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1.  Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis 
Mucosal immunology  2013;7(3):718-729.
The desmosomal cadherin desmoglein-1 (DSG1) is an essential intercellular adhesion molecule that is altered in various human cutaneous disorders; however, its regulation and function in allergic disease remains unexplored. Herein, we demonstrate a specific reduction in DSG1 in esophageal biopsies from patients with eosinophilic esophagitis (EoE), an emerging allergic disorder characterized by chronic inflammation within the esophageal mucosa. Further, we show that DSG1 gene silencing weakens esophageal epithelial integrity, and induces cell separation and impaired barrier function (IBF) despite high levels of desmoglein-3 (DSG3). Moreover, DSG1 deficiency induces transcriptional changes that partially overlap with the transcriptome of inflamed esophageal mucosa; notably, periostin, a multipotent pro-inflammatory extracellular matrix molecule, is the top induced overlapping gene. We further demonstrate that IBF is a pathological feature in EoE, which can be partially induced through the downregulation of DSG1 by interleukin-13 (IL-13). Taken together, these data identify a functional role for DSG1 and its dysregulation by IL-13 in the pathophysiology of EoE and suggest that the loss of DSG1 may potentiate allergic inflammation through the induction of pro-inflammatory mediators such as periostin.
PMCID: PMC3999291  PMID: 24220297
2.  Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice 
Cell Death and Differentiation  2013;20(10):1404-1414.
Chronic inflammation and excessive protease activity have a major role in the persistence of non-healing wounds. Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-established role in initiating apoptotic cell death. GzmB is also capable of acting extracellularly, independent of perforin and can degrade several extracellular matrix (ECM) proteins that are critical during wound healing. We used apolipoprotein E (ApoE) knockout (AKO) mice as a novel model of chronic inflammation and impaired wound healing to investigate the role of GzmB in chronic wounds. Wild-type and AKO mice were grown to 7 weeks (young) or 37 weeks (old) of age on a regular chow or high-fat diet (HFD), given a 1-cm diameter full thickness wound on their mid dorsum and allowed to heal for 16 days. Old AKO mice fed a HFD exhibited reduced wound closure, delayed contraction, chronic inflammation and altered ECM remodeling. Conversely, GzmB/ApoE double knockout mice displayed improved wound closure and contraction rates. In addition, murine GzmB was found to degrade both fibronectin and vitronectin derived from healthy mouse granulation tissue. In addition, GzmB-mediated degradation of fibronectin generated a fragment similar in size to that observed in non-healing mouse wounds. These results provide the first direct evidence that GzmB contributes to chronic wound healing in part through degradation of ECM.
PMCID: PMC3770318  PMID: 23912712
Granzyme B; extracellular matrix; wound healing; skin; inflammation
3.  Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity 
British Journal of Cancer  2013;109(6):1599-1608.
Squamous cell lung cancer (SqCC) is the second most common type of lung cancer in the United States. Previous studies have used gene-expression data to classify SqCC samples into four subtypes, including the primitive, classical, secretory and basal subtypes. These subtypes have different survival outcomes, although it is unknown whether these molecular subtypes predict response to therapy.
Here, we analysed RNAseq data of 178 SqCC tumour samples and characterised the features of the different SqCC subtypes to define signature genes and pathway alterations specific to each subtype. Further, we compared the gene-expression features of each molecular subtype to specific time points in models of airway development. We also classified SqCC-derived cell lines and their reported therapeutic vulnerabilities.
We found that the primitive subtype may come from a later stage of differentiation, whereas the basal subtype may be from an early time. Most SqCC cell lines responded to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), whereas the basal-type cell line EBC-1 was sensitive to three other drugs (PF2341066, AZD6244 and PD-0325901).
Compared with the other three subtypes of cell lines, the secretory-type cell lines were significantly less sensitive to the five most effective drugs, possibly because of their low proliferation activity. We provide a bioinformatics framework to explore drug repurposing for cancer subtypes based on the available genomic profiles of tumour samples, normal cell types, cancer cell lines and data of drug sensitivity in cell lines.
PMCID: PMC3776976  PMID: 24002593
squamous cell lung cancer subtypes; gene expression; RNAseq; microarray; signature genes; cells of origin; representative cell line; drug sensitivity; classification
4.  IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer 
Oncogene  2012;32(2):151-159.
Serine/threonine kinase IKBKE is a newly identified oncogene; however, its regulation remains elusive. Here, we provide evidence that IKBKE is a downstream target of signal transducer and activator of transcription 3 (STAT3) and that tobacco components induce IKBKE expression through STAT3. Ectopic expression of constitutively active STAT3 increased IKBKE mRNA and protein levels, whereas inhibition of STAT3 reduced IKBKE expression. Furthermore, expression levels of IKBKE are significantly associated with STAT3 activation and tobacco use history in non-small cell lung cancer (NSCLC) patients examined. In addition, we show induction of IKBKE by two components of cigarette smoke, nicotine and nicotine-derived nitrosamine ketone (NNK). Upon exposure to nicotine or NNK, cells express high levels of IKBKE protein and mRNA, which are largely abrogated by inhibition of STAT3. Characterization of the IKBKE promoter revealed two STAT3-response elements. The IKBKE promoter directly bound to STAT3 and responded to nicotine and NNK stimulation. Notably, enforcing expression of IKBKE induces chemoresistance, whereas knockdown of IKBKE not only sensitizes NSCLC cells to chemotherapy but also abrogates STAT3- and nicotine-induced cell survival. These data indicate for the first time that IKBKE is a direct target of STAT3 and is induced by tobacco carcinogens through STAT3 pathway. In addition, our study also suggests that IKBKE is an important therapeutic target and could have a pivotal role in tobacco-associated lung carcinogenesis.
PMCID: PMC4109158  PMID: 22330135
IKBKE; STAT3; tobacco carcinogen; chemosensitivity; lung cancer
5.  Manual cataract extraction via a subconjunctival limbus oblique incision for mature cataracts 
Yang, J | Lai, P | Wu, D | Long, Z
Indian Journal of Ophthalmology  2014;62(3):274-278.
To report the technique and outcomes of sutureless manual cataract extraction via a subconjunctival limbus oblique incision for mature cataracts.
Materials and Methods:
This retrospective study comprised of 112 eyes of 83 patients with mature cataract who all had manual cataract extraction via a subconjunctival limbus oblique incision. A transconjunctival tunnel is fashioned with a 3.0 mm keratome, 0.5 mm behind the limbal vascular arcades. A limbal tunnel, with a transverse extent of 9 mm in the cornea and 7.0 mm in the limbus, is created beneath the conjunctival/Tenon's tissue using an angled bevel-up crescent blade. Outcome measures included visual acuity, intraoperative complications, surgically induced astigmatism, endothelial cell loss rate and surgery time.
Self-sealing wound was achieved in 112 eyes (98.2%). The nucleus was delivered in whole in 108 eyes (96.4%). Intraoperative complications included hyphema in 3 eyes (2.7%), iridodialysis in 2 eyes 1.8%), posterior capsular rupture and zonular dialysis in 2 eyes (1.8%). At the 3-month follow-up, 91% patients achieved a best-corrected visual acuity of 20/20 or better, the mean of surgically induced astigmatism was -0.62 ± 0.41 Diopters and endothelial cell loss was 4.2%. Average surgical time was 3.75 min per case.
This subconjunctival limbus oblique incision has the potential to serve as safe and effective technique for mature cataracts.
PMCID: PMC4061661  PMID: 24722270
Limbus incision; subconjunctival incision; sutureless manual small-incision cataract surgery; wound construction
6.  G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation 
Translational stroke research  2012;3(4):418-427.
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ2 analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (χ2=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.
PMCID: PMC3544200  PMID: 23329986
Angiogenesis; Genetics; Intracerebral hemorrhage; Risk factor; Vascular malformation
7.  Application of prospective ECG-triggered dual-source CT coronary angiography for infants and children with coronary artery aneurysms due to Kawasaki disease 
Duan, Y | Wang, X | Cheng, Z | Wu, D | Wu, L
The British Journal of Radiology  2012;85(1020):e1190-e1197.
The aim of this study was to prospectively evaluate the initial application and value of prospective electrocardiogram (ECG)-triggered dual-source CT coronary angiography (DSCTCA) in the diagnosis of infants and children with coronary artery aneurysms due to Kawasaki disease.
19 children [12 males; mean age 13.47 months, range 3 months to 5 years; mean heart rate 112 beats per minute (bpm), range 83–141 bpm] underwent prospective ECG-triggered DSCTCA with free breathing. Subjective image quality was assessed on a five-point scale (1, excellent; 5, non-diagnostic) by two blinded observers. The location, number and size of each aneurysm were observed and compared with those of transthoracic echocardiography (TTE) performed within 1 week. Interobserver agreement concerning the subjective image quality was evaluated with Cohen's κ-test. Bland–Altman analysis was used to evaluate the agreement on measurements (diameter and length of aneurysms) between DSCTCA and TTE. The average effective dose required for DSCTCA was calculated for all children.
All interobserver agreement for subjective image quality assessment was excellent (κ=0.87). The mean±standard deviation (SD) aneurysm diameter with DSCTCA was 0.76±0.36 cm and with TTE was 0.76±0.39 cm. The mean±SD aneurysm length with DSCTCA was 2.06±1.35 cm and with TTE was 2.00±1.22 cm. The Bland–Altman plot for agreement between DSCTCA and TTE measurements showed good agreement. The mean effective dose was 0.36±0.06 mSv.
As an alternative diagnostic modality, prospective ECG-triggered DSCTCA with excellent image quality and low radiation exposure has been proved useful for diagnosing infants and children with coronary artery aneurysms due to Kawasaki disease.
Advances in knowledge
Prospective ECG–triggered DSCTCA for infants and children allows rapid, accurate assessment of coronary aneurysms due to Kawasaki diseases, compared with TTE.
PMCID: PMC3611723  PMID: 22932064
8.  Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters 
Cell Death & Disease  2013;4(11):e907-.
The androgen receptor (AR) has a critical role in promoting androgen-dependent and -independent apoptosis in testicular cells. However, the molecular mechanisms that underlie the ligand-independent apoptosis, including the activity of AR in testicular stem cells, are not completely understood. In the present study, we generated induced pluripotent stem cells (iPSCs) from bovine testicular cells by electroporation of octamer-binding transcription factor 4 (OCT4). The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4, which maintained and stabilized the expression of stemness genes and pluripotency. The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters, including di (2-ethyhexyl) phthalates, di (n-butyl) phthalate, and butyl benzyl phthalate. Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of BAX/BCL-2, thereby favoring apoptosis. Phthalate esters also increased the expression of cyclin-dependent kinase inhibitor 1 (p21Cip1) in a p53-dependent manner and enhanced the transcriptional activity of p53. The forced expression of AR and knockdown of p21Cip1 led to the rescue of the phthalate-mediated apoptosis. Overall, this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency, as well as for identifying the iPSC signaling pathway(s) that are deregulated by these chemicals.
PMCID: PMC3847308  PMID: 24201806
environmental hormone; nuclear reprogramming; p53; testis cells; toxicity screening
9.  Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer 
Current Oncology  2013;20(5):e388-e395.
Recent studies have suggested a controversial role of Helicobacter pylori infection in gastric cancer prognosis. The aim of the present study was to investigate the potential impact of H. pylori status on the prognosis of patients with gastric cancer in a Chinese prospective cohort.
Between 2007 and 2009, 261 patients with curatively resected gastric cancer were enrolled in the study. H. pylori status was defined by means of immunohistochemical staining in tumour and non-neoplastic tissues. Treatment prognosis was measured in terms of cancer-specific survival and disease-free survival (dfs). Univariate and multivariate Cox regression models were used to assess the association between H. pylori status and patient prognosis.
Positivity for H. pylori infection was observed in 188 of the 261 patients (72.0%). In patients positive for H. pylori, mean cancer-specific survival was 55.2 months [95% confidence interval (ci): 53.4 to 56.9 months] and mean dfs was 53.9 months (95% ci: 51.8 to 56.0 months); the same survivals were, respectively, 45.1 months (95% ci: 42.2 to 47.9 months) and 43.7 months (95% ci: 40.4 to 47.0 months) in patients negative for H. pylori. In univariate analysis, positive H. pylori status was associated with better cancer-specific survival [hazard ratio (hr): 0.486; 95% ci: 0.271 to 0.870; p = 0.015] and dfs (hr: 0.540; 95% ci: 0.307 to 0.950; p = 0.033). In multivariate analysis, H. pylori was an independent prognostic factor for cancer-specific survival (hr: 0.485; 95% ci: 0.265 to 0.889; p = 0.019).
Our study demonstrates that positive H. pylori status is a beneficial prognostic indicator in patients with gastric cancer and might suggest possible therapeutic approaches for gastric cancer. Further research is required to better understand inflammation mechanisms and cancer progression.
PMCID: PMC3805408  PMID: 24155636
Helicobacter pylori; gastric cancer; survival; relapse
10.  P2X7 purinoceptors contribute to the death of Schwann cells transplanted into the spinal cord 
Cell Death & Disease  2013;4(10):e829-.
The potential to use Schwann cells (SCs) in neural repair for patients suffering from neurotrauma and neurodegenerative diseases is well recognized. However, significant cell death after transplantation hinders the clinical translation of SC-based therapies. Various factors may contribute to the death of transplanted cells. It is known that prolonged activation of P2X7 purinoceptors (P2X7R) can lead to death of certain types of cells. In this study, we show that rat SCs express P2X7R and exposure of cultured SCs to high concentrations of ATP (3–5 mM) or a P2X7R agonist, 2′(3′)-O-(4-benzoylbenzoyl)ATP (BzATP) induced significant cell death rapidly. High concentrations of ATP and BzATP increased ethidium uptake by SCs, indicating increased membrane permeability to large molecules, a typical feature of prolonged P2X7R activation. SC death, as well as ethidium uptake, induced by ATP was blocked by an irreversible P2X7R antagonist oxidized ATP (oxATP) or a reversible P2X7R antagonist A438079. oxATP also significantly inhibits the increase of intracellular free calcium induced by minimolar ATP concentrations. Furthermore, ATP did not cause death of SCs isolated from P2X7R-knockout mice. All these results suggest that P2X7R is responsible for ATP-induced SC death in vitro. When rat SCs were treated with oxATP before transplantation into uninjured rat spinal cord, 35% more SCs survived than untreated SCs 1 week after transplantation. Moreover, 58% more SCs isolated from P2X7R-knockout mice survived after being transplanted into rat spinal cord than SCs from wild-type mice. This further confirms that P2X7R is involved in the death of transplanted SCs. These results indicate that targeting P2X7R on SCs could be a potential strategy to improve the survival of transplanted cells. As many other types of cells, including neural stem cells, also express P2X7R, deactivating P2X7R may improve the survival of other types of transplanted cells.
PMCID: PMC3824653  PMID: 24091672
purinoceptor; ATP receptor; Schwann cell; cell death; cell transplantation; spinal cord injury
11.  Early responses of the STAT3 pathway to platinum drugs are associated with cisplatin resistance in epithelial ovarian cancer 
Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3) is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705), STAT3α, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727) and STAT3β. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance.
PMCID: PMC3854422  PMID: 23969971
Epithelial ovarian cancer; Cisplatin; Oxaliplatin; Nedaplatin; STAT3
13.  The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular cells 
Cheng, P | Ni, Z | Dai, X | Wang, B | Ding, W | Rae Smith, A | Xu, L | Wu, D | He, F | Lian, J
Cell Death & Disease  2013;4(2):e489-.
Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.
PMCID: PMC3734844  PMID: 23392177
ApoG2; ROS; autophagy; HCC
14.  Molecular detection of persistent postoperative circulating tumour cells in stages II and III colon cancer patients via multiple blood sampling: prognostic significance of detection for early relapse 
British Journal of Cancer  2011;104(7):1178-1184.
The purpose of this study was to detect postoperative persistent circulating tumour cells (CTCs) in stages II and III colon cancer patients undergoing curative resection and so identify a subgroup of patients who are at high risk for early relapse.
Four mRNA molecular markers including human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen (CEA) mRNA were used to detect CTCs in 141 stages II and III colon cancer patients undergoing curative resection to determine the significance of CTCs in postoperative early relapse.
Out of 141 patients, postoperative early relapse and non-early relapse/no relapse was found in 48 (34.0%) patients and 93 (66.0%) patients, respectively. Univariately, postoperative early relapse was significantly correlated with lymph node metastasis (P=0.025), vascular invasion (P=0.002), perineural invasion (P=0.001), laparoscopic surgery (P=0.019), high postoperative serum CEA levels (P=0.001), and presence of persistent postoperative CTCs (P<0.001). Using a multivariate proportional hazards regression analysis, the presence of perineural invasion (P=0.034; HR, 1.974; 95% CI: 1.290–3.861), high postoperative serum CEA levels (P=0.020; HR, 2.377; 95% CI: 1.273–4.255), and the presence of persistent postoperative CTCs (P<0.001; HR, 11.035; 95% CI: 4.396–32.190), were demonstrated to be independent predictors for postoperative early relapse. Furthermore, the presence of persistent postoperative CTCs was strongly correlated with a poorer disease-free and overall survival (both P<0.001).
This study suggests that molecular detection of persistent postoperative CTCs is a prognostic predictor of early relapse in UICC stage II/III colon cancer patients, and thus could help to define patients with this tumour entity for an enhanced follow-up and therapeutic program.
PMCID: PMC3068492  PMID: 21343933
molecular detection; colon cancer; postoperative early relapse; circulating tumour cells; UICC stage II/III
15.  Cardiac T2* Magnetic Resonance for Prediction of Cardiac Complications in Thalassemia Major 
Circulation  2009;120(20):1961-1968.
To determine the predictive value of cardiac T2* magnetic resonance (MR) for heart failure and arrhythmia in thalassemia major.
Methods and results
We analyzed cardiac and liver T2* MR, and serum ferritin on 652 thalassemia major patients from 21 UK centers, with 1,442 MR scans. The relative risk (95% CI) for heart failure with cardiac T2* values <10ms (compared with >10ms) was 160 (39, 653). Heart failure occurred in 47% of patients within one year of a cardiac T2* <6ms with relative risk 270 (64, 1129). The area under the ROC curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589, P<0.001) or serum ferritin (0.629, P<0.001). Cardiac T2* was <10ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20ms (compared with >20ms), was 4.6 (2.66, 7.95). Arrhythmia occurred in 14% of patients within one year of a cardiac T2* of <6ms. The area under the ROC curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514, P<0.001) or serum ferritin (0.518, P<0.001). The cardiac T2* was <20ms in 83% of scans in patients who developed arrhythmia.
Cardiac T2* MR identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major, and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means towards reducing the high burden of cardiac mortality in myocardial siderosis.
PMCID: PMC2784198  PMID: 19801505
Thalassaemia; Cardiac siderosis; T2 star; Magnetic resonance; Heart; Iron overload
16.  Age- and Hormone-Regulation of N-Methyl-d-Aspartate Receptor Subunit NR2b in the Anteroventral Periventricular Nucleus of the Female Rat 
Journal of neuroendocrinology  2009;21(5):506-517.
Glutamate, acting through its N-methyl-d-aspartate (NMDA) and non-NMDA receptors in the hypothalamus, regulates reproductive neuroendocrine functions via direct and indirect actions upon gonadotrophin-releasing hormone (GnRH) neurones. Previous studies indicate that the NMDA receptor subunit NR2b undergoes changes in protein and gene expression in the hypothalamus in general, and on GnRH neurones in particular, during reproductive ageing. In the present study, we examined whether the NR2b-expressing cell population, both alone and in association with the NR1 subunit (i.e. the latter subunit is necessary for a functional NMDA receptor), is altered as a function of age and/or steroid hormone treatment. Studies focused on the anteroventral periventricular (AVPV) nucleus of the hypothalamus, a region critically involved in the control of reproduction. Young (3-5 months), middle-aged (9-12 months), and aged (approximately 22 months) female rats were ovariectomised and, 1 month later, they were treated sequentially with oestradiol plus progesterone, oestradiol plus vehicle, or vehicle plus vehicle, then perfused. Quantitative stereologic analysis of NR2b-immunoreactive cell numbers in the AVPV showed an age-associated decrease in the density of NR2b-immunoreactive cells, but no effect of hormone treatment. In a second study, immunofluorescent double labelling of NR2b and NR1 was analysed by confocal microscopy of fraction volume, a semi-quantitative measure of fluorescence intensity. No effect of ageing was detected for immunofluorescent NR1 or NR2b alone, whereas the NR2b fraction volume increased in the oestradiol plus vehicle group. With ageing, the fraction volume of the NR2b/NR1-colocalised subunits increased. Together with the stereology results, this suggests that, although fewer cells express the NR2b subunit in the ageing AVPV, a greater percentage of these subunits are co-expressed with NR1. Our results suggest that the subunit composition of NMDA receptors in the AVPV undergo both age- and hormonal-regulation, which may be related to previous observations of changes in functional responses of reproductive neuroendocrine systems to NMDA receptor modulators with ageing.
PMCID: PMC2930127  PMID: 19302193
N-methyl-d-aspartate receptor (NMDA receptor); NR2b; reproductive ageing; oestrogen; gonadotrophin-releasing hormone (GnRH); glutamate
17.  Expression of coxsackie and adenovirus receptor distinguishes transitional cancer states in therapy-induced cellular senescence 
Cell Death & Disease  2010;1(9):e70-.
Therapy-induced cellular senescence describes the phenomenon of cell cycle arrest that can be invoked in cancer cells in response to chemotherapy. Sustained proliferative arrest is often overcome as a contingent of senescent tumor cells can bypass this cell cycle restriction. The mechanism regulating cell cycle re-entry of senescent cancer cells remains poorly understood. This is the first report of the isolation and characterization of two distinct transitional states in chemotherapy-induced senescent cells that share indistinguishable morphological senescence phenotypes and are functionally classified by their ability to escape cell cycle arrest. It has been observed that cell surface expression of coxsackie and adenovirus receptor (CAR) is downregulated in cancer cells treated with chemotherapy. We show the novel use of surface CAR expression and adenoviral transduction to differentiate senescent states and also show in vivo evidence of CAR downregulation in colorectal cancer patients treated with neoadjuvant chemoradiation. This study suggests that CAR is a candidate biomarker for senescence response to antitumor therapy, and CAR expression can be used to distinguish transitional states in early senescence to study fundamental regulatory events in therapy-induced senescence.
PMCID: PMC3032339  PMID: 21364674
cellular senescence; coxsackie and adenovirus receptor; transition state; biomarker
18.  Lead-free KNLNT Piezoelectric Ceramics for High-frequency Ultrasonic Transducer Application 
Ultrasonics  2008;49(3):395-398.
This paper presents the latest development of a lead-free piezoelectric ceramic and its application to transducers suitable for high-frequency ultrasonic imaging. A lead-free piezoelectric ceramic with formula of (K0.5Na0.5)0.97Li0.03(Nb0.9 Ta0.1)O3 (abbreviated as KNLNT-0.03/0.10) was fabricated and characterized. The material was found to have a clamped dielectric constant ε33S = ε0 = 890, piezoelectric coefficient d33 = 245 pC/N, electromechanical coupling factor kt = 0.42 and Curie temperature Tc > 300 °C. High-frequency (40 MHz) ultrasound transducers were successfully fabricated with the lead-free material. A representative lead-free transducer had a bandwidth of 45%, two-way insertion loss of −18 dB. This performance is comparable to reported performances of popular lead-based transducers. The comparison results suggest that the lead-free piezoelectric material may serve as an alternative to lead-based piezoelectric materials for high-frequency ultrasonic transducer applications.
PMCID: PMC2867045  PMID: 19121835
Piezoelectric materials; Lead-free; high frequency; ultrasound transducer
19.  Competition Among Stem Cells Gets Sticky 
Cell stem cell  2009;5(5):459-460.
In a recent report in Science, Issigonis et al. (2009) demonstrate that an inhibitor of JAK-STAT signaling controls integrin-mediated niche adhesion in the Drosophila testis, thereby limiting competition between germline and somatic stem cells for niche space.
PMCID: PMC2846513  PMID: 19896435
20.  Iterative Active Deformational Methodology for Tumor Delineation: Evaluation across Radiation Treatment Stage and Volume 
To introduce, implement, and assess an iterative modification to the active deformational image segmentation method as applied to cervical cancer tumors.
Materials and Methods
A comparison by Jaccard similarity (JS) between this active deformational method and manual segmentation was performed on tumors of various sizes across pre-radiation, three weeks post-radiation, and six weeks post-radiation using a General Linear Mixed Model across 121 studies from 52 patients with stage IIB-IV cervical cancers.
The deformable segmentation method produced promising levels of agreement including JS factors of 0.71 ± 0.11 in the pre-radiation studies. The analysis illustrated a rate of improvement in JS with increasing tumor volume that differed between the pre-radiation and six-weeks post-radiation stage (p=0.0474). In the large pre-radiated tumors each additional cm3 of volume was associated with an increase or improvement in JS of 0.0008 (95% CI: 0.0003, 0.0014). In the smaller post-radiation tumors, each additional cm3 of volume was associated with a more robust improvement in JS of 0.0046 (95% CI: 0.0009, 0.0082).
Agreement was strongly affected by tumor volume, and its performance was most impacted across volume in the later stages of radiation therapy. The deformation based segmentation method appears to demonstrate utility for delineating cervical cancer tumors, particularly in the earliest stages of radiation treatment where agreement is greatest.
PMCID: PMC2720022  PMID: 18972365
Active Deformational Model; Volumetric Changes; Cervical Cancer; Radiation Therapy; Image Segmentation; Magnetic Resonance Imaging (MRI)
21.  Enhanced Microwave Absorption Properties of Intrinsically Core/shell Structured La0.6Sr0.4MnO3 Nanoparticles 
Nanoscale Research Letters  2009;4(10):1153-1158.
The intrinsically core/shell structured La0.6Sr0.4MnO3 nanoparticles with amorphous shells and ferromagnetic cores have been prepared. The magnetic, dielectric and microwave absorption properties are investigated in the frequency range from 1 to 12 GHz. An optimal reflection loss of −41.1 dB is reached at 8.2 GHz with a matching thickness of 2.2 mm, the bandwidth with a reflection loss less than −10 dB is obtained in the 5.5–11.3 GHz range for absorber thicknesses of 1.5–2.5 mm. The excellent microwave absorption properties are a consequence of the better electromagnetic matching due to the existence of the protective amorphous shells, the ferromagnetic cores, as well as the particular core/shell microstructure. As a result, the La0.6Sr0.4MnO3 nanoparticles with amorphous shells and ferromagnetic cores may become attractive candidates for the new types of electromagnetic wave absorption materials.
Electronic supplementary material
The online version of this article (doi:10.1007/s11671-009-9374-y) contains supplementary material, which is available to authorized users.
PMCID: PMC2894104  PMID: 20596374
La0.6Sr0.4MnO3 nanoparticles; Core/shell structure; Microwave absorption; Electromagnetic matching
22.  Population Pharmacokinetics of Fluconazole in Young Infants▿  
Antimicrobial Agents and Chemotherapy  2008;52(11):4043-4049.
Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.
PMCID: PMC2573107  PMID: 18809946
23.  Accuracy of point-of-care blood glucose measurements in the medical ICU 
Liu, Y | Wu, D | Song, X | Meng, Y | Weng, L | Du, B
Critical Care  2008;12(Suppl 2):P167.
PMCID: PMC4088538
24.  Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator 
1. S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (also known as S-4) is a non-steroidal selective androgen receptor modulator demonstrating tissue-selective androgenic and anabolic effects. The purpose of the present study was to examine the systemic pharmacokinetics, elimination and oral bioavailability of S-4 in rats.
2. Thirty-five male Sprague–Dawley rats weighing approximately 250 g were randomly assigned to one of seven treatment groups. Intravenous doses of 0.5, 1, 10, and 30 mg kg−1 were given via a jugular catheter. Oral doses of 1, 10 and 30 mg kg−1 were administered via gavage. Plasma concentrations were determined using a validated high-performance liquid chromatography or by a high-performance liquid chromatography/mass spectrometry method.
3. Clearances ranged between 1.0 and 2.1 ml min−1 kg−1 and varied with dose. The volume of distribution was approximately 0.448 l kg−1 in all treatment groups. Oral bioavailability was also dose dependent, with the lower doses showing complete oral bioavailability. The half-life of S-4 over the dose range tested was between 2.6 and 5.3 h.
4. It was demonstrated that S-4 is rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats. The pharmacokinetics and oral bioavailability of S-4 indicate that it is an excellent candidate for clinical development.
PMCID: PMC2040234  PMID: 15204699
25.  Expression of vascular endothelial growth factor, hypoxia inducible factor 1α, and carbonic anhydrase IX in human tumours 
Journal of Clinical Pathology  2004;57(5):504-512.
Aims: To measure vascular endothelial growth factor (VEGF-A) mRNA in a large, diverse cohort of tumours and to investigate whether VEGF-A expression is associated with markers of hypoxia, including hypoxia inducible factor 1α (HIF-1α) and carbonic anhydrase IX (CA9).
Methods: The expression of VEGF-A and CA9 was assessed in 5067 fresh frozen human tissue samples and 238 cell lines by DNA microarray analysis. In addition, tissue microarrays were constructed from 388 malignancies to investigate the expression of VEGF-A and HIF-1α by in situ hybridisation and immunohistochemistry, respectively.
Results: VEGF-A was significantly upregulated in primary malignancies of the breast, cervix, colon and rectum, oesophagus, head and neck, kidney, ovary, skin, urinary system, and white blood cells by DNA microarray analysis. However, VEGF-A expression only correlated with CA9 expression in renal tissues. In the tissue microarrays, HIF-1α positive cores showed a significant increase in VEGF-A expression in lung, ovary, soft tissue, and thyroid malignancies.
Conclusions: The expression of VEGF-A is upregulated in a large proportion of human malignancies, and may be associated with markers of hypoxia. VEGF-A expression can be induced in the absence of hypoxia and hypoxia does not always provoke VEGF-A upregulation in tumours.
PMCID: PMC1770303  PMID: 15113858
vascular endothelial growth factor; hypoxia inducible factor one alpha; carbonic anhydrase IX; angiogenesis; neoplasia

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