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1.  Establishment and Validation of GV-SAPS II Scoring System for Non-Diabetic Critically Ill Patients 
PLoS ONE  2016;11(11):e0166085.
Background and Aims
Recently, glucose variability (GV) has been reported as an independent risk factor for mortality in non-diabetic critically ill patients. However, GV is not incorporated in any severity scoring system for critically ill patients currently. The aim of this study was to establish and validate a modified Simplified Acute Physiology Score II scoring system (SAPS II), integrated with GV parameters and named GV-SAPS II, specifically for non-diabetic critically ill patients to predict short-term and long-term mortality.
Training and validation cohorts were exacted from the Multiparameter Intelligent Monitoring in Intensive Care database III version 1.3 (MIMIC-III v1.3). The GV-SAPS II score was constructed by Cox proportional hazard regression analysis and compared with the original SAPS II, Sepsis-related Organ Failure Assessment Score (SOFA) and Elixhauser scoring systems using area under the curve of the receiver operator characteristic (auROC) curve.
4,895 and 5,048 eligible individuals were included in the training and validation cohorts, respectively. The GV-SAPS II score was established with four independent risk factors, including hyperglycemia, hypoglycemia, standard deviation of blood glucose levels (GluSD), and SAPS II score. In the validation cohort, the auROC values of the new scoring system were 0.824 (95% CI: 0.813–0.834, P< 0.001) and 0.738 (95% CI: 0.725–0.750, P< 0.001), respectively for 30 days and 9 months, which were significantly higher than other models used in our study (all P < 0.001). Moreover, Kaplan-Meier plots demonstrated significantly worse outcomes in higher GV-SAPS II score groups both for 30-day and 9-month mortality endpoints (all P< 0.001).
We established and validated a modified prognostic scoring system that integrated glucose variability for non-diabetic critically ill patients, named GV-SAPS II. It demonstrated a superior prognostic capability and may be an optimal scoring system for prognostic evaluation in this patient group.
PMCID: PMC5100948  PMID: 27824941
2.  STMN1 Promotes Progesterone Production Via StAR Up-regulation in Mouse Granulosa Cells 
Scientific Reports  2016;6:26691.
Stathmin 1 (STMN1) is a biomarker in several types of neoplasms. It plays an important role in cell cycle progression, mitosis, signal transduction and cell migration. In ovaries, STMN1 is predominantly expressed in granulosa cells (GCs). However, little is known about the role of STMN1 in ovary. In this study, we demonstrated that STMN1 is overexpressed in GCs in patients with polycystic ovary syndrome (PCOS). In mouse primary GCs, the overexpression of STMN1 stimulated progesterone production, whereas knockdown of STMN1 decreased progesterone production. We also found that STMN1 positively regulates the expression of Star (steroidogenic acute regulatory protein) and Cyp11a1 (cytochrome P450 family 11 subfamily A member 1). Promoter and ChIP assays indicated that STMN1 increased the transcriptional activity of Star and Cyp11a1 by binding to their promoter regions. The data suggest that STMN1 mediates the progesterone production by modulating the promoter activity of Star and Cyp11a1. Together, our findings provide novel insights into the molecular mechanisms of STMN1 in ovary GC steroidogenesis. A better understanding of this potential interaction between STMN1 and Star in progesterone biosynthesis in GCs will facilitate the discovery of new therapeutic targets in PCOS.
PMCID: PMC4897624  PMID: 27270953
3.  Repeated Radiofrequency Ablation Combined With Ablated Lesion Elimination and Transarterial Chemoembolization Improves the Outcome of Solitary Huge Hepatocellular Carcinomas 10 cm or Larger 
Medicine  2016;95(16):e3393.
This study investigated the effectiveness of a new strategy, repeated radiofrequency (RF) ablation combined with ablated lesion elimination following transarterial chemoembolization (TACE)/transarterial embolization (TAE), for solitary huge hepatocellular carcinoma (SHHCC) 10 cm or larger.
From July 2008 to October 2015, 39 consecutive patients with SHHCC were screened. Of these, 12 were treated with TACE/TAE and repeated RF ablation (TACE/TAE + RF ablation group) and the remaining 27 patients were treated with the aforementioned new strategy (new strategy group). Local tumor progression (LTP)-free survival, intrahepatic distant recurrence (IDR)-free survival, and overall survival (OS) rates were obtained using the Kaplan–Meier method. Univariate and multivariate analyses were performed on several clinicopathological variables to identify factors affecting long-term outcome and intrahepatic recurrence. Correlation analysis was also performed.
The 1-, 2-, and 3-year LTP-free survival rates and OS rates were significantly higher in the new strategy group than in the TACE/TAE + RF ablation group (82.9% vs 58.3%, 73.9% vs 29.2%, 18.5% vs 9.7%, P = 0.002; 92.0% vs 75.0%, 84.0% vs 33.3%, 32.7% vs 16.7%, P = 0.025). However, there was no significant difference between the 2 groups in the 1-, 2-, and 3-year IDR-free survival rates (P = 0.108). Using univariate analysis, alpha-fetoprotein (AFP > 200 ng/mL), ablative margin (AM > 1.0 cm), and well-differentiated cells were found to be significant factors for predicting LTP, IDR, and OS. Surgical elimination was found to be a significant factor only for predicting OS. In multivariate analyses, AFP (>200 ng/mL), AM (>1.0 cm), and well-differentiated cells were found to be significant independent factors linked to LTP, IDR, and OS. Correlation analysis indicated that AM > 1.0 cm was strongly associated with surgical elimination (P < 0.001, correlation coefficient = 0.877).
For patients with SHHCC who were initially excluded from surgery, the new strategy including repeated RF ablation combined with ablated lesion elimination following TACE/TAE should now be considered as an alternative treatment.
PMCID: PMC4845829  PMID: 27100425
4.  Laparoscopic Radiofrequency Ablation for Large Subcapsular Hepatic Hemangiomas: Technical and Clinical Outcomes 
PLoS ONE  2016;11(2):e0149755.
The aim of this study was to evaluate the technical and clinical outcomes of using laparoscopic radiofrequency (RF) ablation for treating large subcapsular hepatic hemangiomas.
We retrospectively reviewed our sequential experience of treating 124 large subcapsular hepatic hemangiomas in 121 patients with laparoscopic RF ablation.
The mean diameter of the 124 hemangiomas was 9.1 ± 3.2 cm (5.0–16.0 cm). RF ablation was performed successfully in all patients. There were 55 complications related to the ablation in 26 patients, including 5 of 69 (7.3%) patients with hemangioma <10 cm and 21 of 52 (40.4%) patients with hemangiomas ≥10 cm (P < 0.001). No injuries to abdominal viscera occurred in all the 121 patients. According to the Dindo–Clavien classification, all the complications were minor in 26 patients (Grade I). Out of 124 hepatic hemangiomas, 118 (95.2%) were completely ablated, including 70 of 72 (97.2%) lesions < 10 cm and 48 of 52 (92.3%) lesions ≥ 10 cm (P = 0.236).
Laparoscopic RF ablation therapy is a safe, feasible and effective procedure for large subcapsular hepatic hemangiomas, even in the hepatic hemangiomas ≥ 10 cm. Its use avoids thermal injury to the abdominal viscera.
PMCID: PMC4765839  PMID: 26901132
5.  Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt 
Oncotarget  2015;6(41):43759-43769.
Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored.
Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists.
The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3.
The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application.
PMCID: PMC4791264  PMID: 26544729
calcium; novel calcium antagonists; KCl-induced aortic ring contraction; synthesis
6.  Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer 
Background: The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumor necrosis factor (TNF)-induced necroptosis. Objective: To evaluate the expression and clinical significance of MLKL in cervical squamous cell carcinoma.Methods: The expression of MLKL in 54 cervical squamous carcinoma samples was detected by immuneohistochemical method. Chi-square, correlation analysis and kaplan-Meier method were used to analyze the data. Results: The MLKL expression in cervical squamous cell carcinoma was higher than that in normal cervical tissues (P = 0.004). The MLKL expression was negatively correlated with histological grade, lymphatic metastasis (P<0.05). Survival analysis showed the low expression of MLKL indicated poor prognosis. Conclusion: MLKL was a prognostic biomarker for cervical squamous cell carcinoma.
PMCID: PMC4713627  PMID: 26823841
Cervical squamous cell carcinoma; MLKL; phosphorylate; immunohistochemistry
7.  Laparoscopic vs computerized tomography-guided radiofrequency ablation for large hepatic hemangiomas abutting the diaphragm 
AIM: To compare safety and therapeutic efficacy of laparoscopic radiofrequency (RF) ablation vs computed tomography (CT)-guided RF ablation for large hepatic hemangiomas abutting the diaphragm.
METHODS: We retrospectively reviewed our sequential experience of treating 51 large hepatic hemangiomas abutting the diaphragm in 51 patients by CT-guided or laparoscopic RF ablation due to either the presence of symptoms and/or the enlargement of hemangioma. Altogether, 24 hemangiomas were ablated via a CT-guided percutaneous approach (CT-guided ablation group), and 27 hemangiomas were treated via a laparoscopic approach (laparoscopic ablation group).
RESULTS: The mean diameter of the 51 hemangiomas was 9.6 ± 1.8 cm (range, 6.0-12.0 cm). There was no difference in the diameter of hemangiomas between the two groups (P > 0.05). RF ablation was performed successfully in all patients. There was no difference in ablation times between groups (P > 0.05). There were 23 thoracic complications in 17 patients: 15 (62.5%, 15/24) in the CT-guided ablation group and 2 (7.4%, 2/27) in the laparoscopic ablation group (P < 0.05). According to the Dindo-Clavien classification, two complications (pleural effusion and diaphragmatic rupture grade III) were major in two patients. All others were minor (grade I). Both major complications occurred in the CT-guided ablation group. The minor complications were treated successfully with conservative measures, and the two major complications underwent treatment by chest tube drainage and thoracoscopic surgery, respectively. Complete ablation was achieved in 91.7% (22/24) and 96.3% (26/27) in the CT-guided and the laparoscopic ablation groups, respectively (P > 0.05).
CONCLUSION: Laparoscopic RF ablation therapy should be used as the first-line treatment option for large hepatic hemangiomas abutting the diaphragm. It avoids thermal injury to the diaphragm and reduces thoracic complications.
PMCID: PMC4438029  PMID: 26019459
Hepatic hemangioma; Radiofrequency ablation; Diaphragm; Computed tomography; Laparoscopy
8.  Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less as first-line treatment 
AIM: To evaluate long-term outcomes of radiofrequency (RF) ablation as first-line therapy for single hepatocellular carcinoma (HCC) ≤ 3 cm and to determine survival and prognostic factors.
METHODS: We included all 184 patients who underwent RF ablation as a first-line treatment for single HCC ≤ 3 cm between April 2005 and December 2013. According to the criteria of Livraghi, the 184 patients were divided into two groups: those suitable for surgical resection (84 cases) and those unsuitable for surgical resection (100 cases). The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness and recurrence rate.
RESULTS: There were 19 (10.3%) cases of ablation related minor complications. The complete tumor ablation rate after one RF session was 97.8% (180/184). The rate of local tumor progression, extrahepatic metastases and intrahepatic distant recurrence were 4.9% (9/184), 9.8% (18/184) and 37.5% (69/184), respectively. In the 184 patients, the 1-, 3-, and 5-year OS rates were 99.5%, 81.0%, and 62.5%, respectively. The 1-, 3-, and 5-year OS rates were 100%, 86.9%, and 71.4%, respectively, in those suitable for surgical resection and 99.0%, 76.0%, and 55.0%, respectively, in those unsuitable for surgical resection (P = 0.021). On univariate and multivariate analyses, poorer OS was associated with Child-Pugh B class and portal hypertension (P < 0.05).
CONCLUSION: RF ablation is a safe and effective treatment for single HCC ≤ 3 cm. The OS rate of patients suitable for surgical resection was similar to those reported in surgical series.
PMCID: PMC4419069  PMID: 25954102
Hepatocellular carcinoma; Radiofrequency ablation; Therapeutic efficacy; Safety; Survival
9.  Body Mass Index Modulates Blood Pressure Heritability: The Family Blood Pressure Program 
American Journal of Hypertension  2013;27(4):610-619.
Candidate gene and twin studies suggest that interactions between body mass index (BMI) and genes contribute to the variability of blood pressure (BP). To determine whether there is evidence for gene–BMI interactions, we investigated the modulation of BP heritability by BMI using 4,153 blacks, 1,538 Asians, 4,013 whites, and 2,199 Hispanic Americans from the Family Blood Pressure Program.
To capture the BP heritability dependence on BMI, we employed a generalized variance components model incorporating linear and Gaussian interactions between BMI and the genetic component. Within each race and network subgroup, we used the Akaike information criterion and likelihood ratio test to select the appropriate interaction function for each BP trait (systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP)) and determine interaction significance, respectively.
BP heritabilities were significantly modified by BMI in the GenNet and SAPPHIRe Networks, which contained the youngest and least-obese participants, respectively. GenNet Whites had unimodal SBP, MAP, and PP heritabilities that peaked between BMI values of 33 and 37kg/m2. The SBP and MAP heritabilities in GenNet Hispanic Americans, as well as the PP heritability in GenNet blacks, were increasing functions of BMI. The DBP and SBP heritabilities in the SAPPHIRe Chinese and Japanese, respectively, were decreasing functions of BMI.
BP heritability differed by BMI in the youngest and least-obese networks, although the shape of this dependence differed by race. Use of nonlinear gene–BMI interactions may enhance BP gene discovery efforts in individuals of European ancestry.
PMCID: PMC3958601  PMID: 24029162
blood pressure; BMI; FBPP; heritability; hypertension; interactions.
10.  N-n-butyl haloperidol iodide inhibits H2O2-induced Na+/Ca2+-exchanger activation via the Na+/H+ exchanger in rat ventricular myocytes 
N-n-butyl haloperidol iodide (F2), a novel compound, has shown palliative effects in myocardial ischemia/reperfusion (I/R) injury. In this study, we investigated the effects of F2 on the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/Na+/H+ exchanger (NHE)/Na+/Ca2+ exchanger (NCX) signal-transduction pathway involved in H2O2-induced Ca2+ overload, in order to probe the underlying molecular mechanism by which F2 antagonizes myocardial I/R injury. Acute exposure of rat cardiac myocytes to 100 μM H2O2 increased both NHE and NCX activities, as well as levels of phosphorylated MEK and ERK. The H2O2-induced increase in NCX current (INCX) was nearly completely inhibited by the MEK inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[o-aminophenylmercapto] butadiene), but only partly by the NHE inhibitor 5-(N,N-dimethyl)-amiloride (DMA), indicating the INCX increase was primarily mediated by the MEK/mitogen-activated protein kinase (MAPK) pathway, and partially through activation of NHE. F2 attenuated the H2O2-induced INCX increase in a concentration-dependent manner. To determine whether pathway inhibition was H2O2-specific, we examined the ability of F2 to inhibit MEK/ERK activation by epidermal growth factor (EGF), and NHE activation by angiotensin II. F2 not only inhibited H2O2-induced and EGF-induced MEK/ERK activation, but also completely blocked both H2O2-induced and angiotensin II-induced increases in NHE activity, suggesting that F2 directly inhibits MEK/ERK and NHE activation. These results show that F2 exerts multiple inhibitions on the signal-transduction pathway involved in H2O2-induced INCX increase, providing an additional mechanism for F2 alleviating intracellular Ca2+ overload to protect against myocardial I/R injury.
PMCID: PMC4166912  PMID: 25246767
N-n-butyl haloperidol; hydrogen peroxide; Na+/Ca2+ exchanger; Na+/H+ exchanger
11.  Enhanced Performance by Time-Frequency-Phase Feature for EEG-Based BCI Systems 
The Scientific World Journal  2014;2014:420561.
We introduce a new motor parameter imagery paradigm using clench speed and clench force motor imagery. The time-frequency-phase features are extracted from mu rhythm and beta rhythms, and the features are optimized using three process methods: no-scaled feature using “MIFS” feature selection criterion, scaled feature using “MIFS” feature selection criterion, and scaled feature using “mRMR” feature selection criterion. Support vector machines (SVMs) and extreme learning machines (ELMs) are compared for classification between clench speed and clench force motor imagery using the optimized feature. Our results show that no significant difference in the classification rate between SVMs and ELMs is found. The scaled feature combinations can get higher classification accuracy than the no-scaled feature combinations at significant level of 0.01, and the “mRMR” feature selection criterion can get higher classification rate than the “MIFS” feature selection criterion at significant level of 0.01. The time-frequency-phase feature can improve the classification rate by about 20% more than the time-frequency feature, and the best classification rate between clench speed motor imagery and clench force motor imagery is 92%. In conclusion, the motor parameter imagery paradigm has the potential to increase the direct control commands for BCI control and the time-frequency-phase feature has the ability to improve BCI classification accuracy.
PMCID: PMC4087262  PMID: 25045733
12.  Expression of three essential antioxidants of Helicobacter pylori in clinical isolates*  
Objective: Helicobacter pylori maintains long-term persistence in the host and combats oxidative stress via many antioxidant proteins, which are expected to be relevant to bacterial-associated gastric diseases. We aimed to investigate the expression of three essential antioxidants in H. pylori strains isolated from patients with different clinical outcomes. Methods: Forty H. pylori strains were isolated from endoscopic biopsy specimens of gastric mucosa from 13 patients with gastric cancer, 13 with peptic ulcer, and 14 with gastritis. The expression of thioredoxin 1 (Trx1), arginase (RocF), and alkyl hydroperoxide reductase (AhpC) in H. pylori was measured by real-time PCR. Comparisons among multiple sample sets were analyzed using a one-way ANOVA test. Pearson’s correlation test was used to assess relationships among multiple continuous variables. Results: Trx1 expression of H. pylori in gastric cancer and peptic ulcer tissues was higher than that in tissues with gastritis. RocF expression of H. pylori in gastric cancer tissues was higher than that in tissues exhibiting peptic ulcer and gastritis. However, we did not find any differences in AhpC expression in samples from patients with different clinical outcomes. The expression of Trx1 and RocF had a positive, linear correlation. The expression of Trx1 and AhpC had a positive correlation without a linear trend. We found no correlation between the expression of RocF and AhpC. Conclusions: Our observations indicate that the expression of Trx1 and RocF in H. pylori might be related to gastric carcinogenesis. In H. pylori, the expression of members of the antioxidant system may be correlated and relevant to gastric cancer.
PMCID: PMC4076607  PMID: 24793768
Antioxidant; Gastric cancer; Helicobacter pylori; Oxidative stress
13.  Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects 
BMC Cancer  2014;14:48.
Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival.
The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy.
The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes.
These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.
PMCID: PMC3922726  PMID: 24475975
Cancer immunotherapy; IL-18; GM-CSF; Cell vaccine; Apoptosis
14.  Expression of serum amyloid A in uterine cervical cancer 
Diagnostic Pathology  2014;9:16.
As an acute-phase protein, serum amyloid A (SAA) is expressed primarily in the liver. However, its expression in extrahepatic tissues, especially in tumor tissues, was also demonstrated recently. In our study, we investigated the expression of SAA in uterine cervical carcinomas, and our results suggested its potential as a serum biomarker.
Quantitative real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the SAA gene and protein expression levels in the tissues and sera of patients with non-neoplastic lesions (NNLs), cervical intraepithelial neoplasia (CIN) and cervical carcinoma (CC).
Compared with NNLs, the SAA gene (SAA1 and SAA4) expression levels were significantly higher in uterine CC (mean copy numbers: 138.7 vs. 5.01, P < 0.000; and 1.8 vs. 0.079, P = 0.001, respectively) by real-time PCR. IHC revealed cytoplasmic SAA protein staining in tissues from adenocarcinoma and squamous cell carcinoma of the cervix. The median serum concentrations (μg/ml) of SAA were 6.02 in patients with NNLs and 10.98 in patients with CIN (P = 0.31). In contrast, the median serum SAA concentration was 23.7 μg/ml in uterine CC patients, which was significantly higher than the SAA concentrations of the NNL group (P = 0.002) and the CIN group (P = 0.024).
Our data suggested that SAA might be a uterine CC cell product. High SAA concentrations in the serum of CC patients may have a role in monitoring disease occurrence and could have therapeutic applications.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3907664  PMID: 24447576
Uterine cervical carcinoma; Serum amyloid A; Tumor marker
15.  Unusual combined thymic mucoepidermoid carcinoma and thymoma: a case report and review of literature 
In rare condition, combined thymic epithelial tumors showing either type A or type B thymomas areas combined with thymic carcinoma components may occur in thymus. Mucoepidermoid carcinoma (MEC) of the thymus is rare in thymic carcinoma, and so far there is no report to describe a combined epithelial tumor of thymus with MEC component. We report an unusual case of combined thymic MEC/type B2 thymoma in a middle-aged male occurring in a mass of anterior mediastinum. Case report: A 51-year-old Chinese male patient presented with a 6-month history of right ptosis and progressive muscle weakness. Computed tomography (CT) examination revealed a solitary, well-circumscribed mass was in the anterior mediastinum with mild heterogeneous enhancement. Histologically, the mass contained two separated components and displayed typically histological features of low-grade MEC and type B2 thymoma, respectively. There was no gradual transition of these two components observed in mass, and no enlarged lymph node was found in the surrounding tissues. A diagnosis of combined thymic MEC/type B2 thymoma was made. The patient received thymectomy to resect the mass totally. After surgery, chemotherapy with regiments of cisplatin and mitomycin, and radiotherapy of the main tumor bed were performed on the patient. There was no evidence of tumor recurrence during the period of 12 months follow-up.
To our best knowledge, this is the first report of combined thymic epithelial tumor with MEC component. Although this tumor is rare, the diagnosis of a thymic MEC should be taken into consideration when a combined epithelial tumor is occasionally encountered in thymus.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3938068  PMID: 24444077
Thymic neoplasm; Combined thymic epithelial tumor; Mucoepidermoid carcinoma; Thymoma; Differential diagnosis
16.  Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: The HyperGEN Study 
Journal of human hypertension  2011;26(2):133-140.
Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (ACE I/D; AGT -6G-A, M235T, -20A-C) in the renin-angiotension system (RAS) on left ventricular mass (LVM) among hypertensive participants in the HyperGEN study.
Included were 2156 participants aged 20–87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: Adjusted mean LVM (g/m2.7) increased with ‘G’ allele copy number (‘AA’:41.2, ‘AG’:42.3, ‘GG’:44.0; p=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction p=0.03): Among ACE ‘DD’ participants, AGT -20A-C ‘C’ allele carriers had lower mean LVM than ‘AA’ homozygotes (‘DD/CC’:39.2, ‘DD/AC’:39.9, ‘DD/AA’:43.9), with no similar significant effect among ACE ‘I’ allele carriers (‘ID/CC’:47.2, ‘ID/AC’:43.4, ‘ID/AA’:42.6; ‘II/CC’: NA, ‘II/AC’:41.3, ‘II/AA’:43.1).
These findings indicate that RAS variants in at least two genes may interact to modulate LVM.
PMCID: PMC3775641  PMID: 21248783
Left ventricular mass; left ventricular hypertrophy; ACE gene; AGT gene; epistasis; hypertension
17.  Ovarian masses in children and adolescents in China: analysis of 203 cases 
The true incidence of ovarian tumors in children is unknown. Few studies beyond case reports and case series have been published concerning pediatric ovarian tumors. Herein we review a large number of ovarian tumor cases.
The charts of 203 patients who presented with adnexal masses were reviewed.
The patient’s ranged in age from 2 to 18 years (mean = 15.6 years), with 30 being premenarchal (14.8%). The incidence of ovarian tumor increases with age, especially in patients older than 14 years. The main complaint was abdominal pain or abdominal distension in 117 patients (57.7%). A high AFP level in a pre-pubic girl with an adnexal mass is indicative of a malignant ovarian tumor. The 214 adnexal masses (11 patients had bilateral cysts) consisted of benign tumorous oophoropathy (107 masses, 50.0%), borderline and malignant tumors (29 masses, 13.6%), and nontumorous oophoropathy (78 masses, 36.5%). Of the 136 neoplasia, germ cell tumors accounted for 71.5%. Surgical intervention was performed in 98.5% of cases. There were statistically decreased blood loss, surgery duration and days of hospitalization with the laparoscopic procedure when compared with open surgery.
Abdominal pain is the most common complaint in young patients with adnexal masses. AFP is the most useful diagnostic biomarker of ovarian tumors in young females. Laparoscopic resection of ovarian cysts is an alternative operation approach.
PMCID: PMC3729529  PMID: 23826706
Ovarian mass; Pediatric; Germ cell; Epithelial tumor; Laparoscope
18.  Mining Gold Dust under the Genome Wide Significance Level: A Two-Stage Approach to Analysis of GWAS 
Genetic epidemiology  2010;35(2):111-118.
We propose a two-stage approach to analyze genome-wide association (GWA) data in order to identify a set of promising single-nucleotide polymorphisms (SNPs). In stage one, we select a list of top signals from single SNP analyses by controlling false discovery rate (FDR). In stage two, we use the least absolute shrinkage and selection operator (LASSO) regression to reduce false positives. The proposed approach was evaluated using simulated quantitative traits based on genome-wide SNP data on 8,861 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC) Study. Our first stage, targeted at controlling false negatives, yields better power than using Bonferroni corrected significance level. The LASSO regression reduces the number of significant SNPs in stage two: it reduces false positive SNPs and it reduces true positive SNPs also at simulated causal loci due to linkage disequilibrium. Interestingly, the LASSO regression preserves the power from stage one, i.e., the number of causal loci detected from the LASSO regression in stage two is almost the same as in stage one, while reducing false positives further. Real data on systolic blood pressure in the ARIC study was analyzed using our two-stage approach which identified two significant SNPs, one of which was reported to be genome-significant in a meta-analysis containing a much larger sample size. On the other hand, a single SNP association scan did not yield any significant results.
PMCID: PMC3624896  PMID: 21254218
LASSO; FDR; multi-marker; association; power
19.  Optimization of Hydrogen Peroxide Detection for a Methyl Mercaptan Biosensor 
Sensors (Basel, Switzerland)  2013;13(4):5028-5039.
Several kinds of modified carbon screen printed electrodes (CSPEs) for amperometric detection of hydrogen peroxide (H2O2) are presented in order to propose a methyl mercaptan (MM) biosensor. Unmodified, carbon nanotubes (CNTs), cobalt phthalocyanine (CoPC), Prussian blue (PB), and Os-wired HRP modified CSPE sensors were fabricated and tested to detect H2O2, applying a potential of +0.6 V, +0.6 V, +0.4 V, −0.2 V and −0.1 V (versus Ag/AgCl), respectively. The limits of detection of these electrodes for H2O2 were 3.1 μM, 1.3 μM, 71 nM, 1.3 μM, 13.7 nM, respectively. The results demonstrated that the Os-wired HRP modified CSPEs gives the lowest limit of detection (LOD) for H2O2 at a working potential as low as −0.1 V. Os-wired HRP is the optimum choice for establishment of a MM biosensor and gives a detection limit of 0.5 μM.
PMCID: PMC3673124  PMID: 23591963
methyl mercaptan; hydrogen peroxide; amperometric sensor; screen printed electrode
20.  Optimum Designs for Next Generation Sequencing to Discover Rare Variants for Common Complex Disease 
Genetic epidemiology  2011;35(6):572-579.
Recent advances in next generation sequencing technologies make it affordable to search for rare and functional variants for common complex diseases systematically. We investigated strategies for enriching rare variants in the samples selected for sequencing so as to optimize the power for their discovery. In particular, we investigated the roles of alternative sources of enrichment in families through computer simulations. We showed that linkage information, extreme phenotype, and non-random ascertainment, such as multiply affected families, constitute different sources for enriching rare and functional variants in a sequencing study design. Linkage is well known to have limited power for detecting small genetic effects, and hence not considered to be a powerful tool for discovering variants for common complex diseases. However, those families with some degree of family-specific linkage evidence provide an effective sampling strategy to sub-select the most linkage-informative families for sequencing. Compared with selecting subjects with extreme phenotypes, linkage evidence performs better with larger families, while extreme-phenotype method is more efficient with smaller families. Families with multiple affected siblings were found to provide the largest enrichment of rare variants. Finally, we showed that combined strategies such as selecting linkage informative families from multiply affected families provides an optimum strategy with much higher enrichment of rare functional variants than either strategy alone.
PMCID: PMC3596871  PMID: 21618604
Next generation sequencing; rare variants; enrichment; study design; complex diseases; linkage
21.  Establishment of a new representative model of human ovarian cancer in mice 
Intraperitoneal (i.p.) models that accurately mimic the feature behavior of human ovarian cancer are required to investigate the pathology and therapeutics of the disease. However, established i.p. models which are well-characterized and reliable are few. The purposes of this study are to establish a representative mice i.p. model of the disease and to analyze the consequent pathology.
Fresh tumor cells fiom the ascites of patient were injected into female NOD/SCID mice intraperitoneally. Histology, Cytogenetic, immunohistochemistry,tumor markers of CA125,AFP, CA-199 and CEA were used to analyze the model.
The mice developed marked abdominal distention within 6 months after inoculated with tumor cells from a patient with epithelial ovarian carcinoma. The mice developed clinically evident intraperitoneal tumors and massive ascites containing numerous tumor cells in clumps. CA125 level in our model was high in both serum and ascites supernatants, while levels of other tumor markers, such as AFP, CA-199 and CEA, were normal. Cytogenetic analysis and immunohistochemical staining confirmed its characteristics resembling human epithelial ovarian tumor.
The model described in this paper accurately mimics the features of ovarian tumor, which may be useful for evaluation of new therapeutics.
PMCID: PMC3573975  PMID: 23384043
Human; Ovary carcinoma; Animal model; CA125; Intraperitoneal
22.  Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure 
Wain, Louise V | Verwoert, Germaine C | O’Reilly, Paul F | Shi, Gang | Johnson, Toby | Johnson, Andrew D | Bochud, Murielle | Rice, Kenneth M | Henneman, Peter | Smith, Albert V | Ehret, Georg B | Amin, Najaf | Larson, Martin G | Mooser, Vincent | Hadley, David | Dörr, Marcus | Bis, Joshua C | Aspelund, Thor | Esko, Tõnu | Janssens, A Cecile JW | Zhao, Jing Hua | Heath, Simon | Laan, Maris | Fu, Jingyuan | Pistis, Giorgio | Luan, Jian’an | Arora, Pankaj | Lucas, Gavin | Pirastu, Nicola | Pichler, Irene | Jackson, Anne U | Webster, Rebecca J | Zhang, Feng | Peden, John F | Schmidt, Helena | Tanaka, Toshiko | Campbell, Harry | Igl, Wilmar | Milaneschi, Yuri | Hotteng, Jouke-Jan | Vitart, Veronique | Chasman, Daniel I | Trompet, Stella | Bragg-Gresham, Jennifer L | Alizadeh, Behrooz Z | Chambers, John C | Guo, Xiuqing | Lehtimäki, Terho | Kühnel, Brigitte | Lopez, Lorna M | Polašek, Ozren | Boban, Mladen | Nelson, Christopher P | Morrison, Alanna C | Pihur, Vasyl | Ganesh, Santhi K | Hofman, Albert | Kundu, Suman | Mattace-Raso, Francesco US | Rivadeneira, Fernando | Sijbrands, Eric JG | Uitterlinden, Andre G | Hwang, Shih-Jen | Vasan, Ramachandran S | Wang, Thomas J | Bergmann, Sven | Vollenweider, Peter | Waeber, Gérard | Laitinen, Jaana | Pouta, Anneli | Zitting, Paavo | McArdle, Wendy L | Kroemer, Heyo K | Völker, Uwe | Völzke, Henry | Glazer, Nicole L | Taylor, Kent D | Harris, Tamara B | Alavere, Helene | Haller, Toomas | Keis, Aime | Tammesoo, Mari-Liis | Aulchenko, Yurii | Barroso, Inês | Khaw, Kay-Tee | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Eyheramendy, Susana | Org, Elin | Sõber, Siim | Lu, Xiaowen | Nolte, Ilja M | Penninx, Brenda W | Corre, Tanguy | Masciullo, Corrado | Sala, Cinzia | Groop, Leif | Voight, Benjamin F | Melander, Olle | O’Donnell, Christopher J | Salomaa, Veikko | d’Adamo, Adamo Pio | Fabretto, Antonella | Faletra, Flavio | Ulivi, Sheila | Del Greco, M Fabiola | Facheris, Maurizio | Collins, Francis S | Bergman, Richard N | Beilby, John P | Hung, Joseph | Musk, A William | Mangino, Massimo | Shin, So-Youn | Soranzo, Nicole | Watkins, Hugh | Goel, Anuj | Hamsten, Anders | Gider, Pierre | Loitfelder, Marisa | Zeginigg, Marion | Hernandez, Dena | Najjar, Samer S | Navarro, Pau | Wild, Sarah H | Corsi, Anna Maria | Singleton, Andrew | de Geus, Eco JC | Willemsen, Gonneke | Parker, Alex N | Rose, Lynda M | Buckley, Brendan | Stott, David | Orru, Marco | Uda, Manuela | van der Klauw, Melanie M | Zhang, Weihua | Li, Xinzhong | Scott, James | Chen, Yii-Der Ida | Burke, Gregory L | Kähönen, Mika | Viikari, Jorma | Döring, Angela | Meitinger, Thomas | Davies, Gail | Starr, John M | Emilsson, Valur | Plump, Andrew | Lindeman, Jan H | ’t Hoen, Peter AC | König, Inke R | Felix, Janine F | Clarke, Robert | Hopewell, Jemma C | Ongen, Halit | Breteler, Monique | Debette, Stéphanie | DeStefano, Anita L | Fornage, Myriam | Mitchell, Gary F | Smith, Nicholas L | Holm, Hilma | Stefansson, Kari | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Samani, Nilesh J | Preuss, Michael | Rudan, Igor | Hayward, Caroline | Deary, Ian J | Wichmann, H-Erich | Raitakari, Olli T | Palmas, Walter | Kooner, Jaspal S | Stolk, Ronald P | Jukema, J Wouter | Wright, Alan F | Boomsma, Dorret I | Bandinelli, Stefania | Gyllensten, Ulf B | Wilson, James F | Ferrucci, Luigi | Schmidt, Reinhold | Farrall, Martin | Spector, Tim D | Palmer, Lyle J | Tuomilehto, Jaakko | Pfeufer, Arne | Gasparini, Paolo | Siscovick, David | Altshuler, David | Loos, Ruth JF | Toniolo, Daniela | Snieder, Harold | Gieger, Christian | Meneton, Pierre | Wareham, Nicholas J | Oostra, Ben A | Metspalu, Andres | Launer, Lenore | Rettig, Rainer | Strachan, David P | Beckmann, Jacques S | Witteman, Jacqueline CM | Erdmann, Jeanette | van Dijk, Ko Willems | Boerwinkle, Eric | Boehnke, Michael | Ridker, Paul M | Jarvelin, Marjo-Riitta | Chakravarti, Aravinda | Abecasis, Goncalo R | Gudnason, Vilmundur | Newton-Cheh, Christopher | Levy, Daniel | Munroe, Patricia B | Psaty, Bruce M | Caulfield, Mark J | Rao, Dabeeru C | Tobin, Martin D | Elliott, Paul | van Duijn, Cornelia M
Nature genetics  2011;43(10):1005-1011.
Numerous genetic loci influence systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans 1-3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N=74,064) and follow-up studies (N=48,607), we identified at genome-wide significance (P= 2.7×10-8 to P=2.3×10-13) four novel PP loci (at 4q12 near CHIC2/PDGFRAI, 7q22.3 near PIK3CG, 8q24.12 in NOV, 11q24.3 near ADAMTS-8), two novel MAP loci (3p21.31 in MAP4, 10q25.3 near ADRB1) and one locus associated with both traits (2q24.3 near FIGN) which has recently been associated with SBP in east Asians. For three of the novel PP signals, the estimated effect for SBP was opposite to that for DBP, in contrast to the majority of common SBP- and DBP-associated variants which show concordant effects on both traits. These findings indicate novel genetic mechanisms underlying blood pressure variation, including pathways that may differentially influence SBP and DBP.
PMCID: PMC3445021  PMID: 21909110
23.  catena-Poly[[[diaqua­diformato­cobalt(II)]-μ-1,4-bis­(1H-benzimidazol-1-yl)benzene] dihydrate] 
In the title coordination polymer, {[Co(CHO2)2(C20H14N4)(H2O)2]·2H2O}n, the CoII atom (site symmetry ) is coordinated by two formate O atoms, two water O atoms and two N atoms from two 1,4-bis­(1H-benzimidazol-1-yl)benzene ligands (L), resulting in a distorted trans-CoN2O4 octa­hedral coordin­ation environment. The complete L ligand is generated by crystallographic inversion symmetry and serves to bridge the cobalt ions into a chain propagating in [1 ]. The dihedral angle between the central benzene ring and the imidazole ring system is 38.48 (12)°. O—H⋯O hydrogen bonds involving both the coordinated and uncoordinated water mol­ecules occur and help to link the chains together.
PMCID: PMC3274843  PMID: 22346892
24.  Enriching rare variants using family-specific linkage information 
BMC Proceedings  2011;5(Suppl 9):S82.
Genome-wide association studies have been successful in identifying common variants for common complex traits in recent years. However, common variants have generally failed to explain substantial proportions of the trait heritabilities. Rare variants, structural variations, and gene-gene and gene-environment interactions, among others, have been suggested as potential sources of the so-called missing heritability. With the advent of exome-wide and whole-genome next-generation sequencing technologies, finding rare variants in functionally important sites (e.g., protein-coding regions) becomes feasible. We investigate the role of linkage information to select families enriched for rare variants using the simulated Genetic Analysis Workshop 17 data. In each replicate of simulated phenotypes Q1 and Q2 on 697 subjects in 8 extended pedigrees, we select one pedigree with the largest family-specific LOD score. Across all 200 replications, we compare the probability that rare causal alleles will be carried in the selected pedigree versus a randomly chosen pedigree. One example of successful enrichment was exhibited for gene VEGFC. The causal variant had minor allele frequency of 0.0717% in the simulated unrelated individuals and explained about 0.1% of the phenotypic variance. However, it explained 7.9% of the phenotypic variance in the eight simulated pedigrees and 23.8% in the family that carried the minor allele. The carrier’s family was selected in all 200 replications. Thus our results show that family-specific linkage information is useful for selecting families for sequencing, thus ensuring that rare functional variants are segregating in the sequencing samples.
PMCID: PMC3287923  PMID: 22373363
25.  Comparative proteome analysis of Helicobacter pylori clinical strains by two-dimensional gel electrophoresis*  
Objective: To investigate the pathogenic properties of Helicobacter pylori by comparing the proteome map of H. pylori clinical strains. Methods: Two wild-type H. pylori strains, YN8 (isolated from biopsy tissue of a gastric cancer patient) and YN14 (isolated from biopsy tissue of a gastritis and duodenal ulcer patient), were used. Proteomic analysis, using a pH range of 3–10 and 5–8, was performed. The individual proteins were identified by quadrupole time-of-flight (Q-TOF) mass spectrometer and protein database search. Results: Variation in spot patterns directed towards differential protein expression levels was observed between the strains. The gel revealed prominent proteins with several protein “families”. The comparison of protein expressions of the two strains reveals a high variability. Differentially present or absent spots were observed. Nine differentially expressed protein spots identified by Q-TOF included adenosine triphosphate (ATP)-binding protein, disulfide oxidoreductase B (DsbB)-like protein, N utilization substance A (NusA), ATP-dependent protease binding subunit/heat shock protein, hydantoin utilization protein A, seryl-tRNA synthetase, molybdenum ABC transporter ModD, and hypothetical proteins. Conclusions: This study suggests that H. pylori strains express/repress protein variation, not only in terms of the virulence proteins, but also in terms of physiological proteins, when they infect a human host. The difference of protein expression levels between H. pylori strains isolated from gastric cancer and gastritis may be the initiator of inflammation, and result in the different clinical presentation. In this preliminary study, we report seven differential proteins between strains, with molecule weights from approximately 10 kDa to approximately 40 kDa. Further studies are needed to investigate those proteins and their function associated with H. pylori colonization and adaptation to host environment stress.
PMCID: PMC3190097  PMID: 21960345
Helicobacter pylori; Proteome; Gastric cancer; Gastritis; Two-dimensional gel electrophoresis

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