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1.  Superconductivity in Strong Spin Orbital Coupling Compound Sb2Se3 
Scientific Reports  2014;4:6679.
Recently, A2B3 type strong spin orbital coupling compounds such as Bi2Te3, Bi2Se3 and Sb2Te3 were theoretically predicated to be topological insulators and demonstrated through experimental efforts. The counterpart compound Sb2Se3 on the other hand was found to be topological trivial, but further theoretical studies indicated that the pressure might induce Sb2Se3 into a topological nontrivial state. Here, we report on the discovery of superconductivity in Sb2Se3 single crystal induced via pressure. Our experiments indicated that Sb2Se3 became superconductive at high pressures above 10 GPa proceeded by a pressure induced insulator to metal like transition at ~3 GPa which should be related to the topological quantum transition. The superconducting transition temperature (TC) increased to around 8.0 K with pressure up to 40 GPa while it keeps ambient structure. High pressure Raman revealed that new modes appeared around 10 GPa and 20 GPa, respectively, which correspond to occurrence of superconductivity and to the change of TC slop as the function of high pressure in conjunction with the evolutions of structural parameters at high pressures.
doi:10.1038/srep06679
PMCID: PMC4202213  PMID: 25327696
2.  Clinical analysis of osteosarcoma patients treated with high-dose methotrexate-free neoadjuvant chemotherapy 
Current Oncology  2014;21(5):e678-e684.
Objective
High-dose methotrexate (hdmtx) is a common therapeutic agent in the treatment of osteosarcoma. However, hdmtx is highly toxic and requires complex pharmacokinetic monitoring and leucovorin rescue. Thus, alternative therapeutic strategies are necessary. Here, we analyzed the clinical efficacy of a dia regimen (cisplatin–ifosfamide–doxorubicin) to evaluate its potential as an alternative to hdmtx–based therapy.
Methods
Patients received 12 cycles of chemotherapy administered over 2 years (2 preoperative cycles and 10 postoperative cycles). Cumulative dose was the same in all cycles: cisplatin 120 mg/m2 on day 1 of week 1, followed by ifosfamide 2.0 g/m2 days 1–5 of week 2, and doxorubicin 20 mg/m2 days 1–3 of week 2.
Results
Between January 2004 and October 2008, 39 eligible patients (median age: 16 years) were enrolled, with 36 being evaluable for the study. Of those 36 patients, 20 (55.6%) had a good histologic response to preoperative chemotherapy (>90% tumour necrosis). The estimated 5-year rates of event-free survival (efs) and overall survival were 54.8% and 61.5% respectively.
Conclusions
The results of our study suggest that, in osteosarcoma patients, the dia regimen produces an efs rate and survival outcomes comparable to those attained with hdmtx–containing regimens, with fewer adverse reactions. The dia regimen is well tolerated, and we observed a high level of patient compliance. Our results demonstrate that hdmtx-free osteosarcoma treatment regimens can be effective, warranting further investigation.
doi:10.3747/co.21.1973
PMCID: PMC4189572  PMID: 25302038
Osteosarcoma; chemotherapy; methotrexate-free regimens; survival
3.  Expression pattern of tumour-associated antigens in hepatocellular carcinoma: association with immune infiltration and disease progression 
British Journal of Cancer  2013;109(4):1031-1039.
Background:
The distinct expression pattern of tumour-associated antigens (TAAs) might be a critical reason for the inefficacy of immunity-based treatments and heterogeneous postsurgical recovery in patients with solid tumours, including hepatocellular carcinoma (HCC). However, little is known about the clinical value of the coexpression patterns of multiple TAAs.
Methods:
We determined the expression of multiple TAAs with identified immunogenicity (GPC3, AFP, SSX-2, NY-ESO-1, EpCAM, midkine) and the density of tumour-infiltrating immune cells by immunohistochemistry in a panel of 362 primary HCC patients. We evaluated the association between the TAAs, immune cell infiltration, clinicopathological parameters, and prognosis.
Results:
Patients who coexpressed more TAAs had better prognosis (P<0.00001, overall survival). The integrated pattern of TAA was associated with good differentiation and small tumour size, and with more CD57+ natural killer and CD20+ B-cell infiltration (P<0.05). Multivariate Cox proportional hazards analysis identified the TAA index as an independent prognostic indicator (hazard ratio 0.625; 95% confidence interval 0.467–0.837; P=0.002), and could further predict patient prognosis in collaboration with local immune infiltration.
Conclusion:
Our results could provide new evidence for the improvement of prognostic molecular signatures in HCC, and a novel rationale for patient enrolment in future immunotherapeutic trials and/or clinical treatments.
doi:10.1038/bjc.2013.390
PMCID: PMC3749565  PMID: 23868000
tumour-associated antigen; immune infiltration; prognosis; hepatocellular carcinoma
4.  Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers 
Journal of human hypertension  2012;27(1):24-30.
The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship.
doi:10.1038/jhh.2011.111
PMCID: PMC4128783  PMID: 22217675
cigarette smoking; CYP2A6; genetic polymorphisms; interaction
5.  Combined effects of goserelin and tamoxifen on estradiol level, breast density, and endometrial thickness in premenopausal and perimenopausal women with early-stage hormone receptor-positive breast cancer: a randomised controlled clinical trial 
Yang, H | Zong, X | Yu, Y | Shao, G | Zhang, L | Qian, C | Bian, Y | Xu, X | Sun, W | Meng, X | Ding, X | Chen, D | Zou, D | Xie, S | Zheng, Y | Zhang, J | He, X | Sun, C | Yu, X | Ni, J
British Journal of Cancer  2013;109(3):582-588.
Background:
This study is to investigate the effects of geserelin+tamoxifen (TAM) on estradiol level, breast density (BD), endometrial thickness (ET), and blood lipids in premenopausal and perimenopausal women with hormone receptor-positive early-stage breast cancer.
Methods:
This study recruited 110 premenopausal and perimenopausal patients with hormone receptor-positive early-stage breast cancer between 22 June 2008 and 31 December 2009 and randomly assigned them to receive either goserelin plus TAM or TAM alone for 1.5 years. Blood levels of sex hormones and lipids and ET were determined at 0, 3, 6, 12, and 18 months. Contralateral BD was also measured at 0, 12, and 18 months.
Results:
Five participants dropped out of the goserelin plus TAM group, and two participants dropped out of the TAM-alone group before initiation of endocrine therapy. The rest of patients received scheduled treatment and 3 years of median follow-up. No serious adverse effects were observed, and only two local recurrences have been observed in these patients. Estradiol level and BD were lower in the goserelin plus TAM group than in the TAM-alone group (P<0.05). The endometrium in the goserelin plus TAM group was significantly thinner than that in the TAM-alone group (P<0.05), and women in the TAM-alone group exhibited endometrial thickening over the course of the study. Furthermore, no significant differences in blood lipid levels were reported between the two groups.
Conclusion:
The data from the current study demonstrated that the addition of goserelin to TAM results in downregulation of estradiol level, followed by significant reduction in BD and ET in premenopausal and perimenopausal women with hormone receptor-positive breast cancer, which may eventually lead to better outcome in these patients.
doi:10.1038/bjc.2013.324
PMCID: PMC3738136  PMID: 23860520
goserelin; tamoxifen; breast cancer; premenopausal; perimenopausal
6.  Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia 
Alpha-toxin (AT) is a major virulence factor in the disease pathogenesis of Staphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model of S. aureus pneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse S. aureus clinical isolates. The lungs of S. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P < 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO2 levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P < 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.
doi:10.1128/AAC.02190-13
PMCID: PMC3910899  PMID: 24295977
7.  Successful management of a childhood osteosarcoma with epiphysiolysis and distraction osteogenesis 
Current Oncology  2014;21(4):e658-e662.
In an 11-year-old boy with osteosarcoma in the proximal tibia (type iii), 2 cycles of dia chemotherapy (cisplatin, ifosfamide, doxorubicin) were administered preoperatively while epiphysiolysis was performed. Clinical response was determined to be complete by radiography and histopathology. Marginal excision was then performed with preservation of the proximal tibial epiphysis. Metaphyseal reconstruction was performed using distraction osteogenesis. Six cycles of dia chemotherapy were administered postoperatively. Twenty months later, the patient had developed no complications and experienced full bone healing, with no limb discrepancy.
In selected adolescent patients with osteosarcoma, in whom the tumour is in full contact with the epiphysis, epiphyseal preservation by epiphysiolysis and reconstruction by distraction osteogenesis can provide an excellent outcome, resulting in a stable reconstruction that functionally restores the native limb.
doi:10.3747/co.21.1956
PMCID: PMC4117631  PMID: 25089114
Osteosarcoma; epiphysis preservation; epiphysiolysis; distraction osteogenesis; limb function; quality of life
8.  Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility 
Oncogene  2012;32(27):3246-3253.
The tumor microenvironment has an important role in cancer progression. Here we show that miR-148a is downregulated in 15 out of 16 samples (94%) of cancer-associated fibroblasts (CAFs) compared with matched normal tissue fibroblasts (NFs) established from patients with endometrial cancer. Laser-capture microdissection of stromal cells from normal tissue and endometrial cancer confirmed this observation. Treatment of cells with 5-aza-deoxycytidine stimulated the expression of miR-148a in the majority of CAFs implicating DNA methylation in the regulation of miR-148a expression. Investigation of miR-148a function in fibroblasts demonstrated that conditioned media (CM) from CAFs overexpressing miR-148a significantly impaired the migration of five endometrial cancer cell lines without affecting their growth rates in co-culture experiments. Among predicted miR-148a target genes are two WNT family members, WNT1 and WNT10B. Activation of the WNT/β-catenin pathway in CAFs was confirmed by microarray analysis of gene expression and increased activity of the SuperTOPFIash luciferase reporter. We found elevated levels of WNT10B protein in CAFs and its level decreased when miR-148a was re-introduced by lentiviral infection. The 3′-UTR of WNT10B, cloned downstream of luciferase cDNA, suppressed luciferase activity when co-expressed with miR-148a indicating that WNT10B is a direct target of miR-148a. In contrast to the effect of miR-148a, WNT10B stimulated migration of endometrial cancer cell lines. Our findings have defined a molecular mechanism in the tumor microenvironment that is a novel target for cancer therapy.
doi:10.1038/onc.2012.351
PMCID: PMC3711253  PMID: 22890324
cancer-associated fibroblasts; endometrial cancer; microRNA; miR-148a; WNT10B
9.  Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR)-γ activation in a rat model of insulin resistance 
Diabetologia  2010;54(4):935-944.
Aims/hypothesis
Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor (PPAR)-γ activation. However, the physiological impact of TRIB3 action in vivo remains controversial.
Methods
We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic–hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist, bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO.
Results
Trib3 ASO treatment specifically reduced Trib3 expression by 70 to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic–hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70%, and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment.
Conclusions/interpretation
These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.
doi:10.1007/s00125-010-1984-5
PMCID: PMC4061906  PMID: 21190014
Antisense oligonucleotide; Euglycaemic–hyperinsulinaemic clamp; Insulin sensitivity; PPAR gamma; TRIB3
10.  CREAM: a database for chemotherapy resistance-associated miRSNP 
Dai, E | Lv, Y | Meng, F | Yu, X | Zhang, Y | Wang, S | Liu, X | Liu, D | Wang, J | Li, X | Jiang, W
Cell Death & Disease  2014;5(5):e1272-.
doi:10.1038/cddis.2014.236
PMCID: PMC4047878  PMID: 24874743
11.  Clinical evaluation of the normalized metal artefact reduction algorithm caused by dental fillings in CT 
Dentomaxillofacial Radiology  2013;42(4):20120105.
Objectives:
The aim of this study was to evaluate the performance of a normalized metal artefact reduction (NMAR) algorithm in patients with high-density dental fillings in CT images, and compare the results with weighted filtered back-projection (WFBP) and linear interpolation metal artefact reduction (MARli) algorithms.
Methods:
A total of 15 patients who had dental fillings were included in this study. The CT raw data sets were processed on an offline workstation. For each data set, one image series was reconstructed with WFBP, one with MARli and one with NMAR. Two observers qualitatively graded the severity of metal artefacts and their impacts on surrounding and distant soft tissue using a five-point scale. Six regions of interest were selected to measure the CT values and the standard deviation (SD) for quantitatively evaluating the effects of artefact reduction.
Results:
A total of 217 slices with metal artefacts from 15 patients were included in the qualitative analysis. The average score (mean ± SD) with the WFBP and MARli algorithms was 2.24 ± 1.06 and 2.71 ± 0.73, respectively. Image artefacts were significantly reduced using the NMAR algorithm compared with the other two algorithms, with an average score of 1.70 ± 0.83. The mean CT value in the most hypodense streak artefacts around the metal fillings was significantly improved with both MARli and NMAR. The mean SDs of measured CT values from surrounding or distant soft tissues were lower in NMAR images than in WFBP and MARli images.
Conclusions:
The NMAR algorithm can significantly reduce the artefacts caused by dental fillings, compared with the WFBP and linear interpolation algorithms.
doi:10.1259/dmfr.20120105
PMCID: PMC3667513  PMID: 23420861
dental filling; metal artefact reduction; CT; X-ray; normalized metal artefact reduction
12.  Suppression of tumor angiogenesis by targeting the protein neddylation pathway 
Cell Death & Disease  2014;5(2):e1059-.
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin–RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
doi:10.1038/cddis.2014.21
PMCID: PMC3944239  PMID: 24525735
neddylation; MLN4924; tumor angiogenesis; cullin–RING ligase
13.  Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment 
Mao, J | Fan, S | Ma, W | Fan, P | Wang, B | Zhang, J | Wang, H | Tang, B | Zhang, Q | Yu, X | Wang, L | Song, B | Li, L
Cell Death & Disease  2014;5(1):e1039-.
The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.
doi:10.1038/cddis.2013.515
PMCID: PMC4040703  PMID: 24481453
Wnt signaling; gastric cancer stem cells; salinomycin
14.  Paediatric bacterial keratitis cases in Shanghai: microbiological profile, antibiotic susceptibility and visual outcomes 
Hong, J | Chen, J | Sun, X | Deng, S X | Chen, L | Gong, L | Cao, W | Yu, X | Xu, J
Eye  2012;26(12):1571-1578.
Purpose
The purpose of this study was to review the microbiological profile, in vitro antibiotic susceptibility and visual outcomes of paediatric microbial keratitis in Shanghai, China over the past 6 years.
Methods
Medical records of patients aged ≤16 years were reviewed, who were diagnosed as having bacterial keratitis between 1 January 2005 and 31 December 2010. Bacterial culture results and in vitro antibiotic susceptibility were analysed. A logistic regression analysis was conducted to evaluate the relationship between visual impairment and possible risk factors.
Results
Eighty consecutive cases of paediatric bacterial keratitis cases were included, among which 59 were identified as having positive culture. Staphylococcus epidermidis was the most commonly isolated organism (n=23; 39.0%), followed by Streptococcus pneumoniae (n=11; 18.6%) and Pseudomonas aeruginosa (n=6; 10.2%). Antibiotic sensitivities revealed that tested bacteria had low resistance rates to fluoroquinolones and aminoglycosides (8.3–18.4% and 12.5–24.4%, respectively). Multivariate logistic regression analysis proved that visual impairment was significantly associated with Gram-negative bacterial infection (odds ratio (OR)=7.626; P=0.043) and an increasing number of resistant antibiotics (OR=0.385; P=0.040).
Conclusions
S. epidermidis was the most common isolated organism in Shanghai paediatric keratitis. The fluoroquinolones and aminoglycosides remained good choices for treating these patients. Gram-negative bacterial infection and an increasing number of resistant antibiotics were associated with worse visual prognoses in paediatric keratitis.
doi:10.1038/eye.2012.210
PMCID: PMC3522844  PMID: 23079751
bacterial keratitis; antibiotics; paediatrics; prognosis; susceptibility
15.  CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma 
Cell Death and Differentiation  2012;19(11):1779-1790.
The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) (−82/−50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment.
doi:10.1038/cdd.2012.60
PMCID: PMC3469060  PMID: 22595757
CD147; unfolded protein response (UPR); hepatocellular carcinoma (HCC); Bip; apoptosis; chemosensitivity
16.  Gene Profile Identifies Zinc Transporters Differentially Expressed in Normal Human Organs and Human Pancreatic Cancer 
Current molecular medicine  2013;13(3):401-409.
Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.
PMCID: PMC3799886  PMID: 23331012
Pancreatic cancer; profile; zinc transporter; ZIP4
17.  Denosumab and giant cell tumour of bone—a review and future management considerations 
Current Oncology  2013;20(5):e442-e447.
Giant cell tumour of bone (gctb) is one type of giant-cell-rich bone lesion characterized by the presence of numerous multinucleated osteoclast-type giant cells. Giant cells are known to express rankl (receptor activator of nuclear factor κB ligand) and are responsible for the aggressive osteolytic nature of the tumour. No available treatment option is definitively effective in curing this disease, especially in surgically unsalvageable cases. In recent years, several studies of denosumab in patients with advanced or unresectable gctb have shown objective changes in tumour composition, reduced bony destruction, and clinical benefit.
Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and specificity to rankl. Several large phase iii studies have shown that denosumab is more effective than bisphosphonates in reducing skeletal morbidity arising from a wide range of tumours and that it can delay bone metastasis. The relevant articles are reviewed here. The controversies related to the future use of denosumab in the treatment of gctb are discussed.
doi:10.3747/co.20.1497
PMCID: PMC3805412  PMID: 24155640
Denosumab; giant cell tumour of bone; receptor activator of nuclear factor κB ligand; rankl; bone turnover
18.  Rapid reuptake of granzyme B leads to emperitosis: an apoptotic cell-in-cell death of immune killer cells inside tumor cells 
Wang, S | He, M-f | Chen, Y-h | Wang, M-y | Yu, X-m | Bai, J | Zhu, H-y | Wang, Y-y | Zhao, H | Mei, Q | Nie, J | Ma, J | Wang, J-f | Wen, Q | Ma, L | Wang, Y | Wang, X-n
Cell Death & Disease  2013;4(10):e856-.
A cell-in-cell process refers to the invasion of one living cell into another homotypic or heterotypic cell. Different from non-apoptotic death processes of internalized cells termed entosis or cannibalism, we previously reported an apoptotic cell-in-cell death occurring during heterotypic cell-in-cell formation. In this study, we further demonstrated that the apoptotic cell-in-cell death occurred only in internalized immune killer cells expressing granzyme B (GzmB). Vacuole wrapping around the internalized cells inside the target cells was the common hallmark during the early stage of all cell-in-cell processes, which resulted in the accumulation of reactive oxygen species and subsequent mitochondrial injury of encapsulated killer or non-cytotoxic immune cells. However, internalized killer cells mediated rapid bubbling of the vacuoles with the subsequent degranulation of GzmB inside the vacuole of the target cells and underwent the reuptake of GzmB by killer cells themselves. The confinement of GzmB inside the vacuole surpassed the lysosome-mediated cell death occurring in heterotypic or homotypic entosis processes, resulting in a GzmB-triggered caspase-dependent apoptotic cell-in-cell death of internalized killer cells. On the contrary, internalized killer cells from GzmB-deficient mice underwent a typical non-apoptotic entotic cell-in-cell death similar to that of non-cytotoxic immune cells or tumor cells. Our results thus demonstrated the critical involvement of immune cells with cytotoxic property in apoptotic cell-in-cell death, which we termed as emperitosis taken from emperipolesis and apoptosis. Whereas entosis or cannibalism may serve as a feed-on mechanism to exacerbate and nourish tumor cells, emperitosis of immune killer cells inside tumor cells may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance.
doi:10.1038/cddis.2013.352
PMCID: PMC3824662  PMID: 24113190
apoptotic cell-in-cell death; emperitosis; immune cytotoxic cells; granzyme B; vacuole formation
19.  Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H2O2 in HL-1 mouse cardiac muscle cells 
Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.
doi:10.1590/1414-431X20132936
PMCID: PMC3854426  PMID: 24036910
Macrophage migration inhibitory factor; HL-1 cells; Hydrogen peroxide; Atrial fibrillation; Protein kinases
20.  Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway 
Deng, Q | Yu, X | Xiao, L | Hu, Z | Luo, X | Tao, Y | Yang, L | Liu, X | Chen, H | Ding, Z | Feng, T | Tang, Y | Weng, X | Gao, J | Yi, W | Bode, A M | Dong, Z | Liu, J | Cao, Y
Cell Death & Disease  2013;4(9):e804-.
Many natural compounds derived from plants or microbes show promising potential for anticancer treatment, but few have been found to target energy-relevant regulators. In this study, we report that neoalbaconol (NA), a novel small-molecular compound isolated from the fungus, Albatrellus confluens, could target 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibit its downstream phosphoinositide-3 kinase (PI3-K)/Akt-hexokinase 2 (HK2) pathway, which eventually resulted in energy depletion. By targeting PDK1, NA reduced the consumption of glucose and ATP generation, activated autophagy and caused apoptotic and necroptotic death of cancer cells through independent pathway. Necroptosis was remarkably induced, which was confirmed by several necroptosis-specific markers: the activation of autophagy, presence of necrotic morphology, increase of receptor-interacting protein 1 (RIP1)/RIP3 colocalization and interaction and rescued by necroptosis inhibitor necrostatin-1. The possibility that Akt overexpression reversed the NA-induced energy crisis confirmed the importance of the PDK1-Akt-energy pathway in NA-mediated cell death. Moreover, NA shows the capability to inhibit PI3-K/Akt signaling and suppress tumor growth in the nasopharyngeal carcinoma (NPC) nude mouse model. These results supported the feasibility of NA in anticancer treatments.
doi:10.1038/cddis.2013.324
PMCID: PMC3789182  PMID: 24052072
neoalbaconol; PDK1; PI3-K/Akt; energy depletion; cancer cell death
21.  Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus 
Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.
doi:10.1590/1414-431X20133103
PMCID: PMC3859333  PMID: 23903678
Elongation of long-chain fatty acids family member 6; Single nucleotide polymorphism; Type 2 diabetes mellitus; Insulin resistance; β-cell function
22.  Superconductivity in Topological Insulator Sb2Te3 Induced by Pressure 
Scientific Reports  2013;3:2016.
Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.
doi:10.1038/srep02016
PMCID: PMC3687246  PMID: 23783511
24.  Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma 
Yu, X | Zhen, Y | Yang, H | Wang, H | Zhou, Y | Wang, E | Marincola, F M | Mai, C | Chen, Y | Wei, H | Song, Y | Lyu, X | Ye, Y | Cai, L | Wu, Q | Zhao, M | Hua, S | Fu, Q | Zhang, Y | Yao, K | Liu, Z | Li, X | Fang, W
Cell Death & Disease  2013;4(5):e634-.
Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.
doi:10.1038/cddis.2013.153
PMCID: PMC3674361  PMID: 23681229
CTGF; NPC; miR-18b; PI3K/AKT
25.  Association of Suboptimal Health Status and Cardiovascular Risk Factors in Urban Chinese Workers 
Suboptimal health status (SHS) has become a new public health challenge in urban China. Despite indications that SHS may be associated with progression or development of chronic diseases such as cardiovascular and metabolic diseases, there are few reports on SHS investigations. To explore the relationship between SHS and traditional cardiovascular risk factors, a cross-sectional study was conducted in a sample of 4,881 workers employed in 21 companies in urban Beijing. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), cortisol, and body mass index were measured. SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). Univariate analysis and linear two-level model were used to analyze the association of SHS with the cardiovascular risk factors. Serum cortisol level was much higher among the SHS high-score group than that among the low SHS score group (204.31 versus 161.33 ng/ml, P < 0.001). In a linear two-level model, we found correlation between SHS and systolic blood pressure, diastolic blood pressure, plasma glucose, total cholesterol, and HDL cholesterol among men, and correlation between SHS and systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, and HDL cholesterol among women after controlling for age, education background, occupation, smoking, and physical activity. SHS is associated with cardiovascular risk factors and contributes to the development of cardiovascular disease. SHS should be recognized in the health care system, especially in primary care.
doi:10.1007/s11524-011-9636-8
PMCID: PMC3324604  PMID: 22203493
Suboptimal health status; Cardiovascular disease; Risk factors

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