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1.  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.
PMCID: PMC3964407
Adjuvant chemotherapy; Gastric cancer; Lymphadenectomy; Fluoropyrimidine; Platinum
2.  Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals 
Neurobiology of aging  2012;34(3):822-831.
The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline.
PMCID: PMC3518678  PMID: 22878163
3.  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.
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.
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.
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.
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.
PMCID: PMC3938426  PMID: 24586342
4.  Outbreaks of the Brown Planthopper Nilaparvata lugens (Stål) in the Yangtze River Delta: Immigration or Local Reproduction? 
PLoS ONE  2014;9(2):e88973.
An effective control strategy for migratory pests is difficult to implement because the cause of infestation (i.e., immigration or local reproduction) is often not established. In particular, the outbreak mechanisms of the brown planthopper, Nilaparvata lugens (Stål), an insect causing massive losses in rice fields in the Yangtze River Delta in China, are frequently unclear. Field surveys of N. lugens were performed in Jiangsu and Zhejiang Provinces in 2008 to 2010 and related historical data from 2003 onwards were collected and analyzed to clarify the cause of these infestations. Results showed that outbreaks of N. lugens in the Yangtze River Delta were mostly associated with an extremely high increase in population. Thus, reproduction rather than immigration from distant sources were the cause of the infestations. Although mass migration occurred late in the season (late August and early September), the source areas of N. lugens catches in the Yangtze River Delta were mainly located in nearby areas, including the Yangtze River Delta itself, Anhui and northern Jiangxi Provinces. These regions collectively form the lower-middle reaches of the Yangtze River, and the late migration can thus be considered as an internal bioflow within one population.
PMCID: PMC3928339  PMID: 24558459
5.  TFIIB-Related Factor 2 Over Expression Is a Prognosis Marker for Early-Stage Non-Small Cell Lung Cancer Correlated with Tumor Angiogenesis 
PLoS ONE  2014;9(2):e88032.
The aim of this study was to examine BRF2 expression in patients with non-small cell lung cancer (NSCLC) and explore the relationship of BRF2 protein with clinicopathologic factors, tumor angiogenesis and prognosis.
Both BRF2 protein and intratumoral microvessels were examined by immunohistochemical staining in 107 non-small cell lung cancer patients. Intratumoral m icrovessel density (MVD) was measured by counting CD-34 positive immunostained endothelial cells. Western blot and RT-PCR analyses were utilized to investigate the BRF2 expression status in tissues
A notably higher level of BRF2 expression was found in NSCLC tissues at protein levels. In addition, univariate and multivariate analysis demonstrated that BRF2 protein over-expression and high MVD were significantly associated with tumor relapse. Although BRF2 overexpression and high MVD indicated poor 5-year overall survival (p = 0.004 and p = 0.019, respectively), multivariate analysis demonstrated that only BRF2 overexpression was an independent prognostic factor for unfavorable overall survival (P = 0.021).
BRF2 is a promising biomarker to identify individuals with poor prognostic potential and a possible target for anti-angiogenic therapy for patients with early-stage NSCLC.
PMCID: PMC3921153  PMID: 24523874
6.  Kir6.2-containing ATP-sensitive K+ channel is required for cardioprotection of resveratrol in mice 
Resveratrol is a natural compound that affects energy metabolism and is also known to possess an array of cardioprotective effects. However, its overall effects on energy metabolism and the underlying mechanism involved in cardioprotection require further investigation. Herein we hypothesize that ATP-sensitive potassium (K-ATP) channels as molecular sensors of cellular metabolism may mediate the cardioprotective effects of resveratrol.
Kir6.2 knockout, Kir6.1 heterozygous and wild-type (WT) mice were subjected to ischemia/reperfusion injury and were injected with resveratrol (10 mg/kg, i.p). Myocardial infarct size, serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities were determined. Neonatal cardiomyocytes were used in in vitro assays to investigate the underlying mechanism of resveratrol in cardioprotection.
Resveratrol treatment significantly reduced myocardial infarct size and serum LDH and CK activity and inhibited oxygen-glucose deprivation/reoxygenation – induced cardiomyocyte apoptosis in WT and Kir6.1 heterozygous mice, but Kir6.2 deficiency can abolish the cardioprotective effects of resveratrol in vivo and in vitro. We further found that resveratrol enhanced 5′-AMP-activated protein kinase (AMPK) phosphorylation and promoted the association of AMPK with Kir6.2. Suppression of AMPK attenuated and activation of AMPK mimicked the cardioprotective effects of resveratrol in cardiomyocytes. Notably, Kir6.2 knockout also reversed the cardioprotection of AMPK activator.
Our study demonstrates that resveratrol exerts cardioprotective effects through AMPK -Kir6.2/K-ATP signal pathway and Kir6.2-containing K-ATP channel is required for cardioprotection of resveratrol.
PMCID: PMC3916794  PMID: 24498880
Resveratrol; ATP-sensitive potassium channel; Kir6.2; Myocardial Ischemia/reperfusion; 5′-AMP-activated protein kinase
7.  Bilateral C1–C2 Transarticular Screw and C1 Laminar Hook Fixation and Bone Graft Fusion for Reducible Atlantoaxial Dislocation: A Seven-Year Analysis of Outcome 
PLoS ONE  2014;9(1):e87676.
Bilateral C1-2 transarticular screw and C1 laminar hook fixation was developed on the basis of transarticular screws fixation. The modified technique has showed a better biomechanical stability than established techniques in previous study. However, long-term (minimum follow-up 7 years) outcomes of patients with reducible atlantoaxial dislocation who underwent this modified fixation technique have not still been reported.
A retrospective study was conducted to evaluate the outcome of 36 patients who underwent this modified technique. Myelopathy was assessed using the Ranawat myelopathy score and Myelopathy Disability Index. Pain scores were assessed using Visual Analogue Scale. Radiological imaging was assessed and the following data were extracted: the atlantodental intervals, the space available for cord, presence of spinal cord signal change on T2 weighted image, C1–C2 angle, C2–C7 angle and fusion rates.
All patients achieved a minimum seven-year follow up. 95% patients with neck and suboccipital pain improved after surgery; in their Visual Analogue pain scores, there was a greater than 50% improvement in their VAS scores with a drop of 5 points on the VAS (P<0.05). 92% of patients improved in the Ranawat myelopathy grade; the Myelopathy Disability Index assessment showed a preoperative mean score of 35.62 with postoperative mean 12.75(P<0.05). There was not any significant atlantoaxial instability at each follow-up time. The space available for cord increased in all patients. Postoperative sagittal kyphosis of the subaxial spine was not observed. After six months after surgery, bone grafts of all patients were fused. No complications related to surgery were found in the period of follow-up.
The long-term outcomes of this case series demonstrate that under the condition of thorough preoperative preparations, bilateral C1–C2 transarticular screw and C1 laminar hook fixation and bone graft fusion is a reliable posterior atlantoaxial fusion technique for reducible atlantoaxial dislocation.
PMCID: PMC3909196  PMID: 24498163
8.  Towards photonic quantum simulation of ground states of frustrated Heisenberg spin systems 
Scientific Reports  2014;4:3583.
Photonic quantum simulators are promising candidates for providing insight into other small- to medium-sized quantum systems. Recent experiments have shown that photonic quantum systems have the advantage to exploit quantum interference for the quantum simulation of the ground state of Heisenberg spin systems. Here we experimentally characterize this quantum interference at a tuneable beam splitter and further investigate the measurement-induced interactions of a simulated four-spin system by comparing the entanglement dynamics using pairwise concurrence. We also study theoretically a four-site square lattice with next-nearest neighbor interactions and a six-site checkerboard lattice, which might be in reach of current technology.
PMCID: PMC3884522  PMID: 24394808
9.  Characterization of integrons among Escherichia coli in a region at high incidence of ESBL-EC 
Objective : The aim of study was to investigate the distribution of the integrons in Escherichia coli (E. coli) isolates, and analyze the possible relationship between the antimicrobial resistance profiles and the integrons.
Methods : The antimicrobial profiles of 376 E. coli strains were analysed by disk diffusion test. The integron genes and variable regions were detected by PCR. Some amplicons were sequenced to determine the gene cassettes style.
Results : Of 376 isolates, 223 isolates (59.3%) were confirmed as ESBL-EC. Comparison to ESBL-negative E. coli, the high rates of resistance to the third and fourth generation of cephalosporins, penicillins and amikacin were found in ESBL-EC. Only class 1 was integron detected in the isolates, and the prevalence of it was 66.5%. It was commonly found in ESBL-EC (77.6%, 173/223), which was higher than that of ESBL-negative E. coli (50.3%, 77/153) (p<0.001). Six different genes cassettes were detected in this study and were classified into three groups: dfr17-aadA5, dfrA12-aadA2 and aacA4-CmlA1. Additionally, more than one gene array harboured in 13.9% isolates of ESBL-EC, while in 9.1% isolates of ESBL-negative E.coli.
Conclusion : The high incidence of ESBL-EC with resistance to multiple antibiotics were detected in the isolates from Blood stream infection (BSI). More resistant gene cassettes in ESBL-EC may partially underlie the high resistance to amikacin, while no relation exists between the high incidence of ESBL-EC and classes 1~ 3 integrons in this region.
PMCID: PMC3955567  PMID: 24639856
Blood stream infection; ESBL-EC; Integron; Gene cassette.
10.  Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy 
PLoS ONE  2013;8(12):e83059.
To investigate the association of Mannose-binding lectin (MBL) and the MBL2 gene with type 2 diabetes and diabetic nephropathy and the influence of MBL2 polymorphisms on serum MBL levels.
The study population included 675 type 2 diabetic patients with or without nephropathy and 855 normoglycemic controls. The single nucleotide polymorphisms (SNPs) of rs1800450, rs1800451, and rs11003125 of the MBL2 gene were determined by the Multiplex Snapshot method. Serum MBL levels were measured by enzyme-linked immune sorbent assay.
Rs1800450 and rs11003125 SNPs demonstrated strong linkage disequilibrium in the study population (r2 = 0.97). The haplotypes constructed from the G allele of rs1800450 and the C allele of rs11003125 increased the risk for type 2 diabetes (OR = 1.2, 95% CI = 1.1–1.4, P = 0.01). For rs1800450, GG and GA genotypes were associated with type 2 diabetes (P = 0.02, 0.01, respectively). For rs11003125, the GC genotype frequency was significantly different between patients and controls (18.1% vs. 24.9%, P = 0.001). Analyses of genotypes and allele frequency distributions among patients with normal UAE, microalbuminuria, and macroalbuminuria showed that there was no obvious evidence of association between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels.
The rs1800450 and rs11003125 SNPs of the MBL2 gene have strong linkage disequilibrium and are associated with type 2 diabetes in the North Chinese Han population. No association was observed between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels. An association between elevated serum MBL and diabetic nephropathy was also observed.
PMCID: PMC3869742  PMID: 24376633
11.  A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family 
To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND).
Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken.
Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids.
A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation.
PMCID: PMC3874509  PMID: 24392318
Norrie disease; pseudoglioma; mutation; Chinese
12.  Diapause, signal and molecular characteristics of overwintering Chilo suppressalis (Insecta: Lepidoptera: Pyralidae) 
Scientific Reports  2013;3:3211.
Diapause is a complex and dynamic process. Chilo suppressalis, an important rice pest in Asia enters facultative diapause as larvae. Our results demonstrated in Yangzhou, China, diapause was initiated between September 4 and 12, 2010. After diapause termination, C. suppressalis remained in quiescence in the field for as long as three months. The average time between collection of field larvae of C. suppressalis and their pupation decreased as the season progressed from fall to next spring. Unexpectedly, the pupated ratio of female to male in the initiation of diapause was 0.22. The abundance of hsp90, hsp70, hsp60 and CsAQP1 all peaked on January 8 or 15, 2011. Nitric oxide (NO) is a secondary messenger that is positively correlated with the diapause of C. suppressalis. Among several geographically separated populations of C. suppressalis, there are no significant differences in the mRNA levels of hsp70, hsp60 or CsAQP1.
PMCID: PMC3827604  PMID: 24226906
13.  Importance of b value in diffusion weighted imaging for the diagnosis of pancreatic cancer 
AIM: To investigate the use of multi-b-value diffusion-weighted imaging in diagnosing pancreatic cancer.
METHODS: We retrospectively analyzed 33 cases of pancreatic cancer and 12 cases of benign pancreatic tumors at the Second Affiliated Hospital of Kunming Medical University from December 2008 to January 2011. The demographic characteristics, clinical presentation, routine magnetic resonance imaging and diffusion weighted imaging (DWI) features with different b values were reviewed. Continuous data were expressed as mean ± SD. Comparisons between pancreatic cancer and benign pancreatic tumors were performed using the Student’s t test. A probability of P < 0.05 was considered statistically significant.
RESULTS: Thirty-three patients with pancreatic cancer were identified. The mean age at diagnosis was 60 ± 5.6 years. The male: female ratio was 21:12. Twenty cases were confirmed by surgical resection and 13 by biopsy of metastases. T1 weighted images demonstrated a pancreatic head mass in 16 patients, a pancreatic body mass in 10 cases, and a pancreatic tail mass with pancreatic atrophy in 7 cases. Eight patients had hepatic metastases, 13 had invasion or envelopment of mesenteric vessels, 4 had bone metastases, and 8 had lymph node metastases. DWI demonstrated an irregular intense mass with unclear margins. Necrotic tissue demonstrated an uneven low signal. A b of 1100 s/mm2 was associated with a high intensity signal with poor anatomical delineation. A b of 700 s/mm2 was associated with apparent diffusion coefficients (ADCs) that were useful in distinguishing benign and malignant pancreatic tumors (P < 0.05). b values of 50, 350, 400, 450 and 1100 s/mm2 were associated with ADCs that did not differentiate the two tumors.
CONCLUSION: Low b value images demonstrated superior anatomical details when compared to high b value images. Tumor tissue definition was high and contrast with the surrounding tissues was good. DWI was useful in diagnosing pancreatic cancer.
PMCID: PMC3801382  PMID: 24151395
Pancreatic cancer; Magnetic resonance imaging; b value; Apparent diffusion coefficient; Diffusion weighted imaging
14.  Increased Risk of Primary Sjögren's Syndrome in Female Patients with Thyroid Disorders: A Longitudinal Population-Based Study in Taiwan 
PLoS ONE  2013;8(10):e77210.
A number of reports have indicated an association between thyroid diseases and primary Sjögren's syndrome (pSS). However, fewer studies have investigated whether the presence of thyroid diseases is associated with increased risk of developing pSS. Thus, the aim of our study was to use a nationwide health claims database to explore the prevalence and risk of pSS in female patients with thyroid diseases.
From the Registry of Catastrophic Illness database in the National Health Insurance Research Database in Taiwan, we identified 389 female patients with a diagnosis of pSS from 2005 to 2010. We also obtained 1945 control subjects frequency-matched on sex, 10-year age interval, and year of index date from the Longitudinal Health Insurance Database (LHID2000). Both groups were retrospectively traced back to a period of eight years to obtain diagnosis of thyroid diseases prior to index date.
A significantly higher risk of pSS was associated with the presence of thyroid diseases (adjusted odds ratio (AOR) = 2.1, 95% confidence interval (CI) = 1.6–2.9). Among the sub-categories of thyroid diseases, patients with thyroiditis (AOR = 3.6, 95% CI = 1.7–7.5), thyrotoxicosis (AOR = 2.5, 95% CI = 1.6–3.8), and unspecified hypothyroidism (AOR = 2.4, 95% CI = 1.2–4.6), and simple and unspecified goiter (AOR = 2.0, 95% CI = 1.3–3.3) were significantly associated with increased risk of pSS. The associations were generally stronger in the mid-forties to mid-sixties age group, except in patients with unspecified hypothyroidism.
The risk of pSS was significantly increased in female patients with thyroid diseases, particularly those in their mid-forties to mid-sixties. An increased awareness of the possibility of pSS in perimenopausal females with thyroid diseases is important to preserve their quality of life and to avoid comorbidity.
PMCID: PMC3799635  PMID: 24204772
15.  Targeted Delivery of an Antigenic Peptide to the Endoplasmic Reticulum: Application for Development of a Peptide Therapy for Ankylosing Spondylitis 
PLoS ONE  2013;8(10):e77451.
The development of suitable methods to deliver peptides specifically to the endoplasmic reticulum (ER) can provide some potential therapeutic applications of such peptides. Ankylosing spondylitis (AS) is strongly associated with the expression of human leukocytic antigen-B27 (HLA-B27). HLA-B27 heavy chain (HC) has a propensity to fold slowly resulting in the accumulation of misfolded HLA-B27 HC in the ER, triggering the unfolded protein response, and forming a homodimer, (B27-HC)2. Natural killer cells and T-helper 17 cells are then activated, contributing to the major pathogenic potentials of AS. The HLA-B27 HC is thus an important target, and delivery of an HLA-B27-binding peptide to the ER capable of promoting HLA-B27 HC folding is a potential mechanism for AS therapy. Here, we demonstrate that a His6-ubiquitin-tagged Tat-derived peptide (THU) can deliver an HLA-B27-binding peptide to the ER promoting HLA-B27 HC folding. The THU-HLA-B27-binding peptide fusion protein crossed the cell membrane to the cytosol through the Tat-derived peptide. The HLA-B27-binding peptide was specifically cleaved from THU by cytosolic ubiquitin C-terminal hydrolases and subsequently transported into the ER by the transporter associated with antigen processing. This approach has potential application in the development of peptide therapy for AS.
PMCID: PMC3796468  PMID: 24155957
16.  Mass spectrometry (LC-MS/MS) identified proteomic biosignatures of breast cancer in proximal fluid 
Journal of proteome research  2012;11(10):5034-5045.
We have begun an early phase of biomarker discovery in three clinically important types of breast cancer using a panel of human cell lines: HER2 positive, HER2 negative and hormone receptor positive and triple negative (HER2−, ER−, PR−). We identified and characterized the most abundant secreted, sloughed, or leaked proteins released into serum free media from these breast cancer cell lines using a combination of protein fractionation methods before LC-MS/MS mass spectrometry analysis. A total of 249 proteins were detected in the proximal fluid of 7 breast cancer cell lines. The expression of a selected group of high abundance and/or breast cancer specific potential biomarkers including thromobospondin 1, galectin-3 binding protein, cathepsin D, vimentin, zinc-α2-glycoprotein, CD44, and EGFR from the breast cancer cell lines and in their culture media were further validated by Western blot analysis. Interestingly, mass spectrometry identified a cathepsin D protein single-nucleotide polymorphism (SNP) by alanine to valine replacement from the MCF-7 breast cancer cell line. Comparison of each cell line media proteome displayed unique and consistent biosignatures regardless of the individual group classifications demonstrating the potential for stratification of breast cancer. Based on the cell line media proteome, predictive Tree software was able to categorize each cell line as HER2 positive, HER2 negative and hormone receptor positive and triple negative based on only two proteins, muscle fructose 1,6-bisphosphate aldolase and keratin 19. In addition, the predictive Tree software clearly identified MCF-7 cell line overexpresing the HER2 receptor with the SNP cathepsin D biomarker.
PMCID: PMC3521600  PMID: 22934887
breast cancer; biomarkers; blood assay; proteomics; mass spectrometry; single-nucleotide polymorphism (SNP); HER2; triple negative; proximal fluid
17.  Influence of Severity of Anemia on Clinical Findings in Infants with Sickle Cell Anemia: Analyses from the BABY HUG Study 
Pediatric blood & cancer  2011;59(4):675-678.
Clinical complications of sickle cell anemia begin in infancy. BABY HUG (, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9–18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry.
Infants were categorized by: 1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9 to12 months old: <8.0 gm/dL and >10.0gm/dL; 12 to 18 months old: <8.1 gm/dL and >9.9gm/dL) and 2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n=25), PL HiHb (n=27), hydroxyurea (HU) LoHb (n=21), and HU HiHb (n=18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup.
Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings.
Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.
PMCID: PMC3337342  PMID: 22190441
Sickle Cell Anemia; Hydroxyurea; Acute Chest Syndrome; Pain; Transcranial Doppler; Renal; Spleen
18.  The Relationship between Intestinal Motility and Interstitial Cells of Cajal in Nonalcoholic Fatty Liver Mice 
Hepatitis Monthly  2013;13(10):e13674.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in western world. However, NAFLD shows an increasing trend in China every year, which has attracted the attention of national health authorities. The previous studies have shown that NAFLD caused severe gastrointestinal motor disorders, but little is known about the interstitial cells of Cajal (ICC) role in gastrointestinal motor disorders.
The aim of this study was to observe the ICC in jejunum of nonalcoholic fatty liver mice by immunohistochemistry and assessed the relationship between intestinal motility and ICC.
Materials and Methods
Thirty five Sprague-Dawley (SD) rats were randomly divided into nonalcoholic fatty liver (n = 25) and control groups (n = 10), rats were housed individually in cages and had free access to food and water, nonalcoholic fatty liver group was duplicated by high-fat diet (consisted of ordinary food, 20 g/kg cholesterol and 100 g/kg fat) feeding. Dextran blue-2000 was used to monitor the intestinal motility. The proximal small intestine was harvested to investigate the C-kit positive ICC. The hepatic tissue slices were used for pathological observation.
Nonalcoholic fatty liver disease was successfully established. The intestinal motility in nonalcoholic fatty liver group (49.5 ± 10.9) was weaker compared to the control group (57.3 ± 8.9), P < 0.05. The rate of ICC also have shown statistically significant differences between nonalcoholic fatty liver (4.87 ± 2.97/mm 2) and control groups (6.54 ± 3.13/mm 2), P < 0.05.
ICC may be related to the intestinal motility in nonalcoholic fatty liver mice.
PMCID: PMC3842523  PMID: 24348640
Nonalcoholic Fatty Liver; Interstitial Cells of Cajal; Intestinal Motility
19.  Computational prediction of associations between long non-coding RNAs and proteins 
BMC Genomics  2013;14:651.
Though most of the transcripts are long non-coding RNAs (lncRNAs), little is known about their functions. lncRNAs usually function through interactions with proteins, which implies the importance of identifying the binding proteins of lncRNAs in understanding the molecular mechanisms underlying the functions of lncRNAs. Only a few approaches are available for predicting interactions between lncRNAs and proteins. In this study, we introduce a new method lncPro.
By encoding RNA and protein sequences into numeric vectors, we used matrix multiplication to score each RNA–protein pair. This score can be used to measure the interactions between an RNA–protein pair. This method effectively discriminates interacting and non-interacting RNA–protein pairs and predicts RNA–protein interactions within a given complex. Applying this method on all human proteins, we found that the long non-coding RNAs we collected tend to interact with nuclear proteins and RNA-binding proteins.
Compared with the existing approaches, our method shortens the time for training matrix and obtains optimal results based on the model being used. The ability of predicting the associations between lncRNAs and proteins has also been enhanced. Our method provides an idea on how to integrate different information into the prediction process.
PMCID: PMC3827931  PMID: 24063787
Long non-coding RNA; RNA–protein interaction; Computation
20.  The Neuroprotection of Hydrogen Sulfide Against MPTP-Induced Dopaminergic Neuron Degeneration Involves Uncoupling Protein 2 Rather Than ATP-Sensitive Potassium Channels 
Antioxidants & Redox Signaling  2012;17(6):849-859.
Aims: Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized to protect neurons from overexcitation by enhancing the activity of the adenosine triphosphate-sensitive potassium (K-ATP) channel. However, no direct evidence supports that the K-ATP channel contributes to the neuroprotective effect of H2S in neurodegeneration. Herein, wild-type and Kir6.2 knockout (Kir6.2−/−) mice were used to establish the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD) so as to investigate the involvement of K-ATP channels in the neuroprotection of H2S. Results: Systemic administration of sodium hydrosulfide (NaHS) (an H2S donor, 5.6 mg/kg/day) for 7 days rescued MPTP-induced loss of dopaminergic (DA) neurons in substantia nigra compacta of both Kir6.2+/+ and Kir6.2−/− mice. Consistently, NaHS (100 μM) protected primary mesencephalic neurons against 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity in both genotypes. We further found that deficiency of mitochondrial uncoupling protein 2 (UCP2), which reduces reactive oxygen species (ROS) production and functions as upstream to the K-ATP channel in determining vulnerability of DA neurons, abolished the protective effects of H2S against either DA neuron degeneration in the PD mouse model or MPP+-induced injury in primary mesencephalic neurons. Rationally, UCP2 evokes mild uncoupling, which in turn diminishes ROS accumulation in DA neurons. Furthermore, H2S exerted neuroprotective effect via enhancing UCP2-mediated antioxidation and subsequently suppressing ROS-triggered endoplasmic reticulum stress as well as ultimately inhibiting caspase 12-induced neuronal apoptosis. Innovation and Conclusion: H2S protects DA neurons against degeneration in a UCP2 rather than Kir6.2/K-ATP channel-dependent mechanism, which will give us an insight into the potential of H2S in terms of opening up new therapeutic avenues for PD. Antioxid. Redox Signal. 17, 849–859.
PMCID: PMC3392622  PMID: 22360462
21.  Practice guidelines for ultrasound-guided percutaneous microwave ablation for hepatic malignancy 
Primary liver cancer and liver metastases are among the most frequent malignancies worldwide, with an increasing number of new cases and deaths every year. Traditional surgery is only suitable for a limited proportion of patients and imaging-guided percutaneous thermal ablation has achieved optimistic results for management of hepatic malignancy. This synopsis outlines the first clinical practice guidelines for ultrasound-guided percutaneous microwave ablation therapy for hepatic malignancy, which was created by a joint task force of the Society of Chinese Interventional Ultrasound. The guidelines aim at standardizing the microwave ablation procedure and therapeutic efficacy assessment, as well as proposing the criteria for the treatment candidates.
PMCID: PMC3761095  PMID: 24023485
Practice guidelines; Microwave radiation; Catheter ablation; Liver cancer; Ultrasound
22.  Aspirin attenuates angiotensin II-induced inflammation in bone marrow mesenchymal stem cells via the inhibition of ERK1/2 and NF-κB activation 
Biomedical Reports  2013;1(6):930-934.
Angiotensin II (Ang II) is a peptide hormone that plays a critical role in numerous physiological and pathophysiological processes. It is also commonly used as an inducer for the directional differentiation of bone marrow mesenchymal stem cells (bmMSCs). Previous studies demonstrated that Ang II induces inflammatory responses in endothelial cells, smooth muscle cells and fibroblasts. Aspirin is generally used as analgesic, antipyretic and occasionally anti-inflammatory medication. Whether aspirin suppresses inflammatory responses in bmMSCs has not been elucidated. In this study, we investigated the effect of aspirin on Ang II-induced inflammation in bmMSCs. Our results demonstrated that Ang II (10 nM-10 μM) increased the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-6 from bmMSCs in a dose-dependent manner. This result was further confirmed by a reverse transcription-polymerase chain reaction (RT-PCR) assay, which demonstrated a dose-dependent increase in the mRNA expression of TNF-α, IL-6, IL-1β and monocyte chemotactic protein-1 (MCP-1) in bmMSCs following exposure to Ang II. Furthermore, it was also observed that Ang II increased the expression of phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) and phospho-nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-p65 in bmMSCs. The application of aspirin (0.1 mM) significantly inhibited the activation of ERK1/2 and NF-κB, the expression of TNF-α, IL-6, IL-1β and MCP-1 genes and the secretion of TNF-α and IL-6. Our findings indicated that aspirin may attenuate Ang II-induced inflammation in bmMSCs via the inhibition of ERK1/2 and NF-κB activation.
PMCID: PMC3917042  PMID: 24649055
aspirin; angiotensin II; bone marrow mesenchymal stem cells; inflammation; extracellular signal-regulated kinase 1/2; nuclear factor κ-light-chain-enhancer of activated B cells
23.  Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli 
OncoTargets and therapy  2013;6:1129-1138.
Overexpression of the sonic hedgehog (SHH) signaling pathway is an essential characteristic of pancreatic cancer stem cells (PCSCs) and arsenic trioxide (ATO) is described as a SHH inhibitor. This study evaluates whether ATO has the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins.
Cell counting kit-8 and flow cytometry were used for analyzing apoptosis in cells in vitro. The animal model was an athymic nude mouse model bearing subcutaneous xenografts of SW1990 pancreatic cancer cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry were used for tumor tissue analysis. The interaction between Gli1 and ATO was examined by a confocal system and an ultraviolet absorption spectrum assay.
ATO induced apoptosis in pancreatic cancer cells, especially CD24+CD44+ cells in vitro. Combination treatment of ATO and low dose gemcitabine inhibited tumor growth by 60.9% (P = 0.004), and decreased the expression of CD24, CD44, and aldehyde dehydrogenase 1 family, member A1 significantly in vivo. ATO changed the structure of the recombinant Gli1 zinc finger peptides in a cell-free condition and the binding action of ATO to recombinant Gli1 was observed in cultured pancreatic cancer cells.
ATO may have the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins in vitro and in vivo.
PMCID: PMC3753152  PMID: 23990729
pancreatic cancer; stem cells; gemcitabine; arsenic trioxide; sonic hedgehog; Gli
24.  Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection for circumferential mixed hemorrhoids 
AIM: To identify a more effective treatment protocol for circumferential mixed hemorrhoids.
METHODS: A total of 192 patients with circumferential mixed hemorrhoids were randomized into the treatment group, where they underwent Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection, or the control group, where traditional external dissection and internal ligation were performed. Postoperative recovery and complications were monitored.
RESULTS: The time to wound healing was 12.96 ± 2.25 d in the treatment group shorter than 19.58 ± 2.71 d in the control group. Slight pain rate was 58.3% in the treatment group higher than 22.9% in the control group; moderate pain rate was 33.3% in the treatment group lower than 56.3% in the control group severe pain rate was 8.4% in the treatment group lower than 20.8% in the control group. No edema rate was 70.8% in the treatment group higher than 43.8% in the control group; mild local edema rate was 26% in the treatment group lower than 39.6% in the control group obvious local edema was 3.03% in the treatment group lower than 16.7% in the control group. No stenosis rate was 85.4% in the treatment group higher than 63.5% in the control group; moderate stenosis rate was 14.6% in the treatment group Lower than 27.1% in the control group severe anal stenosis rate was 0% in the treatment group lower than 9.4% in the control group.
CONCLUSION: Milligan-Morgan hemorrhoidectomy with anal cushion suspension and partial internal sphincter resection is the optimal treatment for circumferential mixed hemorrhoids and can be widely applied in clinical settings.
PMCID: PMC3740434  PMID: 23946609
Milligan-Morgan hemorrhoidectomy; Mixed hemorrhoids; Anal cushion; Internal sphincter
25.  Production of ACAT1 56-kDa isoform in human cells via trans-splicing involving the ampicillin resistance gene 
Cell Research  2013;23(8):1007-1024.
Trans-splicing, a process involving the cleavage and joining of two separate transcripts, can expand the transcriptome and proteome in eukaryotes. Chimeric RNAs generated by trans-splicing are increasingly described in literatures. The widespread presence of antibiotic resistance genes in natural environments and human intestines is becoming an important challenge for public health. Certain antibiotic resistance genes, such as ampicillin resistance gene (Ampr), are frequently used in recombinant plasmids. Until now, trans-splicing involving recombinant plasmid-derived exogenous transcripts and endogenous cellular RNAs has not been reported. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key enzyme involved in cellular cholesterol homeostasis. The 4.3-kb human ACAT1 chimeric mRNA can produce 50-kDa and 56-kDa isoforms with different enzymatic activities. Here, we show that human ACAT1 56-kDa isoform is produced from an mRNA species generated through the trans-splicing of an exogenous transcript encoded by the antisense strand of Ampr (asAmp) present in common Ampr-plasmids and the 4.3-kb endogenous ACAT1 chimeric mRNA, which is presumably processed through a prior event of interchromosomal trans-splicing. Strikingly, DNA fragments containing the asAmp with an upstream recombined cryptic promoter and the corresponding exogenous asAmp transcripts have been detected in human cells. Our findings shed lights on the mechanism of human ACAT1 56-kDa isoform production, reveal an exogenous-endogenous trans-splicing system, in which recombinant plasmid-derived exogenous transcripts are linked with endogenous cellular RNAs in human cells, and suggest that exogenous DNA might affect human gene expression at both DNA and RNA levels.
PMCID: PMC3731566  PMID: 23835473
trans-splicing; chimeric RNA; ampicillin resistance gene; recombinant plasmid; ACAT1

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