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1.  Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer 
Cancer research  2014;74(15):4099-4110.
Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to anti-estrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In this study, we used a rat model of ERα+ MCF-7 tumor xenografts to demonstrate how altering light/dark cycles with dim LEN (dLEN) speeds the development of breast tumors, increasing their metabolism and growth and conferring an intrinsic resistance to tamoxifen therapy. These characters were not produced in animals where circadian rhythms were not disrupted, or in animals subjected to dLEN if they received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor and a circadian-regulated kinase inhibitor to re-establish the sensitivity of breast tumors to tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.
doi:10.1158/0008-5472.CAN-13-3156
PMCID: PMC4119539  PMID: 25062775
Melatonin; Tamoxifen; Circadian; Breast; Warburg
2.  Dynamics of serotype 14 Streptococcus pneumoniae population causing acute respiratory infections among children in China (1997–2012) 
BMC Infectious Diseases  2015;15:266.
Background
In the last decade, the Streptococcus pneumoniae population has changed, mainly due to the abuse of antibiotics. The aim of this study was to determine the genetic structure of 144 S. pneumonia serotype 14 isolates collected from children with acute respiratory infections during 1997–2012 in China.
Methods
All isolated pneumococci were tested for their sensitivity to 11 kinds of antibiotics with the E-test method or disc diffusion. The macrolides resistance genes ermB and mefA, as well as the sulfamethoxazole-trimethoprim resistance gene dihydrofolate reductase (DHFR) were detected by polymerase chain reaction (PCR). The sequence types (STs) were analyzed with multilocus sequence typing (MLST).
Results
From 1997 to 2012, the percentage of serotype 14 S. pneumonia isolates in the whole isolates increased. All of the 144 serotype 14 S. pneumonia isolates were susceptible to amoxicillin-clavulanic acid, vancomycin and levofloxacin. No penicillin resistant isolate was found, and the intermediate rate was as low as 0.7 %. Erythromycin resistance was confirmed among 143 isolates. The ermB gene was determined in all erythromycin resistant isolates, and the mefA gene was positive additionally in 13 of them. The non-susceptibility rate to the tested cephalosporins increased from 1997–2012. All trimethoprim-resistant isolates contained the Ile100-Leu mutation. Overall, 30 STs were identified, among which ST876 was the most prevalent, followed by ST875. During the study period, the percentage of CC876 increased from 0 % in 1997–2000 to 96.4 % in 2010–2012, whereas CC875 decreased from 84.2 to 0 %. CC876 showed higher non-susceptibility rates to β-lactam antibiotics than CC875.
Conclusion
The percentage of serotype 14 S. pneumonia isolates increased over time in China. The increase of resistance to β-lactam antibiotics in this serotype isolates was associated with the spread of CC876.
doi:10.1186/s12879-015-1008-7
PMCID: PMC4499228  PMID: 26163293
Streptococcus pneumoniae; Serotypes; Antibiotic resistance; Children; Epidemiology
3.  Conservation of imprinting of Neuronatin (Nnat) in rabbits 
SpringerPlus  2015;4:257.
Although the expression and epigenetic status of imprinted genes have been extensively studied in a number of species, less is known about the genomic imprinting in rabbits. Neuronatin (Nnat) plays significant roles in the brain development and metabolic regulation and has been identified to be imprinted and paternally expressed in humans, mice and pigs; however, it has not yet been investigated in rabbits. In this study, we confirmed the expression of two isoforms of the rabbit Nnat (Nnat-a and Nnat-β) identified in Genbank and Ensembl by quantitative real-time PCR. In addition, we also determined the methylation profile of the CpG island in the promoter region of the rabbit Nnat using bisulfite sequencing PCR and combined bisulfite restriction analysis. Here, we provide the first evidence that Nnat has two transcripts in rabbit. Additionally, the CpG island located in the promoter region shows oocyte-specific methylation and may be the differentially methylated region of Nnat in rabbits.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-015-1054-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s40064-015-1054-z
PMCID: PMC4467822  PMID: 26090304
DMR; Imprinted gene; Nnat; Paternally expressed; Promoter; Rabbit
4.  CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation 
Cell Research  2014;24(6):742-761.
Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3β, leading to the stabilization of CKIP-1 and β-catenin proteins. β-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1−/− mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.
doi:10.1038/cr.2014.53
PMCID: PMC4042176  PMID: 24777252
macrophage proliferation; Akt signaling; TRAF6; GSK3β; CKIP-1
5.  Circulating miR-497 and miR-663b in plasma are potential novel biomarkers for bladder cancer 
Scientific Reports  2015;5:10437.
MicroRNAs (miRNAs), abundant and highly stable in the plasma, have been widely reported. This greatly pursued us to investigate whether plasma miRNAs could be considered as powerful biomarkers for diagnosing bladder cancer (BC). We performed a plasma miRNAs profile with the TaqMan Low Density Array, and a two-phase validation to detect the candidate miRNAs expression by quantitative PCR. The receiver operating characteristic curve (ROC) and the area under curve (AUC) were used to evaluate diagnostic accuracy. A total of eight plasma miRNAs abnormally expressed between BC patients and healthy controls in microarray analysis (i.e., elevated miRNAs for miR-505, miR-363 and miR-663b, and decreased for miR-99a, miR-194, miR-100, miR-497 and miR-1 in BC plasma). In further independent cohorts, miR-497 and miR-663b with significantly differential expression were confirmed. Moreover, the AUC, sensitivity and specificity were raised to 0.711 (95% CI = 0.641-0.780), 69.7% and 69.6%, respectively, when miR-497 and miR-663b were integrated. This is the first study systematically exploring the existence of specific plasma miRNAs as early diagnostic biomarkers for BC in Chinese population; and these findings supported that plasma miR-497 and miR-663b could be promising novel circulating biomarkers in clinical detection of BC.
doi:10.1038/srep10437
PMCID: PMC4444850  PMID: 26014226
6.  Antioxidant Activities In Vitro and Hepatoprotective Effects of Nelumbo Nucifera Leaves In Vivo 
Background
Herbal medicines played a major role in the treatment of hepatic disorders, and a number of medicinal plants and their compounds were widely used for the treatment of these disorders, and oxidant stress injury was one of the mechanism of liver injury.
Materials and Methods
Antioxidant activity of Nelumbo nucifera leaves (NU) extracts was assayed by the methods of scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzo-thiazoline-6-sulfonicacid) (ABTS) radical and ferric reducing antioxidant power (FRAP) in vitro. By intraperitoneal injection carbon tetrachloride (CCl4) to establish acute liver injury model in mice, the levels of Glutamic-pyruvic transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), superoxide dismutase (SOD) and the content of and maleicdialdehyde (MDA) were detected to evaluate hepatoprotective effect of NU using corresponding test kit.
Results
EtOAC (NUEA) and n-BuOH extracts (NUBU) of N. nucifera leaves had good scavenging DPPH and ABTS radical activity and ferric reducing antioxidant power in vitro. DPPH radical scavenging activity and ferric reducing antioxidant power of NUEA (IC50= 6.68±0.29 µg/mL, RACT50=1749.82±67.03 µmol/g) and NUBU (IC50= 4.61±0.01 µg/mL, RACT50=1995.27±135.71 µmol/g ) were higher than that of BHT (IC50=8.76±0.20 µg/mL, RACT50=1581.68±97.41 µmol/g) and Dangfeiliganning (IC50=28.06±0.17 µg/mL, RACT50=1028.55±3.28 µmol/g). ABTS radical scavenging activity of NUEA (IC50= 5.32±0.12 µg/mL) and NUBU (IC50= 8.16±0.27 µg/mL) were higher than that of Dangfeiliganning (IC50= 9.76±0.16 µg/mL). Thus, hepatoprotective effect of NUEA and NUBU was evaluated on CCl4-induced acute liver injury mice. The results showed that the levels of GOT and GPT in each treatment group significantly decreased (p<0.001 and p<0.01, p<0.05, respectively) except for the group of NUEA (130.8 mg/kg) (p>0.05). The contents of malondialdehyde (MDA) in liver in groups of NUEA (523 mg/kg), NUBU (840.5 and 420.5 mg/kg, repectively) had significant decrease (p<0.001 and p<0.05, respectively), and the level of SOD in liver for each treatment group could significantly decrease (p<0.001, p<0.05, respectively).
Conclusion
NUEA and NUBU had significantly hepatoprotective effect for Calcium tetrachloride CCl4-induced liver injury, which might be attributable to its antioxidant activity.
PMCID: PMC4202423  PMID: 25371567
Antioxidant activity; Carbon tetrachloride (CCl4); hepatoprotective effect; Nelumbo nucifera leaves
7.  The effect of depression on the thermal nociceptive thresholds in rats with spontaneous pain 
Neuroscience bulletin  2010;26(6):429-436.
Objective
Recently, there has been growing interest in the interaction between depressive disorders and pain. The purpose of this study was to examine whether depression would lead to a decreased sensitivity to noxious stimuli in rats with spontaneous pain.
Methods
The olfactory bulbectomized rats were used as a model of depression. The depression-like behaviors were assessed by open field test and changes in body weight. Formalin solution was injected into the rat hindpaw to produce ongoing pain. Noxious thermal stimuli were applied onto the hindpaw contralateral to formalin injection, and the withdrawal thresholds were measured.
Results
In non-depressive rats, the formalin-treated paw developed hypoalgesia to noxious stimuli while the contralateral paw was not affected. The depressive rats, however, showed a significantly lower sensitivity to noxious thermal stimulus, represented as higher withdrawal thresholds of the contralateral paw, when compared to the non-depressive rats.
Conclusion
These results demonstrate that depression can alleviate the stimulus-evoked pain even in the context of formalin inflammatory pain, consistent with the previous clinical observations that patients suffering from both depression and persistent pain have decreased sensitivities to noxious experimental stimuli.
doi:10.1007/s12264-010-0932-1
PMCID: PMC4382591  PMID: 21113193
depression; evoked pain; formalin; olfactory bulbectomy; thermal stimulation
8.  Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China 
Journal of neurovirology  2013;19(2):144-149.
In the current era of highly active antiretroviral therapy (HAART), the incidence of HIV dementia has declined, but the prevalence of HIV-associated neurocognitive disorder (HAND) remains high. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. Changes in cytokine levels in the cerebrospinal fluid (CSF) during HIV infection might help to identify HAND. To investigate whether the cytokine profile of the CSF during HIV infection could be used as a biomarker of HAND, we compared cytokine levels in the CSF of HIV-infected cases with and without neurocognitive impairment. Cytokine concentrations in the CSF were measured by quantification bioassays (Luminex xMAP). HIV-infected cases with neurocognitive impairment demonstrated higher levels of interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, induced protein (IP)-10, and granulocyte colony-stimulating factor (G-CSF) in the CSF than those without neurocognitive impairment (G-CSF (p=0.0003), IL-8 (p=0.0046), IP-10 (p<0.0001), and MCP-1 (p<0.0001)). There was no significant impact of HAART on cytokine levels in the CSF, except for IP-10, which was higher in HAART-treated patients with impaired cognition (p=0.0182). Findings from this preliminary study suggest that elevated levels of the cytokines IL-8, MCP-1, G-CSF, and IP-10 in the CSF are associated with neurocognitive impairment in HIV infection, and these cytokines likely represent a biomarker profile for HAND.
doi:10.1007/s13365-013-0150-5
PMCID: PMC4363104  PMID: 23389619
HIV; Neurocognitive disorder; Cytokines; CSF; Biomarker
9.  The Relationship of CSF and Plasma Cytokine Levels in HIV Infected Patients with Neurocognitive Impairment 
BioMed Research International  2015;2015:506872.
Although HAD is now rare due to HAART, the milder forms of HAND persist in HIV-infected patients. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. The levels of cytokines in CSF were associated with neurocognitive impairment in HIV infection. However, the changes of cytokines involved in cognition impairment in plasma have not been shown, and their relationships between CSF and plasma require to be addressed. We compared cytokine levels in paired CSF and plasma samples from HIV-infected individuals with or without neurocognitive impairment. Cytokine concentrations were measured by Luminex xMAP. In comparing the expression levels of cytokines in plasma and CSF, IFN-α2, IL-8, IP-10, and MCP-1 were significantly higher in CSF. Eotaxin was significantly higher in plasma, whereas G-CSF showed no difference between plasma and CSF. G-CSF (P = 0.0079), IL-8 (P = 0.0223), IP-10 (P = 0.0109), and MCP-1 (P = 0.0497) in CSF showed significant difference between HIV-CI and HIV-NC group, which may indicate their relationship to HIV associated neurocognitive impairment. In addition, G-CSF (P = 0.0191) and IP-10 (P = 0.0377) in plasma were significantly higher in HIV-CI than HIV-NC. The consistent changes of G-CSF and IP-10 in paired plasma and CSF samples might enhance their potential for predicting HAND.
doi:10.1155/2015/506872
PMCID: PMC4363531  PMID: 25821806
10.  EIF4EBP1 Overexpression Is Associated with Poor Survival and Disease Progression in Patients with Hepatocellular Carcinoma 
PLoS ONE  2015;10(2):e0117493.
Objective
EIF4EBP1 acts as a crucial effector in mTOR signaling pathway. Studies have suggested that EIF4EBP1 plays a critical role in carcinogenesis. However, the clinical significance and biological role of EIF4EBP1 in hepatocellular carcinoma (HCC) have not been elucidated. Therefore, we aimed to investigate the clinical significance of EIF4EBP1 in HCC.
Methods
Total 128 cases of HCCs were included in this study. EIF4EBP1 expression in HCC tissues was detected by qRT-PCR, Western blot and immunohistochemistry, respectively. Then the relationships between EIF4EBP1 expression and clinical features as well as survival were analyzed.
Results
The expression level of EIF4EBP1 mRNA is significantly higher in 60% (24/40) of fresh HCC tissues than that in the matched adjacent nontumor liver (NCL) tissues (P = 0.044). Similarly, EIF4EBP1 protein is notably upregulated in 8 HCC tissues (randomly selected from the 40 HCCs) measured by Western blot and is significantly increased in another 88 paraffin-embedded HCCs (53%, 47/88) by immunohistochemistry compared with the matched NCLs (P < 0.001). EIF4EBP1 protein expression in HCC tissues is significantly correlated with serum AFP (P = 0.003) and marginally significantly associated with pathological grade (P = 0.085), tumor number (P = 0.084), tumor embolus (P = 0.084) and capsulation (P = 0.073). Patients with higher EIF4EBP1 protein expression have a much worse 5-year overall survival (40.3% vs 73.6%) and 5-year disease-free survival (33.0% vs 49.0%) than those with low expression. Furthermore, Cox regression analysis shows that EIF4EBP1 protein is an independent prognostic factor for overall survival (HR, 2.285; 95% CI, 1.154–4.527; P = 0.018) and disease-free survival (HR, 1.901; 95% CI, 1.067–3.386; P = 0.029) in HCC patients.
Conclusions
Our results demonstrate for the first time that EIF4EBP1 mRNA and protein are markedly up-regulated in HCC tissues, and the protein overexpression is significantly associated with poor survival and progression, which provide a potential new prognostic marker and therapeutic target for HCC patients.
doi:10.1371/journal.pone.0117493
PMCID: PMC4319970  PMID: 25658620
11.  Nasopharyngeal carriage and antimicrobial susceptibility of Haemophilus influenzae among children younger than 5 years of age in Beijing, China 
BMC Microbiology  2015;15:6.
Background
Haemophilus influenzae is one of the main pathogens that cause community-acquired respiratory infections in children. Our previous study showed that H. influenzae is the second most common pathogen causing pneumonia and accounts for 30–50% of bacterial meningitis among Chinese children. H. influenzae carriage in children and its resistance to commonly used antimicrobials varies widely both geographically and over time.
Results
Surveys of the nasopharyngeal carriage of H. influenzae in children younger than 5 years of age with acute respiratory tract infection (ARI) were conducted in Beijing Children’s Hospital, China in 2000, 2002, 2010, and 2012. The overall annual carriage rates of H. influenzae among children younger than 5 years of age with ARI were 35.5%, 20.6%, 14.4%, and 18.7%, and the percentages of H. influenzae isolates producing β-lactamase were 4%, 13%, 27.1%, and 31%, respectively. The percentages of susceptibility to ampicillin progressively decreased from 96% (2000) to 87% (2002) to 63% (2010) to 61% (2012). All of the ampicillin-resistant isolates were found to be beta-lactamase producers. The susceptibility to tetracycline increased from 54% (2000) to 60% (2002) to 91.5% (2010) to 94.5% (2012). No statistically significant differences were observed in the susceptibility to cefaclor, cefuroxime, sulfamethoxazole, and chloramphenicol. Amoxicillin/clavulanic acid and ceftriaxone were the most effective antimicrobials for the isolates of H. influenzae across the 10-year period.
Conclusions
This report on the H. influenzae carriage rates in children and the susceptibility of these bacteria to commonly used antibiotics showed that H. influenzae carriage decreased from 2000 to 2012. Additionally, the percentage of β-lactamase-producing isolates increased while their susceptibility to ampicillin progressively decreased during this time. These results indicate that the appropriate empirical antimicrobial therapy should be changed for pediatric patients in China.
doi:10.1186/s12866-015-0350-7
PMCID: PMC4332420  PMID: 25648185
Haemophilus influenzae; Antimicrobial susceptibility; Acute upper respiratory tract infection; Pediatrics
13.  Association of THBS1 rs1478605 T>C in 5′-untranslated regions with the development and progression of gastric cancer 
Biomedical Reports  2015;3(2):207-214.
Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single-nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the THBS1 gene on the development and progression of gastric cancer. In the case-control study, 275 gastric cancer patients and 275 cancer-free controls were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism. The data demonstrated that THBS1 rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39-0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23-0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14-0.52; P<0.001). The THBS1 CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33-0.93; P=0.02). By contrast, no association was observed between THBS1 rs3743125 and the development and progression of gastric cancer. These results suggest that THBS1 rs1478605 represents a potential molecular marker for gastric cancer.
doi:10.3892/br.2015.414
PMCID: PMC4448071  PMID: 26075074
gastric cancer; THBS1; single-nucleotide polymorphism
14.  Qualitative and quantitative determination of 15 main active constituents in Fructus Sophorae pill by liquid chromatography tandem mass spectrometry 
Pharmacognosy Magazine  2015;11(41):196-207.
Background:
Fructus Sophorae pill, one of the traditional Chinese medicine, was widely used for hemorrhoids, hypertension and odontalgia. This paper describes a sensitive and specific assay for the determination of the 15 active constituents (sophoricoside, genistin, genistein, rutin, quercetin, kaempferol, baicalein, baicalin, naringin, naringenin, hesperidin, neohesperidin, wogonin and cimifugin, prim-O-glucosylcimifugin) in Fructus Sophorae pill.
Materials and Methods:
Chromatographic separation was performed on a C18 column with acidified aqueous methanol gradients at a flow rate of 0.8 mL/min. The identification and quantification of the analytes were achieved by use of a hybrid quadrupole linear ion trap mass spectrometer. Multiple-reaction monitoring scanning was applied to quantification with switching electrospray ion source polarity between positive and negative modes.
Results:
The proposed method was used to analyze 40 batches of samples with good linearity (r, 0.9990-0.9999), intraday precisions (RSD, 0.14-2.55%), interday precisions (RSD, 0.51-2.81%), stability (RSD, 0.31-2.65%), and recovery (RSD, 1.29-2.95%) of the 15 compounds. In addition, the hierarchical cluster analysis, including a method called furthest neighbor and nearest neighbor, was employed to classify samples according to characteristics of the 15 constituents.
Conclusion:
The results indicated that the analytical method was rapid, reliable, simple and suitable for the quality evaluation of Fructus Sophorae pill.
doi:10.4103/0973-1296.149739
PMCID: PMC4329624  PMID: 25709233
Dosage form; Fructus Sophorae pill; Hierarchical cluster analysis; HPLC-ESI-MS/MS; Qualitative and quantitative determination
15.  Relationship of High‐Density Lipoprotein Cholesterol With Periprocedural Myocardial Injury Following Elective Percutaneous Coronary Intervention in Patients With Low‐Density Lipoprotein Cholesterol Below 70 mg/dL 
Background
Recent data showed inconsistent association of high‐density lipoprotein cholesterol (HDL‐C) with cardiovascular risk in patients with different levels of low‐density lipoprotein cholesterol (LDL‐C) or intensive statin therapy. This study sought to determine the relationship of HDL‐C with periprocedural myocardial injury following elective percutaneous coronary intervention (PCI) across a range of LDL‐C levels, especially in patients with LDL‐C <70 mg/dL.
Methods and Results
We enrolled 2529 consecutive patients with normal preprocedural cardiac troponin I (cTnI) who underwent elective PCI. The association between preprocedural HDL‐C and periprocedural myocardial injury was evaluated across LDL‐C levels, especially in patients with LDL‐C <70 mg/dL. The HDL‐C level was not predictive of periprocedural myocardial injury across the entire study cohort. However, among patients with LDL‐C <70 mg/dL, a 1 mg/dL increase in HDL‐C was associated with a 3% reduced risk for postprocedural cTnI above 1×upper limit of normal (ULN) (odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.004), a 3% reduced risk for postprocedural cTnI above 3×ULN odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.022), and a 3% reduced risk for postprocedural cTnI above 5×ULN (odds ratio: 0.97; 95% CI: 0.95 to 0.99; P=0.017). The relation between plasma HDL‐C level and risk of postprocedural cTnI elevation above 1×ULN, 3×ULN, and 5×ULN was modified by LDL‐C level (all P for interaction <0.05).
Conclusions
Higher HDL‐C levels were associated with reduced risk of periprocedural myocardial injury only in patients with LDL‐C <70 mg/dL.
doi:10.1161/JAHA.114.001412
PMCID: PMC4330066  PMID: 25572484
high‐density lipoprotein cholesterol; low‐density lipoprotein cholesterol; percutaneous coronary intervention; periprocedural myocardial injury
16.  A novel antisense long noncoding RNA regulates the expression of MDC1 in bladder cancer 
Oncotarget  2014;6(1):484-493.
Antisense long noncoding RNAs (lncRNAs) play important roles in regulating the expression of coding genes in post-transcriptional level. However, detailed expression profile of lncRNAs and functions of antisense lncRNAs in bladder cancer remains unclear. To investigate regulation of lncRNAs in bladder cancer and demonstrate their functions, we performed lncRNAs microarray analysis in 3 paired bladder cancer tissues. Further molecular assays were conducted to determine the potential role of identified antisense lncRNA MDC1-AS. As a result, a series of lncRNAs were differentially expressed in bladder cancer tissues in microarray screen. In a larger size of samples validation, we found that the expression levels of MDC1-AS and MDC1 was down-regulated in bladder cancer. After over-expression of MDC1-AS, increased levels of MDC1 were observed in bladder cancer cells. We also found a remarkably inhibitory role of antisense lncRNA MDC1-AS on malignant cell behaviors in bladder cancer cells EJ and T24. Subsequently, knockdown of MDC1 revealed that suppressing role of MDC1-AS was attributed to up-regulation of MDC1. In summary, we have identified a novel antisense lncRNA MDC1-AS, which may participate in bladder cancer through up-regulation of its antisense tumor-suppressing gene MDC1. Further studies should be conducted to demonstrate detailed mechanism of our findings.
PMCID: PMC4381609  PMID: 25514464
antisense lncRNAs; MDC1-AS; expression regulation; bladder cancer
17.  Relation of plasma PCSK9 levels to lipoprotein subfractions in patients with stable coronary artery disease 
Background
Plasma PCSK9 levels was positively associated with low-density lipoprotein (LDL) cholesterol (LDL-C) and atherosclerosis, while PCSK9 may also be implicated in the metabolism of lipoprotein subfractions. The study was to examine the association of plasma PCSK9 with lipoprotein subfractions in patients with stable coronary artery disease (CAD).
Methods
A total of 281 consecutive, stable CAD patients who were not treated with lipid-lowering drugs were enrolled. The baseline clinical characteristics were collected, the plasma PCSK9 levels were determined using ELISA, and the LDL and high-density lipoprotein (HDL) subfractions were analyzed by Lipoprint System. The association of plasma PCSK9 levels with the lipoprotein subfractions was investigated.
Results
In the overall population, plasma PCSK9 levels were positively associated with the concentration of LDL-C, intermediate LDL-C, small LDL-C, and LDL score, while negatively correlated with mean LDL particle size. PCSK9 levels were positively associated with the concentration of HDL-C, intermediate HDL-C and small HDL-C. Multivariable regression analysis revealed that the plasma PCSK9 levels were significantly and independently associated with the concentration of intermediate LDL-C (β = 0.152, p = 0.013), small LDL-C (β = 0.179, p = 0.004), LDL score (β = 0.121, p = 0.043), and mean LDL particle size (β = -0.130, p = 0.035), while not HDL subfractions. Interestingly, when investigated in male and female patients separately, these relationships were only found in male but not in female, and the small HDL-C exhibited an association with PCSK9 levels in male patients (β = 0.149, p = 0.045).
Conclusions
PCSK9 levels were independently associated with the changes of lipoprotein subfractions, suggesting a potential interaction between PCSK9 and lipoprotein subfractions in CAD.
doi:10.1186/1476-511X-13-188
PMCID: PMC4292809  PMID: 25496400
Proprotein convertase subtilisin kexin type 9; LDL subfractions; HDL subfractions; Coronary artery disease
18.  Gene differential coexpression analysis based on biweight correlation and maximum clique 
BMC Bioinformatics  2014;15(Suppl 15):S3.
Differential coexpression analysis usually requires the definition of 'distance' or 'similarity' between measured datasets. Until now, the most common choice is Pearson correlation coefficient. However, Pearson correlation coefficient is sensitive to outliers. Biweight midcorrelation is considered to be a good alternative to Pearson correlation since it is more robust to outliers. In this paper, we introduce to use Biweight Midcorrelation to measure 'similarity' between gene expression profiles, and provide a new approach for gene differential coexpression analysis. Firstly, we calculate the biweight midcorrelation coefficients between all gene pairs. Then, we filter out non-informative correlation pairs using the 'half-thresholding' strategy and calculate the differential coexpression value of gene, The experimental results on simulated data show that the new approach performed better than three previously published differential coexpression analysis (DCEA) methods. Moreover, we use the maximum clique analysis to gene subset included genes identified by our approach and previously reported T2D-related genes, many additional discoveries can be found through our method.
doi:10.1186/1471-2105-15-S15-S3
PMCID: PMC4271563  PMID: 25474074
19.  Aberrant Expression of Xist in Aborted Porcine Fetuses Derived from Somatic Cell Nuclear Transfer Embryos 
Cloned pigs generated by somatic cell nuclear transfer (SCNT) show a greater ratio of early abortion during mid-gestation than normal controls. X-linked genes have been demonstrated to be important for the development of cloned embryos. To determine the relationship between the expression of X-linked genes and abortion of cloned porcine fetuses, the expression of X-linked genes were investigated by quantitative real-time polymerase chain reaction (q-PCR) and the methylation status of Xist DMR was performed by bisulfate-specific PCR (BSP). q-PCR analysis indicated that there was aberrant expression of X-linked genes, especially the upregulated expression of Xist in both female and male aborted fetuses compared to control fetuses. Results of BSP suggested that hypomethylation of Xist occurred in aborted fetuses, whether male or female. These results suggest that the abnormal expression of Xist may be associated with the abortion of fetuses derived from somatic cell nuclear transfer embryos.
doi:10.3390/ijms151221631
PMCID: PMC4284668  PMID: 25429426
porcine; somatic cell nuclear transfer; DNA methylation; Xist
20.  Synchronous poorly-differentiated neuroendocrine carcinoma and gastrointestinal stromal tumor of the stomach: a case report with immunohistochemical and molecular genetic analyses of KIT and PDGFRA 
Although the stomach is the most common location for gastrointestinal stromal tumor (GIST) with co-primary tumors, the synchronous appearance of a poorly differentiated neuroendocrine carcinoma (NEC) and GIST in the stomach is extremely rare. To the best of our knowledge, this is the first case of gastric GIST coexisting with gastric NEC to be reported in the literature. The current study reports the case of a 71-year-old male with gastric poorly differentiated NEC and GIST discovered incidentally during surgical treatment of the NEC. Immunohistochemistry analysis showed that the NEC tumor cells were positive for CK (cytokeratin), CD57, synaptophysin, chromogranin, CD117 (KIT protein), Dog-1 (discovered on GIST-1 protein) and CD34. The synchronous GIST immunophenotype showed positivity for CD117, Dog-1 and CD34 (100%), whereas staining for CK, SMA, desmin and S100 was negative. Ki-67 labeling of proliferating cells was 90% in NEC and 1% in GIST. An accurate diagnosis was confirmed by immunohistochemical findings. Furthermore, genetic analysis using PCR direct sequencing identified no mutations in the KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. The patient developed lymph node metastases and underwent cisplatin-based chemotherapy after the operation. This is the first documented case of synchronous gastric GIST and NEC with the examination of protein expression and gene mutations in KIT and PDGFRA, which will help to further understand the etiology and pathogenesis of NEC coexisting with GIST in a gastric location.
PMCID: PMC4313951  PMID: 25674291
Snchronous tumor; neuroendocrine; carcinoma; GIST; gastric
21.  Higher Fibrinogen Level is Independently Linked with the Presence and Severity of New-Onset Coronary Atherosclerosis among Han Chinese Population 
PLoS ONE  2014;9(11):e113460.
Background
Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size.
Methods and Results
We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082–1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889–1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383–2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833–1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155–2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L.
Conclusions
Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population.
doi:10.1371/journal.pone.0113460
PMCID: PMC4245131  PMID: 25426943
22.  Role of BC040587 as a predictor of poor outcome in breast cancer 
Background
Accumulating studies have focused on the oncogenic and tumor suppressive roles of the newly identified lncRNAs. A novel lncRNA BC040587 in 3q13.31 locus which exists frequent copy number alterations was found to be associated with poor survival of osteosarcoma patients. However, its role in breast cancer (BC) remains unknown. The aim of this study was to examine the expression pattern of BC040587 in BC and to evaluate its biological role and clinical significance in prediction of prognosis.
Methods
Expression of BC040587 was analyzed in 20 pairs of BC cancer tissues and adjacent noncancerous tissues (ANCT), also in 151 BC tissues, 9 BC cell lines and one normal breast cell line by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Differences between groups were tested for significance using Student’s t-test (two-tailed). Then we analyzed the potential relationship between BC040587 expression and clinic pathological features of BC patients. The correlation was analyzed by SPSS software.
Results
It showed that BC040587 expression was down regulated both in BC samples and in BC cell lines compared with corresponding normal control. BC040587 expression was correlated with menopausal status (p = 0.040) and tumor differentiation (p = 0.035). The Kaplan-Meier survival curves indicated that the overall survival (OS) was significantly poor in low BC040587 expression BC patients (p = 0.023). Furthermore, expression of BC040587 was significantly associated with worse prognosis and was shown to be an independent prognostic marker breast cancer (p = 0.032). Our studies indicate that BC040587 may represent a new marker of prognosis in breast cancer.
Conclusion
Our studies indicate that BC040587 is significantly down-regulated in BC tissues and BC cell lines. BC040587 may represent a new marker of prognosis in breast cancer.
doi:10.1186/s12935-014-0123-7
PMCID: PMC4246536  PMID: 25435812
BC040587; Breast cancer; Tumor suppressor; Prognosis; Long non-coding RNA
23.  Different Inhibitory Effect and Mechanism of Hydroxyapatite Nanoparticles on Normal Cells and Cancer Cells In Vitro and In Vivo 
Scientific Reports  2014;4:7134.
Hydroxyapatite (HAP), similar to inorganic phase in bones, shows good biocompatibility and bioactivity as bone defect repairing material. Recently, nanoscaled HAP shows the special properties differing from bulk HAP in physics, chemistry and biology. This paper demonstrates that HAP nanoparticle (nHAP) possesses the ability for inhibiting cancer cell growth in vitro and in vivo. In vitro, after treatment with nHAP for 3 days, proliferation of human cancer cells are inhibited by more than 65% and by less than 30% for human normal cells. In vivo, injection of nHAP in transplanted tumor results in significant reduction (about 50%) of tumor size. The anticancer effect of nHAP is mainly attributed to high amount by endocytosis in cancer cells and inhibition on protein synthesis in cells. The abundant nHAP internalized in cancer cells around endoplasmic reticulum may inhibit the protein synthesis by decreasing the binding of mRNA to ribosome due to its high adsorption capacity for ribosome and arrest cell cycle in G0/G1 phase. nHAP shows no ROS-involved cytotoxicity and low cytotoxicity to normal cells. These results strongly suggest that nHAP can inhibit cancer cell proliferation and have a potential application in cancer treatment.
doi:10.1038/srep07134
PMCID: PMC4238015  PMID: 25409543
24.  Policosanol Attenuates Statin-Induced Increases in Serum Proprotein Convertase Subtilisin/Kexin Type 9 When Combined with Atorvastatin 
Objective. Statin treatment alone has been demonstrated to significantly increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The effect of policosanol combined with statin on PCSK9 is unknown. Methods. Protocol I: 26 patients with atherosclerosis were randomly assigned to receive either atorvastatin 20 mg/d or policosanol 20 mg/d + atorvastatin 20 mg/d for 8 weeks. Protocol II: 15 healthy volunteers were randomly assigned to either policosanol 20 mg/d or a control group for 12 weeks. Serum levels of PCSK9 were determined at day 0 and the end of each protocol. Results. Protocol I: atorvastatin 20 mg/d significantly increased serum PCSK9 level by 39.4% (256 ± 84 ng/mL versus 357 ± 101 ng/mL, P = 0.002). However, policosanol 20 mg/d + atorvastatin 20 mg/d increased serum PCSK9 level by only 17.4% without statistical significance (264 ± 60 ng/mL versus 310 ± 86 ng/mL, P = 0.184). Protocol II: there was a trend toward decreasing serum PCSK9 levels in the policosanol group (289 ± 71 ng/mL versus 235 ± 46 ng/mL, P = 0.069). Conclusion. Policosanol combined with statin attenuated the statin-induced increase in serum PCSK9 levels. This finding indicates that policosanol might have a modest effect of lowering serum PCSK9 levels.
doi:10.1155/2014/926087
PMCID: PMC4247936  PMID: 25478000
25.  Resting heart rate as a marker for identifying the risk of undiagnosed type 2 diabetes mellitus: a cross-sectional survey 
BMC Public Health  2014;14:1052.
Background
Fast resting heart rate might increase the risk of developing type 2 diabetes mellitus (T2DM). However, it is unclear whether resting heart rate could be used to predict the risk of undiagnosed T2DM. Therefore, the purposes of this study were to examine the association between resting heart rate and undiagnosed T2DM, and evaluate the feasibility of using resting heart rate as a marker for identifying the risk of undiagnosed T2DM.
Methods
A cross-sectional survey was conducted. Resting heart rate and relevant covariates were collected and measured. Fasting blood samples were obtained to measure blood glucose using the modified hexokinase enzymatic method. Predictive performance was analyzed by Receiver Operating Characteristic (ROC) curve.
Results
This study included 16, 636 subjects from rural communities aged 35–78 years. Resting heart rate was significantly associated with undiagnosed T2DM in both genders. For resting heart rate categories of <60, 60–69, 70–79, and ≥80 beats/min, adjusted odds ratios for undiagnosed T2DM were 1.04, 2.32, 3.66 and 1.05, 1.57, 2.98 in male and female subjects, respectively. For male subjects, resting heart rate ≥70 beats/min could predict undiagnosed T2DM with 76.56% sensitivity and 48.64% specificity. For female subjects, the optimum cut-off point was ≥79 beats/min with 49.72% sensitivity and 67.53% specificity. The area under the ROC curve for predicting undiagnosed T2DM was 0.65 (95% CI: 0.64-0.66) and 0.61(95% CI: 0.60-0.62) in male and female subjects, respectively.
Conclusions
Fast resting heart rate is associated with an increased risk of undiagnosed T2DM in male and female subjects. However, resting heart rate as a marker has limited potential for screening those at high risk of undiagnosed T2DM in adults living in rural areas.
doi:10.1186/1471-2458-14-1052
PMCID: PMC4210587  PMID: 25297916
Marker; Resting heart rate; Type 2 diabetes mellitus

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