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1.  Association of Leukocyte Telomere Length With Breast Cancer Risk: Nested Case-Control Findings From the Shanghai Women's Health Study 
American Journal of Epidemiology  2013;177(7):617-624.
Telomeres are specialized chromatin structures essential for the maintenance of chromosomal integrity and stability. Telomere shortening has been linked to multiple aging-related diseases, including cancer. Evidence associating telomere length with breast cancer risk—most of which has been from retrospective case-control studies—is conflicting. We conducted a nested case-control study based on the Shanghai Women's Health Study (1997–2009) in which we evaluated the association of telomere length and breast cancer risk using peripheral blood samples collected before cancer diagnosis (601 cases and 695 controls). We used monochrome multiplex quantitative polymerase chain reaction to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios with 95% confidence intervals as the measure of association. Telomere length was inversely correlated with age (r = −0.22). Women with moderately long telomeres (those in the fourth quintile) had the lowest breast cancer risk. Risk increased in a dose-response manner with decreasing quintile of telomere length; odds ratios were 1.39 (95% confidence interval (CI): 0.95, 2.04), 1.79 (95% CI: 1.17, 2.75), and 2.39 (95% CI: 1.45, 3.92), respectively, for the third, second, and first quintiles compared with the fourth quintile. A slightly elevated risk of breast cancer (odds ratio = 1.35, 95% CI: 0.90, 2.04), although one that was not statistically significant, was found in the top quintile (longest telomeres). Our results support the hypothesis that telomere shortening is associated with increased risk of breast cancer and suggest a possible elevated risk associated with long telomeres.
doi:10.1093/aje/kws291
PMCID: PMC3657533  PMID: 23444102
breast cancer; biomarkers; epidemiology; genetic factors; telomere
2.  Role of Investment Heterogeneity in the Cooperation on Spatial Public Goods Game 
PLoS ONE  2014;9(3):e91012.
Public cooperation plays a significant role in the survival and maintenance of biological species, to elucidate its origin thus becomes an interesting question from various disciplines. Through long-term development, the public goods game has proven to be a useful tool, where cooperator making contribution can beat again the free-rides. Differentiating from the traditional homogeneous investment, individual trend of making contribution is more likely affected by the investment level of his neighborhood. Based on this fact, we here investigate the impact of heterogeneous investment on public cooperation, where the investment sum is mapped to the proportion of cooperators determined by parameter . Interestingly, we find, irrespective of interaction networks, that the increment of (increment of heterogeneous investment) is beneficial for promoting cooperation and even guarantees the complete cooperation dominance under weak replication factor. While this promotion effect can be attributed to the formation of more robust cooperator clusters and shortening END period. Moreover, we find that this simple mechanism can change the potential interaction network, which results in the change of phase diagrams. We hope that our work may shed light on the understanding of the cooperative behavior in other social dilemmas.
doi:10.1371/journal.pone.0091012
PMCID: PMC3954582  PMID: 24632779
3.  Ratiometric electrochemical proximity assay for sensitive one-step protein detection 
Scientific Reports  2014;4:4360.
This work proposes the concept of ratiometric electrochemical proximity assay (REPA), which can be used for one-step, highly sensitive and selective detection of protein. The assay strategy was achieved on a sensing interface that was formed by hybridization of methylene blue (MB)-labeled antibody-DNA probe (MB-DNA1-Ab1) with ferrocene (Fc)-labeled DNA capture probe (Fc-P) modified gold electrode. On the interface the target protein could trigger the formation of immunocomplex between MB-DNA1-Ab1 and detection antibody-DNA probe (Ab2-DNA2) and subsequently the proximity hybridization of DNA1-DNA2, which led to the departure of MB-DNA1-Ab1 from the interface. The remained Fc-P could form a hairpin structure to take Fc group to electrode surface. Therefore, the recognition of target protein to Ab1 and Ab2 resulted in both the “signal-off” of MB and the “signal-on” of Fc for dual-signal electrochemical ratiometric readout. The proposed REPA could be carried out in one-step with 40-min duration and showed a wide detection range from 0.05 to 100 ng/mL with pg/mL limit of detection, displaying great potential for convenient point-of-care testing and commercial application.
doi:10.1038/srep04360
PMCID: PMC3950580  PMID: 24618513
4.  Association of gyrA/B mutations and resistance levels to fluoroquinolones in clinical isolates of Mycobacterium tuberculosis 
To evaluate the association between mutations in the genes gyrA/B and resistance levels to fluoroquinolones in clinical isolates of Mycobacterium tuberculosis, a total of 80 ofloxacin-resistant isolates collected in 2009 by the Shanghai Municipal Centers for Disease Control and Prevention were studied. The minimum inhibitory concentration (MIC) of ofloxacin, moxifloxacin and gatifloxacin for each isolate was determined using the microscopic observation drug susceptibility assay. Sequencing was used to identify mutations in the quinolone resistance-determining region (QRDR) of the gyrA and gyrB genes. In total, 68 isolates had mutations in gyrA, three isolates had mutations in gyrB, six isolates had mutations in both gyrA and gyrB, and three isolates had no mutations. Two common mutations in gyrA, the D94G and D94N mutations, were associated with higher-level resistance to all three fluoroquinolones than two other common mutations (A90V and D94A). Understanding the relationship between MICs and mutations in ofloxacin-resistant isolates will facilitate the optimization of the use of new-generation fluoroquinolones to treat patients with ofloxacin-resistant tuberculosis (TB).
doi:10.1038/emi.2014.21
PMCID: PMC3974338
fluoroquinolones; MICs; M. tuberculosis; mutations
5.  Correction: Network Evolution Induced by Asynchronous Stimuli through Spike-Timing-Dependent Plasticity 
PLoS ONE  2014;9(1):10.1371/annotation/417c1eb3-1de1-4d04-8c1d-3f73ffc57f26.
doi:10.1371/annotation/417c1eb3-1de1-4d04-8c1d-3f73ffc57f26
PMCID: PMC3905992
6.  Growth Arrest Specific 2 Is Up-Regulated in Chronic Myeloid Leukemia Cells and Required for Their Growth 
PLoS ONE  2014;9(1):e86195.
Although the generation of BCR-ABL is the molecular hallmark of chronic myeloid leukemia (CML), the comprehensive molecular mechanisms of the disease remain unclear yet. Growth arrest specific 2 (GAS2) regulates multiple cellular functions including cell cycle, apoptosis and calpain activities. In the present study, we found GAS2 was up-regulated in CML cells including CD34+ progenitor cells compared to their normal counterparts. We utilized RNAi and the expression of dominant negative form of GAS2 (GAS2DN) to target GAS2, which resulted in calpain activity enhancement and growth inhibition of both K562 and MEG-01 cells. Targeting GAS2 also sensitized K562 cells to Imatinib mesylate (IM). GAS2DN suppressed the tumorigenic ability of MEG-01 cells and impaired the tumour growth as well. Moreover, the CD34+ cells from CML patients and healthy donors were transduced with control and GAS2DN lentiviral vectors, and the CD34+ transduced (YFP+) progeny cells (CD34+YFP+) were plated for colony-forming cell (CFC) assay. The results showed that GAS2DN inhibited the CFC production of CML cells by 57±3% (n = 3), while affected those of normal hematopoietic cells by 31±1% (n = 2). Next, we found the inhibition of CML cells by GAS2DN was dependent on calpain activity but not the degradation of beta-catenin. Lastly, we generated microarray data to identify the differentially expressed genes upon GAS2DN and validated that the expression of HNRPDL, PTK7 and UCHL5 was suppressed by GAS2DN. These 3 genes were up-regulated in CML cells compared to normal control cells and the growth of K562 cells was inhibited upon HNRPDL silence. Taken together, we have demonstrated that GAS2 is up-regulated in CML cells and the inhibition of GAS2 impairs the growth of CML cells, which indicates GAS2 is a novel regulator of CML cells and a potential therapeutic target of this disease.
doi:10.1371/journal.pone.0086195
PMCID: PMC3897655  PMID: 24465953
7.  Correlates of 25-Hydroxyvitamin D among Chinese Breast Cancer Patients 
PLoS ONE  2014;9(1):e86467.
Background
Few studies have investigated vitamin D status in association with modifiable lifestyle factors and clinical characteristics among breast cancer patients, with no studies among Chinese women, who may be at higher risk of vitamin D deficiency. We aimed to evaluate circulating 25-hydroxyvitamin D (25(OH)D) levels in association with clinical and lifestyle factors among 1,940 Chinese breast cancer patients.
Methods
Participants included breast cancer cases aged 22–77 from a population-based case-control study conducted in Shanghai, China during 1996–1998 (n = 1,044) and 2002–2005 (n = 896). Circulating 25(OH)D levels were measured in plasma samples (95% collected ≤6 months post-diagnosis). Prevalence ORs and 95% CIs were derived from multinomial logistic regression models, adjusting for age, season, and other factors.
Results
About 23% and 48% of women were vitamin D deficient (<30 nmol/L) or insufficient (30–50 nmol/L), respectively. Tumor characteristics were not associated with vitamin D status. Higher BMI was associated with increased odds of vitamin D deficiency (ORs (95% CIs): 1 (reference), 1.12 (0.85,1.47), and 1.57 (1.02,2.42), for <23, 23–<27.5, and ≥27.5 kg/m2, respectively, Ptrend <0.06). Total physical activity was associated with reduced odds of vitamin D deficiency (ORs (95% CIs):1 (reference), 0.84 (0.59,1.20), 0.65 (0.45,0.93), and 0.69 (0.48,1.00), for <7.65, 7.65–<10.6, 10.6–<13.5, ≥13.5 MET-hours/day, respectively, Ptrend <0.02). Smoking was associated with vitamin D insufficiency and deficiency (ORs (95% CIs): 2.50 (1.07,5.84) and 2.78 (1.11,6.95), respectively).
Conclusions
In the largest study to date, the prevalence of low vitamin D status was high among Chinese breast cancer patients and associated with higher BMI, smoking, and lower physical activity. Our findings support careful monitoring of vitamin D status and recommendations for supplementation and other lifestyle modifications that may improve vitamin D status in breast cancer patients.
doi:10.1371/journal.pone.0086467
PMCID: PMC3897707  PMID: 24466109
8.  Systemic Spread and Propagation of a Plant-Pathogenic Virus in European Honeybees, Apis mellifera 
mBio  2014;5(1):e00898-13.
ABSTRACT
Emerging and reemerging diseases that result from pathogen host shifts are a threat to the health of humans and their domesticates. RNA viruses have extremely high mutation rates and thus represent a significant source of these infectious diseases. In the present study, we showed that a plant-pathogenic RNA virus, tobacco ringspot virus (TRSV), could replicate and produce virions in honeybees, Apis mellifera, resulting in infections that were found throughout the entire body. Additionally, we showed that TRSV-infected individuals were continually present in some monitored colonies. While intracellular life cycle, species-level genetic variation, and pathogenesis of the virus in honeybee hosts remain to be determined, the increasing prevalence of TRSV in conjunction with other bee viruses from spring toward winter in infected colonies was associated with gradual decline of host populations and winter colony collapse, suggesting the negative impact of the virus on colony survival. Furthermore, we showed that TRSV was also found in ectoparasitic Varroa mites that feed on bee hemolymph, but in those instances the virus was restricted to the gastric cecum of Varroa mites, suggesting that Varroa mites may facilitate the spread of TRSV in bees but do not experience systemic invasion. Finally, our phylogenetic analysis revealed that TRSV isolates from bees, bee pollen, and Varroa mites clustered together, forming a monophyletic clade. The tree topology indicated that the TRSVs from arthropod hosts shared a common ancestor with those from plant hosts and subsequently evolved as a distinct lineage after transkingdom host alteration. This study represents a unique example of viruses with host ranges spanning both the plant and animal kingdoms.
IMPORTANCE
Pathogen host shifts represent a major source of new infectious diseases. Here we provide evidence that a pollen-borne plant virus, tobacco ringspot virus (TRSV), also replicates in honeybees and that the virus systemically invades and replicates in different body parts. In addition, the virus was detected inside the body of parasitic Varroa mites, which consume bee hemolymph, suggesting that Varroa mites may play a role in facilitating the spread of the virus in bee colonies. This study represents the first evidence that honeybees exposed to virus-contaminated pollen could also be infected and raises awareness of potential risks of new viral disease emergence due to host shift events. About 5% of known plant viruses are pollen transmitted, and these are potential sources of future host-jumping viruses. The findings from this study showcase the need for increased surveillance for potential host-jumping events as an integrated part of insect pollinator management programs.
doi:10.1128/mBio.00898-13
PMCID: PMC3903276  PMID: 24449751
9.  Network Evolution Induced by Asynchronous Stimuli through Spike-Timing-Dependent Plasticity 
PLoS ONE  2013;8(12):e84644.
In sensory neural system, external asynchronous stimuli play an important role in perceptual learning, associative memory and map development. However, the organization of structure and dynamics of neural networks induced by external asynchronous stimuli are not well understood. Spike-timing-dependent plasticity (STDP) is a typical synaptic plasticity that has been extensively found in the sensory systems and that has received much theoretical attention. This synaptic plasticity is highly sensitive to correlations between pre- and postsynaptic firings. Thus, STDP is expected to play an important role in response to external asynchronous stimuli, which can induce segregative pre- and postsynaptic firings. In this paper, we study the impact of external asynchronous stimuli on the organization of structure and dynamics of neural networks through STDP. We construct a two-dimensional spatial neural network model with local connectivity and sparseness, and use external currents to stimulate alternately on different spatial layers. The adopted external currents imposed alternately on spatial layers can be here regarded as external asynchronous stimuli. Through extensive numerical simulations, we focus on the effects of stimulus number and inter-stimulus timing on synaptic connecting weights and the property of propagation dynamics in the resulting network structure. Interestingly, the resulting feedforward structure induced by stimulus-dependent asynchronous firings and its propagation dynamics reflect both the underlying property of STDP. The results imply a possible important role of STDP in generating feedforward structure and collective propagation activity required for experience-dependent map plasticity in developing in vivo sensory pathways and cortices. The relevance of the results to cue-triggered recall of learned temporal sequences, an important cognitive function, is briefly discussed as well. Furthermore, this finding suggests a potential application for examining STDP by measuring neural population activity in a cultured neural network.
doi:10.1371/journal.pone.0084644
PMCID: PMC3877323  PMID: 24391971
10.  The High Prevalence of Vitamin D Deficiency and Its Related Maternal Factors in Pregnant Women in Beijing 
PLoS ONE  2013;8(12):e85081.
Maternal vitamin D deficiency has been suggested to influence fetal and neonatal health. Little is known about vitamin D status in Chinese pregnant women. The purpose of this study was to assess the vitamin D status of pregnant women residing in Beijing in winter and evaluate the impact of maternal factors on serum 25-hydroxyvitamin D [25(OH)D] levels. The study was conducted on 125 healthy pregnant women. For each individual, data concerning pre-pregnancy weight, educational status, use of multivitamins and behavioral factors such as daily duration of computer use, walking and sun exposure were obtained. Serum concentrations of 25(OH)D were measured by enzyme-linked immunosorbent assay. The prevalence of vitamin D deficiency (25(OH)D < 50 nmol/L) was 96.8% and almost half (44.8%) of women were severely vitamin D deficiency (25(OH)D < 25 nmol/L). The concentration of 25(OH)D was lower in women with shorter duration of sun exposure (≤ 0.5 h/day, 25.3 ± 8.9 nmol/L) than that in women with longer duration of sun exposure (> 0.5 h/day; 30.3± 9.5 nmol/L; P = 0.003). Thirty six women (28.8%) had sun exposure duration ≥ 1.5h/day. The 25(OH)D concentration in these women was 31.5 ± 9.4 nmol/L which was also much lower than the normal level. Women who reported taking a multivitamin supplement had significantly higher 25(OH)D concentrations (32.3 ± 9.5 nmol/L) when compared with non-users (24.9 ± 8.2 nmol/L; P < 0.001). Pregnant women in Beijing are at very high risk of vitamin D deficiency in winter. Duration of Sun exposure and the use of multivitamin were the most important determinants for vitamin D status. However, neither prolonging the time of sunlight exposure nor multivitamin supplements can effectively prevent pregnant women from vitamin D deficiency. Other measures might have to be taken for pregnant women to improve their vitamin D status in winter.
doi:10.1371/journal.pone.0085081
PMCID: PMC3873449  PMID: 24386450
11.  Rapid microsatellite development for tree peony and its implications 
BMC Genomics  2013;14:886.
Background
Microsatellites are ubiquitous in genomes of various organisms. With the realization that they play roles in developmental and physiological processes, rather than exist as ‘junk’ DNA, microsatellites are receiving increasing attention. Next-generation sequencing allows acquisition of large-scale microsatellite information, and is especially useful for plants without reference genome sequences.
Results
In this study, enriched DNA libraries of tree peony, a well-known ornamental woody shrub, were used for high-throughput microsatellite development by 454 GS-FLX Titanium pyrosequencing. We obtained 675,221 reads with an average length of 356 bp. The total size of examined sequences was 240,672,018 bp, from which 237,134 SSRs were identified. Of these sequences, 164,043 contained SSRs, with 27% featuring more than one SSR. Interestingly, a high proportion of SSRs (43%) were present in compound formation. SSRs with repeat motifs of 1–4 bp (mono-, di-, tri-, and tetra-nucleotide repeats) accounted for 99.8% of SSRs. Di-nucleotide repeats were the most abundant. As in most plants, the predominant motif in tree peony was (A/T)n, with (G/C)n less common. The lengths of SSRs were classified into 11 groups. The shortest SSRs (10 bp) represented 1% of the total number, whereas SSRs 21–30 and 101–110 bp long accounted for 26% and 29%, respectively, of all SSRs. Many sequences (42,111) were mapped to CDS (coding domain sequence) regions using Arabidopsis as a reference. GO annotation analysis predicted that CDSs with SSRs performed various functions associated with cellular components, molecular functions, and biological processes. Of 100 validated primer pairs, 24 were selected for polymorphism analysis among 23 genotypes; cluster analysis of the resulting data grouped genotypes according to known relationships, confirming the usefulness of the developed SSR markers.
Conclusions
The results of our large-scale SSR marker development using tree peony are valuable for investigating plant genomic structural evolution and elucidating phenotypic variation in this species during its evolution and artificial selection. The newly identified SSRs should be useful for genetic linkage map construction, QTL mapping, gene location and cloning, and molecular marker-assisted breeding. In addition, the genome-wide marker resources generated in this study should aid genomic studies of tree peony and related species.
doi:10.1186/1471-2164-14-886
PMCID: PMC3878651  PMID: 24341681
zzzMicrosatellite; Next-generation sequencing; Tree peozzzzny; Ornamental; SSR marker
12.  Angiotensin-converting enzyme gene 2350 G/A polymorphism and susceptibility to atrial fibrillation in Han Chinese patients with essential hypertension 
Clinics  2013;68(11):1428-1432.
OBJECTIVE:
The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension.
METHODS:
A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies.
RESULTS:
The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively).
CONCLUSIONS:
The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension.
doi:10.6061/clinics/2013(11)08
PMCID: PMC3812555  PMID: 24270955
Angiotensin-converting enzyme; Genetic polymorphism; Atrial fibrillation; Essential hypertension; China
13.  JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations 
Scientific Reports  2013;3:3042.
Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer.
doi:10.1038/srep03042
PMCID: PMC3807107  PMID: 24154688
14.  A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation 
The Journal of Neuroscience  2013;33(17):7253-7263.
There is a significantly elevated incidence of epilepsy in Alzheimer's disease (AD). Moreover, there is neural hyperexcitation/synchronization in transgenic mice expressing abnormal levels or forms of amyloid precursor protein and its presumed, etiopathogenic product, amyloid-β1–42 (Aβ). However, the underlying mechanisms of how Aβ causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of Aβ induces Aβ form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, Aβ exposure increases levels of nicotinic acetylcholine receptor (nAChR) α7 subunit protein on the cell surface and α7-nAChR function, but not α7 subunit mRNA, suggesting post-translational upregulation of functional α7-nAChRs. These effects are prevented upon coexposure to brefeldin A, an inhibitor of endoplasmic reticulum-to-Golgi protein transport, consistent with an effect on trafficking of α7 subunits and assembled α7-nAChRs to the cell surface. Aβ exposure-induced α7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an α7-nAChR antagonist or genetic deletion of nAChR α7 subunits prevents induction and expression of neuronal hyperexcitation. Collectively, these results, confirmed in studies using slice cultures, indicate that functional activity and perhaps functional upregulation of α7-nAChRs are necessary for production of Aβ-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving α7-nAChRs in mediation of Aβ effects provides potentially new therapeutic targets for treatment of AD.
doi:10.1523/JNEUROSCI.3235-12.2013
PMCID: PMC3865500  PMID: 23616534
15.  Association of leukocyte telomere length with colorectal cancer risk: nested case-control findings from the Shanghai Women's Health Study 
Background
Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Abnormal alteration of telomere length has been linked to several cancers; however, epidemiologic evidence regarding the association of telomere length with colorectal cancer risk has been conflicting.
Methods
We conducted a nested case-control study to evaluate the association between telomere length and colorectal cancer risk using peripheral blood samples collected prior to cancer diagnosis. The study included 441 women with incident colorectal cancer and 549 matched controls. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios (OR) with 95% confidence intervals (CI) as the measure of association between telomere length and subsequent colorectal cancer risk.
Results
A U-shaped association was observed between telomere length and colorectal cancer risk (test for nonlinearity P = 0.0112). Women with telomere length in the third quintile (40th to 60th percentiles) had the lowest risk of colorectal cancer, and the risks were elevated with a shorter or longer telomere length. This U-shaped association did not statistically differ for colon cancer and rectum cancer.
Conclusions and Impact
Our prospective study revealed a U-shaped association between telomere length in peripheral blood cells and colorectal cancer risk. Our findings provide strong evidence that both very short and very long telomeres are associated with increased risk of colorectal cancer.
doi:10.1158/1055-9965.EPI-12-0657
PMCID: PMC3467322  PMID: 22911335
16.  Mapping Single Cell-Substrate Interactions by Surface Plasmon Resonance Microscopy 
We report on imaging of cell-substrate adhesion of a single cell with sub-cellular spatial resolution. Osmotic pressure was introduced to provide a controllable mechanical stimulation to the cell attached to a substrate, and high-resolution surface plasmon resonance microscopy was used to map the response of the cell, from which local cell-substrate adhesion was determined. In addition to high spatial resolution, the approach is non-invasive and fast, and allows for continuously mapping of cell-substrate interactions and single cell movements.
doi:10.1021/la301712h
PMCID: PMC3660850  PMID: 22920036
Single cell imaging; Surface Plasmon Resonance imaging; osmotic effect; cell adhesion
17.  Selective endoscopic ligation for treatment of upper gastrointestinal protuberant lesions 
This study explored the clinical value of endoscopic ligation for the treatment of upper gastrointestinal (GI) protuberant lesions in children. According to the appearance and size of lesions, we used different ligation techniques for the treatment of the lesions. Endoscopic ultrasonography was used for preliminary characterization of the lesions. One case diagnosed with Peutz-Jeghers syndrome was successfully treated by a detachable snare. Two cases with semi-pedunculated or broad-base lesions originating from the submucosal layer of the upper GI were treated with endoscopic variceal ligation; endoscopic examination showed that one case had complete healing 11 wk after ligation, while an ulcer scar was observed at the ligation site after 6 wk in the other case. All lesions were successfully ligated at the first attempt. No significant complications occurred either during or after the procedure. Selective endoscopic ligation of upper GI lesions is an effective and safe treatment for upper GI protuberant lesions in children.
doi:10.3748/wjg.v19.i33.5581
PMCID: PMC3761114  PMID: 24023504
Endoscopy; Ligation; Endoscopic ultrasonography; Protuberant lesion; Children
18.  4-Eth­oxy-N-(4-eth­oxy­phen­yl)-N-(4-nitro­phen­yl)aniline 
In the title mol­ecule, C22H22N2O4, the eth­oxy­phenyl rings are oriented at dihedral angles of 69.31 (13) and 75.90 (13)° to the nitro­phenyl ring and are twisted to each other, making a dihedral angle of 78.55 (13)°. In the crystal, weak C—H⋯O hydrogen bonds and C—H⋯π inter­action link the mol­ecules into a three-dimensional supra­molecular architecture.
doi:10.1107/S1600536813023386
PMCID: PMC3884502  PMID: 24427092
19.  Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism 
The aim of this study was to assess the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic micro-embolism (CME). CME was induced by injecting 0.199 ml saline containing 5 mg of automicrothrombotic particulates (∼10 μm) into the aorta of Sprague Dawley rats. The injection was carried out over 10 sec using a tuberculin syringe with a 28-gauge needle. The CME model rats were randomly divided into untreated (CME, n=38) and diltiazem-treated (CME+DIL, n=38) groups. Diltiazem (1 mg/ml, 50 μg/min/kg) was intravenously injected using an infusion pump through the tail vein for 175 min, 5 min following the injection of the automicrothrombotic particulates. Hemodynamic measurements, echocardiography and pathohistological examinations were performed at various time-points (3 h, 24 h and 7 and 28 days) postoperatively. Arteriolar thrombosis, multifocal myocardial necrosis, inflammatory cell infiltration with markedly increased myocardial tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) expression, reduced left ventricular (LV) systolic function and increased plasma von Willebrand factor (vWF), endothelin-1 (ET-1) and serum c-troponin I (c-TnI) levels (indicating vascular endothelial injury and myocardial necrosis) were observed in the CME model rats. These pathological responses in CME rats were partly attenuated by intravenous diltiazem treatment. The present CME model is suitable for evaluating the therapeutic effects of intravenous diltiazem; intravenous diltiazem treatment significantly improved cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat model of CME.
doi:10.3892/etm.2013.1263
PMCID: PMC3797315  PMID: 24137281
coronary thrombosis; microembolism; no flow phenomenon; diltiazem
20.  (E)-3-[5-(Di­phenyl­amino)­thio­phen-2-yl]-1-(pyridin-3-yl)prop-2-en-1-one 
In the title compound, C24H18N2OS, the pyridine and the two phenyl rings are oriented at dihedral angles of 10.1 (5), 71.7 (6) and 68.7 (5)°, respectively, to the central thio­phene ring. In the crystal, pairs of weak C—H⋯O hydrogen bonds link inversion-related mol­ecules, forming dimers. The dimers are linked by further weak C—H⋯O hydrogen bonds, forming chains running along the a-axis direction.
doi:10.1107/S1600536813021946
PMCID: PMC3884491  PMID: 24427043
21.  Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro 
Background
Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells.
Methods
The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression.
Results
The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins.
Conclusions
Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.
doi:10.1186/1748-717X-8-195
PMCID: PMC3751121  PMID: 23915425
Boron neutron capture therapy; Glioma stem/progenitor cells; Radiosensitivity
22.  Effect of a Neurokinin-1 Receptor Antagonist in a Rat Model of Colitis-Associated Colon Cancer 
Anticancer research  2010;30(9):3345-3353.
Background/Aim
The role of substance P and the neurokinin-1 receptor (NK-1R) in the transition from inflammation to dysplasia in inflammatory bowel disease is not clear.
Methods
Colitis-associated dysplasia was induced in Sprague-Dawley rats by intracolonic, then systemic, administration of trinitrobenzene sulfonic acid. One group of animals received the NK-1R antagonist SR140333; the rest received vehicle. Colons were removed and analyzed for damage and expression of NK-1R downstream components.
Results
The NK-1R antagonist-treated animals had significantly reduced macroscopic and microscopic damage and decreased incidence of inflammatory bowel disease. Twice as many of these animals had a normal diagnosis in any region of the colon. A decrease in proliferation index, Cox-2 expression, and active Erk1/2 was found compared with the vehicle-treated group. In Caco-2 cells, Erk1/2 was activated by substance P and prostaglandin E2.
Conclusion
A selective NK-1R antagonist may delay the development of further colonic damage, offering a potential treatment for patients with long-standing colitis.
PMCID: PMC3733557  PMID: 20944107
Animal model; antagonist; colitis; dysplasia; neurokinin
23.  Promotion of the induction of cell pluripotency through metabolic remodeling by thyroid hormone triiodothyronine-activated PI3K/AKT signal pathway 
Biomaterials  2012;33(22):5514-5523.
Generation of induced pluripotent stem cells (iPSCs) from somatic cells by defined factors is a mechanism-unknown, yet extremely time-consuming process. Inefficient reprogramming leads to prolonged periods of in vitro iPSC selection, resulting in subtle genetic and epigenetic abnormalities. To facilitate pluripotent reprogramming, we have identified the thyroid hormone triiodothyronine (T3) as an endogenous factor that can enhance reprogramming of human dermal fibroblasts (HDF) and umbilical cord mesenchymal stem cells (UCMSC). This potentiation of iPSC induction is associated with metabolic remodeling activity, including up-regulation of key glycolytic genes, an increase in cell proliferation, and the induction of mesenchymal-epithelial transition (MET). We further identify the activation of the PI3K/AKT signal pathway by T3 as an underlying mechanism for the enhanced conversion to cell pluripotency in this model. These studies demonstrate that T3 enhances metabolic remodeling of donor cells in potentiating cell reprogramming.
doi:10.1016/j.biomaterials.2012.04.001
PMCID: PMC3358472  PMID: 22575839
T3; thyroid hormone; PI3K/AKT signal pathway; Induced pluripotent stem cell; iPSC; reprogramming; metabolic remodeling
24.  Prevalence of hyperuricemia and its related risk factors in healthy adults from Northern and Northeastern Chinese provinces 
BMC Public Health  2013;13:664.
Background
Hyperuricemia (HUA) is a potential risk factor for developing insulin resistance, hypertension, dyslipidemia and cardiovascular disease. Therefore, we studied the prevalence of HUA and associated risk factors in the population of two provinces in northern China.
Methods
Based on the research of Chinese Physiological Constant and Health Conditions conducted in 2008–2010, we enrolled 29,639 subjects in a randomized, stratified study in four sampling areas in Heilongjiang Province and the Inner Mongolia Autonomous Region. We collected 13,140 serum samples to determine biochemical indicators including uric acid(UA), glucose, blood lipids, liver function, and renal function, and finally a representative sample of 8439 aged 18 years and older was determined. We also defined and stratified HUA, hypertension, diabetes, obesity and lipid abnormalities according to international guidelines.
Results
There were significant differences in the UA levels between different genders and regions. The total prevalence of HUA is 13.7%. Men had a higher prevalence of HUA than women (21% vs. 7.9%; P < 0.0001). As age increased, HUA prevalence decreased in men but rose in women. The suburbs of big cities had the highest HUA prevalence (18.7%), and in high-prevalence areas the proportion of women with HUA also increased. A stepwise logistic regression model was used to filter out twelve HUA risk factors, including age, gender, residence, hypercholesterolemia, hypertriglyceridemia, impaired fasting glucose, hypertension, obesity, abdominal obesity, CKD, drinking and sleeping. After adjusting for these factors, the odds ratio of HUA was 1.92 times higher in men than in women. Compared with agricultural and pastoral areas, the odds ratio of having HUA was 2.14 for participants in the suburbs of big cities and 1.57 in the center of big cities.
Conclusions
The prevalence of HUA is high in northern China. The differences in HUA prevalence by geographic region suggested that unbalanced economic development and health education, therefore HUA prevention measures should be strengthened to improve quality of life and reduce health care costs.
doi:10.1186/1471-2458-13-664
PMCID: PMC3722003  PMID: 23866159
Prevalence; Hyperuricemia; Risk factors
25.  Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2 
Cancer Letters  2012;320(1):81-85.
Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.
doi:10.1016/j.canlet.2012.01.034
PMCID: PMC3319810  PMID: 22306001
Shp2; STAT1; Melanoma; Interferon

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