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1.  Association of glutathione peroxidase-1 (GPx-1) rs1050450 Pro198Leu and Pro197Leu polymorphisms with cardiovascular risk: a meta-analysis of observational studies 
To clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 (GPx-1) and the risk of cardiovascular diseases (CVD) by performing a meta-analysis of published studies. There is growing evidence from different study types for an association of the GPx-1 polymorphism and cardiovascular outcomes, but observational studies have so far shown inconsistent results.
Relevant publications were searched through PubMed, Embase database databases and the Cochrane Library. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of association under the best genetic model. Both Q statistic and the I2 were used to check heterogeneity. Meta-regression analysis was performed to explore heterogeneity source. Sensitivity analysis, cumulative meta-analysis analysis and publication bias were used to test the reliability of the results.
Data were available from two cohort studies and 8 case-control studies involving 1,430 cases and 3,767 controls. The pooled ORs for overall CVD risk was 1.36 with 95% CI: 1.08–1.70 under a co-dominant model, and that for East Asian subgroup was 1.84 (95% CI: 1.39–2.43). Substantial heterogeneity for ORs were detected among all the included studies, mainly caused by ethnic differences between East Asian and non-East Asian populations. Although Egger's regression test suggested no statistical significant publication bias, Begg's funnel plot exhibited obvious asymmetry. The statistical significance disappeared after adjusting for potential publication bias in the overall studies. However, no substantial publication bias was found in the East Asian subgroup.
GPx-1 gene Pro198Leu and Pro197Leu polymorphisms considerably increased the risk of CVD in the East Asian population. Large-scale investigations are needed to confirm the results in different ethnicities.
PMCID: PMC4076455  PMID: 25009565
Glutathione peroxidase-1; Cardiovascular diseases; Polymorphism; Meta-analysis
2.  LKB1 Tumor Suppressor: Therapeutic Opportunities Knock when LKB1 Is Inactivated 
Genes & Diseases  2014;1(1):64-74.
LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome, and somatic inactivation of LKB1 is found in non-small cell lung cancer, melanoma, and cervical cancers. However, unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death, one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions. This unique, pro-survival function of LKB1 has led to the discovery of reagents, such as phenformin, that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress. Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent. This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.
PMCID: PMC4323096
Tumor Suppressor; tumor vulnerability; targeted therapy; metabolic stress
3.  MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/β-catenin pathway 
Scientific Reports  2015;5:8087.
Accumulating evidences indicate that microRNAs play a vital role in regulating tumor progression. However, the roles of miR-148b in hepatocellular carcinoma (HCC) are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 40 pairs of human HCC tissues. Further, the deregulated miR-148b was significantly correlated with larger tumor size, more tumor number, metastasis and worse prognosis in HCC. Overexpression of miR-148b inhibited HCC HepG2 cells proliferation and tumorigenicity. Further, miR-148b induced cells apoptosis by activating caspase- 3 and caspase-9, and induced S phase arrest by regulating cyclinD1 and p21, and also inhibited cell invasion. Data from the dual-luciferase reporter gene assay showed that WNT1 was a direct target of miR-148b, and overexpressed WNT1 inversely correlated with miR-148b levels in HCC tissues. Silencing of WNT1 inhibited the growth of HCC cells, and also induced cells apoptosis and inhibited invasion, which is consistent with the effects of miR-148b overexpression. MiR-148b downregulated expression of WNT1, β-catenin and C-myc, while upregulated E-cadherin expression. We conclude that the frequently downregulated miR-148b can regulate WNT1/β-catenin signalling pathway and function as a tumor suppressor in HCC. These findings suggest that miR-148b may serve as a novel therapeutic target for HCC.
PMCID: PMC4310092  PMID: 25627001
4.  Intraoperative Scintigraphy Using a Large Field-of-View Portable Gamma Camera for Primary Hyperparathyroidism: Initial Experience 
BioMed Research International  2015;2015:930575.
Background. We investigated a novel technique, intraoperative 99 mTc-Sestamibi (MIBI) imaging (neck and excised specimen (ES)), using a large field-of-view portable gamma camera (LFOVGC), for expediting confirmation of MIBI-avid parathyroid adenoma removal. Methods. Twenty patients with MIBI-avid parathyroid adenomas were preoperatively administered MIBI and intraoperatively imaged prior to incision (neck) and immediately following resection (neck and/or ES). Preoperative and intraoperative serum parathyroid hormone monitoring (IOPTH) and pathology (path) were also performed. Results. MIBI neck activity was absent and specimen activity was present in 13/20 with imaging after initial ES removal. In the remaining 7/20 cases, residual neck activity and/or absent ES activity prompted excision of additional tissue, ultimately leading to complete hyperfunctioning tissue excision. Postexcision LFOVGC ES imaging confirmed parathyroid adenoma resection 100% when postresection imaging qualitatively had activity (ES) and/or no activity (neck). The mean ± SEM time saving using intraoperative LFOVGC data to confirm resection versus first IOPTH or path result would have been 22.0 ± 2 minutes (specimen imaging) and 26.0 ± 3 minutes (neck imaging). Conclusion. Utilization of a novel real-time intraoperative LFOVGC imaging approach can provide confirmation of MIBI-avid parathyroid adenoma removal appreciably faster than IOPTH and/or path and may provide a valuable adjunct to parathyroid surgery.
PMCID: PMC4300023  PMID: 25629056
5.  Subunit- and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina 
Retinal ganglion cells (RGCs) receive excitatory glutamatergic input from ON and OFF bipolar cells in distinct sublaminae of the inner plexiform layer (IPL). AMPA and NMDA receptors (AMPARs and NMDARs) mediate excitatory inputs in both synaptic layers, but specific roles for NMDARs at RGC synapses remain unclear. NMDARs comprise NR1 and NR2 subunits and are anchored by membrane associated guanylate kinases (MAGUKs), but it is unknown whether particular NR2 subunits associate preferentially with particular NR1 splice variants and MAGUKs. Here, we used postembedding immunogold electron microscopy (EM) techniques to examine the subsynaptic localization of NMDAR subunits and MAGUKs at ON and OFF synapses onto rat RGCs. We found that the NR2A subunit, the NR1C2‘ splice variant and MAGUKs PSD-95 and PSD-93 are localized to the postsynaptic density (PSD), preferentially at OFF synapses, whereas the NR2B subunit, the NR1C2 splice variant and the MAGUK SAP102 are localized perisynaptically, with NR2B exhibiting a preference for ON synapses. Consistent with these anatomical data, spontaneous EPSCs (sEPSCs) recorded from OFF cells exhibited an NMDAR component that was insensitive to the NR2B antagonist Ro 25-6981. In ON cells, sEPSCs expressed an NMDAR component, partially sensitive to Ro 25-6981, only when glutamate transport was inhibited, indicating perisynaptic expression of NR2B NMDARs. These results provide the first evidence for preferential association of particular NR1 splice variants, NR2 subunits and MAGUKs at central synapses and suggest that different NMDAR subtypes may play specific roles at functionally distinct synapses in the retinal circuitry.
PMCID: PMC4283557  PMID: 19339621
6.  Massive-Training Artificial Neural Network Coupled With Laplacian-Eigenfunction-Based Dimensionality Reduction for Computer-Aided Detection of Polyps in CT Colonography 
IEEE transactions on medical imaging  2010;29(11):1907-1917.
A major challenge in the current computer-aided detection (CAD) of polyps in CT colonography (CTC) is to reduce the number of false-positive (FP) detections while maintaining a high sensitivity level. A pattern-recognition technique based on the use of an artificial neural network (ANN) as a filter, which is called a massive-training ANN (MTANN), has been developed recently for this purpose. The MTANN is trained with a massive number of subvolumes extracted from input volumes together with the teaching volumes containing the distribution for the “likelihood of being a polyp;” hence the term “massive training.” Because of the large number of subvolumes and the high dimensionality of voxels in each input subvolume, the training of an MTANN is time-consuming. In order to solve this time issue and make an MTANN work more efficiently, we propose here a dimension reduction method for an MTANN by using Laplacian eigenfunctions (LAPs), denoted as LAP-MTANN. Instead of input voxels, the LAP-MTANN uses the dependence structures of input voxels to compute the selected LAPs of the input voxels from each input subvolume and thus reduces the dimensions of the input vector to the MTANN. Our database consisted of 246 CTC datasets obtained from 123 patients, each of whom was scanned in both supine and prone positions. Seventeen patients had 29 polyps, 15 of which were 5–9 mm and 14 were 10–25 mm in size. We divided our database into a training set and a test set. The training set included 10 polyps in 10 patients and 20 negative patients. The test set had 93 patients including 19 polyps in seven patients and 86 negative patients. To investigate the basic properties of a LAP-MTANN, we trained the LAP-MTANN with actual polyps and a single source of FPs, which were rectal tubes. We applied the trained LAP-MTANN to simulated polyps and rectal tubes. The results showed that the performance of LAP-MTANNs with 20 LAPs was advantageous over that of the original MTANN with 171 inputs. To test the feasibility of the LAP-MTANN, we compared the LAP-MTANN with the original MTANN in the distinction between actual polyps and various types of FPs. The original MTANN yielded a 95% (18/19) by-polyp sensitivity at an FP rate of 3.6 (338/93) per patient, whereas the LAP-MTANN achieved a comparable performance, i.e., an FP rate of 3.9 (367/93) per patient at the same sensitivity level. With the use of the dimension reduction architecture, the time required for training was reduced from 38 h to 4 h. The classification performance in terms of the area under the receiver-operating-characteristic curve of the LAP-MTANN (0.84) was slightly higher than that of the original MTANN (0.82) with no statistically significant difference (p-value).
PMCID: PMC4283824  PMID: 20570766
Computer-aided diagnosis (CAD); nonlinear dimension reduction; pixel-based machine learning; virtual colonoscopy
7.  Passive Diffusion as a Mechanism Underlying Ribbon Synapse Vesicle Release and Resupply 
The Journal of Neuroscience  2014;34(27):8948-8962.
Synaptic ribbons are presynaptic protein structures found at many synapses that convey graded, “analog” sensory signals in the visual, auditory, and vestibular pathways. Ribbons, typically anchored to the presynaptic membrane and surrounded by tethered synaptic vesicles, are thought to regulate or facilitate vesicle delivery to the presynaptic membrane. No direct evidence exists, however, to indicate how vesicles interact with the ribbon or, once attached, move along the ribbon's surface to reach the presynaptic release sites at its base. To address these questions, we have created, validated, and tested a passive vesicle diffusion model of retinal rod bipolar cell ribbon synapses. We used axial (bright-field) electron tomography in the scanning transmission electron microscopy to obtain 3D structures of rat rod bipolar cell terminals in 1-μm-thick sections of retinal tissue at an isotropic spatial resolution of ∼3 nm. The resulting structures were then incorporated with previously published estimates of vesicle diffusion dynamics into numerical simulations that accurately reproduced electrophysiologically measured vesicle release/replenishment rates and vesicle pool sizes. The simulations suggest that, under physiologically realistic conditions, diffusion of vesicles crowded on the ribbon surface gives rise to a flow field that enhances delivery of vesicles to the presynaptic membrane without requiring an active transport mechanism. Numerical simulations of ribbon–vesicle interactions predict that transient binding and unbinding of multiple tethers to each synaptic vesicle may achieve sufficiently tight association of vesicles to the ribbon while permitting the fast diffusion along the ribbon that is required to sustain high release rates.
PMCID: PMC4078077  PMID: 24990916
diffusion; tether; vesicle
8.  Integrated IVUS-OCT for Real-Time Imaging of Coronary Atherosclerosis 
JACC. Cardiovascular imaging  2014;7(1):101-103.
Combined use of optical coherence tomography (OCT) and intravascular ultrasound (IVUS) is a potential method for accurate assessment of plaques characteristics and vulnerability. The aim of this study is to develop and evaluate the feasibility of a fully integrated intracoronary OCT-IVUS imaging technique to visualize plaques in living animals.
In vivo imaging of plaques by an integrated OCT-IVUS system has not been reported.
Simultaneous real-time OCT-IVUS imaging is performed using an integrated OCT-IVUS system and a single fully-integrated catheter with a 3.6F outer-diameter same as a commercial IVUS catheter.
To verify in vivo imaging capability of this technique, five atherosclerotic-model rabbits and a swine were imaged. Images were obtained in these animals without complications. Linear regression shows a high correlation between rabbit plaque sizes determined from histology and OCT/IVUS estimated plaque sizes (R2=0.955, P<0.001 between OCT and histology; R2=0.970, P<0.001 between IVUS and histology). Classification of plaque types and quantitative analysis of plaque sizes were performed in vitro using cadaver coronary segments (n=14).
For the first time, this study shows that an integrated intracoronary OCT-IVUS system is feasible and safe to use in vivo to detect atherosclerotic plaques. This technique provides high resolution and deep penetration capability simultaneously which can facilitate a more powerful tool to explore the development of plaques and may lead to a more accurate assessment of vulnerable plaques in patients.
PMCID: PMC3970778  PMID: 24433713
Vulnerable plaque; intravascular ultrasound; optical coherence tomography; intracoronary imaging
9.  Creating the feedback loop: Closed Loop Neurostimulation 
PMCID: PMC4058859  PMID: 24262909
Deep Brain Stimulation; Closed-Loop; Local Field Potentials; Oscillations; Subthalamic Nucleus; Control Systems; Machine Learning
10.  Quantitative Hepatitis B Core Antibody Level Is a New Predictor for Treatment Response In HBeAg-positive Chronic Hepatitis B Patients Receiving Peginterferon 
Theranostics  2015;5(3):218-226.
A recent study revealed that quantitative hepatitis B core antibody (qAnti-HBc) level could serve as a novel marker for predicting treatment response. In the present study, we further investigated the predictive value of qAnti-HBc level in HBeAg-positive patients undergoing PEG-IFN therapy. A total of 140 HBeAg-positive patients who underwent PEG-IFN therapy for 48 weeks and follow-up for 24 weeks were enrolled in this study. Serum samples were taken every 12 weeks post-treatment. The predictive value of the baseline qAnti-HBc level for treatment response was evaluated. Patients were further divided into 2 groups according to the baseline qAnti-HBc level, and the response rate was compared. Additionally, the kinetics of the virological and biochemical parameters were analyzed. Patients who achieved response had a significantly higher baseline qAnti-HBc level (serological response [SR], 4.52±0.36 vs. 4.19±0.58, p=0.001; virological response [VR], 4.53±0.35 vs. 4.22±0.57, p=0.005; combined response [CR], 4.50±0.36 vs. 4.22±0.58, p=0.009)). Baseline qAnti-HBc was the only parameter that was independently correlated with SR (p=0.008), VR (p=0.010) and CR(p=0.019). Patients with baseline qAnti-HBc levels ≥30,000 IU/mL had significantly higher response rates, more HBV DNA suppression, and better hepatitis control in PEG-IFN treatment. In conclusion, qAnti-HBc level may be a novel biomarker for predicting treatment response in HBeAg-positive patients receiving PEG-IFN therapy.
PMCID: PMC4279186  PMID: 25553110
quantitative anti-HBc;  chronic hepatitis B; PEG-IFN treatment; treatment response prediction; pretreatment biomarker.
11.  Methylenetetrahydrofolate Reductase 677TT Genotype may be Associated with an Increased Lung Cancer Risk in North China: An Updated Meta 
Although many epidemiology studies have investigated the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their associations with lung cancer (LC), definite conclusions cannot be drawn. To clarify the effects of MTHFR polymorphisms on the risk of LC, we performed a meta-analysis in Chinese populations.
Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) until 16 February 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations.
A total of 11 studies with 2487 LC cases and 3228 controls were included in this meta-analysis. Overall, no significant association was found between MTHFR C677T polymorphism and LC risk when all studies in Chinese populations were pooled into this meta-analysis. In subgroup analyses stratified by geographical location and source of controls, significantly increased risk was found in North China (T vs. C: OR=1.28, 95% CI: 1.14–1.44; TT vs. CC: OR=1.67, 95% CI: 1.33–2.10; TT + CT vs. CC, OR=1.39, 95% CI=1.15–1.69; TT vs. CC + CT: OR=1.46, 95% CI: 1.03–2.06) and in population-based studies (TT vs. CC: OR=1.37, 95% CI: 1.14–1.65; TT vs. CC + CT: OR=1.25, 95% CI: 1.07–1.45).
This meta-analysis provides evidence that MTHFR C677T polymorphism may contribute to LC development in North China. Studies with larger sample sizes and wider spectrum of populations are warranted to verify this finding.
PMCID: PMC4285940  PMID: 25544260
5,10-Methylenetetrahydrofolate Reductase (FADH2); Lung Neoplasms; Meta-Analysis
12.  Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure 
World Journal of Gastroenterology : WJG  2014;20(48):18458-18465.
AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) for treating liver failure due to chronic hepatitis B.
METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a “tonifying qi and detoxification” (“TQD”) group (72 patients); and (3) a “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the “TQD” group were given a TCM formula “tonifying qi and detoxification” and general internal medicine treatment; patients in the “TTK” group were given a TCM formula of “TTK” and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.
RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, “TQD”, and “TTK” groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the “TTK” group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the “TQD” group and “TTK” group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the “TQD” group and one case of gastrointestinal side effect in the “TTK” group.
CONCLUSION: Treatment with “TTK” improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.
PMCID: PMC4277987  PMID: 25561817
Clinical study; “Tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”); Liver regeneration; Treatment with integrated traditional and Western medicine; Chronic hepatitis B-associated liver failure
13.  The Synergistic Repressive Effect of NF-κB and JNK Inhibitor on the Clonogenic Capacity of Jurkat Leukemia Cells 
PLoS ONE  2014;9(12):e115490.
Deregulation of Nuclear Transcription Factor-κB (NF-κB) and Jun N-terminal kinase (JNK) signaling is commonly detected in leukemia, suggesting an important role for these two signaling pathways in the pathogenesis of leukemia. In this study, using Jurkat cells, an acute T-lymphoblastic leukemia (T-ALL) cell line, we evaluated the effects of an NF-κB inhibitor and a JNK inhibitor individually and in combination on the proliferation, survival and clonogenic capacity of leukemic cells. We found that leukemic stem/progenitor cells (LSPCs) were more sensitive to NF-κB inhibitor treatment than were healthy hematopoietic stem/progenitor cells (HSPCs), as shown by a reduction in the clonogenic capacity of the former. Inactivation of NF-κB leads to the activation of JNK signaling in both leukemic cells and healthy HSPCs. Interestingly, JNK inhibitor treatment enhanced the repressive effects of NF-κB inhibitor on LSPCs but prevented such repression in HSPCs. Our data suggest that JNK signaling stimulates proliferation/survival in LSPCs but is a death signal in HSPCs. The combination of NF-κB inhibitor and JNK inhibitor might provide a better treatment for T-ALL leukemia by synergistically killing LSPCs while simultaneously preventing the death of normal HPCs.
PMCID: PMC4272284  PMID: 25526629
14.  Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer 
Scientific Reports  2014;4:7035.
Secreted protein acidic and rich in cysteine (SPARC) gene has been shown to be epigenetically silenced in several cancers. We investigated the loss of expression and promoter methylation of this tumor suppressor gene in gastric cancers and correlated the data with clinicopathological features. We observed the loss of SPARC mRNA and SPARC protein expression in 7 of 10 (70%) gastric cancer cell lines. Upon treatment of expression-negative cell lines with a demethylating agent, expression of mRNA and protein was restored in all cells. Methylation rate of SPARC gene was 80% in ten gastric cancer cell lines and 74% (163 of 220) in primary tumors, while it was 5% in normal gastric mucosa (n = 40). In intestinal gastric cancer, SPARC methylation correlated with a negative prognosis (P < 0.001; relative risk 2.754, 95% confidence interval 1.780–4.261). Immunostaining revealed that SPARC protein was overexpressed in stromal fibroblasts adjacent to neoplastic epithelium but rarely expressed in the primary gastric cancer cells. These results implicate SPARC promoter methylation as an important factor in the tumorigenesis of gastric carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and the potential clinical importance in human gastric cancers.
PMCID: PMC4268651  PMID: 25516351
15.  Free-standing Fe2O3 nanomembranes enabling ultra-long cycling life and high rate capability for Li-ion batteries 
Scientific Reports  2014;4:7452.
With Fe2O3 as a proof-of-concept, free-standing nanomembrane structure is demonstrated to be highly advantageous to improve the performance of Li-ion batteries. The Fe2O3 nanomembrane electrodes exhibit ultra-long cycling life at high current rates with satisfactory capacity (808 mAh g−1 after 1000 cycles at 2 C and 530 mAh g−1 after 3000 cycles at 6 C) as well as repeatable high rate capability up to 50 C. The excellent performance benefits particularly from the unique structural advantages of the nanomembranes. The mechanical feature can buffer the strain of lithiation/delithiation to postpone the pulverization. The two-dimensional transport pathways in between the nanomembranes can promote the pseudo-capacitive type storage. The parallel-laid nanomembranes, which are coated by polymeric gel-like film and SEI layer with the electrolyte in between layers, electrochemically behave like numerous “mini-capacitors” to provide the pseudo-capacitance thus maintain the capacity at high rate.
PMCID: PMC4264016  PMID: 25503055
16.  Secular trends in age at menarche among women born between 1955 and 1985 in Southeastern China 
BMC Women's Health  2014;14(1):1.
Improvements in socioeconomic conditions and population health have been linked to declining age at menarche. In China, secular trends in age at menarche following extensive economic reform during recent decades have not been thoroughly investigated. This study examined the overall trend in age at menarche and assessed differences in the rate of change of age at menarche over time, and between urban and rural populations and education levels in southeastern China.
Age at menarche was retrospectively collected from 1,167,119 Han Chinese women born 1955–1985, who registered in the Perinatal Health Care Surveillance System in 19 cities and counties in two southeast provinces during 1993–2005. Multivariable linear regression was used to estimate trends in age at menarche overall and stratified by urban/rural residence and education level.
Age at menarche declined by 0.33 [95% CI 0.33, 0.32] years/decade overall, with the fastest decline in women born in 1966–1975. For the earliest birth cohorts (1955–1965), age at menarche declined faster in urban versus rural regions, and for women with high school education or above versus primary school or less. In contrast, age at menarche declined slower among urban women born 1976–1985, and among those with higher education born 1966–1985.
Mean age at menarche declined for women born in 1955–1985 in southeast China. Further study is warranted to identify specific factors contributing to earlier age at menarche and associated health outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12905-014-0155-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4275952
Epidemiology; Puberty; Menarcheal age; Socio-economic status; China
17.  Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML 
The Journal of Experimental Medicine  2014;211(6):1093-1108.
TNF signaling inactivation sensitizes AML cells to NF-kB inhibition but protects healthy hematopoietic stem progenitor cells from this treatment.
Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK–AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF–JNK–AP1 signaling pathway. Our data suggest that co-inhibition of both TNF–JNK–AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
PMCID: PMC4042653  PMID: 24842373
18.  HOTAIR, a cell cycle–associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma 
Neuro-Oncology  2013;15(12):1595-1603.
Long noncoding RNA Hox transcript antisense intergenic RNA (HOTAIR) has been characterized as a negative prognostic factor in breast and colon cancer patients. The clinical significance and function of HOTAIR in glioma remains unclear.
We analyzed the clinical significance of HOTAIR in 3 different glioma cohorts with gene expression data, including correlation with tumor grade, prognosis, and molecular subtype. The function of HOTAIR in glioma was explored by performing gene set enrichment analysis and in vitro and in vivo experiments.
HOTAIR expression was closely associated with glioma grade and poor prognosis. Multivariate Cox regression analysis revealed that HOTAIR was an independent prognostic factor in glioblastoma multiforme patients. HOTAIR expression correlated with glioma molecular subtype, including those of The Cancer Genome Atlas. HOTAIR was preferentially expressed in the classical and mesenchymal subtypes compared with the neural and proneural subtypes. A gene set enrichment analysis designed to show gene set differences between patients with high and low HOTAIR expression indicated that HOTAIR expression was associated with gene sets involved in cell cycle progression. HOTAIR reduction induced colony formation suppression, cell cycle G0/G1 arrest, and orthotopic tumor growth inhibition.
Our data establish that HOTAIR is an important long noncoding RNA that primarily serves as a prognostic factor for glioma patient survival, as well as a biomarker for identifying glioma molecular subtypes, a critical regulator of cell cycle progression.
PMCID: PMC3829598  PMID: 24203894
cell cycle; glioma; HOTAIR; molecular subtype; survival
19.  Advances in the understanding of the Fanconi anemia tumor suppressor pathway 
Cancer Biology & Therapy  2013;14(12):1089-1091.
Extremely high cancer incidence in Fanconi anemia (FA) patients has long suggested that the FA signaling pathway is a tumor suppressor pathway. Indeed, our recent findings, for the first time, indicate that the FA pathway plays a significant role in suppressing the development of non-FA human cancer. Also our studies on FA group D2 protein (FANCD2) have, among the first, documented the crosstalks between the FA and Rad6/Rad18 (HHR6) pathways upon DNA damage. In this review, we will discuss how our studies enhance the understanding of the FA tumor suppressor pathway.
PMCID: PMC3912030  PMID: 24025411
the FA tumor suppressor pathway; Rad6/Rad18 pathway; DNA damage; DNA polymerase eta; translesion synthesis; non-FA human tumors
20.  p27kip1 Maintains a Subset of Leukemia Stem Cells in the Quiescent State in Murine MLL-Leukemia 
Molecular oncology  2013;7(6):1069-1082.
MLL (mixed-lineage leukemia)-fusion genes induce the development of leukemia through deregulation of normal MLL target genes, such as HOXA9 and MEIS1. Both HOXA9 and MEIS1 are required for MLL-fusion gene-induced leukemogenesis. Co-expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL-fusion genes are over-expressed. p27kip1 (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up-regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL-leukemia, we examined the effects of p27 deletion (p27-/-) on MLL-AF9 (MA9)-induced murine AML development. HOXA9/MEIS1 (H/M)-induced, p27 wild-type (p27+/+) and p27-/- AML were studied in parallel as controls. We found that LCs from both MA9-AML and H/M-AML can be separated into three fractions, a CD117-CD11bhi differentiated fraction as well as CD117+CD11bhi and CD117+CD11blo, two less differentiated fractions. The CD117+CD11blo fraction, comprising only 1-3% of total LCs, expresses higher levels of early hematopoietic progenitor markers but lower levels of mature myeloid cell markers compared to other populations of LCs. p27 is expressed and is required for maintaining the quiescent and drug-resistant states of the CD117+CD11blo fraction of MA9-LCs but not of H/M-LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117+CD11blo MA9-LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H/M-LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117-CD11bhi fraction in both types of LCs. Furthermore, we found that c-Myc expression is required for maintaining LCs in an undifferentiated state independently of proliferation. We concluded that p27 represses the proliferation of LCs, which is specifically required for maintaining the quiescent and drug-resistant states of a small subset of MA9-LSCs in collaboration with the differentiation blockage function of c-Myc.
PMCID: PMC3898829  PMID: 23988911
MLL-leukemia; p27kip1; leukemia stem cell; quiescence
21.  Vitamin D Status and Related Factors in Newborns in Shanghai, China 
Nutrients  2014;6(12):5600-5610.
With the increasing recognition of the importance of the non-skeletal effects of vitamin D (VitD), more and more attention has been drawn to VitD status in early life. However, the VitD status of newborns and factors that influence VitD levels in Shanghai, China, remain unclear. A total of 1030 pregnant women were selected from two hospitals in Shanghai, one of the largest cities in China located at 31 degrees north latitude. Umbilical cord serum concentrations of 25-hydroxy vitamin D [25(OH)D] were measured by LC-MS-MS, and questionnaires were used to collect information. The median cord serum 25(OH)D concentration was 22.4 ng/mL; the concentration lower than 20 ng/mL accounted for 36.3% of the participants, and the concentration lower than 30 ng/mL for 84.1%. A multivariable logistic regression model showed that the determinants of low 25(OH)D status were being born during autumn or winter months and a lack of VitD-related multivitamin supplementation. The relative risk was 1.7 for both autumn (95% CI, 1.1–2.6) and winter (95% CI, 1.1–2.5) births (p < 0.05). VitD-related multivitamin supplementation more than once a day during pregnancy reduced the risk of VitD deficiency [adjusted OR (aOR) = 0.6, 95% CI (0.45–1.0) for VitD supplementation] (p < 0.05). VitD deficiency and insufficiency are common in newborns in Shanghai, China, and are independently associated with season and VitD supplementation. Our findings may assist future efforts to correct low levels of 25(OH)D in Shanghai mothers and their newborn children.
PMCID: PMC4276986  PMID: 25486368
vitamin D; related factors; newborn
22.  A Pyridine-Containing Cu2+-Selective Probe Based on Naphthalimide Derivative 
Sensors (Basel, Switzerland)  2014;14(12):24146-24155.
A new fluorescent probe P derived from naphthalimide bearing a pyridine group has been synthesized and characterized. The proposed probe P shows high selectivity and sensitivity to Cu2+ in aqueous media. Under optimized conditions, the linear response of P (2 μM) toward Cu2+ was 0.05–0.9 μM in ethanol-water solution (3:2, v:v, 50 mM HEPES, pH 7.4), and the detection limit was 0.03 μM.
PMCID: PMC4299103  PMID: 25517693
fluorescent probe; naphthalimide; Cu2+; schiff base; pyridine
23.  Recognizing Objects in 3D Point Clouds with Multi-Scale Local Features 
Sensors (Basel, Switzerland)  2014;14(12):24156-24173.
Recognizing 3D objects from point clouds in the presence of significant clutter and occlusion is a highly challenging task. In this paper, we present a coarse-to-fine 3D object recognition algorithm. During the phase of offline training, each model is represented with a set of multi-scale local surface features. During the phase of online recognition, a set of keypoints are first detected from each scene. The local surfaces around these keypoints are further encoded with multi-scale feature descriptors. These scene features are then matched against all model features to generate recognition hypotheses, which include model hypotheses and pose hypotheses. Finally, these hypotheses are verified to produce recognition results. The proposed algorithm was tested on two standard datasets, with rigorous comparisons to the state-of-the-art algorithms. Experimental results show that our algorithm was fully automatic and highly effective. It was also very robust to occlusion and clutter. It achieved the best recognition performance on all of these datasets, showing its superiority compared to existing algorithms.
PMCID: PMC4299104  PMID: 25517694
object recognition; point cloud; local feature; clutter; occlusion
24.  The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway 
Cancer Cell International  2014;14(1):126.
The mechanism underlying the differential cytotoxicity of curcumin in various cancer types, however, remains largely unclear. The aims of this study is to examine the concentration- and time-related effects of curcumin on two different breast cancer cells, MCF-7 and MDA-MB-231, and investigated the functional changes induced by curcumin treatment, as well as their relationship to the PI3K/Akt-SKP2-Cip/Kips pathway.
First, WST-1 and clonogenic assay were performed to determine the cytotoxicity of curcumin in MCF-7 and MDA-MB-231 cells. Then, the expression of CDK interacting protein/Kinase inhibitory protein (Cip/Kips) members (p27, p21 and p57) and S-phase kinase-associated protein-2 (SKP2) was investigated by QRT PCR and Western Blotting. Curcumin’s effect on PI3K (phosphatidylinositol 3-kinase) /Akt and its substrates Foxo1 and Foxo3a were then studied by Western Blotting. Small interfering RNAs (siRNAs) targeting SKP2 was used to explore the relationship between SKP2 and Cip/Kips members. Finally, WST-1 assay was tested to explore the concomitant treatment with curcumin and the inhibition of PKB or SKP2 signaling on curcumin sensitivity in MCF-7 and MDA-MB-231 cells.
We demonstrated MCF-7 and MDA-MB-231 cells exhibited differential responses to curcumin by WST-1 and clonogenic assay (MDA-MB-231 cells was sensitive, and MCF-7 cells was resistant), which were found to be related to the differential curcumin-mediated regulation of SKP2-Cip/Kips (p21 and p27 but not p57) signaling. The differential cellular responses were further linked to the converse effects of curcumin on PI3K/Akt and its substrates Foxo1 and Foxo3a. Importantly, PI3K inhibitor wortmannin could counteract both curcumin-induced phosphorylation of Akt and up-regulation of SKP2 in MCF-7 cells. Subsequent WST-1 assay demonstrated concomitant treatment with curcumin and wortmannin or SKP2 siRNA not only further augmented curcumin sensitivity in MDA-MB-231 cells but also overcame curcumin resistance in MCF-7 cells.
Our study established PI3K/Akt-SKP2-Cip/Kips signaling pathway is involved in the mechanism of action of curcumin and revealed that the discrepant modulation of this pathway by curcumin is responsible for the differential susceptibilities of these two cell types to curcumin.
PMCID: PMC4272549  PMID: 25530715
Curcumin sensitivity; Breast cancer; PI3K; SKP2; FOXO; Cip/Kips
25.  Unusual synchronous skeletal muscle and lung metastasis in papillary thyroid cancer: A case report and review of the literature 
Oncology Letters  2014;9(2):727-730.
Papillary thyroid cancer (PTC) frequently metastasizes to the cervical lymph region and less often to the lung and bone. Metastasis to the skeletal muscles from PTC is extremely rare, especially concurrent lung and skeletal muscle metastases. The present study reports the case of a 31-year-old man with synchronous metastasis to the skeletal muscle and lung from PTC, six years following total thyroidectomy and consecutive 131Iodine treatments. Magnetic resonance imaging (MRI) revealed a 1.7×1.2×1.5 cm mass in the left gastrocnemius muscle, indicating a neurogenic tumor. The mass was subsequently resected and confirmed via histopathology to be metastatic PTC. We propose that, in the follow-up of patients with PTC, the measurable serum thyroglobulin level, whole body scan and other imaging modalities including MRI or positron emission tomography/computed tomography, must be closely monitored for potential distant metastases, particularly in cases of PTC with aggressive pathological behavior.
PMCID: PMC4301470  PMID: 25621043
papillary thyroid cancer; skeletal muscle metastasis; lung metastasis

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