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1.  Recurrent abdominal liposarcoma: Analysis of 19 cases and prognostic factors 
AIM: To evaluate the clinical outcome of re-operation for recurrent abdominal liposarcoma following multidisciplinary team cooperation.
METHODS: Nineteen consecutive patients who had recurrent abdominal liposarcoma underwent re-operation by the retroperitoneal sarcoma team at our institution from May 2009 to January 2012. Patient demographic and clinical data were reviewed retrospectively. Multidisciplinary team discussions were held prior to treatment, and re-operation was deemed the best treatment. The categories of the extent of resection were as follows: gross total resection (GTR), palliative resection and partial resection. Surgical techniques were divided into discrete lesion resection and combined contiguous multivisceral resection (CMR). Tumor size was determined as the largest diameter of the specimen. Patients were followed up at approximately 3-monthly intervals. For survival analysis, a univariate analysis was performed using the Kaplan-Meier method, and a multivariate analysis was performed using the Cox proportional hazards model.
RESULTS: Nineteen patients with recurrent abdominal liposarcoma (RAL) underwent 32 re-operations at our institute. A total of 51 operations were reviewed with a total follow-up time ranging from 4 to 120 (47.4 ± 34.2) mo. The GTR rate in the CMR group was higher than that in the non-CMR group (P = 0.034). CMR was positively correlated with intra-operative bleeding (correlation coefficient = 0.514, P = 0.010). Six cases with severe postoperative complications were recorded. Patients with tumor sizes greater than 20 cm carried a significant risk of profuse intra-operative bleeding (P = 0.009). The ratio of a highly malignant subtype (dedifferentiated or pleomorphic) in recurrent cases was higher compared to primary cases (P = 0.027). Both single-factor survival using the Kaplan-Meier model and multivariate analysis using the Cox proportional hazards model showed that overall survival was correlated with resection extent and pathological subtype (P < 0.001 and P = 0.02), however, relapse-free interval (RFI) was only correlated with resection extent (P = 0.002).
CONCLUSION: Close follow-up should be conducted in patients with RAL. Early re-operation for relapse is preferred and gross resection most likely prolongs the RFI.
PMCID: PMC3703193  PMID: 23840151
Overall survival; Recurrent abdominal liposarcoma; Relapse-free interval
2.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Results from this study improve the understanding of the genetic basis for breast cancer.
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
3.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
PMCID: PMC3658167  PMID: 23535825
4.  Total Chemical Synthesis of Dengue 2 Virus Capsid Protein via Native Chemical Ligation: Role of the Conserved Salt-bridge1 
Bioorganic & medicinal chemistry  2013;21(12):3443-3449.
The dengue capsid protein C is a highly basic alpha-helical protein of ~100 amino acid residues that forms an emphipathic homodimer to encapsidate the viral genome and to interact with viral membranes. The solution structure of dengue 2 capsid protein C (DEN2C) has been determined by NMR spectroscopy, revealing a large dimer interface formed almost exclusively by hydrophobic residues. The only acidic residue (Glu87) conserved in the capsid proteins of all four serotypes of dengue virus forms a salt bridge with the side chains of Lys45 and Arg55′. To understand the structural and functional significance of this conserved salt bridge, we chemically synthesized an N-terminally truncated form of DEN2C (WTDEN2C) and its salt bridge-void analog E87ADEN2C using the native chemical ligation technique developed by Kent and colleagues. Comparative biochemical and biophysical studies of these two synthetic proteins using circular dichroism spectroscopy, fluorescence polarization, protein thermal denaturation, and proteolytic susceptibility assay demonstrated that the conserved salt bridge contributed to DEN2C dimerization and stability as well as its resistance to proteolytic degradation. Our work provided insight into the role of a fully conserved structural element of the dengue capsid protein C and paved the way for additional functional studies of this important viral protein.
PMCID: PMC3726205  PMID: 23673222
Dengue capsid protein; Native chemical ligation; Solid phase peptide synthesis; Salt bridge; DEN2C
5.  Evidence for trapped surface bubbles as the cause for the twinkling artifact in ultrasound imaging 
Ultrasound in medicine & biology  2013;39(6):1026-1038.
The mechanism of the twinkling artifact (TA) that occurs during Doppler ultrasound imaging of kidney stones was investigated. The TA expresses itself in Doppler images as time-varying color. To quantitatively define the TA, beamforming and Doppler processing were performed on raw per-channel radio-frequency (RF) data collected when imaging human kidney stones in vitro. Suppression of twinkling by an ensemble of computer generated replicas of a single RF received signal demonstrated that the TA arises from variability among the acoustic signals and not from electronic signal capture or processing. This variability was found to be random. Its suppression by elevated static pressure and return when the pressure was released suggest the presence of bubbles on the stone surface is the mechanism that gives rise to the TA.
PMCID: PMC3646957  PMID: 23562014
ultrasound imaging; twinkling artifact; kidney stones; Doppler processing; overpressure; microbubbles
6.  Post-diagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project 
Vitamin supplement use after breast cancer diagnosis is common, but little is known about long-term effects on recurrence and survival. We examined post-diagnosis supplement use and risk of death or recurrence in the After Breast Cancer Pooling Project, a consortium of 4 cohorts of 12,019 breast cancer survivors from the United States and China.
Post-treatment supplement use (Vitamins A, B, C, D, E, and multivitamins) was assessed one to five years post-diagnosis. Associations with risk of recurrence, breast cancerspecific mortality, or total mortality were analyzed in Cox proportional hazards models separately by cohort. Individual cohort results were combined using random effects metaanalysis. Interactions with smoking, treatment, and hormonal status were examined.
In multivariate models, vitamin E was associated with a decreased risk of recurrence (RR: 0.88; 95% CI: 0.79–0.99) and vitamin C with decreased risk of death (RR: 0.81; 95% CI: 0.72–0.92) However, when supplements were mutually adjusted, all associations were attenuated. There were no statistically significant associations with breast cancer mortality. Use of anti-oxidant supplements (multivitamins, vitamin C or E) was not associated with recurrence, but was associated with a 16% decreased risk of death (95% CI: 0.72–0.99). Additionally, vitamin D was associated with decreased risk of recurrence among ER positive, but not ER negative tumors (p-interaction=0.01).
In this large consortium of breast cancer survivors, post-treatment use of vitamin supplements was not associated with increased risk of recurrence or death. Post-treatment use of anti-oxidant supplements were associated with improved survival, but the associations with individual supplement were difficult to determine. Stratification by ER status and considering antioxidants as a group may be more clinically relevant when evaluating associations with cancer risk and mortality.
PMCID: PMC3698864  PMID: 23660948
breast cancer; vitamins; survival; mortality
7.  Damage Identification for Large Span Structure Based on Multiscale Inputs to Artificial Neural Networks 
The Scientific World Journal  2014;2014:540806.
In structural health monitoring system, little research on the damage identification from different types of sensors applied to large span structure has been done in the field. In fact, it is significant to estimate the whole structural safety if the multitype sensors or multiscale measurements are used in application of structural health monitoring and the damage identification for large span structure. A methodology to combine the local and global measurements in noisy environments based on artificial neural network is proposed in this paper. For a real large span structure, the capacity of the methodology is validated, including the decision on damage placement, the discussions on the number of the sensors, and the optimal parameters for artificial neural networks. Furthermore, the noisy environments in different levels are simulated to demonstrate the robustness and effectiveness of the proposed approach.
PMCID: PMC4058217  PMID: 24977207
8.  Voltage-independent sodium channels emerge for an expression of activity-induced spontaneous spikes in GABAergic neurons 
Molecular Brain  2014;7:38.
Cerebral overexcitation needs inhibitory neurons be functionally upregulated to rebalance excitation vs. inhibition. For example, the intensive activities of GABAergic neurons induce spontaneous spikes, i.e., activity-induced spontaneous spikes (AISS). The mechanisms underlying AISS onset remain unclear. We investigated the roles of sodium channels in AISS induction and expression at hippocampal GABAergic neurons by electrophysiological approach.
AISS expression includes additional spike capability above evoked spikes, and the full spikes in AISS comprise early phase (spikelets) and late phase, implying the emergence of new spikelet component. Compared with the late phase, the early phase is characterized as voltage-independent onset, less voltage-dependent upstroke and sensitivity to TTX. AISS expression and induction are independent of membrane potential changes. Therefore, AISS’s spikelets express based on voltage-independent sodium channels. In terms of AISS induction, the facilitation of voltage-gated sodium channel (VGSC) activation accelerates AISS onset, or vice versa.
AISS expression in GABAergic neurons is triggered by the spikelets based on the functional emergence of voltage-independent sodium channels, which is driven by intensive VGSCs’ activities.
PMCID: PMC4039334  PMID: 24886791
Action potential; Spontaneous spikes; Threshold potential; Sodium channel; Hippocampus; GABAergic neurons
9.  Pulsed electromagnetic field improves cardiac function in response to myocardial infarction 
Extracorporeal pulsed electromagnetic field (PEMF) has been shown the ability to improve regeneration in various ischemic episodes. Here, we examined whether PEMF therapy facilitate cardiac recovery in rat myocardial infarction (MI), and the cellular/molecular mechanisms underlying PEMF-related therapy was further investigated. The MI rats were exposed to active PEMF for 4 cycles per day (8 minutes/cycle, 30 ± 3 Hz, 5 mT) after MI induction. The data demonstrated that PEMF treatment significantly inhibited cardiac apoptosis and improved cardiac systolic function. Moreover, PEMF treatment increased capillary density, the levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor-1α in infarct border zone. Furthermore, the number and function of circulating endothelial progenitor cells were advanced in PEMF treating rats. In vitro, PEMF induced the degree of human umbilical venous endothelial cells tubulization and increased soluble pro-angiogenic factor secretion (VEGF and nitric oxide). In conclusion, PEMF therapy preserves cardiac systolic function, inhibits apoptosis and trigger postnatal neovascularization in ischemic myocardium.
PMCID: PMC4058309  PMID: 24936220
Pulsed electromagnetic field; cardiac function; angiogenesis; apoptosis; ischemic myocardium
10.  Tanshinone IIA Induces Apoptosis in Human Oral Cancer KB Cells through a Mitochondria-Dependent Pathway 
BioMed Research International  2014;2014:540516.
Tanshinone IIA (Tan IIA), an active phytochemical in the dried root of Salvia miltiorrhiza Bunge, has shown an antiproliferative activity on various human cancer cell lines including nasopharyngeal carcinoma cells. However, the effects of Tan IIA on human oral cancer cells are still unknown. This study aimed to investigate the antiproliferative effects of Tan IIA on human oral cancer KB cells and explored the possible underlying mechanism. Treatment of KB cells with Tan IIA suppressed cell proliferation/viability and induced cell death in a dose-dependent manner through sulforhodamine B colorimetric assay. Observation of cell morphology revealed the involvement of apoptosis in the Tan IIA-induced growth inhibition on KB cells. Cell cycle analysis showed a cell cycle arrest in G2/M phase on Tan IIA-treated cells. The dissipation of mitochondrial membrane potential observed by flow cytometry and the expression of activated caspases with the cleaved poly (ADP-ribose) polymerase under immunoblotting analysis indicated that Tan IIA-induced apoptosis in KB cells was mediated through the mitochondria-dependent caspase pathway. These observations suggested that Tan IIA could be a potential anticancer agent for oral cancer.
PMCID: PMC4036409  PMID: 24900970
11.  The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function 
Neuron  2013;78(3):433-439.
The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development.
PMCID: PMC3666354  PMID: 23664612
12.  Comorbidities and breast cancer survival: a report from the Shanghai Breast Cancer Survival Study 
We investigated the association of major comorbidities with breast cancer outcomes using the Shanghai Breast Cancer Survival Study, a population-based, prospective cohort study of Chinese women diagnosed with breast cancer.
Analyses included 4,664 women diagnosed with stage I-III incident breast cancer aged 20–75 years (median age=51) during 2002–2006. Women were interviewed at 3–11 months post-diagnosis (median=6.4) and followed up by in-person interviews and linkage with the vital statistics registry. Multivariable hazard ratios (HRs) and (95% confidence intervals (CIs)) for the associations of comorbidities with breast cancer outcomes were estimated using Cox regression models.
After a median follow-up of 5.3 years (range: 0.64–8.9), 647 women died (516 from breast cancer) and 632 recurrence/metastases were documented. The main comorbidities reported included: hypertension (22.4%), chronic gastritis (14.3%), diabetes mellitus (6.2%), chronic bronchitis/asthma (5.8%), coronary heart disease (5.0%), and stroke (2.2). Diabetes was associated with increased risk of total mortality (adjusted HR: 1.40 (1.06–1.85)) and non-breast cancer mortality (adjusted HR: 2.64 (1.63–4.27)), but not breast cancer-specific mortality (adjusted HR: 0.98 (0.68–1.41)), adjusting for socio-demographics, clinical characteristics, selected lifestyle factors, and other comorbidities. Women with a history of stroke had a non-significant increased risk of total mortality (adjusted HR: 1.42 (0.91–2.22)) and a significant increased risk of non-breast cancer mortality (adjusted HR: 2.52 (1.33–4.78)), but not breast cancer-specific mortality (adjusted HR: 0.78 (0.38–1.62)). Overall, none of the comorbidities investigated were significantly associated with recurrence.
In this large prospective cohort of breast cancer survivors, diabetes was significantly associated with increased risk of total and non-breast cancer mortality, and history of stroke was associated was associated with increased risk of non-breast cancer mortality.
PMCID: PMC3712758  PMID: 23605082
breast cancer; prognosis; survival; comorbidity
13.  Cell-Permeable 99mTc(CO3)-Labeled Fluorogenic Caspase 3 Substrate for Dual-Modality Detection of Apoptosis 
PMCID: PMC3998829  PMID: 19637160
Apoptosis; Caspase 3; Dual Modality; DEVD; Technetium99m; Gamma imaging; Optical Imaging
14.  LTP requires a reserve pool of glutamate receptors independent of subunit type 
Nature  2012;493(7433):495-500.
Long-term potentiation (LTP) of synaptic transmission is thought to be a key cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic tail of the AMPA receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In striking contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with dramatically decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.
PMCID: PMC3998843  PMID: 23235828
15.  A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk 
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.
Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10−4) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10−22). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10−24).
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
PMCID: PMC3627644  PMID: 23411593
16.  Cardioprotective activity of placental growth factor in a rat model of acute myocardial infarction: nanoparticle-based delivery versus direct myocardial injection 
To comparatively evaluate the cardioprotective activity of placental growth factor (PGF) delivered through direct injection and a nanoparticle-based system respectively and to study the underlying mechanisms in a rat model of acute myocardial infarction (AMI).
Poly lactic-co-glycolic acid (PLGA)-based PGF-carrying nanoparticles (PGF-PLGANPs) were created. The mean size and morphology of particles were analyzed with particle size analyzer and transmission electronic microscopy (TEM). Encapsulation efficiency and sustained-release dose curve were analyzed by ELISA. Sprague-Dawley rats were randomized into four groups (n = 10). While animals in the first group were left untreated as controls, those in the other 3 groups underwent surgical induction of AMI, followed by treatment with physiological saline, PGF, and PGF-PLGANPs, respectively. Cardiac function was evaluated by transthoracic echocardiography at 4 weeks after treatment. At 6 weeks, rats were sacrificed, infarction size was analyzed with Masson trichrome staining, and protein contents of TIMP-2, MT1-MMP and MMP-2 at the infarction border were determined by immunohistochemistry and western blotting analysis.
PGF was released for at least 15 days, showing successful preparation of PGF-PLGANPs. Coronary artery ligation successfully induced AMI. Compared to physiological saline control, PGF, injected to the myocardium either as a nude molecule or in a form of nanoparticles, significantly reduced infarction size, improved cardiac function, and elevated myocardial expression of TIMP-2, MT1-MMP, and MMP-2 (P < 0.05). The effect of PGF-PLGANPs was more pronounced than that of non-encapsulated PGF (P < 0.05).
Target PGF delivery to myocardium may improve cardiac function after AMI in rats. PLGA-based nanoparticles appear to be a better approach to delivery PGF. PGF exerts its cardioprotective effect at least partially through regulating metalloproteinase-mediated myocardial tissue remodeling.
PMCID: PMC4014437  PMID: 24742302
Placental growth factor; Acute myocardial infarction; Cardiac function; Nanoparticles-mediated drug delivery; Vicious ventricular remodeling
17.  Spatial-Temporal FDG-PET Features for Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemoradiotherapy 
To extract and study comprehensive spatial–temporal 18F-FDG PET features for the prediction of pathologic tumor response to neoadjuvant chemoradiotherapy (CRT) in esophageal cancer.
Methods and Materials
Twenty patients with esophageal cancer were treated with trimodality therapy (CRT plus surgery) and underwent FDG PET/CT scans both before (pre-CRT) and after (post-CRT) CRT. The two scans were rigidly registered. A tumor volume was semiautomatically delineated using a threshold of standardized uptake value (SUV) ≥ 2.5, followed by manual editing. Comprehensive features were extracted to characterize the SUV intensity distribution, spatial patterns (texture), tumor geometry, and associated changes resulting from CRT. The usefulness of each feature in predicting pathologic tumor response to CRT was evaluated using the area under the receiver operating characteristic curve (AUC).
The best traditional response measure was maximum SUV (SUVmax) decline (AUC 0.76). Two new intensity features (SUVmean decline and skewness) and three texture features (inertia, correlation, and cluster prominence) were found to be significant predictors with AUCs ≥ 0.76. According to these features, a tumor was more likely a responder when the mean SUV decline was larger, when there were relatively fewer voxels with higher SUVs pre-CRT, or when FDG uptake post-CRT was relatively homogeneous. All of the most accurate predictive features were extracted from the entire tumor rather than from the most active part of the tumor. For SUV intensity features and tumor size features, changes were more predictive than pre- or post-CRT assessments alone.
Spatial–temporal FDG PET features were found to be useful predictors of pathologic tumor response to neoadjuvant chemoradiotherapy in esophageal cancer. Key words: FDG PET/CT, Tumor response, Esophageal cancer, Quantitative image analysis
PMCID: PMC3606641  PMID: 23219566
FDG PET/CT; Tumor response; Esophageal cancer; Quantitative image analysis
18.  Prevalence of Anti-deamidated Gliadin Peptide Antibodies in Asian Patients With Irritable Bowel Syndrome 
Non-celiac gluten sensitivity has been increasingly recognized as a predisposing factor for irritable bowel syndrome (IBS)-like symptoms in Western populations where celiac disease (CD) is relatively common. In Asia where CD is rare, we wish to determine the prevalence of gluten protein associated serology in IBS patients, which has not been formally studied, and its relation to histological and human leukocyte antigen (HLA) markers.
We reviewed a consecutive cohort of Asian patients with IBS, who had undergone serologic testing for IgA against deamidated gliadin peptide antibodies (IgA DGP) and IgA anti-endomysium antibodies, and who also had duodenal biopsies during clinical workup. In addition, a subset of Chinese patients with positive serology was further tested for HLA-DQ2 and HLA-DQ8.
Of 186 patients, 34 (18%) were positive for IgA DGP; bloating, abdominal pain, belching and diarrhea were the most commonly reported symptoms but diarrhea as the most bothersome symptom was significantly more common in IgA DGP positive patients. Mildly increased intra-epithelial lymphocytes on duodenal biopsy was also more common (29% vs. 9%, P = 0.001). Nine of 21 Chinese patients tested as IgA DGP positive undertook HLA-DQ2/DQ8 testing, with only 2 being positive for HLA-DQ8. All patients with positive IgA DGP reported symptom improvement with gluten withdrawal.
We have described a series of Asian, mainly Chinese, patients with IBS who were tested positive for IgA DGP, and improved on a gluten exclusion diet. We believe this is the first report of non-celiac gluten sensitivity in Asia, a region where CD is uncommon.
PMCID: PMC4015193  PMID: 24840376
Asian; Celiac disease; Gliadin; Gluten sensitive enteropathy; Irritable bowel syndrome
19.  CRISPR/Cas9 mediated multiplex genome editing and heritable mutagenesis of BmKu70 in Bombyx mori 
Scientific Reports  2014;4:4489.
CRISPR/Cas9, a bacterial adaptive immune system derived genome-editing technique, has become to be one of the most compelling topics in biotechnology. Bombyx mori is an economically important insect and a model organism for studying lepidopteran and arthropod biology. Here we reported highly efficient and multiplex genome editing in B. mori cell line and heritable site-directed mutagenesis of Bmku70, which is required for NHEJ pathway and also related to antigen diversity, telomere length maintenance and subtelomeric gene silencing, using CRISPR/Cas9 system. We established a simple and practicable method and obtained several Bmku70 knockout B. mori lines, and showed that the frequency of HR was increased in embryos of the Bmku70 knockout B. mori. The mutant lines obtained in this study could be a candidate genetic resource for efficient knock-in and fundamental research of DNA repair in B. mori. We also provided a strategy and procedure to perform heritable genome editing of target genes with no significant phenotype effect.
PMCID: PMC3967148  PMID: 24671069
20.  Integer Programming-Based Method for Designing Synthetic Metabolic Networks by Minimum Reaction Insertion in a Boolean Model 
PLoS ONE  2014;9(3):e92637.
In this paper, we consider the Minimum Reaction Insertion (MRI) problem for finding the minimum number of additional reactions from a reference metabolic network to a host metabolic network so that a target compound becomes producible in the revised host metabolic network in a Boolean model. Although a similar problem for larger networks is solvable in a flux balance analysis (FBA)-based model, the solution of the FBA-based model tends to include more reactions than that of the Boolean model. However, solving MRI using the Boolean model is computationally more expensive than using the FBA-based model since the Boolean model needs more integer variables. Therefore, in this study, to solve MRI for larger networks in the Boolean model, we have developed an efficient Integer Programming formalization method in which the number of integer variables is reduced by the notion of feedback vertex set and minimal valid assignment. As a result of computer experiments conducted using the data of metabolic networks of E. coli and reference networks downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we have found that the developed method can appropriately solve MRI in the Boolean model and is applicable to large scale-networks for which an exhaustive search does not work. We have also compared the developed method with the existing connectivity-based methods and FBA-based methods, and show the difference between the solutions of our method and the existing methods. A theoretical analysis of MRI is also conducted, and the NP-completeness of MRI is proved in the Boolean model. Our developed software is available at “”
PMCID: PMC3961429  PMID: 24651476
21.  Active Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Regulates NMDA Receptor Mediated Postischemic Long-Term Potentiation (i-LTP) by Promoting the Interaction between CaMKII and NMDA Receptors in Ischemia 
Neural Plasticity  2014;2014:827161.
Active calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to take a critical role in the induction of long-term potentiation (LTP). Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR)-mediated postischemic long-term potentiation (NMDA i-LTP). Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs) at different time points following ischemia onset in vitro oxygen and glucose deprivation (OGD) ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min) or longer (25 min) OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia both in vitro OGD or in vivo photothrombotic lesion (PT) models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.
PMCID: PMC3964903  PMID: 24734203
22.  Interaction of Acetylcholinesterase with Neurexin-1β regulates Glutamatergic Synaptic stability in Hippocampal neurons 
Molecular Brain  2014;7:15.
Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses.
The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O–glycosylated neurexin-1β, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE.
Excessive glycosylated AChE could competitively disrupt a subset of the neurexin–neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration.
PMCID: PMC3973991  PMID: 24594013
Protein interaction; Glycosylation; Neurodegeneration; Synaptic apoptosis
23.  No Association between Ovarian Cancer Susceptibility Variants and Breast Cancer Risk among Chinese Women 
As breast and ovarian cancers may have similar etiologies, this study aimed to evaluate the hypothesis that breast cancer shares common genetic susceptibility variants with ovarian cancer.
Ten genetic variants in 9 loci were previously identified to be associated with ovarian cancer risk among Caucasian women; an additional 353 variants in high linkage disequilibrium (r2≥0.6) among Han Chinese were identified. Data were available from the Affymetrix Genome Wide Array (6.0) or MACH imputation for 25 and 78 common genetic variants (minor allele frequency (MAF) ≥0.05), respectively. Associations with breast cancer risk were evaluated by additive logistic regression models among 2, 918 breast cancer cases and 2, 324 controls.
No associations with breast cancer risk were evident for 103 ovarian cancer susceptibility variants in five loci. Four loci were not evaluated, as they included only rare variants (MAF<0.05).
Ovarian cancer susceptibility variants identified in Caucasian women were not associated with breast cancer risk among 5, 242 Chinese women.
These findings suggest that breast and ovarian cancer may not share common susceptibility variants among Chinese women.
PMCID: PMC3596432  PMID: 23292081
Genetic Variants; Breast Cancer; Ovarian Cancer
24.  The relationship between serum hypoxia-inducible factor 1α and coronary artery calcification in asymptomatic type 2 diabetic patients 
Hypoxia-inducible factor 1 (HIF-1), a master regulator of oxygen homeostasis, is a heterodimer consisting of HIF-1α and HIF-1β subunits, and is implicated in calcification of cartilage and vasculature. The goal of this study was to determine the relationship between serum HIF-1α with coronary artery calcification (CAC) in patients with type 2 diabetes.
The subjects were 405 (262 males, 143 females, age 51.3 ± 6.4 years) asymptomatic patients with type 2 diabetes mellitus. Serum HIF-1α and interleukin-6 (IL-6) levels were measured by ELISA. CAC scores were assessed by a 320-slice CT scanner. The subjects were divided into 4 quartiles depending on serum HIF-1α levels.
Average serum HIF-1α was 184.4 ± 66.7 pg/ml. Among patients with higher CAC scores, HIF-1α levels were also significantly increased (p <0.001). HIF-1α levels positively correlated with CRP, IL-6, UKPDS risk score, HbA1c, FBG, and CACS, but did not correlate with diabetes duration, age, and LDL. According to the multivariate analysis, HIF-1α levels significantly and independently predict the presence of CAC. ROC curve analysis showed that the serum HIF-1α level can predict the extent of CAC, but the specificity was lower than the traditional risk factors UKPDS and HbA1c.
As a marker of hypoxia, serum HIF-1α level may be an independent risk factor for the presence of CAC. These findings indicate that elevated serum HIF-1α may be involved in vascular calcification in patients with type 2 diabetes mellitus.
PMCID: PMC3938975  PMID: 24564828
Hypoxia-inducible factor 1α; Coronary artery calcification; Atherosclerosis; Type 2 diabetes mellitus
25.  Effects of Multimicronutrient Supplementation during Pregnancy on Postnatal Growth of Children under 5 Years of Age: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(2):e88496.
The beneficial effect of antenatal multiple micronutrients supplementation on infant birth outcomes has been proposed by previous meta-analyses. However, their benefits on postnatal health of children have not been summarized. A meta-analysis of randomized controlled trials was conducted to evaluate the effect of maternal multimicronutrient supplementation on postnatal growth of children under 5 years of age.
We searched both published and ongoing trials through the PubMed, EMBASE, CENTRAL (OVID platform), Web of Science, BIOSIS Previews, Chinese Science Citation Database, Scopus, ProQuest,, Chinese Biomedical Database, and WANFANG database for randomized controlled trials. Reference lists of included studies and relevant reviews were also reviewed for eligible studies. Standard mean difference (SMD) was employed as the index for continuous variables by using fixed effects models. Trend analysis by visual inspection was applied to evaluate the change of mean difference of weight and height between the groups over time.
Nine trials (12 titles) from nine different countries were retrieved for analysis. Pooled results showed that antenatal multimicronutrient supplementation increased child head circumference (SMD = 0.08, 95% CI: 0.00–0.15) compared with supplementation with two micronutrient or less. No evidence was found for the benefits of antenatal multimicronutrient supplementation on weight (P = 0.11), height (P = 0.66), weight-for-age z scores (WAZ) (P = 0.34), height-for-age z scores (HAZ) (P = 0.81) and weight-for-height z scores (WHZ) (P = 0.22). A positive effect was found on chest circumference based on two included studies.
Antenatal multimicronutrient supplementation has a significant positive effect on head circumference of children under 5 years. No impact of the supplementation was found on weight, height, WAZ, HAZ and WHZ.
PMCID: PMC3930526  PMID: 24586335

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