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1.  Early-Life Exposure to Bisphenol A Induces Liver Injury in Rats Involvement of Mitochondria-Mediated Apoptosis 
PLoS ONE  2014;9(2):e90443.
Exposure to bisphenol A (BPA), a monomer widely used to manufacture polycarbonate plastics, has been reported to be associated with abnormalities of liver function and hepatic damage. However, the molecular mechanism under the pathogenesis of hepatic injury is unclear. In this study, the effect of perinatal exposure to BPA at the reference dose of 50 µg/kg/day on the apoptotic index in the liver of rat offspring was investigated. Increased levels of ALT and enhanced cell apoptosis were observed in the liver of rat offspring at 15 and 21 weeks, and significantly increased activity of caspase-3 and caspase-9 and elevated levels of cytochrome c were also confirmed. In addition, significant change in the expression levels of Bcl-2 and Bax were found in BPA-treated offspring at 21 weeks. For in vitro experiments, liver mitochondria were isolated from neonatal rats and were treated with BPA. BPA treatment led to a significant increase in mitochondrial permeability transition. Moreover, the supernatant from BPA-treated mitochondria significantly increased apoptotic changes in nuclei isolated from liver tissue. In conclusion, the study demonstrates that BPA induces mitochondria-mediated apoptosis in hepatic cells, which may contribute to long-term hepatotoxicity induced by early-life exposure to BPA.
PMCID: PMC3938763  PMID: 24587367
2.  Differential mortality and the excess burden of end-stage renal disease among First Nations people with diabetes mellitus: a competing-risks analysis 
Diabetes-related end-stage renal disease disproportionately affects indigenous peoples. We explored the role of differential mortality in this disparity.
In this retrospective cohort study, we examined the competing risks of end-stage renal disease and death without end-stage renal disease among Saskatchewan adults with diabetes mellitus, both First Nations and non–First Nations, from 1980 to 2005. Using administrative databases of the Saskatchewan Ministry of Health, we developed Fine and Gray subdistribution hazards models and cumulative incidence functions.
Of the 90 429 incident cases of diabetes, 8254 (8.9%) occurred among First Nations adults and 82 175 (90.9%) among non–First Nations adults. Mean age at the time that diabetes was diagnosed was 47.2 and 61.6 years, respectively (p < 0.001). After adjustment for sex and age at the time of diabetes diagnosis, the risk of end-stage renal disease was 2.66 times higher for First Nations than non–First Nations adults (95% confidence interval [CI] 2.24–3.16). Multivariable analysis with adjustment for sex showed a higher risk of death among First Nations adults, which declined with increasing age at the time of diabetes diagnosis. Cumulative incidence function curves stratified by age at the time of diabetes diagnosis showed greatest risk for end-stage renal disease among those with onset of diabetes at younger ages and greatest risk of death among those with onset of diabetes at older ages.
Because they are typically younger when diabetes is diagnosed, First Nations adults with this condition are more likely than their non–First Nations counterparts to survive long enough for end-stage renal disease to develop. Differential mortality contributes substantially to ethnicity-based disparities in diabetes-related end-stage renal disease and possibly to chronic diabetes complications. Understanding the mechanisms underlying these disparities is vital in developing more effective prevention and management initiatives.
PMCID: PMC3903736  PMID: 24295857
3.  Glyceryl Trinitrate Complements Citrate and Ethanol in a Novel Antimicrobial Catheter Lock Solution To Eradicate Biofilm Organisms 
Antimicrobial catheter lock therapy is practiced to prevent lumenal-sourced infections of central venous catheters. Citrate has been used clinically as an anticoagulant in heparin-free catheter locks. Ethanol has also been widely studied as an antimicrobial lock solution component. This study reports on the synergy of glyceryl trinitrate (GTN) with citrate and ethanol in rapidly eradicating methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans biofilms in an in vitro model for catheter biofilm colonization. GTN has a long history of intravenous use as a hypotensive agent. It is potentially attractive as a component of a catheter lock solution because its physiologic half-life is quite short and its metabolic pathways are known. A lock containing 7% citrate and 20% ethanol required 0.01% GTN to fully eradicate biofilms of all test organisms within 2 h in the model. This GTN concentration is below the levels where clinically significant hypotensive effects are expected.
PMCID: PMC3719749  PMID: 23669393
4.  The Asia Oceania Human Proteome Organisation Membrane Proteomics Initiative. Preparation and characterization of the carbonate-washed membrane standard 
Proteomics  2010;10(22):4142-4148.
The Asia Oceania Human Proteome Organisation has embarked on a Membrane Proteomics Initiative with goals of systematic comparison of strategies for analysis of membrane proteomes and discovery of membrane proteins. This multi-laboratory project is based on analysis of a subcellular fraction from mouse liver that contains endoplasmic reticulum and other organelles. Here we present the strategy used for preparation and initial characterisation of the membrane sample, including validation that the carbonate-washing step enriches for integral and lipid-anchored membrane proteins. Analysis of seventeen independent datasets from five types of proteomic workflows is in progress.
PMCID: PMC3891941  PMID: 20486120
AOHUPO; Integral membrane proteins; Liver; Membrane proteomics
5.  Proteomic Analysis of Cellular Response Induced by Multi-Walled Carbon Nanotubes Exposure in A549 Cells 
PLoS ONE  2014;9(1):e84974.
The wide application of multi-walled carbon nanotubes (MWCNT) has raised serious concerns about their safety on human health and the environment. However, the potential harmful effects of MWCNT remain unclear and contradictory. To clarify the potentially toxic effects of MWCNT and to elucidate the associated underlying mechanisms, the effects of MWCNT on human lung adenocarcinoma A549 cells were examined at both the cellular and the protein level. Cytotoxicity and genotoxicity were examined, followed by a proteomic analysis (2-DE coupled with LC-MS/MS) of the cellular response to MWCNT. Our results demonstrate that MWCNT induces cytotoxicity in A549 cells only at relatively high concentrations and longer exposure time. Within a relatively low dosage range (30 µg/ml) and short time period (24 h), MWCNT treatment does not induce significant cytotoxicity, cell cycle changes, apoptosis, or DNA damage. However, at these low doses and times, MWCNT treatment causes significant changes in protein expression. A total of 106 proteins show altered expression at various time points and dosages, and of these, 52 proteins were further identified by MS. Identified proteins are involved in several cellular processes including proliferation, stress, and cellular skeleton organization. In particular, MWCNT treatment causes increases in actin expression. This increase has the potential to contribute to increased migration capacity and may be mediated by reactive oxygen species (ROS).
PMCID: PMC3891800  PMID: 24454774
6.  Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T cell exhaustion in reducing T cell responses 
Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.
PMCID: PMC3691077  PMID: 23419694
Merkel cell carcinoma; immune evasion; T cell dysfunction; PD-1
7.  Identification and Functional Analysis of Flowering Related microRNAs in Common Wild Rice (Oryza rufipogon Griff.) 
PLoS ONE  2013;8(12):e82844.
MicroRNAs (miRNAs) is a class of non-coding RNAs involved in post- transcriptional control of gene expression, via degradation and/or translational inhibition. Six-hundred sixty-one rice miRNAs are known that are important in plant development. However, flowering-related miRNAs have not been characterized in Oryza rufipogon Griff. It was approved by supervision department of Guangdong wild rice protection. We analyzed flowering-related miRNAs in O. rufipogon using high-throughput sequencing (deep sequencing) to understand the changes that occurred during rice domestication, and to elucidate their functions in flowering.
Three O. rufipogon sRNA libraries, two vegetative stage (CWR-V1 and CWR-V2) and one flowering stage (CWR-F2) were sequenced using Illumina deep sequencing. A total of 20,156,098, 21,531,511 and 20,995,942 high quality sRNA reads were obtained from CWR-V1, CWR-V2 and CWR-F2, respectively, of which 3,448,185, 4,265,048 and 2,833,527 reads matched known miRNAs. We identified 512 known rice miRNAs in 214 miRNA families and predicted 290 new miRNAs. Targeted functional annotation, GO and KEGG pathway analyses predicted that 187 miRNAs regulate expression of flowering-related genes. Differential expression analysis of flowering-related miRNAs showed that: expression of 95 miRNAs varied significantly between the libraries, 66 are flowering-related miRNAs, such as oru-miR97, oru-miR117, oru-miR135, oru-miR137, et al. 17 are early-flowering -related miRNAs, including osa-miR160f, osa-miR164d, osa-miR167d, osa-miR169a, osa-miR172b, oru-miR4, et al., induced during the floral transition. Real-time PCR revealed the same expression patterns as deep sequencing. miRNAs targets were confirmed for cleavage by 5′-RACE in vivo, and were negatively regulated by miRNAs.
This is the first investigation of flowering miRNAs in wild rice. The result indicates that variation in miRNAs occurred during rice domestication and lays a foundation for further study of phase change and flowering in O. rufipogon. Complicated regulatory networks mediated by multiple miRNAs regulate the expression of flowering genes that control the induction of flowering.
PMCID: PMC3875430  PMID: 24386120
8.  Fabricating Reversible and Regenerable Raman-active Substrate with Biomolecule-controlled DNA Nanomachine 
Journal of the American Chemical Society  2012;134(49):19957-19960.
A DNA configuration switch was designed to fabricate a reversible and regenerable Raman-active substrate. The substrate is composed of an Au film and hairpin-shaped DNA strand (hot spot generation probes, HSGPs) labeled with dye-functionalized silver nanoparticle (AgNP). Another ssDNA that recognizes a specific trigger was used as an antenna. The HSGPs are immobilized on the Au film to draw the dye-functionalized AgNPs close to the Au surface and create an intense electromagnetic field. Hybridization of HSGP with the two arm segments of the antenna forms a triplex-stem structure to separate the dye-functionalized AgNP from the Au surface and cause a quenching of the Raman signal. Interaction with its trigger leads to release of the antenna from the triplex-stem structure, and the hairpin structure of the HSGP is restored, thereby creating an effective “off” to “on” state of the Raman signal. Nucleic acid sequence associated with the HIV-1 U5 long terminal repeat sequences and ATP are used as the triggers. The substrate shows excellent reversibility, reproducibility and controllability of SERS effects, which are significant requirements for practical SERS sensor applications.
PMCID: PMC3568521  PMID: 23190376
9.  Rare opportunistic (non-Candida, non-Cryptococcus) Yeast Bloodstream Infections in Patients with Cancer 
The Journal of infection  2011;64(1):10.1016/j.jinf.2011.11.002.
Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections (ROYBSIs) are rare, even in cancer patients.
We retrospectively reviewed all episodes of ROYBSIs occurring from 1998 to 2010 in our cancer center.
Of 2984 blood cultures positive for Candida and non-Candida yeasts, 94 (3.1%) were positive for non-Candida yeasts, representing 41 ROYBSIs (incidence, 2.1 cases/100,000 patient-days). Catheter-associated fungemia occurred in 21 (51%) patients. Breakthrough ROYBSIs occurred in 20 (49%) patients. The yeast species distribution was Rhodotorula in 21 (51%) patients, Trichosporon in 8 (20%) patients, Saccharomyces cerevisiae in 8 (20%) patients, Geotrichum in 2 (5%) patients, Pichia anomala, and Malassezia furfur in 1 patient each. All tested Trichosporon, Geotrichum, and Pichia isolates were azole-susceptible, whereas the Rhodotorula isolates were mostly azole-resistant. We noted echinocandin nonsusceptibility (minimal inhibitory concentration ≥ 2 mg/L) in all but the S. cerevisiae isolates. Most of the isolates (28/33 [85%]) were susceptible to amphotericin B. The mortality rate in all patients at 30 days after ROYBSIs diagnosis was 34%. Multivariate survival analysis revealed increased risk of death in patients with S. cerevisiae infections (hazard ratio, 3.7), Geotrichum infections (hazard ratio, 111.3), or disseminated infections (hazard ratio, 33.4) and reduced risk in patients who had catheter removal (hazard ratio, 0.1).
ROYBSIs are uncommon in patients with cancer, and catheters are common sources of them. Half of the ROYBSIs occurred as breakthrough infections, and in vitro species-specific resistance to echinocandins and azoles was common. Disseminated infections resulted in the high mortality rate.
PMCID: PMC3855381  PMID: 22101079
Non-Candida yeast; Cancer; Immunosuppression
10.  Protective Effect of Ginsenoside Rb1 against Intestinal Ischemia-Reperfusion Induced Acute Renal Injury in Mice 
PLoS ONE  2013;8(12):e80859.
Ginsenoside Rb1 (RB1), the most clinically effective constituent of ginseng, possesses a variety of biological activities. The objectives of this study were to investigate the protective effects of RB1 and its underlying mechanism on renal injury induced by intestinal ischemia-reperfusion (IIR) in mice. RB1 was administered prior to inducing IIR achieved by occluding the superior mesenteric artery for 45 min followed by 120 min of reperfusion. All-trans-retinoic acid (ATRA) was used as an inhibitor of NF-E2-related factor-2 (Nrf2) signaling. Adult male C57BL/6J mice were randomly divided into six groups: (1) sham group, (2) IIR group, (3) RB1 group, (4) sham + ATRA group, (5) IIR + ATRA group, and (6) RB1 + ATRA group. Intestinal histology and pathological injury score were observed. Intestinal mucosal injury was also evaluated by measuring serum diamine oxidase (DAO). Renal injury induced by IIR was characterized by increased levels of histological severity score, blood urea nitrogen (BUN), serum creatinine (Scr) and neutrophil gelatinase-associated lipocalin (NGAL), which was accompanied with elevated renal TUNEL-positive cells and the Bcl-2/Bax expression ratio. RB1 significantly reduced renal injury and apoptosis as compared with IIR group, which was reversed by ATRA treatment. Immunohistochemistry and Western blot analysis demonstrated that RB1 significantly upregulated the protein expression of heme oxygenase-1 (HO-1) and Nrf2, which were attenuated by ATRA treatment. Taken together, these results suggest that the protective effects of RB1 pretreatment against renal injury induced by IIR are associated with activation of the Nrf2/ anti-oxidant response element (ARE) pathway.
PMCID: PMC3851764  PMID: 24324637
11.  Evidence of the two surface states of (Bi0.53Sb0.47)2Te3 films grown by van der Waals epitaxy 
Scientific Reports  2013;3:3406.
The discovery of topological insulators (TIs) has led to numerous exciting opportunities for studying topological states of quantum physics and for exploring spintronic applications due to the new physics arising from their robust metallic surface states. Here, we report the high-quality topological insulator (BixSb1−x)2Te3 thin films using a single van der Waals GaSe buffer layer. As a result, ultra-low surface carrier density of 1.3 × 1012 cm−2 and a high Hall mobility of 3100 cm2/Vs have been achieved for (Bi0.53Sb0.47)2Te3. The high-quality films enable us to observe quantum oscillations associated with the top and bottom surface states and to manipulate the Dirac electrons and bulk holes' conduction properties. The observation of the two surface states may lead to a path towards the implementation of TIs in spintronics.
PMCID: PMC3847703  PMID: 24297036
12.  Demonstration of surface transport in a hybrid Bi2Se3/Bi2Te3 heterostructure 
Scientific Reports  2013;3:3060.
In spite of much work on topological insulators (TIs), systematic experiments for TI/TI heterostructures remain absent. We grow a high quality heterostructure containing single quintuple layer (QL) of Bi2Se3 on 19 QLs of Bi2Te3 and compare its transport properties with 20 QLs Bi2Se3 and 20 QLs Bi2Te3. All three films are grown on insulating sapphire (0001) substrates by molecular beam epitaxy (MBE). In situ angle-resolved photoemission spectroscopy (ARPES) provides direct evidence that the surface state of 1 QL Bi2Se3/19 QLs Bi2Te3 heterostructure is similar to the surface state of the 20 QLs Bi2Se3 and different with that of the 20 QLs Bi2Te3. In ex situ transport measurements, the observed linear magnetoresistance (MR) and weak antilocalization (WAL) of the hybrid heterostructure are similar to that of the pure Bi2Se3 film and not the Bi2Te3 film. This suggests that the single Bi2Se3 layer on top of 19 QLs Bi2Te3 dominates its transport properties.
PMCID: PMC3808819  PMID: 24162440
13.  MADM-ML, a Mouse Genetic Mosaic System with Increased Clonal Efficiency 
PLoS ONE  2013;8(10):e77672.
Mosaic Analysis with Double Markers (MADM) is a mouse genetic system that allows simultaneous gene knockout and fluorescent labeling of sparse, clonally-related cells within an otherwise normal mouse, thereby circumventing embryonic lethality problems and providing single-cell resolution for phenotypic analysis in vivo. The clonal efficiency of MADM is intrinsically low because it relies on Cre/loxP-mediated mitotic recombination between two homologous chromosomes rather than within the same chromosome, as in the case of conditional knockout (CKO). Although sparse labeling enhances in vivo resolution, the original MADM labels too few or even no cells when a low-expressing Cre transgene is used or a small population of cells is studied. Recently, we described the usage of a new system, MADM-ML, which contains three mutually exclusive, self-recognizing loxP variant sites as opposed to a single loxP site present in the original MADM system (referred to as MADM-SL in this paper). Here we carefully compared the recombination efficiency between MADM-SL and MADM-ML using the same Cre transgene, and found that the new system labels significantly more cells than the original system does. When we established mouse medulloblastoma models with both the original and the new MADM systems, we found that, while the MADM-SL model suffered from varied tumor progression and incomplete penetrance, the MADM-ML model had consistent tumor progression and full penetrance of tumor formation. Therefore MADM-ML, with its higher recombination efficiency, will broaden the applicability of MADM for studying many biological questions including normal development and disease modeling at cellular resolution in vivo.
PMCID: PMC3797059  PMID: 24143253
14.  Long-term follow-up of kidney transplant recipients: comparison of hospitalization rates to the general population 
Kidney transplant recipients are recognized as a vulnerable population that is at increased risk of adverse health outcomes. However, there have been few studies that have compared hospital-related morbidity of these patients to the general population, and how this differs with respect to time since transplantation. Such analyses are useful in estimating the health burden in this patient population.
We assembled a population-based Canadian cohort (excluding Quebec) of 6,116 kidney transplant recipients who underwent transplantation between 1 April 2001 and 31 December 2008. Record linkage was used to identify hospital discharge records of these patients from 1 April 2001 through 31 March 2009. Hospital discharges were tabulated across the main disease chapters of the ICD10, and person-years of follow-up were calculated across age and sex strata. Comparisons of hospital-related morbidity to the general population were made by using a standardized hospitalization ratio (SHR). For those who underwent transplantation in 2004, stratified analyses were performed to explore differences in hospital discharge rates both before and after transplantation.
After excluding hospitalizations due to complications from transplantation, when compared to the general population, transplant recipients were approximately 6.4 (95% CI: 6.3, 6.5) times more likely to be hospitalized during follow-up. The SHRs were highest during the time periods proximate to transplantation, and then decreased to approximately a five-fold increase from 3 years post transplantation onwards. The largest disease-specific excesses were observed with infectious diseases and diseases of the endocrine system. Among those who underwent transplantation in 2004, the SHR decreased from 11.2 to 5.0 in the periods before and after surgery, respectively.
Our results indicate that, even more than 5-years post transplantation, there remains a more than six-fold difference in hospitalization rates relative to the general population. Additional work is needed to confirm these findings, and to develop strategies to reduce long-term morbidity in this patient population.
PMCID: PMC3766211  PMID: 23971626
Cohort study; Kidney transplantation; Record linkage; Standardized hospitalization ratio
15.  Foxo3a Expression Is a Prognostic Marker in Breast Cancer 
PLoS ONE  2013;8(8):e70746.
The forkhead box transcription factor Foxo3a has been implicated to play a critical role in various cancers by suppressing tumor growth. Recent studies have identified Foxo3a as a key regulator of Estrogen Receptor-α (ERα). In the present study, we examined the expression of Foxo3a, and investigated its clinical significance and correlation with ER and prognostic role in patients with breast cancer. Immunohistochemical analysis was performed on tumors from 70 breast cancer patients. Interpretable Foxo3a expression was analyzed along with major clinicopathologic variables, and a comparison was made with corresponding 5-year clinical follow-up data. Foxo3a protein expression correlated with ER positivity (P<0.001), histologic grade (1, 2) (P = 0.002), axillary lymph node negativity (P<0.001) and TNM stage (1, 2) (P<0.001). Moreover, the Kaplan-Meier survival curves of the study population showed that a high expression level of Foxo3a was significantly correlated with long-term survival (P<0.0001). In a multivariate analysis, Foxo3a expression was identified as a favorable independent prognostic factor in overall survival (P = 0.038). In conclusion, our results indicated that Foxo3a expression is a favorable prognostic marker in breast cancer. In addition, Foxo3a staining could potentially be used in patient stratification in conjunction with other prognostic markers.
PMCID: PMC3742799  PMID: 23967095
16.  Nemo-Like Kinase Associated with Proliferation and Apoptosis by c-Myb Degradation in Breast Cancer 
PLoS ONE  2013;8(7):e69148.
Nemo-like kinase (NLK), a mediator of the Wnt signaling pathway, binds directly to c-Myb, leading to its phosphorylation, ubiquitination and proteasome-dependent degradation. NLK was significantly downregulated in the breast cancer tissues compared to corresponding normal tissues. NLK expression was negatively correlated with c-Myb expression. NLK suppressed proliferation, induced apoptosis and mediated c-Myb degradation in MCF-7 cells via a mechanism that seems to involve c-myc and Bcl2. These findings might provide a novel target for therapeutic intervention in patients with breast cancer.
PMCID: PMC3720543  PMID: 23935942
17.  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
18.  Clinical, radiographic characteristics and immunomodulating changes in neuromyelitis optica with extensive brain lesions 
BMC Neurology  2013;13:72.
Neuromyelitis optica (NMO) shows various brain magnetic resonance imaging (MRI) abnormalities with recurrent central nervous system (CNS) attacks, although predominantly affecting the spinal cord and optic nerve. However, NMO with extensive involvement of the brain has infrequently been studied. We investigated the clinical, radiographic features and immunomodulating changes of NMO patients with extensive brain lesions (EBLs) in China.
NMO patients (including 16 NMO patients with EBLs and 53 NMO patients without EBLs) hospitalized during January 2006 and February 2010 were recruited and analyzed retrospectively. Data of clinical characteristics, magnetic resonance imaging (MRI) features, laboratory abnormalities, treatment details and outcomes were analyzed. All the patients received the follow-up visits for two years.
EBLs in NMO were classified into four categories according to their respective MRI characteristics: 1) Tumefactive-like lesions (n=4, 25%); 2) Acute disseminated encephalomyelitis (ADEM)-like lesions (n=6, 37.5%); 3) Multiple sclerosis (MS)-like lesions (n=5, 31.25%); 4) Posterior reversible encephalopathy syndrome (PRES)-like lesions (n=1, 6.25%). NMO patients with EBLs had higher rates of encephalopathy symptoms (37.5% vs. 5.6%, p = 0.004), homonymous hemianopia (18.8% vs. 0%, p = 0.011) and AQP4 seropositivity (100% vs. 69.8%, p = 0.008) than NMO patients without EBLs (NEBLs). Immunomodulating changes (including the levels of C3, C4, ESR and CRP) were significantly higher in patients with EBLs than those without EBLs. The relapse times in EBLs during the follow-up period were more frequent than those happened in NEBLs (1.88 ± 0.30 vs. 1.23 ± 0.14, p = 0.04). The EDSS scores in EBLs patients were also much higher than those in NEBLs throughout all the whole visits of follow-up.
The presence of EBLs in NMO may indicate a higher diseases activity and portend a worse prognosis. CRP is a useful marker in monitoring diseases activity. Systemic inflammation may be crucial to the formation of EBLs in NMO.
PMCID: PMC3725153  PMID: 23819854
Aquaporin-4; Complement; C-reactive Protein; Erythrocyte sedimentation rate; Extensive brain lesions; Magnetic resonance imaging; Neuromyelitis optica
19.  The prevalence of human papillomavirus and its impact on cervical dysplasia in Northern Canada 
Certain types of the Human Papillomavirus (HPV) are sexually transmitted and highly associated with development of cervical dysplasia and cervical cancer but the distribution of HPV infection in the North, particularly amongst First Nations, Metis, and Inuit peoples, is little known. The purposes of the study are to identify the prevalence of type-specific HPV infections and the association of different HPV types with cervical dysplasia among women in Northern Canada.
This was a cross-sectional study with attendants of the routine or scheduled Pap testing program in the Northwest Territories (NWT), Nunavut, Labrador and Yukon, Canada. Approximately half of each sample was used for Pap test and the remaining was used for HPV genotyping using a Luminex-based method. Pap test results, HPV types, and demographic information were linked for analyses.
Results from 14,598 specimens showed that HPV infection was approximately 50% higher among the Aboriginal than the non-Aboriginal population (27.6% vs. 18.5%). Although the most common HPV type detected was HPV 16 across region, the prevalence of other high risk HPV types was different. The age-specific HPV prevalence among Aboriginal showed a ‘U’ shape which contrasted to non-Aboriginal. The association of HPV infection with cervical dysplasia was similar in both Aboriginal and non-Aboriginal populations.
The HPV prevalence was higher in Northern Canada than in other Areas in Canada. The prevalence showed a higher rate of other high risk HPV infections but no difference of HPV 16/18 infections among Aboriginal in comparison with non-Aboriginal women. This study provides baseline information on HPV prevalence that may assist in surveillance and evaluation systems to track and assess HPV vaccine programs.
PMCID: PMC3728116  PMID: 23816397
Human papillomavirus; Prevalence; Pap abnormality; Northern region
20.  An integrated genome-wide approach to discover tumor specific antigens as potential immunological and clinical targets in cancer 
Cancer research  2012;72(24):6351-6361.
Tumor-specific antigens (TSAs) are central elements in the immune control of cancers. To systematically explore the TSA genome, we developed a computational technology called Heterogeneous Expression Profile Analysis (HEPA), which can identify genes relatively uniquely expressed in cancer cells in contrast to normal somatic tissues. Rating human genes by their HEPA score enriched for clinically useful TSA genes, nominating candidate targets whose tumor-specific expression was verified by RT-PCR. Coupled with HEPA, we designed a novel assay termed Protein A/G based Reverse Serological Evaluation (PARSE) for quick detection of serum autoantibodies against an array of putative TSA genes. Remarkably, highly tumor-specific autoantibody responses against seven candidate targets were detected in 4–11% of patients, resulting in distinctive autoantibody signatures in lung and stomach cancers. Interrogation of a larger cohort of 149 patients and 123 healthy individuals validated the predictive value of the autoantibody signature for lung cancer. Together, our results establish an integrated technology to uncover a cancer-specific antigen genome offering a reservoir of novel immunological and clinical targets.
PMCID: PMC3525759  PMID: 23135912
Tumor specific antigen; TSA; Gene expression profiling; New algorithims; Immunodiagnosis; Autoantibody signatures
21.  Transgenerational Glucose Intolerance With Igf2/H19 Epigenetic Alterations in Mouse Islet Induced by Intrauterine Hyperglycemia 
Diabetes  2012;61(5):1133-1142.
Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C♂-C♀, C♂-GDM♀, GDM♂-C♀, and GDM♂-GDM♀. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission.
PMCID: PMC3331740  PMID: 22447856
22.  Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E- selectin expression in human squamous cell carcinomas 
Squamous cell carcinomas (SCC) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCC evade immune detection at least in part by down-regulating E-selectin on tumor vessels, thereby restricting entry of skin homing T cells into tumors. We find that nitric oxide potently suppresses E-selectin expression on human endothelial cells and that SCC are infiltrated by nitric oxide-producing iNOS+ CD11b+ CD33+ CD11c− HLA-DR− myeloid-derived suppressor cells (MDSC). MDSC from SCC produced NO, TGFβ and arginase and inhibited endothelial E-selectin expression in vitro. MDSC from SCC expressed the chemokine receptor CCR2 and tumors expressed the CCR2 ligand HBD3, suggesting CCR2-HBD3 interactions may contribute to MDSC recruitment to SCC. Treatment of SCC in vitro with the iNOS inhibitor L-NNA induced E-selectin expression at levels comparable to imiquimod-treated SCC undergoing immunologic destruction. Our results suggest that local production of NO in SCC may impair vascular E-selectin expression. We show that MDSC are critical producers of NO in SCC and that NO inhibition restores vascular E-selectin expression, potentially enhancing T cell recruitment. iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCC and their premalignant precursor lesions actinic keratoses.
PMCID: PMC3449043  PMID: 22718118
23.  Asbestos and Asbestos-related Diseases in Vietnam: In reference to the International Labor Organization/World Health Organization National Asbestos Profile 
Safety and Health at Work  2013;4(2):117-121.
This paper describes progress on formulating a national asbestos profile for the country of Vietnam. The Center of Asbestos Resource, Vietnam, formulated a National Profile on Asbestos-related Occupational Health, with due reference to the International Labor Organization/World Health Organization National Asbestos Profile. The Center of Asbestos Resource was established by the Vietnamese Health Environment Management Agency and the National Institute of Labor Protection, with the support of the Australian Agency for International Development, as a coordinating point for asbestos-related issues in Vietnam. Under the National Profile on Asbestos-related Occupational Health framework, the Center of Asbestos Resource succeeded in compiling relevant information for 15 of the 18 designated items outlined in the International Labor Organization/World Health Organization National Asbestos Profile, some overlaps of the information items notwithstanding. Today, Vietnam continues to import and use an average of more than 60,000 metric tons of raw asbestos per year. Information on asbestos-related diseases is limited, but the country has begun to diagnose mesothelioma cases, with the technical cooperation of Japan. As it stands, the National Profile on Asbestos-related Occupational Health needs further work and updating. However, we envisage that the National Profile on Asbestos-related Occupational Health will ultimately facilitate the smooth transition to an asbestos-free Vietnam.
PMCID: PMC3732140  PMID: 23961336
asbestos; asbestos-related diseases; ILO/WHO National Asbestos Profile; ILO/WHO; Vietnam
24.  Description and Nomenclature of Neisseria meningitidis Capsule Locus 
Emerging Infectious Diseases  2013;19(4):566-573.
Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference.
PMCID: PMC3647402  PMID: 23628376
Neisseria meningitidis; capsule; serogroup; bacteria; nomenclature
25.  The pattern of Phosphate transporter 1 genes evolutionary divergence in Glycine max L. 
BMC Plant Biology  2013;13:48.
The Phosphate transporter 1 (PHT1) gene family has crucial roles in phosphate uptake, translocation, remobilization, and optimization of metabolic processes using of Pi. Gene duplications expand the size of gene families, and subfunctionalization of paralog gene pairs is a predominant tendency after gene duplications. To date, experimental evidence for the evolutionary relationships among different paralog gene pairs of a given gene family in soybean is limited.
All potential Phosphate transporter 1 genes in Glycine max L. (GmPHT1) were systematically analyzed using both bioinformatics and experimentation. The soybean PHT1 genes originated from four distinct ancestors prior to the Gamma WGT and formed 7 paralog gene pairs and a singleton gene. Six of the paralog gene pairs underwent subfunctionalization, and while GmPHT1;4 paralog gene experienced pseudogenization. Examination of long-term evolutionary changes, six GmPHT1 paralog gene pairs diverged at multiple levels, in aspects of spatio-temporal expression patterns and/or quanta, phosphates affinity properties, subcellular localization, and responses to phosphorus stress.
These characterized divergences occurred in tissue- and/or development-specific modes, or conditional modes. Moreover, they have synergistically shaped the evolutionary rate of GmPHT1 family, as well as maintained phosphorus homeostasis at cells and in the whole plant.
PMCID: PMC3621523  PMID: 23510338
Phosphate transporter 1; Gene duplication; Gene divergence; Phosphorus homeostasis; Evolution; Glycine max L.

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