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1.  NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B 
Scientific Reports  2016;6:38778.
A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.
doi:10.1038/srep38778
PMCID: PMC5150634  PMID: 27941937
2.  STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer 
Molecular Cancer  2016;15:79.
Background
STAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC).
Methods
STAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses.
Results
Hyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3+/EZH2+ or p-STAT3+/EZH2+ had a worse outcome than others (P < 0.001); Besides, high levels of STAT3 and EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment.
Conclusions
Our results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor might be a novel therapy in GC treatment. Collectively, STAT3, p-STAT3 and EZH2 expression were provided for the precision medicine in GC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-016-0561-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12943-016-0561-z
PMCID: PMC5148878  PMID: 27938379
EZH2; STAT3; p-STAT3; 3-deazaneplanocin A; Gastric cancer; Prognosis
3.  In Vitro Differentiation of Bone Marrow Mesenchymal Stem Cells into Neuron-Like Cells by Cerebrospinal Fluid Improves Motor Function of Middle Cerebral Artery Occlusion Rats 
Bone marrow mesenchymal stem cells (BMSCs) represent a promising tool for stem cell-based therapies. However, the majority of BMSC transplants only allow for limited recovery of the lost functions. We previously found that human cerebrospinal fluid (hCSF) is more potent than growth factors in differentiating human BMSCs into neuron-like cells in vitro. In this study, we studied the effect of transplantation of rat BMSC-derived neuron-like cells (BMSC-Ns) induced by hCSF into rat brain with middle cerebral artery occlusion (MCAO). The survival and differentiation of the transplanted cells were determined using immunofluorescence staining of bromodeoxyuridine. The recovery of neurological function were observed by the modified neurological severity score (modified NSS) at 4, 15, and 32 days after cell transplantation, HE staining for determination of the infarct volume at day 32 after cell transplantation. Transplantation of BMSC-Ns or BMSCs significantly improved indexes of neurological function and reduced infarct size in rats previously subjected to MCAO compared with those in the control group. Remarkably, 32 days after transplantation, rats treated with BMSC-Ns presented a smaller infarct size, higher number of neuron-specific, enolase-positive, and BrdU-positive cells, and improved neurological function compared with BMSC group. Our results demonstrate that transplantation of hCSF-treated BMSC-Ns significantly improves neurological function and reduces infarct size in rats subjected to MCAO. This study may pave a new avenue for the treatment of MCAO.
doi:10.3389/fneur.2016.00183
PMCID: PMC5081354  PMID: 27833584
cerebrospinal fluid; bone marrow mesenchymal stem cells; BMSC-derived neural cells; middle cerebral artery occlusion
4.  Assessment of two alternative standardised tests for the vascular component of the hand–arm vibration syndrome (HAVS) 
Background
Vibration-induced white finger (VWF) is the vascular component of the hand–arm vibration syndrome (HAVS). Two tests have been standardised so as to assist the diagnosis of VWF: the measurement of finger rewarming times and the measurement of finger systolic blood pressures (FSBPs).
Objectives
This study investigates whether the two tests distinguish between fingers with and without symptoms of whiteness and compares individual results between the two test methods.
Methods
In 60 men reporting symptoms of the HAVS, the times for their fingers to rewarm by 4°C (after immersion in 15°C water for 5 min) and FSBPs at 30°C, 15°C and 10°C were measured on the same day.
Results
There were significant increases in finger rewarming times and significant reductions in FSBPs at both 15°C and 10°C in fingers reported to suffer blanching. The FSBPs had sensitivities and specificities >90%, whereas the finger rewarming test had a sensitivity of 77% and a specificity of 79%. Fingers having longer rewarming times had lower FSBPs at both temperatures.
Conclusions
The findings suggest that, when the test conditions are controlled according to the relevant standard, finger rewarming times and FSBPs can provide useful information for the diagnosis of VWF, although FSBPs are more sensitive and more specific.
doi:10.1136/oemed-2016-103688
PMCID: PMC5036229  PMID: 27535036
Vibration-induced white finger; Hand-arm vibration syndrome; Hand-transmitted vibration; Finger skin temperature; Finger systolic blood pressure
5.  JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers 
Background
Lung remodeling and pulmonary fibrosis are serious, life-threatening conditions resulting from diseases such as chronic severe asthma and idiopathic pulmonary fibrosis (IPF). Preclinical evidence suggests that JNK enzyme function is required for key steps in the pulmonary fibrotic process. However, a selective JNK inhibitor has not been investigated in translational models of lung fibrosis with clinically relevant biomarkers, or in IPF patients.
Methods
The JNK inhibitor CC-930 was evaluated in the house dust mite-induced fibrotic airway mouse model, in a phase I healthy volunteer pharmacodynamic study, and subsequently in a phase II multicenter study of mild/moderate IPF (n = 28), with a 4-week, placebo-controlled, double-blind, sequential ascending-dose period (50 mg QD, 100 mg QD, 100 mg BID) and a 52-week open-label treatment-extension period.
Results
In the preclinical model, CC-930 attenuated collagen 1A1 gene expression, peribronchiolar collagen deposition, airway mucin MUC5B expression in club cells, and MMP-7 expression in lung, bronchoalveolar lavage fluid, and serum. In the phase I study, CC-930 reduced c-Jun phosphorylation induced by UV radiation in skin. In the phase II IPF study, there was a CC-930 dose-dependent trend in reduction of MMP-7 and SP-D plasma protein levels. The most commonly reported adverse events were increased ALT, increased AST, and upper respiratory tract infection (six subjects each, 21.4 %). A total of 13 subjects (46.4 %) experienced adverse events that led to discontinuation of study drug. Nine out of 28 subjects experienced progressive disease in this study. The mean FVC (% predicted) declined after 26–32 weeks at doses of 100 mg QD and 100 mg BID. Changes in MMP-7, SP-D, and tenascin-C significantly correlated with change in FVC (% predicted).
Conclusions
These results illustrate JNK enzymatic activity involvement during pulmonary fibrosis, and support systemic biomarker use for tracking disease progression and the potential clinical benefit of this novel intervention in IPF.
Trial registration ClinicalTrials.gov NCT01203943
Electronic supplementary material
The online version of this article (doi:10.1186/s40169-016-0117-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40169-016-0117-2
PMCID: PMC5010551  PMID: 27590145
Biomarkers; CC-930; Idiopathic pulmonary fibrosis; JNK; Matrix metalloproteinase 7; Surfactant protein D; Tenascin-C
6.  Prognostic significance of computed tomography-detected extramural vascular invasion in colon cancer 
World Journal of Gastroenterology  2016;22(31):7157-7165.
AIM
To compare disease-free survival (DFS) between extramural vascular invasion (EMVI)-positive and -negative colon cancer patients evaluated by computed tomography (CT).
METHODS
Colon cancer patients (n = 194) undergoing curative surgery between January 2009 and December 2013 were included. Each patient’s demographics, cancer characteristics, EMVI status, pathological status and survival outcomes were recorded. All included patients had been routinely monitored until December 2015. EMVI was defined as tumor tissue within adjacent vessels beyond the colon wall as seen on enhanced CT. Disease recurrence was defined as metachronous metastases, local recurrence, or death due to colon cancer. Kaplan-Meier analyses were used to compare DFS between the EMVI-positive and -negative groups. Cox’s proportional hazards models were used to measure the impact of confounding variables on survival rates.
RESULTS
EMVI was observed on CT (ctEMVI) in 60 patients (30.9%, 60/194). One year after surgery, there was no statistically significant difference regarding the rates of progressive events between EMVI-positive and -negative patients [11.7% (7/60) and 6.7% (9/134), respectively; P = 0.266]. At the study endpoint, the EMVI-positive patients had significantly more progressive events than the EMVI-negative patients [43.3% (26/60) and 14.9% (20/134), respectively; odds ratio = 4.4, P < 0.001]. Based on the Kaplan-Meier method, the cumulative 1-year DFS rates were 86.7% (95%CI: 82.3-91.1) and 92.4% (95%CI: 90.1-94.7) for EMVI-positive and EMVI-negative patients, respectively. The cumulative 3-year DFS rates were 49.5% (95%CI: 42.1-56.9) and 85.8% (95%CI: 82.6-89.0), respectively. Cox proportional hazards regression analysis revealed that ctEMVI was an independent predictor of DFS with a hazard ratio of 2.15 (95%CI: 1.12-4.14, P = 0.023).
CONCLUSION
ctEMVI may be helpful when evaluating disease progression in colon cancer patients.
doi:10.3748/wjg.v22.i31.7157
PMCID: PMC4988302  PMID: 27610025
Colon cancer; Extramural vascular invasion; Disease-free survival; Neoplasm invasion; Risk assessment
7.  Identifying a Safe Range of Stimulation Current for Intraoperative Neuromonitoring of the Recurrent Laryngeal Nerve: Results from a Canine Model 
Chinese Medical Journal  2016;129(15):1830-1834.
Background:
Intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) has been widely applied during thyroid surgery. However, the safe range of stimulation intensity for IONM remains undetermined.
Methods:
Total thyroidectomies were performed on twenty dogs, and their RLNs were stimulated with a current of 5–20 mA (step-wise in 5 mA increments) for 1 min. The evoked electromyography (EMG) of vocal muscles before and after supramaximal stimulation were recorded and compared. Acute microstructural morphological changes in the RLNs were observed immediately postoperatively under an electron microscope.
Results:
The average stimulating threshold for RLNs stimulated with 15 mA and 20 mA showed no significant changes compared to the unstimulated RLNs (15 mA group: 0.320 ± 0.123 mA vs. 0.315 ± 0.097 mA, P = 0.847; 20 mA group: 0.305 ± 0.101 mA vs. 0.300 ± 0.103 mA, P = 0.758). Similar outcomes were shown in average evoked EMG amplitude (15 mA group: 1,026 ± 268 μV vs. 1,021 ± 273 μV, P = 0.834; 20 mA group: 1,162 ± 275 μV vs. 1,200 ± 258 μV, P = 0.148). However, obvious acute microstructural morphological changes were observed in the nerves that were stimulated with 20 mA.
Conclusions:
A stimulation intensity less than 15 mA might be safe for IONM of the RLN.
doi:10.4103/0366-6999.186636
PMCID: PMC4976572  PMID: 27453233
Canine Model; Neuromonitoring; Recurrent Laryngeal Nerve; Safe Stimulation Intensity; Thyroid Surgery
8.  Involvement of Cl−/HCO3− exchanger SLC26A3 and SLC26A6 in preimplantation embryo cleavage 
Scientific Reports  2016;6:28402.
Bicarbonate (HCO3−) is essential for preimplantation embryo development. However, the mechanism underlying the HCO3− transport into the embryo remains elusive. In the present study, we examined the possible involvement of Cl−/HCO3− exchanger in mediating HCO3− transport into the embryo. Our results showed that depletion of extracellular Cl−, even in the presence of HCO3−, suppressed embryo cleavage in a concentration-dependent manner. Cleavage-associated HCO3−-dependent events, including increase of intracellular pH, upregulation of miR-125b and downregulation of p53, also required Cl−. We further showed that Cl−/HCO3− exchanger solute carrier family 26 (SLC26) A3 and A6 were expressed at 2-cell through blastocyst stage. Blocking individual exchanger’s activity by inhibitors or gene knockdown differentially decreased embryo cleavage and inhibited HCO3−-dependent events, while inhibiting/knocking down both produced an additive effect to an extent similar to that observed when CFTR was inhibited. These results indicate the involvement of SLC26A3 and A6 in transporting HCO3− essential for embryo cleavage, possibly working in concert with CFTR through a Cl− recycling pathway. The present study sheds light into our understanding of molecular mechanisms regulating embryo cleavage by the female reproductive tract.
doi:10.1038/srep28402
PMCID: PMC4921817  PMID: 27346053
9.  Increase in the Prevalence of Resistance Determinants to Trimethoprim/Sulfamethoxazole in Clinical Stenotrophomonas maltophilia Isolates in China 
PLoS ONE  2016;11(6):e0157693.
Aims
This study was carried to reveal the genetic mechanisms of trimethoprim/sulfamethoxazole (SXT) resistance.
Methods
Among 300 clinical Stenotrophomonas maltophilia isolates from China, resistance determinants such as sul and dfrA genes, integrons and transposase were examined using PCR, DNA sequencing and thermal asymmetric interlaced PCR (TAIL-PCR). Data were analyzed using SPSS 20.0.
Results
Of the 300 isolates, 116 (38.7%) were resistant to SXT. An alarming trend of increased resistance to SXT were found over the 10-year period. The positive rates of sul and class 1 integrase (intI1) increased gradually with the development of SXT resistance over the 10-year period. Multiple logistic regression analyses indicated that the genes of qacEΔ1-sul1 (81% vs 46.2%, p = 0.000), sul2 (50.9% vs 9.8%, p = 0.000), intI1 (83.6% vs 65.8%, p = 0.000), dfrA12 (25% vs 3.3%, p = 0.000), dfrA17 (15.5% vs 3.8%, p = 0.000) and dfrA27 (4.3% vs 1.6%, p = 0.01) were more prevalent in SXT-resistant isolates than SXT-susceptible isolates except dfrA1(p = 0.83) and dfrA5(p = 0.18). Sequencing data revealed 12 types of resistance gene cassettes (aar-3-dfrA27, dfrA12–aadA2, dfrA17–aadA5, cmlA1, aacA4, aadA5, arr-3-aacA4, aadA1, aadB–aadA4, aacA4–catB8–aadA1, aadB–aac(6′)-II–blaCARB-8 and aac(6′)-II–blaCARB-8) located in the class 1 integron in 163 isolates (87% SXT-resistant vs 33.7% SXT-susceptible isolates, p = 0.000). A novel finding was the aar-3-dfrA27 (KC748137) gene cassette. The gene of sul2 linked to transposase in 50 SXT- resistant and 7 SXT- susceptible isolates was detected by TAIL-PCR.
Conclusions
The findings demonstrated a higher prevalence of sul, dfrA, intI1 and resistance gene cassettes in class 1 integron in SXT-resistant clinical S. maltophilia isolates in China. The sul1 and dfrA genes located in integrons and the sul2 linked to transposase may imply wide and rapid dissemination of resistance gene in bacteria.
doi:10.1371/journal.pone.0157693
PMCID: PMC4911037  PMID: 27310255
10.  Downregulation of miR-199b is associated with distant metastasis in colorectal cancer via activation of SIRT1 and inhibition of CREB/KISS1 signaling 
Oncotarget  2016;7(23):35092-35105.
The progression of distant metastasis cascade is a multistep and complicated process, frequently leading to a poor prognosis in cancer patients. Recently, growing evidence has indicated that deregulation of microRNAs (miRNAs) contributes to tumorigenesis and tumor progression in colorectal cancer (CRC). In the present study, by comparing the miRNA expression profiles of CRC tissues and corresponding hepatic metastasis tissues, we established the downregulation of miR-199b in CRC metastasis tissues. The decrease in miR-199b expression was significantly correlated to late TNM stage and distant metastasis. Moreover, Kaplan–Meier curves showed that CRC patients with high expression level of miR-199b had a longer median survival. Functional assays results indicated that the restoration of miR-199b considerably reduced cell invasion and migration in vitro and in vivo, and increased the sensitivity to 5-FU and oxaliplatin. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-199b in CRC. The expression of miR-199b was inversely correlated with SIRT1 in CRC specimens. SIRT1 knockdown produced effects on biological behavior that were similar to those of miR-199b overexpression. Furthermore, through Human Tumor Metastasis PCR Array we discovered KISS1 was one of the downstream targets of SIRT1. Silencing of SIRT1 upregulated KISS1 expression by enhancing the acetylation of the transcription factor CREB. The latter was further activated via binding to the promoter of KISS1 to induce transcription. Thus, we concluded that miR-199b regulates SIRT1/CREB/KISS1 signaling pathway and might serve as a prognosis marker or a novel therapeutic target for patients with CRC.
doi:10.18632/oncotarget.9042
PMCID: PMC5085212  PMID: 27145368
miR-199b; SIRT1; KISS1; colorectal cancer; metastasis
11.  CD3brightCD56+ T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients 
Scientific Reports  2016;6:25567.
Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3brightCD56+ T cells, a newly identified CD56+ T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3brightCD56+ T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3brightCD56+ T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3brightCD56+ T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3brightCD56+ T cell population preferentially shown in CHB patients, and indicated that the presence of CD3brightCD56+ T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.
doi:10.1038/srep25567
PMCID: PMC4865958  PMID: 27174425
12.  Chemopreventive Effect of Dietary Glutamineon Colitis-Associated Colorectal Cancer Is Associated with Modulation of the DEPTOR/mTOR Signaling Pathway 
Nutrients  2016;8(5):261.
Glutamine plays a protective role in colitis and colitis-associated colorectal cancer (CAC); however, the protective mechanisms are largely unknown to date. DEP domain-containing mTOR-interacting protein (DEPTOR)/mammalian Target of Rapamycin (mTOR) signaling plays an important role in carcinogenesis. The present study investigated the potential molecular mechanisms for the protective effect of glutamine in a murine model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC. The effects of glutamine on DEPTOR/mTOR signaling and protein light chain 3 (LC3) were evaluated. Administration of glutamine was associated with attenuated development of CAC. Increased expression of DEPTOR and decreased expressions of factors of mTOR signaling, including phospho-mTOR, phospho-STAT3, phospho-Akt, and phospho-S6, were observed in AOM/DSS mice administered glutamine. Furthermore, oral glutamine was associated with increased LC3-II expression in AOM/DSS mice. The present study indicates that regulation of DEPTOR/mTOR signaling may be an important mechanism for glutamine in prevention against the development of CAC. In addition, the chemopreventive effect of dietary glutamine on CAC is, at least in part, associated with the induction of autophagy.
doi:10.3390/nu8050261
PMCID: PMC4882674  PMID: 27144580
colitis; colorectal cancer; glutamine; DEPTOR; mTOR signaling
13.  Inhibitory Effects of Angelica Polysaccharide on Activation of Mast Cells 
This study was designed to investigate the inhibitory effects of Angelica polysaccharide (AP) on activation of mast cells and its possible molecular mechanism. In our study, we determined the proinflammatory cytokines and allergic mediators in anti-DNP IgE stimulated RBL-2H3 cells and found that AP (50, 100, and 200 μg/mL) significantly decreased the release of histamine, β-hexosaminidase, leukotrienes C4 (LTC4), IL-1, IL-4, TNF-α, IL-6, and human monocyte chemotactic protein-1 (MCP-1/CCL2) (p < 0.05). In addition, Ca2+ entry was inhibited by treatment with AP. AP also downregulated the protein expressions of p-Fyn, p-Akt, p-P38, IL-4, TNF-α, and NF-κB p65 in both Fyn gene upregulated and normal RBL-2H3 cells (p < 0.05). Collectively, our results showed that AP could inhibit the activation of mast cells via suppressing the releases of proinflammatory cytokines allergic mediators, Gab2/PI3-K/Akt and Fyn/Syk pathways.
doi:10.1155/2016/6063475
PMCID: PMC4854997  PMID: 27200102
14.  Assessment of the Access AMH assay as an automated, high-performance replacement for the AMH Generation II manual ELISA 
Background
The manual Generation II (Gen II) ELISA method used to measure Anti-Müllerian Hormone (AMH) from Beckman Coulter has recently been superseded by a fully automated AMH immunoassay. The aim of this study was to evaluate the performance of the Access AMH assay and directly compare it to the modified Gen II ELISA method. A secondary aim was to verify that the fertile age-related AMH range previously established using the Gen II ELISA could be used to interpret results from the new automated Access assay.
Methods
The precision, stability, linearity, measurement range and detection limits were determined using recombinant AMH and patient serum samples. Different diluents and their effects on AMH concentration were compared. A correlation study was performed on patient samples to compare the Access AMH assay to the ELISA method on the Access2 and DxI800 analysers. The fertile AMH range was verified by comparing the 10th, 50th and 90th percentile values from both methods obtained from 489 natural conception pregnant women.
Results
The Access AMH assay showed good performance across the measuring range for both intra-assay (CV 1.41–3.30 %) and inter-assay (CV 3.04–5.76 %) precision and acceptable sample stability. Dilution of the high concentration samples with the recommended diluent resulted in a small but significant downward shift in values. The assay was linear over the range of values recommended by the manufacturer, allowing for accurate reporting within the reported range. The two assay types were highly correlated (R2 = 0.9822 and 0.9832 for Access2 and DxI800, respectively), and the differences observed between the Access2 and DxI800 analysers were within clinically acceptable ranges, indicating that the methods are interchangeable. Furthermore, we demonstrated that results from the published reference range for the Gen II ELISA correlate with those from the automated Access AMH assay.
Conclusion
Here, we verified the published performance of the Access AMH assay and showed excellent correlation with the Gen II ELISA method. Moreover, we validated this correlation by confirming that the results from a fertile AMH reference range established using the preceding Gen II ELISA are interchangeable with the new automated Access AMH assay.
Electronic supplementary material
The online version of this article (doi:10.1186/s12958-016-0143-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12958-016-0143-3
PMCID: PMC4754992  PMID: 26879773
Anti-Müllerian Hormone; AMH; Assay; Immunoassay; ELISA; Beckman Coulter; Automated; Reference range
15.  Up-regulation of REG3A in colorectal cancer cells confers proliferation and correlates with colorectal cancer risk 
Oncotarget  2015;7(4):3921-3933.
Colorectal cancer (CRC) is one of the most common malignancies in the world. Previous studies have investigated the altered expression of regenerating islet-derived 3 alpha (REG3A) in various cancers. We aimed at exploring the biological function and the underlying molecular mechanism of REG3A in CRC. In this study, REG3A was found elevated in CRC compared with normal tissues. Further, high REG3A expression level was correlated with bigger tumor size, poorer differentiation, higher tumor stage and lower survival rate. Knockdown of REG3A in two CRC cell lines, LOVO and RKO, significantly inhibited cell proliferation, and increased cells population in G1 phase and cell apoptotic rate. We also found that down-regulation of REG3A in CRC cells notably inhibited cell migration and invasion. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that Kyoto Encyclopedia of Genes and Genomes (KEGG) DNA replication and base excision repair (BER) pathways were correlative with the REG3A expression, which was further confirmed in CRC cells by Western blot. Moreover, we confirmed the interaction of REG3A and fibronectin in CRC cells. We also found that there was a positive correlation between REG3A expression level and the AKT and ERK1/2 phosphorylation status. These collective data indicated that REG3A overexpression promotes CRC tumorigenesis by activating AKT and ERK1/2 pathways. REG3A may serve as a promising therapeutic strategy for CRC.
doi:10.18632/oncotarget.6473
PMCID: PMC4826180  PMID: 26646797
colorectal cancer; REG3A; AKT; ERK1/2
16.  MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway  
Cell Cycle  2015;14(7):1046-1058.
Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding noncancerous tissues. Decreased miR-194 expression was obviously associated with tumor size and tumor differentiation, as well as TNM stage. Both Kaplan–Meier and multivariate survival analysis showed that downregulated miR-194 was associated with overall survival. Moreover, functional assays indicated that overexpression of miR-194 in CRC cell lines inhibited cell proliferation both in vitro and in vivo. In addition, using dual-luciferase reporter gene assay, we found MAP4K4 was the direct target of miR-194. Silencing of MAP4K4 resulted in similar biological behavior changes to that of overexpression of miR-194. We also observed through Human Gene Expression Array that MDM2 was one of the downstream targets of MAP4K4. Knockdown of MAP4K4 downregulated MDM2 expression through transcription factor c-Jun binding to the −1063 to -1057 bp of the promoter. These results suggest that miR-194, regulating the MAP4K4/c-Jun/MDM2 signaling pathway, might act as a tumor suppressor and serve as a novel target for CRC prevention and therapy.
doi:10.1080/15384101.2015.1007767
PMCID: PMC4615039  PMID: 25602366
apoptosis; c-Jun; colorectal cancer; miR-194; MAP4K4; MDM2; proliferation
18.  Genetic Population Structure of Macridiscus multifarius (Mollusca: Bivalvia) on the Basis of Mitochondrial Markers: Strong Population Structure in a Species with a Short Planktonic Larval Stage 
PLoS ONE  2015;10(12):e0146260.
The clam Macridiscus multifarius with a planktonic larval stage of about 10 days is an ecologically and economically important species in the coastal regions of China. In this study, 3 mt-DNA markers (COI, 12S rRNA, and ND1) were used to investigate the population structure and demography of wild M. multifarius populations in 3 coastal localities of the East China Sea (ZS and ZP populations) and Beibu Gulf in the South China Sea (BH population). Sequences of 685 bp in COI, 350 bp in 12S rRNA, and 496 bp in ND1 were determined. High level and significant FST values were obtained among the different localities on the basis of either COI (FST = 0.100–0.444, p < 0.05) or 12S rRNA (FST = 0.199–0.742, p < 0.05) gene, indicating a high degree of genetic differentiation among the populations. FST values were significant but weak for the ND1 gene because it is highly conservative. The median-joining network suggested an obvious genetic differentiation between ZS and BH populations, and the finding is consistent with the results of our demographic analyses using the unweighted pair group method with arithmetic mean. Our study unraveled the extant population genetic structure of M. multifarius and explained the strong population structure of a species with a short planktonic larval stage species; this information could be useful for fishery management measures, including artificial breeding and conservation.
doi:10.1371/journal.pone.0146260
PMCID: PMC4697803  PMID: 26720602
19.  CT pelvimetry and clinicopathological parameters in evaluation of the technical difficulties in performing open rectal surgery for mid-low rectal cancer 
Oncology Letters  2015;11(1):31-38.
The present study aimed to evaluate the predictive value of pelvic anatomical and clinicopathological parameters for use in the estimation of the likely technical difficulties that may be encountered when performing open rectal surgery for mid-low rectal cancer. Sixty consecutive patients, undergoing open rectal surgery for mid-low rectal cancer were recruited between June 2009 and April 2014. All of the surgical procedures conducted, were low anterior resection (LAR) or abdominoperineal resection (APR). The operations were performed by the same surgeon and surgical team. Pelvic dimensions and angles were measured using three-dimensional reconstruction of spiral computerized tomography (CT) images. Operative time and intraoperative blood loss were used as indicators of operative difficulty. The independent variables were pelvic anatomical and clinicopathological parameters, and the dependent variables were operative time and intraoperative blood loss. Univariate and multivariate analyses were performed in order to determine the predictive significance of these variables. The pelvis width was significantly wider in females than in males (P<0.05), while the sacrococcygeal bending degree was significantly greater in males than in females (P<0.05). No significant difference were detected between the pelvis depth of females and males (P>0.05). Multivariate analyses showed that body mass index (BMI), tumor height, lymph node metastasis, anteroposterior diameter of the pelvic inlet, anteroposterior diameter of the pelvic outlet, height of the pubic symphysis, the sacrococcygeal distance, sacrococcygeal-pubic angle and diameter of the upper pubis to the coccyx were the main factors affecting the operative time (all P<0.05), while the maximum diameter of the tumor was the primary factor affecting intraoperative blood loss (P<0.05). Between the two procedures, the clinicopathological parameters appeared to be more valuable for predicting difficulty in LAR, in which operative time was associated with tumor height and tumor staging (RC2=0.312; P<0.001). By contrast, the pelvic anatomical parameters appeared to be more valuable predictors of variation in APR, in which intraoperative blood loss was associated with the anteroposterior diameter of the mid-pelvis, the anteroposterior diameter of the pelvic outlet, the interspinous diameter, the depth of the sacral curvature and the sacropubic distance (RC2=0.608; P=0.002). BMI, tumor height and the maximum diameter of the tumor may be used to predict the operative difficulty in performing open rectal surgery for mid-low rectal cancer. In addition to the associated clinicopathological parameters, wider, shallower and less curved pelvises may make the greatest contribution to reducing operative time and intraoperative blood loss. Operative difficulty is likely to be increased in deeper and narrower pelvises, or in those with greater sacrococcygeal curvature.
doi:10.3892/ol.2015.3827
PMCID: PMC4727119  PMID: 26870163
computerized tomography; rectal cancer; pelvimetry; clinicopathological parameters; operative time; intraoperative blood loss; three-dimensional reconstruction
20.  Effectiveness and Safety of Patient Activation Interventions for Adults with Type 2 Diabetes: Systematic Review, Meta-Analysis, and Meta-regression 
Journal of General Internal Medicine  2014;29(8):1166-1176.
ABSTRACT
BACKGROUND
Patient activation interventions (PAIs) engage patients in care by promoting increased knowledge, confidence, and/or skills for disease self-management. However, little is known about the impact of these interventions on a wide range of outcomes for adults with type 2 diabetes (DM2), or which of these interventions, if any, have the greatest impact on glycemic control.
METHODS
Electronic databases were searched from inception through November 2011. Of 16,290 citations, two independent reviewers identified 138 randomized trials comparing PAIs to usual care/control groups in adults with DM2 that reported intermediate or long-term outcomes or harms. For meta-analyses of continuous outcomes, we used a random-effects model to derive pooled weighted mean differences (WMD). For all-cause mortality, we calculated the pooled odds ratio (OR) using Peto’s method. We assessed statistical heterogeneity using the I2 statistic and conducted meta-regression using a random-effects model when I2 > 50 %. A priori meta-regression primary variables included: intervention strategies, intervention leader, baseline outcome value, quality, and study duration.
RESULTS
PAIs modestly reduced intermediate outcomes [A1c: WMD 0.37 %, CI 0.28–0.45 %, I2 83 %; SBP: WMD 2.2 mmHg, CI 1.0–3.5 mmHg, I2 72 %; body weight: WMD 2.3 lbs, CI 1.3–3.2 lbs, I2 64 %; and LDL-c: WMD 4.2 mg/dL, CI 1.5–6.9 mg/dL, I2 64 %]. The evidence was moderate for A1c, low/very low for other intermediate outcomes, low for long-term mortality and very low for complications. Interventions had no effect on hypoglycemia (evidence: low) or short-term mortality (evidence: moderate). Higher baseline A1c, pharmacist-led interventions, and longer follow-up were associated with larger A1c improvements. No intervention strategy outperformed any other in adjusted meta-regression.
CONCLUSIONS
PAIs modestly improve A1c in adults with DM2 without increasing short-term mortality. These results support integration of these interventions into primary care for adults with uncontrolled glycemia, and provide evidence to insurers who do not yet cover these programs.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-014-2855-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-014-2855-4
PMCID: PMC4099447  PMID: 24733301
type 2 diabetes; patient activation; interventions
21.  New Delhi Metallo-β-Lactamase-Mediated Carbapenem Resistance: Origin, Diagnosis, Treatment and Public Health Concern 
Chinese Medical Journal  2015;128(14):1969-1976.
Objective:
To review the origin, diagnosis, treatment and public health concern of New Delhi metallo-β-lactamase (NDM)-producing bacteria.
Data Sources:
We searched database for studies published in English. The database of PubMed from 2007 to 2015 was used to conduct a search using the keyword term “NDM and Acinetobacter or Enterobacteriaceae or Pseudomonas aeruginosa.”
Study Selection:
We collected data including the relevant articles on international transmission, testing methods and treatment strategies of NDM-positive bacteria. Worldwide NDM cases were reviewed based on 22 case reports.
Results:
The first documented case of infection caused by bacteria producing NDM-1 occurred in India, in 2008. Since then, 13 blaNDM variants have been reported. The rise of NDM is not only due to its high rate of genetic transfer among unrelated bacterial species, but also to human factors such as travel, sanitation and food production and preparation. With limited treatment options, scientists try to improve available therapies and create new ones.
Conclusions:
In order to slow down the spread of these NDM-positive bacteria, a series of measures must be implemented. The creation and transmission of blaNDM are potentially global health issues, which are not issues for one country or one medical community, but for global priorities in general and for individual wound care practitioners specifically.
doi:10.4103/0366-6999.160566
PMCID: PMC4717920  PMID: 26168840
Bacterial; Carbapenem Resistance; Drug Resistance; New Delhi Metallo-β-Lactamase
22.  Chinese medicinal plants for advanced endometriosis after conservative surgery: a prospective, multi-center and controlled trial 
The trial was to explore the effects of Chinese medicinal plants (CMP) treatment on the advanced endometriosis (stage III-IV) after conservative surgery. A prospective, multi-center and controlled trial was conducted from June 2012 to September 2013. Sixty-five post-operative women with advanced endometriosis (stage III-IV) after conservative surgery were included in the trial. They had undergone laparoscopic surgical excision of the endometriosis lesions and the diagnosis of endometriosis was confirmed by pathological examination. The patients received either CMP treatment or goserelin acetate sustained-release depot treatment (as comparison) according to the willingness of the patients. In the post-treatment follow-up visit at 6 and 12 months, the patients were respectively undergone ultrasonic and gynecological examinations. The serum levels of cancer antigen 125 (CA-125) and interleukin 18 (IL-18) were also detected in the post-treatment follow-up visit at 12 months. We found that in the post-treatment follow-up visit at 6 months, the recurrence rate of CMP group and comparison group was 1/31 (3.23%) and 1/34 (2.94%), respectively. In the post-treatment follow-up visit at 12 months, the recurrence rate of CMP group and comparison group was 5/31 (16.13%) and 6/34 (17.65%), respectively. There were no significant differences between the two groups (P>0.05). The serum levels of CA-125 and IL-18 significantly decreased in both of the two groups (P<0.05) and no marked differences existed between them on the serum levels of IL-18 (P>0.05). The serum CA-125 levels of CMP group were significantly lower than those of the comparison group (P<0.05). No adverse effect was reported in both of the two groups during the research and the follow-up period. It concluded that CMP showed promise in preventing the recurrence of stage III-IV endometriosis after conservative surgery, although the conclusion is somewhat limited due to the small size of the trial.
PMCID: PMC4565323  PMID: 26379940
Chinese medicinal plants (CMP); endometriosis; cancer antigen 125 (CA-125); interleukin 18 (IL-18)
23.  The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies: a prospective study 
Scientific Reports  2015;5:11685.
The underlying cause of neutropenia may be difficult to determine due to similar clinical presentation in many neutropenic conditions. The neutrophil protein hCAP-18 (pro-LL-37) is a major component of neutrophil secondary granules and in this prospective study we assessed the use of hCAP-18 levels in blood plasma for differential diagnosis of neutropenic patients (n = 133) of various aetiologies. Plasma levels of hCAP-18 were determined using immunoblot and ELISA. Patients with severe congenital neutropenia (n = 23) presented with the lowest levels of plasma hCAP-18 and differential diagnostic accuracy revealed high sensitivity (100%) and specificity (98.8%) for hCAP-18 ELISA. The correlation coefficient of the hCAP-18 ELISA versus immunoblotting was (R = 0.831) and that of the peptide LL-37 ELISA versus immunoblotting was (R = 0.405) (P < 0.001). Plasma hCAP-18 levels thus displayed high diagnostic value in differential diagnosis of chronic neutropenia. Neutropenic patients with Shwachman-Diamond syndrome, Barth syndrome, Cohen syndrome, acute myeloid leukaemia and specific granule deficiency presented with reduced plasma hCAP-18 levels as well. The blood plasma level of hCAP-18 was thus low in conditions in which the neutrophil antibacterial propeptide hCAP-18 is deficient, i.e. severe congenital neutropenia and neutrophil-specific granule deficiency, and in conditions in which bone marrow myelopoiesis is negatively affected.
doi:10.1038/srep11685
PMCID: PMC4484407  PMID: 26119962
24.  MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism 
BMC Cancer  2015;15:437.
Background
Recent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown.
Methods
We examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1.
Results
Our data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR-217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3′-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth.
Conclusions
Our findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1438-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1438-z
PMCID: PMC4446846  PMID: 26016795
miR-217; AEG-1; colorectal cancer; proliferation; invasion
25.  The Phosphate Transporter Gene OsPht1;4 Is Involved in Phosphate Homeostasis in Rice 
PLoS ONE  2015;10(5):e0126186.
A total of 13 phosphate transporters in rice (Oryza sative) have been identified as belonging to the Pht1 family, which mediates inorganic phosphate (Pi) uptake and transport. We report the biological property and physiological role of OsPht1;4 (OsPT4). Overexpressing OsPT4 resulted in significant higher Pi accumulation in roots, straw and brown rice, and suppression of OsPT4 caused decreased Pi concentration in straw and brown rice. Expression of the β-glucuronidase reporter gene driven by the OsPT4 promoter showed that OsPT4 is expressed in roots, leaves, ligules, stamens, and caryopses under sufficient Pi conditions, consistent with the expression profile showing that OsPT4 has high expression in roots and flag leaves. The transcript level of OsPT4 increased significantly both in shoots and roots with a long time Pi starvation. OsPT4 encoded a plasma membrane—localized protein and was able to complement the function of the Pi transporter gene PHO84 in yeast. We concluded that OsPT4 is a functional Pi-influx transporter involved in Pi absorption in rice that might play a role in Pi translocation. This study will enrich our understanding about the physiological function of rice Pht1 family genes.
doi:10.1371/journal.pone.0126186
PMCID: PMC4430236  PMID: 25970642

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