBS (Kappa value = 0.174, P<0.05). The accuracy was 57.7% and 59.6%, respectively, for CT and MRI when the lymph node border information was used as the criteria, and was 57.7% and 61.5%, respectively, for enhanced CT and MRI when the lymph node enhancement pattern was used as the criteria.
Conclusion
MRI is more accurate than CT in predicting nodal involvement in primary rectal carcinoma patients in the absence of tumor invasion into pelvic structures. DWIBS has a great diagnostic value in differentiating small malignant from benign lymph nodes.
doi:10.1371/journal.pone.0092779
PMCID: PMC3973633  PMID: 24695111
4.  In vivo evaluation of medical device-associated inflammation using a macrophage-specific Positron Emission Tomography (PET) imaging probe 
To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared by conjugating folic acid (FA) and 2,2′,2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetracetic acid (DOTA) to polyethylene glycol (PEG) and then labeling the conjugate with Ga-68. In vivo PET imaging evaluations demonstrate that the probe is able to detect foreign body reactions, and more importantly, quantify the degree of inflammatory responses to an implanted medical device. These results were further validated by histological analysis.
doi:10.1016/j.bmcl.2013.02.004
PMCID: PMC3602365  PMID: 23481649
Folic acid; Biomaterial implant; Inflammation; Biocompatibility; PET imaging
5.  Parkin deficiency contributes to pancreatic tumorigenesis by inducing spindle multipolarity and misorientation 
Cell Cycle  2013;12(7):1133-1141.
Parkin, an E3 ubiquitin ligase well known for its role in the pathogenesis of juvenile Parkinson disease, has been considered as a candidate tumor suppressor in certain types of cancer. It remains unknown whether parkin is involved in the development of pancreatic cancer, the fourth leading cause of cancer-related deaths worldwide. Herein, we demonstrate the downregulation and copy number loss of the parkin gene in human pancreatic cancer specimens. The expression of parkin negatively correlates with clinicopathological parameters indicating the malignancy of pancreatic cancer. In addition, knockdown of parkin expression promotes the proliferation and tumorigenic properties of pancreatic cancer cells both in vitro and in mice. We further find that parkin deficiency increases the proportion of cells with spindle multipolarity and multinucleation. Parkin-depleted cells also show a significant increase in spindle misorientation. These findings indicate crucial involvement of parkin deficiency in the pathogenesis of pancreatic cancer.
doi:10.4161/cc.24215
PMCID: PMC3646869  PMID: 23470638
parkin; pancreatic cancer; cell proliferation; spindle multipolarity; spindle misorientation
6.  Retrospective analysis of adjuvant chemotherapy for curatively resected gastric cancer 
AIM: To determine the efficacy of adjuvant chemotherapy for gastric cancer in clinical practice, a retrospective analysis was conducted in a high-volume Chinese cancer center.
METHODS: Between November 1995 and June 2007, a total of 423 gastric or esophagogastric adenocarcinoma patients who did (Arm A, n = 300) or did not (Arm S, n = 123) receive radical gastrectomy followed by postoperative chemotherapy were enrolled in this retrospective analysis. In Arm A, monotherapy(fluoropyrimidines, n = 25), doublet (platinum/fluoropyrimidines, n = 164), or triplet regimens [docetaxel/cisplatin/5FU (DCF), or modified DCF, epirubicin/cisplatin/5FU (ECF) or modified ECF, etoposide/cisplatin/FU, n = 111] were administered. Disease-free survival (DFS) and overall survival (OS) were compared between the two arms. A subgroup analysis was carried out in Arm A. A multivariate analysis of prognostic factors was conducted.
RESULTS: Stage I, II and III cancers accounted for 9.7%, 35.7% and 54.6% of the cases, respectively, according to the American Joint Committee on Cancer (AJCC) staging system, 7th edition. Only 178 (42.1%) patients had more than 15 lymph nodes harvested. Hazard ratio estimates for Arm A compared with Arm S were 0.47 (P < 0.001) for OS and 0.59 (P < 0.001) for DFS. The 5-year OS rate was 52% in Arm A vs 36% in Arm S (P = 0.01); the adverse events in Arm A were mild and easily controlled. Ultimately, 73 patients (26.5%) who received doublet or triplet regimens switched to monotherapy with fluoropyrimidines. The OS and DFS did not differ between monotherapy and the combination regimens, however, both were statistically improved in the subgroup of patients who were switched to monotherapy with fluoropyrimidines after doublet or triplet regimens as well as patients who received ≥ 8 cycles of chemotherapy.
CONCLUSION: In clinical practice, platinum/fluoropyrimidines with adequate treatment duration is recommended for stage II/III gastric cancer patients accordingto the 7th edition of the AJCC staging system after curative gastrectomyeven with limited lymphadenectomy.
doi:10.3748/wjg.v20.i12.3356
PMCID: PMC3964407
Adjuvant chemotherapy; Gastric cancer; Lymphadenectomy; Fluoropyrimidine; Platinum
7.  Cytohesins/ARNO: The Function in Colorectal Cancer Cells 
PLoS ONE  2014;9(3):e90997.
Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) are critical regulators of cell differentiation, survival, proliferation, and migration in cancers. This study found that ARNO (cytohesin-2), an activator of the EGF and IGF-I pathways, was more highly expressed in colorectal cancer tissue than in benign adjacent colorectal tissue. When ARNO-siRNA or the chemical inhibitor SecinH3 blocked ARNO, the downstream of the EGF and IGF-I pathways decreased in colorectal cell lines HT29 and HCT116. This blocking also weakened cell proliferation, invasion, and migration in vitro. Furthermore, EGF receptor (EGFR)-dependent colorectal tumor xenografts in nude mouse exerted anti-proliferative and growth suppression effects by injecting secineH3. These data suggested that inhibiting cytohesins or ARNO as cytoplasmic activators of EGFR and IGF-I in colorectal cancer resulted in anti-proliferation, reduced invasion, decreased migration, and suppressed growth in vivo and in vitro. Therefore, cytohesins or ARNO may be a potential therapy target for some colorectal cancer.
doi:10.1371/journal.pone.0090997
PMCID: PMC3950297  PMID: 24618737
8.  Microtubule Stabilization by Mdp3 Is Partially Attributed to Its Modulation of HDAC6 in Addition to Its Association with Tubulin and Microtubules 
PLoS ONE  2014;9(3):e90932.
Microtubule-mediated cellular events such as intracellular transport and the maintenance of cell polarity are highly dependent upon microtubule stability, which is controlled by a repertoire of microtubule-associated proteins (MAPs) in the cell. MAP7 domain-containing protein 3 (Mdp3) has recently been identified as a critical regulator of microtubule stability. However, it remains elusive how Mdp3 carries out this function. In this study, by examination of tubulin partitioning between the polymer and soluble dimer forms, we found that Mdp3 could protect microtubules from cold- or nocodazole-induced depolymerization. Immunoblotting and immunofluorescence microscopy showed that knockdown of Mdp3 expression significantly reduced the level of tubulin acetylation. In vitro tubulin polymerization assays revealed that the amino-terminal region of Mdp3 was necessary for its ability to stabilize microtubules. Immunoprecipitation and pulldown experiments showed that the amino-terminal region mediated the interaction of Mdp3 with histone deacetylase 6 (HDAC6), in addition to its association with tubulin and microtubules. Immunofluorescence microscopy further demonstrated that endogenous Mdp3 and HDAC6 colocalized in the cytoplasm. Moreover, depletion of Mdp3 dramatically increased the activity of HDAC6 toward tubulin deacetylation. These findings suggest that Mdp3 controls microtubule stability through its binding to tubulin and microtubules as well as its regulation of HDAC6 activity.
doi:10.1371/journal.pone.0090932
PMCID: PMC3948737  PMID: 24614595
9.  Effectiveness and Toxicities of Intensity-Modulated Radiation Therapy for Patients with T4 Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(3):e91362.
Objective
To evaluate the effectiveness and toxicities in T4 nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT) combined with chemotherapy.
Methods
This is a retrospective analysis of 81 patients treated with intensity-modulated radiotherapy (IMRT). All the primary tumors were attributed to T4 stage according to the AJCC2010 staging system. And the distribution of disease by N stage was N0 in 13.6%, N1 in 30.9%, N2 in 37%, and N3 in 18.5%. Cisplatin-based chemotherapy was offered to all patients. Radiotherapy-related toxicities were graded according to the Acute and the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group (RTOG) scoring criteria. Chemotherapy-related toxicities were graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. Prognostic factors were assessed by univariate analysis.
Results
With a median follow-up of 37 months, 12 patients experienced local regional failure and total distant metastasis occurred in 18 patients, representing the major mode of failure. Ten patients died. Among them, 70% died of distant metastasis. The 3-year actuarial rates of local failure–free survival (LFFS), regional failure–free survival (RFFS), distant failure–free survival (DFFS), overall survival (OS), and progression–free survival (PFS) were 83.8%, 97.4%, 81.3%, 90%, and 69.7%, respectively. Acute and late toxicities were mild or moderate.
Conclusions
IMRT provides excellent local-regional control for T4 NPC. Distant metastasis remains the major cause of treatment failure. Further explorations of the sequence and regimen of systemic therapy are needed in the future.
doi:10.1371/journal.pone.0091362
PMCID: PMC3946722  PMID: 24608637
10.  Enhanced Temperature Control Method Using ANFIS with FPGA 
The Scientific World Journal  2014;2014:239261.
Temperature control in etching process is important for semiconductor manufacturing technology. However, pressure variations in vacuum chamber results in a change in temperature, worsening the accuracy of the temperature of the wafer and the speed and quality of the etching process. This work develops an adaptive network-based fuzzy inference system (ANFIS) using a field-programmable gate array (FPGA) to improve the effectiveness. The proposed method adjusts every membership function to keep the temperature in the chamber stable. The improvement of the proposed algorithm is confirmed using a medium vacuum (MV) inductively-coupled plasma- (ICP-) type etcher.
doi:10.1155/2014/239261
PMCID: PMC3971550  PMID: 24715808
11.  Change of Body Weight and Macrophage Inhibitory Cytokine-1 during Chemotherapy in Advanced Gastric Cancer: What Is Their Clinical Significance? 
PLoS ONE  2014;9(2):e88553.
Background
Weight loss in advanced gastric cancer (GC) has been widely acknowledged to be a predictor for poor survival. However, very few studies have investigated the weight loss that occurs during chemotherapy. Therefore, we focused on weight loss during chemotherapy in patients with advanced GC and investigated the concentrations of macrophage inhibitory cytokine-1 (MIC-1), which has been recognized as a probable etiological factor in anorexia and weight loss.
Methods
We analyzed 384 patients with inoperable locally advanced or metastatic GC receiving first-line chemotherapy. Patients were assigned to one of two groups on the basis of their weight change during chemotherapy: >3% weight loss and ≤3% weight loss. Serum MIC-1 and C-reactive protein (CRP) concentrations were also assessed in these patients.
Results
The >3% weight loss group had shorter overall survival (OS; 12.0 months vs. 17.5 months, P = 0.000) than the ≤3% weight loss group, and the survival rates improved if the weight loss was reversed during chemotherapy. Although the MIC-1 concentrations were not correlated with weight loss before (P = 0.156) or during chemotherapy (P = 0.164), it correlated significantly with the CRP concentration (P = 0.001). Furthermore, elevated MIC-1 concentrations before chemotherapy (P = 0.017) and increased MIC-1 concentrations during chemotherapy (P = 0.001) were both found to be predictors of poor OS.
Conclusions
Changes in the body weight during chemotherapy could influence the prognosis in patients with advanced GC, and the MIC-1 might be a potential predictive and prognostic biomarker in those patients.
doi:10.1371/journal.pone.0088553
PMCID: PMC3938426  PMID: 24586342
12.  Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats 
PLoS ONE  2014;9(2):e89752.
Baicalin has been used as mainly bioactive constituent of about 100 kinds of traditional Chinese medicines in Chinese pharmacopoeia. The effect of baicalin on cytochrome P450 should be paid more attention because baicalin was used widely. The aim of this study was to investigate whether baicalin could inhibit CYP1A2 in pooled human liver microsomes (HLMs) and in rats in vivo and the gene polymorphisms could affect inter-individual variation in IC50 in 28 human livers. Phenacetin was used as probe of CYP1A2. Kinetic parameter of CYP1A2 and IC50 of baicalin on CYP1A2 to each sample were measured and the common CYP1A2 polymorphisms (−3860G>A and −163C>A) were genotyped. The results showed that baicalin exhibited a mixed-type inhibition in pooled HLMs, with a Ki value of 25.4 µM. There was substantial variation in Km, Vmax, CLint of CYP1A2 and IC50 of baicalin on CYP1A2 (3∼10-fold). The range was from 26.6 to 114.8 µM for Km, from 333 to 1330 pmol·min−1·mg−1protein for Vmax and from 3.8 to 45.3 µL·min−1·mg−1 protein for CLint in HLMs (n = 28). The Mean (range) value of IC50 in 28 HLMs was 36.3 (18.9 to 56.1) µM. The genotypes of −3860G>A and −163C>A had no significant effect on the inhibition of baicalin on CYP1A2. The animal experiment results showed that baicalin (450 mg/kg, i.v.) significantly decreased the Cmax and CL of phenacetin, and increased C60 min, t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C60 min, t1/2, CL, AUC of phenacetin and Cmax of baicalin in 11 rats (P<0.05). Protein binding experiments in vitro showed that baicalin (0–2000 mg/L) increased the unbound phenacetin from 14.5% to 28.3%. In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism. Baicalin can change the pharmacokinetics of phenacetin in rats.
doi:10.1371/journal.pone.0089752
PMCID: PMC3935934  PMID: 24587011
13.  Association of Renal Biochemical Parameters with Left Ventricular Diastolic Dysfunction in a Community-Based Elderly Population in China: A Cross-Sectional Study 
PLoS ONE  2014;9(2):e88638.
Background
Relationship of left ventricular diastolic dysfunction (LVDD) with parameters that could provide more information than hemodynamic renal indexes has not been clarified. We aimed to explore the association of comprehensive renal parameters with LVDD in a community-based elderly population.
Methods
1,166 community residents (aged ≥ 65 years, 694 females) participating in the Shanghai Heart Health Study with complete data of renal parameters were investigated. Echocardiography was used to evaluate diastolic function with conventional and tissue Doppler imaging techniques. Serum urea, creatinine, urea-to-creatinine ratio, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were analyzed on their associations with LVDD.
Results
The prevalence of LVDD increased in proportion to increasing serum urea, urea-to-creatinine ratio and UACR. These three renal parameters were found negatively correlated to peak early (E) to late (A) diastolic velocities ratio (E/A), and positively to left atrial volume index; UACR also positively correlated with E to peak early (E’) diastolic mitral annular velocity ratio (E/E’). Serum urea, urea-to-creatinine ratio and UACR correlated with LVDD in logistic univariate regression analysis, and urea-to-creatinine ratio remained independently correlated to LVDD [Odds ratio (OR) 2.82, 95% confidence interval (CI) 1.34–5.95] after adjustment. Serum urea (OR 1.18, 95%CI 1.03–1.34), creatinine (OR 6.53, 95%CI 1.70­–25.02), eGFR (OR 0.22, 95%CI 0.07–0.65) and UACR (OR 2.15, 95%CI 1.42–3.24) were revealed independent correlates of advanced (moderate and severe) LVDD.
Conclusions
Biochemical parameters of renal function were closely linked with LVDD. This finding described new cardio-renal relationship in the elderly population.
doi:10.1371/journal.pone.0088638
PMCID: PMC3922995  PMID: 24533126
14.  Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells 
Protein & Cell  2014;5(3):214-223.
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.
doi:10.1007/s13238-013-0010-3
PMCID: PMC3967059  PMID: 24474193
pancreatic cancer; cell motility; cell migration; cell proliferation; cell cycle
15.  Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells 
Protein & Cell  2014;5(3):214-223.
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.
doi:10.1007/s13238-013-0010-3
PMCID: PMC3967059  PMID: 24474193
pancreatic cancer; cell motility; cell migration; cell proliferation; cell cycle
16.  Outcome of nephrostomy balloon dilation for vesicourethral anastomotic strictures following radical prostatectomy: A retrospective study 
Asian Journal of Andrology  2013;16(1):115-119.
To evaluate the efficacy of nephrostomy balloon dilation (NBD) for patients who developed vesicourethral anastomotic stricture (VAS) following radical prostatectomy. NBD was performed in patients who developed VAS following radical prostatectomy. Quality of life (QoL), International Prostate Symptom Score (IPSS) and maximal urinary flow rate (Qmax) were evaluated. Four hundred and sixty-three prostate cancer patients underwent radical retropubic prostatectomy (RRP), and 86 underwent laparoscopic radical prostatectomy (LRP). Most patients (90.3%) had T2 or T3 prostate cancer and a pathological Gleason score of ≤ 7. Forty-five (8.2%) and four (4.7%) patients developed VAS due to radical or LRP, respectively. Forty (89%) patients underwent NBD, including three cases of repeat dilation. The median Qmax was 4 ml s−1 (interquartile range (IQR), 2.3-5.6) before dilation and improved to 16 ml s−1 (IQR, 15–19) and 19 ml s−1 (IQR, 18-21) at the 1- and 12-month follow-up, respectively (P < 0.01). Fifteen (37.5%) patients had urinary incontinence prior to dilation, whereas only three (7.5%) patients had incontinence 12 months following dilation (P < 0.01). The median IPSS score improved from 19 (IQR, 17–24) before dilation to 7 (IQR, 6–8) at 12 months following dilation, and the QoL score improved from 5 (IQR, 4–6) before dilation to 2 (IQR, 2–3) at 12 months following dilation (P < 0.01 in both). VAS occurs in a small but significant proportion of patients following radical prostatectomy. NBD offers an effective remedy for VAS.
doi:10.4103/1008-682X.122348
PMCID: PMC3901868  PMID: 24369143
nephrostomy balloon dilation (NBD); quality of life (QoL); radical prostatectomy; vesicourethral anastomotic stricture (VAS)
17.  Ferroportin in the progression and prognosis of hepatocellular carcinoma 
Background
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor in men and the seventh in women and understanding the molecular mechanisms of HCC and establishing more effective therapies are critical and urgent issues. Our objective was to study the expression of ferroportin in hepatocellular carcinoma (HCC) tissue samples and the relationship between ferroportin expression and HCC characteristics.
Methods
Sixty HCC tissues and their corresponding para-cancer liver tissues (PCLT) were obtained from sixty HCC patients who had undergone hepatectomy in the Second Xiangya Hospital of Central South University. Ten normal liver tissue samples were also obtained as a control. Immunohistochemistry (IHC) was performed to analyze the ferroportin expression in HCC, and the relationship between ferroportin expression and HCC clinical pathological characteristics also was analyzed. For the evaluation of IHC results, the comprehensive scoring criteria were met according to the staining intensity and the number of positive staining cells. Western blotting was performed to detect the expression level of ferroportin in HCC cell lines.
Results
Ferroportin expression in HCC tissue was significantly lower compared to PCLT and normal liver tissue (P <0.05). Moreover, ferroportin expression was related to liver cancer cell de-differentiation, the severity degree in TNM staging, Edmondson-Steiner grading, intrahepatic metastasis and portal vein invasion. In addition, high expression of ferroportin was observed in normal human liver cell lines L02 and HL7702, whereas weak positive expression and even negative expression of ferroportin were observed in HCC cell lines FOCUS, MHCC-97H, HepG2 and SMMC-7721. Furthermore, among the four kinds of HCC cell lines, the expression level of ferroportin was the lowest in MHCC-97H cells.
Conclusions
Ferroportin expression level declines along with the progression of liver cancer, suggesting that the reduction of ferroportin may serve as an important marker for poor HCC prognosis and as a new therapeutic target.
doi:10.1186/2047-783X-18-59
PMCID: PMC3878504  PMID: 24360312
Ferroportin; Hepatocellular carcinoma; Prognosis
18.  Reactive oxygen species (ROS)-induced actin glutathionylation controls actin dynamics in neutrophils 
Immunity  2012;37(6):1037-1049.
Summary
The regulation of actin dynamics is pivotal for cellular processes such as cell adhesion, migration, and phagocytosis, and thus is crucial for neutrophils to fulfill their roles in innate immunity. Many factors have been implicated in signal-induced actin polymerization, however the essential nature of the potential negative modulators are still poorly understood. Here we report that NADPH oxidase-dependent physiologically generated reactive oxygen species (ROS) negatively regulate actin polymerization in stimulated neutrophils via driving reversible actin glutathionylation. Disruption of glutaredoxin 1 (Grx1), an enzyme that catalyzes actin deglutathionylation, increased actin glutathionylation, attenuated actin polymerization, and consequently impaired neutrophil polarization, chemotaxis, adhesion, and phagocytosis. Consistently, Grx1-deficient murine neutrophils showed impaired in vivo recruitment to sites of inflammation and reduced bactericidal capability. Together, these results present a physiological role for glutaredoxin and ROS- induced reversible actin glutathionylation in regulation of actin dynamics in neutrophils.
doi:10.1016/j.immuni.2012.08.017
PMCID: PMC3525814  PMID: 23159440
19.  A Reference Methylome Database and Analysis Pipeline to Facilitate Integrative and Comparative Epigenomics 
PLoS ONE  2013;8(12):e81148.
DNA methylation is implicated in a surprising diversity of regulatory, evolutionary processes and diseases in eukaryotes. The introduction of whole-genome bisulfite sequencing has enabled the study of DNA methylation at a single-base resolution, revealing many new aspects of DNA methylation and highlighting the usefulness of methylome data in understanding a variety of genomic phenomena. As the number of publicly available whole-genome bisulfite sequencing studies reaches into the hundreds, reliable and convenient tools for comparing and analyzing methylomes become increasingly important. We present MethPipe, a pipeline for both low and high-level methylome analysis, and MethBase, an accompanying database of annotated methylomes from the public domain. Together these resources enable researchers to extract interesting features from methylomes and compare them with those identified in public methylomes in our database.
doi:10.1371/journal.pone.0081148
PMCID: PMC3855694  PMID: 24324667
20.  Folic Acid Protects against Lipopolysaccharide-Induced Preterm Delivery and Intrauterine Growth Restriction through Its Anti-Inflammatory Effect in Mice 
PLoS ONE  2013;8(12):e82713.
Increasing evidence demonstrates that maternal folic acid (FA) supplementation during pregnancy reduces the risk of neural tube defects, but whether FA prevents preterm delivery and intrauterine growth restriction (IUGR) remains obscure. Previous studies showed that maternal lipopolysaccharide (LPS) exposure induces preterm delivery, fetal death and IUGR in rodent animals. The aim of this study was to investigate the effects of FA on LPS-induced preterm delivery, fetal death and IUGR in mice. Some pregnant mice were orally administered with FA (0.6, 3 or 15 mg/kg) 1 h before LPS injection. As expected, a high dose of LPS (300 μg/kg, i.p.) on gestational day 15 (GD15) caused 100% of dams to deliver before GD18 and 89.3% of fetuses dead. A low dose of LPS (75 μg/kg, i.p.) daily from GD15 to GD17 resulted in IUGR. Interestingly, pretreatment with FA prevented LPS-induced preterm delivery and fetal death. In addition, FA significantly attenuated LPS-induced IUGR. Further experiments showed that FA inhibited LPS-induced activation of nuclear factor kappa B (NF-κB) in mouse placentas. Moreover, FA suppressed LPS-induced NF-κB activation in human trophoblast cell line JEG-3. Correspondingly, FA significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 in mouse placentas. In addition, FA significantly reduced the levels of interleukin (IL)-6 and keratinocyte-derived cytokine (KC) in amniotic fluid of LPS-treated mice. Collectively, maternal FA supplementation during pregnancy protects against LPS-induced preterm delivery, fetal death and IUGR through its anti-inflammatory effects.
doi:10.1371/journal.pone.0082713
PMCID: PMC3855776  PMID: 24324824
21.  Transduction of Schistosoma japonicum schistosomules with vesicular stomatitis virus glycoprotein pseudotyped murine leukemia retrovirus and expression of reporter human telomerase reverse transcriptase in the transgenic schistosomes 
Molecular and biochemical parasitology  2010;174(2):10.1016/j.molbiopara.2010.07.007.
Although draft genome sequences of two of the major human schistosomes, Schistosoma japonicum and S. mansoni are available, the structures and characteristics of most genes and the influence of exogenous genes on the metabolism of schistosomes remain uncharacterized. Furthermore, which functional genomics approaches will be tractable for schistosomes are not yet apparent. Here, the vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped pantropic retroviral vector pBABE-puro was modified to incorporate the human telomerase reverse transcriptase gene (hTERT) as a reporter, under the control of the retroviral long terminal repeat (LTR). Pseudotyped virions were employed to transduce S. japonicum to investigate the utility of retrovirus-mediated transgenesis of S. japonicum and the activity of human telomerase reverse transcriptase as a reporter transgene in schistosomes. Schistosomules perfused from experimentally infected rabbits were cultured for six days after exposure to the virions after which genomic DNAs from virus-exposed and control worms were extracted. Analysis of RNA from transduced parasites and immunohistochemistry of thin parasite sections revealed expression of hTERT in the transduced worms. Expression of hTERT was also confirmed by immunoblot analysis. These findings indicated that S. japonicum could be effectively transduced by VSVG pseudotyped retrovirus carrying the hTERT gene. Given the potential of hTERT to aid in derivation of immortalized cells, these findings suggest that this pantropic retroviral approach can be employed to transduce cells from specific tissues and organs of schistosomes to investigate the influence of transgene hTERT on growth and proliferation of schistosome cells.
doi:10.1016/j.molbiopara.2010.07.007
PMCID: PMC3836731  PMID: 20692298
Schistosoma japonicum; glycoprotein of vesicular stomatitis virus (VSVG); pantropic retrovirus; murine leukemia virus; transgene; telomerase
22.  KAT5 and KAT6B are in positive regulation on cell proliferation of prostate cancer through PI3K-AKT signaling 
Histone modifications play important roles in the tumorigenesis and progression of prostate cancer (PCa) and genes involved in histone modifications are seemed as ideal targets for treatment of PCa patients. However, clinical trials have shown that those existing drugs exert the minimal antitumor activity and excess adverse effects on PCa patients. Therefore, it is of great interest to figure out novel specific biomarkers to guide the development of new drugs. In present study, an RNAi screening with 44 genes involved in histone modifications was applied to a PCa cell line, Du145. The results showed that nine genes were in positive regulation of Du145 cell growth. Then four selected genes (KAT2B, KAT5, KAT6B and HDAC1) were found to exert this effect by a gene-specific manner when silenced. And then KAT5 or KAT6B silenced cells were subjected to DNA microarray analysis. The common differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) and found that PDEF signaling, EIF2 signaling and PI3K signaling was suppressed following by KAT5 or KAT6B silencing. Subsequent immunoblotting assay showed that AKT signaling was inhibited, which suggested that KAT5 or KAT6B regulates cancer cell growth through PI3K-AKT signaling. Together with our published data [31] that AURKA inhibitoin increased drug sensitivity of DU145, our work demonstrated the underlying mechanism that how the acetylation enzyme regulates cancer cells survial and might provide potential therapeutic targets for prostate cancer patients in future epigenetic drug development.
PMCID: PMC3843266  PMID: 24294372
Prostate cancer; histone modifications; RNAi screening; KAT5; KAT6B; PI3K-AKT signaling
23.  A new technique for the obliterative urethral strictures 
There have been a troublesome problem to treat with obliterative urethral strictures, the challenge is how to reduce wound of surgery and improve therapeutic success rates. In this study, we reported single-hospital institution case-series including 97 patients with obliterative urethral strictures were enrolled with “three lines lie within one imaginary plane (TLLWOIP)” to treat with patients with the obliterative urethral strictures. Perioperative variables and success rates were evaluated. Urinary flow rate, residual urine (RU) volume and quality-of-life score (QoLs) of patients were analyzed. In the obliterative urethral strictures, postoperative maximum urinary flow rate was 24.36±10.69 ml, and postoperative RU volume and QoLs outcomes were significantly lower than preoperative outcomes with TLLWOIP. A total of success rate was 62.9% with TLLWOIP. Our results suggested that it was ideal candidates for initial treatment with TLLWOIP for the obliterative urethral strictures.
PMCID: PMC3843281  PMID: 24294387
Obliterative urethral strictures; TLLWOIP
24.  Zinc Finger 280B Regulates sGCα1 and p53 in Prostate Cancer Cells 
PLoS ONE  2013;8(11):e78766.
The Zinc Finger (ZNF) 280B protein was identified as an unexpected target of an shRNA designed for sGCα1. Further analysis showed that these two proteins are connected in another way, with 280B up-regulation of sGCα1 expression. Knock-down and over-expression experiments showed that 280B serves pro-growth and pro-survival functions in prostate cancer. Surprisingly however, these pro-cancer functions of 280B are not mediated by sGCα1, which itself has similar functions in prostate cancer, but by down-regulated p53. The p53 protein is a second target of 280B in prostate cancer, but unlike sGCα1, p53 is down-regulated by 280B. 280B induces p53 nuclear export, leading to subsequent proteasomal degradation. The protein responsible for p53 regulation by 280B is Mdm2, the E3 ubiquitin ligase that promotes p53 degradation by inducing its nuclear export. We show here that 280B up-regulates expression of Mdm2 in prostate cancer cells, and this regulation is via the Mdm2 promoter. To demonstrate an in vivo relevance to this interaction, expression studies show that 280B protein levels are up-regulated in prostate cancer and these levels correspond to reduced levels of p53. Thus, by enhancing the expression of Mdm2, the uncharacterized 280B protein provides a novel mechanism of p53 suppression in prostate cancer.
doi:10.1371/journal.pone.0078766
PMCID: PMC3827277  PMID: 24236047
25.  Novel Thermogelling Dispersions of Polymer Nanoparticles for Controlled Protein Release 
A novel poly(oligo(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) ethyl ether methacrylate)/ poly(acrylic acid) interpenetrating network (IPN) nanoparticle was synthesized. The temperature-responsive properties of the IPN nanoparticles were investigated by dynamic light scattering method. Atomic force microscopic images confirm the homogenous and mono-disperse morphology of the IPN nanoparticles. Both visual observation and viscosity testing demonstrated that the IPN nanoparticles exhibit thermogelling properties at body temperature, 37°C. Subsequent studies verified that such temperature sensitive properties of IPN nanoparticles allow their ease of injection and then slow release of model proteins, both in vitro and in vivo. Histological analysis showed that our IPN implants exerted minimal inflammation following subcutaneous implantation. Our results support that, by simply mixing with proteins of interest, the novel IPN nanoparticles can be used to form in situ thermogelling devices for controlled protein release.
doi:10.1016/j.nano.2012.02.002
PMCID: PMC3371180  PMID: 22349097
Temperature-sensitive nanoparticle; injectable; thermogelling; controlled drug release

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