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1.  Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways 
PLoS ONE  2014;9(3):e91245.
We previously reported that calycosin, a natural phytoestrogen structurally similar to estrogen, successfully triggered apoptosis of estrogen receptor (ER)-positive breast cancer cell line, MCF-7. To better understand the antitumor activities of calycosin against breast cancer, besides MCF-7 cells, another ER-positive cell line T-47D was analyzed here, with ER-negative cell lines (MDA-231, MDA-435) as control. Notably, calycosin led to inhibited cell proliferation and apoptosis only in ER-positive cells, particularly in MCF-7 cells, whereas no such effect was observed in ER-negative cells. Then we investigated whether regulation of ERβ, a subtype of ER, contributed to calycosin-induced apoptosis in breast cancer cells. The results showed that incubation of calycosin resulted in enhanced expression ERβ in MCF-7 and T-47D cells, rather than MDA-231 and MDA-435 cells. Moreover, with the upregulation of ERβ, successive changes in downstream signaling pathways were found, including inactivation of insulin-like growth factor 1 receptor (IGF-1R), then stimulation of p38 MAPK and suppression of the serine/threonine kinase (Akt), and finally poly(ADP-ribose) polymerase 1 (PARP-1) cleavage. However, the other two members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were not consequently regulated by downregulated IGF-1R, indicating ERK 1/2 and JNK pathways were not necessary to allow proliferation inhibition by calycosin. Taken together, our results indicate that calycosin tends to inhibit growth and induce apoptosis in ER-positive breast cancer cells, which is mediated by ERβ-induced inhibition of IGF-1R, along with the selective regulation of MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.
doi:10.1371/journal.pone.0091245
PMCID: PMC3949755  PMID: 24618835
2.  A Comparison of Referral Criteria used by the PlusoptiX Photoscreener 
Strabismus  2013;21(3):10.3109/09273972.2013.811606.
Purpose
To evaluate the sensitivity, specificity, and predictive value of 7 different referral criteria used for the plusoptiX photoscreener on the same cohort of children.
Methods
Retrospective chart review of patients presenting to a pediatric ophthalmology clinic who underwent plusoptiX photoscreening as part of a comprehensive examination. We applied multiple referral criteria from previously published studies as well as the manufacturer’s criteria in order to calculate specificity, sensitivity, and predictive value differences between the various referral criteria. We compared all criteria to the results of a pediatric ophthalmology examination based upon the 2003 American Association for Pediatric Ophthalmology and Strabismus (AAPOS) criteria, as well as the newly accepted revision of the AAPOS referral criteria.
Results
109 children were examined with a thorough pediatric ophthalmic exam and with the plusoptiX photoscreener. Of these, 58 (53%) were confirmed to demonstrate amblyopia risk factors, according to 2003 AAPOS criteria. The plusoptiX referral criteria were adjusted to match 7 different published plusoptiX referral paradigms so that the differing referral paradigms could be analyzed for sensitivity and specificity. When comparing the differing plusoptiX referral paradigms to 2003 AAPOS criteria, the sensitivity/specificity of the 7 different paradigms were respectively: Matta/Silbert 98%/80%, Arthur (2) 67%/96%, Arnold 81%/96%, Arthur 81%/92%, PediaVision 80%/94%, plusoptiX 98%/41%, AAPOS 74%/86%. When comparing the 7 differing referral paradigms to the newly approved (2013) AAPOS criteria, the sensitivity/specificity were respectively: Matta/Silbert 98%/68%, Arthur (2) 73%/92%, Arnold 92%/90%, Arthur 86%/85%, PediaVision 90%/92%, plusoptiX 98%/35%, AAPOS 87%/87%.
Conclusion
There are multiple referral criteria available for the plusoptiX photoscreener. Screening programs need to evaluate their own requirements with respect to desired sensitivity and specificity and decide on the most appropriate referral criteria for their program. The “Arnold” criteria is the best at maximizing sensitivity and specificity utilizing the 2003 “AAPOS” criteria and the “Arnold” and “PediaVision” were best at maximizing sensitivity and specificity for the newly accepted AAPOS referral criteria. Screening programs will need to decide the level of sensitivity and specificity that they wish to obtain, but for most screening programs the “Arnold” criteria may be preferred.
doi:10.3109/09273972.2013.811606
PMCID: PMC3820012  PMID: 23978147
Amblyopia; pediatric; strabismus screening; vision screening; vision screening/diagnosis
3.  Genetic variant in SWI/SNF complexes influences hepatocellular carcinoma risk: a new clue for the contribution of chromatin remodeling in carcinogenesis 
Scientific Reports  2014;4:4147.
Chromatin remodeling has been newly established as an important cancer genome characterization and recent exome and whole-genome sequencing studies of hepatocellular carcinoma (HCC) showed that recurrent inactivating mutations in SWI/SNF subunits involved in the molecular basis of hepatocarcinogenesis. To test the hypothesis that genetic variants in the key subunits of SWI/SNF complexes may contribute to HCC susceptibility, we systematically assessed associations of genetic variants in SWI/SNF complexes with HCC risk using a two-staged case-control study in Chinese population. A set of 24 single nucleotide polymorphisms (SNPs) in SWI/SNF complexes were examined in stage 1 with 502 HCC patients and 487 controls and three promising SNPs (SMARCA4 rs11879293, rs2072382 and SMARCB1 rs2267032) were further genotyped in stage 2 comprising 501 cases and 545 controls for validation. SMARCA4 rs11879293 presented consistently significant associations with the risk of HCC at both stages, with an OR of 0.73 (95% CI: 0.62–0.87) using additive model in combined analysis. Moreover, the decreased risk of HCC associated with SMARCA4 rs11879293 AG/AA was more evident among HBsAg positive individuals (OR = 0.47, 95% CI: 0.27–0.80) in combined analysis. The study highlighted the potential role of the SWI/SNF complexes in conferring susceptibility to HCC, especially modified HCC risk by HBV infection.
doi:10.1038/srep04147
PMCID: PMC3930892  PMID: 24556940
4.  Association Between Accommodative Amplitudes and Amblyopia 
Strabismus  2013;21(2):10.3109/09273972.2013.786737.
Purpose
To evaluate the relationship between amblyopia and accommodative ability.
Methods
The open-field Grand Seiko binocular autorefractor has become the gold standard for automated measurement of static accommodation. We measured the accommodation amplitudes in 52 children ages 3 to 14 years employing the Grand Seiko auto refractor. Children wore their glasses for this test, which was prescribed based on a cycloplegic refraction performed by one pediatric ophthalmologist. No readings could be obtained for 9 eyes (5 patients).
Results
Normal accommodation with correction utilizing full accommodative effort at 1/3 meter is 3D assuming no accommodative lag, and would generate a reading of −3.00D from the Grand Seiko auto refractor. Lack of any accommodative should give a reading of 0.00D. Accommodative gradually declined as the acuity worsened.
Conclusion
Our results suggest that amblyopic eyes do not accommodate as well as non-amblyopic eyes. Because accommodation amplitude is not subjective it may be a more sensitive indicator of regression of amblyopia than visual acuity. The Grand Seiko autorefractor could prove to be a useful tool to monitor the progress of patients with amblyopia.
doi:10.3109/09273972.2013.786737
PMCID: PMC3820007  PMID: 23713938
Accommodation; amblyopia; amblyopia treatment; pharmacology
5.  A Comparison of the PlusoptiX S04 and A09 Photoscreeners 
Strabismus  2013;21(2):10.3109/09273972.2013.786735.
Purpose
We compare the plusoptiX S04 and A09 photoscreeners on a single cohort of children.
Methods
One hundred and thirteen children were evaluated on both the plusoptiX S04 and A09 photoscreener. A lay screener performed all of the testing prior to a pediatric ophthalmology examination. The order was alternated so that the S04 was performed first on one patient then second on the next to minimize fatigue bias.
Results
Utilizing our modified criteria previously published, the plusoptiX S04 was found to have a sensitivity of 85%, specificity of 94%, false positive rate of 15%, and false negative rate of 6% in detecting American Association for Pediatric Ophthalmology and Strabismus–defined amblyopia factors. The plusoptiX A09 was found to have a sensitivity of 92%, specificity of 88%, false positive rate of 11%, and false negative rate of 8%.
Conclusion
The plusoptiX S04 and A09 photoscreeners perform similarly when used by a lay screener to evaluate the same population of children.
doi:10.3109/09273972.2013.786735
PMCID: PMC3832944  PMID: 23713927
Pediatric; screening and infant vision development; strabismus; strabismus screening; vision screening; vision screening/diagnosis
6.  A novel role for caveolin-1 in regulating endothelial nitric oxide synthase activation in response to H2O2 and shear stress 
Free radical biology & medicine  2010;49(2):10.1016/j.freeradbiomed.2010.03.023.
Previous studies have shown that acute increases in oxidative stress induced by the addition of hydrogen peroxide (H2O2) can increase endothelial nitric oxide synthase (eNOS) catalytic activity via an increase in the phosphorylation of eNOS at serine 1177. However, it is unclear how increased H2O2 affects nitric oxide (NO) signaling when endothelial cells are exposed to biomechanical forces. Thus, the purpose of this study was to evaluate the acute effects of H2O2 on NO signaling in the presence or absence of laminar shear stress. We found that acute sustained increases in cellular H2O2 levels in bovine aortic endothelial cells did not alter basal NO generation but the NO produced in response to shear stress was significantly increased. This amplification in NO signaling was found to correlate with an H2O2-induced increase in eNOS localized to the plasma membrane and an increase in total caveolin-1 protein levels. We further demonstrated that overexpressing caveolin-1 increased eNOS localized to the plasma membrane again without altering total eNOS protein levels. We also found that caveolin-1 overexpression increased NO generation in response to shear stress but only in the presence of H2O2. Conversely, depleting caveolin-1 with an siRNA decreased eNOS localized to the plasma membrane and abolished the enhanced NO generation. Finally, we found that expressing a caveolin-1 binding-site deletion mutant of eNOS in COS-7 cells decreased its plasma membrane localization and resulted in attenuated NO production in response to calcium activation. In conclusion, we have identified a new role for caveolin-1 in enhancing eNOS trafficking to the plasma membrane that seems to be involved in priming eNOS for flow-mediated activation under conditions of oxidative stress. To our knowledge, this is the first report that H2O2 modulates eNOS activity by altering its subcellular location and that caveolin-1 can play a stimulatory role in NO signaling.
doi:10.1016/j.freeradbiomed.2010.03.023
PMCID: PMC3815623  PMID: 20353820
Oxidative stress; Protein trafficking; Gene expression; Free radicals
7.  Galectin-1 Is an Interactive Protein of Selenoprotein M in the Brain 
Selenium, an essential trace element for human health, mainly exerts its biological function through selenoproteins. Selenoprotein M (SelM) is one of the highly expressed selenoproteins in the brain, but its biological effect and molecular mechanism remain unclear. Thus, the interactive protein of SelM was investigated in this paper to guide further study. In order to avoid protein translational stop, the selenocysteine-encoding UGA inside the open reading frame of SelM was site-directly changed to the cysteine-encoding UGC to generate the SelM′ mutant. Meanwhile, its N terminal transmembrane signal peptide was also cut off. This truncated SelM′ was used to screen a human fetal brain cDNA library by the yeast two-hybrid system. A new interactive protein of SelM′ was found to be galectin-1 (Gal-1). This protein-protein interaction was further verified by the results of fluorescence resonance energy transfer techniques, glutathione S-transferase pull-down and co-immunoprecipitation assays. As Gal-1 plays important roles in preventing neurodegeneration and promoting neuroprotection in the brain, the interaction between SelM′ and Gal-1 displays a new direction for studying the biological function of SelM in the human brain.
doi:10.3390/ijms141122233
PMCID: PMC3856062  PMID: 24284396
selenoprotein M (SelM); galectin-1 (Gal-1); protein-protein interaction; yeast two-hybridization; fluorescence resonance energy transfer (FRET); co-immunoprecipitation; Glutathione S-transferase pull-down (GST pull-down)
8.  Twelve Weeks of Pioglitazone Therapy Significantly Attenuates Dysmetabolism and Reduces Inflammation in Continuous Ambulatory Peritoneal Dialysis Patients—a Randomized Crossover Trial 
♦ Background: The aim of the present study was to investigate the effect of oral pioglitazone (PIO) on lipid metabolism, insulin resistance, inflammation, and adipokine metabolism in continuous ambulatory peritoneal dialysis (CAPD) patients.
♦ Methods: In this randomized crossover trial, 36 CAPD patients with serum triglyceride levels above 1.8 mmol/L were randomly assigned to receive either oral PIO 15 mg once daily or no PIO for 12 weeks. Then, after a 4-week washout, the patients were switched to the alternative regimen. The primary endpoint was change in serum triglycerides during the PIO regimen compared with no PIO. Secondary endpoints included changes in other lipid levels, homeostatic model assessment of insulin resistance (HOMA-IR), adipocytokines, and C-reactive protein (CRP).
♦ Results: All 36 CAPD patients (age: 64 ± 11 years; 33% men; 27.8% with diabetes mellitus) completed the study. Comparing patients after PIO and no PIO therapy, we found no significant differences in mean serum triglycerides (3.83 ± 1.49 mmol/L vs 3.51 ± 1.98 mmol/L, p = 0.2). However, mean high-density lipoprotein (0.94 ± 0.22 mmol/L vs 1.00 ± 0.21 mmol/L, p = 0.004) and median total adiponectin [10.34 μg/mL (range: 2.59 - 34.48 μg/mL) vs 30.44 μg/mL (3.47 - 93.41 μg/mL), p < 0.001] increased significantly. Median HOMA-IR [7.51 (1.39 - 45.23) vs 5.38 (0.97 - 14.95), p = 0.006], mean fasting blood glucose (7.31 ± 2.57 mmol/L vs 6.60 ± 2.45 mmol/L, p = 0.01), median CRP [8.78 mg/L (0.18 - 53 mg/L) vs 3.50 mg/L (0.17 - 26.30 mg/L), p = 0.005], and mean resistin (32.70 ± 17.17 ng/mL vs 28.79 ± 11.83 ng/mL, p = 0.02) all declined. The PIO was well tolerated, with only one adverse event: lower-extremity edema in a patient with low residual renal function.
♦ Conclusions: Blood triglycerides were not altered after 12 weeks of PIO 15 mg once daily in CAPD patients, but parameters of dysmetabolism were markedly improved, including insulin resistance, inflammation, and adipokine balance, suggesting that PIO could be of value for this high-risk patient group. Larger, more definitive studies are needed to confirm these findings.
doi:10.3747/pdi.2011.00116
PMCID: PMC3524878  PMID: 22383630
Pioglitazone; lipid dysmetabolism; insulin resistance; inflammation; adipocytokines
9.  Mst1 and Mst2 kinases: regulations and diseases 
Cell & Bioscience  2013;3:31.
The Hippo signaling pathway has emerged as a critical regulator for organ size control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway controlling the cell proliferation, differentiation, and apoptosis during development. Mst1/2 can be activated by cellular stressors and the activation of Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels through several mechanisms, in which regulation of cellular redox state might represent a tumor suppressor function of Mst1/2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in multiple organs, although considerable diversification in the pathway composition and regulation is observed in some of them. Generally, loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by the reduction or elimination of YAP. The Hippo pathway integrates with other signaling pathways e.g. Wnt and Notch pathways and coordinates with them to impact on the tumor pathogenesis and development. Furthermore, Mst1/2 kinases also act as an important regulator in immune cell activation, adhesion, migration, growth, and apoptosis. This review will focus on the recent updates on those aspects for the roles of Mst1/2 kinases.
doi:10.1186/2045-3701-3-31
PMCID: PMC3849747  PMID: 23985272
The Hippo pathway; Mst1; Mst2; Reactive oxygen species; YAP; Cancer; Immune diseases
10.  PRESERVING MITOCHONDRIAL FUNCTION PREVENTS THE PROTEASOMAL DEGRADATION OF GTP CYCLOHYDROLASE I 
Free radical biology & medicine  2012;53(2):216-229.
The development of pulmonary hypertension is a common accompaniment of congenital heart disease (CHD) with increased pulmonary blood flow. Our recent evidence suggests that asymmetric dimethylarginine (ADMA)-induced mitochondrial dysfunction causes endothelial nitric oxide synthase (eNOS) uncoupling secondary to a proteasome-dependent degradation of GTP cyclohydrolase I (GCH1) that results in a decrease in the NOS co-factor, tetrahydrobiopterin (BH4). Decreases in NO signaling are thought to be an early hallmark of endothelial dysfunction. As L-carnitine plays an important role in maintaining mitochondrial function in this study we examined the protective mechanisms and the therapeutic potential of L-carnitine on NO signaling in pulmonary arterial endothelial cells (PAEC) and in a lamb model of CHD and increased pulmonary blood flow (Shunt). Acetyl L-carnitine (ALC) attenuated the ADMA-mediated proteasomal degradation of GCH1. This preservation was associated with a decrease in the association of GCH1 with the Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) and a decrease in its ubiquitination. This in turn prevented the decrease in BH4 levels induced by ADMA and preserved NO signaling. Treatment of Shunt lambs with L-carnitine also reduced GCH1/CHIP interactions, attenuated the ubiquitination and degradation of GCH1, and increased BH4 levels compared to vehicle treated Shunt lambs. The increases in BH4 were associated with decreased NOS uncoupling and enhanced NO generation. Thus, we conclude that L-carnitine may have a therapeutic potential in the treatment of pulmonary hypertension in children with CHD with increased pulmonary blood flow.
doi:10.1016/j.freeradbiomed.2012.03.016
PMCID: PMC3527085  PMID: 22583703
mitochondrial dysfunction; BH4; Hsp90; Hsp70; CHIP; ubiquitination
11.  Association of c-Jun Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Chinese Population 
DNA and Cell Biology  2012;31(7):1274-1278.
C-Jun has been proved as playing an important role in the pathogenesis of tumors, as a main component of Activator protein 1 and c-Jun gene polymorphisms are associated with colorectal cancer. However, the relationship between the c-Jun gene polymorphism and the susceptibility to systemic lupus erythematosus (SLE) has not been known. Our purpose is to evaluate whether the c-Jun gene polymorphism (SNP rs3748814) is associated with susceptibility to SLE in a Chinese population. In this study, we enrolled 502 SLE patients and 652 healthy controls. The c-Jun polymorphism (rs3748814) was specified from genomic DNA using the TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of the A/G genotype in SLE patients was lower than in healthy controls, whereas the frequency of the G/G genotype was significantly higher in SLE patients than in healthy controls (A/G vs. G/G p=8.670e-08, odds ratio [OR]=0.290, 95% confidence interval [CI]=0.184–0.456). In addition, the frequency of allele A in the patients group was significantly lower than in the control group (A vs. G p=5.221e-09, OR=0.308, 95% CI=0.212–0.466). The distribution of genotype and allele frequency in SLE patients with lupus nephritis (LN) compared with SLE patients without LN was not statistically significant (A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785; A vs. G p=0.748, OR=1.152, 95% CI=0.486–2.734; A/A+A/G vs. G/G p=0.744, OR=1.157, 95% CI=0.481–2.785). Furthermore, we did not find any significant association between other clinical features and genotypes. Our findings suggest that the c-Jun polymorphism (rs3748814) may be significantly associated with the susceptibility to SLE in a Chinese population.
doi:10.1089/dna.2011.1536
PMCID: PMC3391490  PMID: 22489574
12.  Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer’s Disease 
PLoS ONE  2013;8(6):e66384.
Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer′s disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention.
doi:10.1371/journal.pone.0066384
PMCID: PMC3689823  PMID: 23805218
13.  Clustering-Based Multiple Imputation via Gray Relational Analysis for Missing Data and Its Application to Aerospace Field 
The Scientific World Journal  2013;2013:720392.
A large number of scientific researches and industrial applications commonly suffer from missing data. Some inappropriate techniques of missing value treatment compromise data quality, which detrimentally influences the knowledge discovery. In this paper, we propose a missing data completion method named CBGMI. Firstly, it separates the nonmissing data instances into several clusters by excluding the missing-valued entries. Then, it utilizes the entropy of the proximal category for each incomplete instance in terms of the similarity metric based on gray relational analysis. Experiments on UCI datasets and aerospace datasets demonstrate that the superiority of our algorithm to other approaches on validity.
doi:10.1155/2013/720392
PMCID: PMC3659482  PMID: 23737724
14.  Increased Attentional Focus Modulates Eye Movements in a Mixed Antisaccade Task for Younger and Older Adults 
PLoS ONE  2013;8(4):e61566.
We examined performance in the antisaccade task for younger and older adults by comparing latencies and errors in what we defined as high attentional focus (mixed antisaccades and prosaccades in the same block) and low attentional focus (antisaccades and prosaccades in separate blocks) conditions. Shorter saccade latencies for correctly executed eye movements were observed for both groups in mixed, compared to blocked, antisaccade tasks, but antisaccade error rates were higher for older participants across both conditions. The results are discussed in relation to the inhibitory hypothesis, the goal neglect theory and attentional control theory.
doi:10.1371/journal.pone.0061566
PMCID: PMC3631188  PMID: 23620767
15.  Treatment of stage IIIb/IV non-small cell lung cancer with Pemetrexed plus Oxaliplatin after failure of Erlotinib as second-line treatment 
To determine the efficacy and toxicity of Pemetrexed plus Oxaliplatin in patients suffering from stage IIIb or IV lung adenocarcinoma and being treated with Erlotinib as second-line treatment, a total of 45 patients were randomly divided into two groups. One group was treated with 500 mg/m2 Pemetrexed plus 100 mg/m2 Oxaliplatin, and the other was treated with 500 mg/m2 Pemetrexed plus 75 mg/m2 Cisplatin. All drugs were administered on day one of a 21-day cycle. In the Oxaliplatin group, 3 patients (13.6 %) experienced partial response (PR), 9 patients (41.0 %) showed stable disease (SD), and 10 patients (45.5 %) had progressive disease (PD). In the Cisplatin group, 2 patients (8.7 %) experienced PR, 7 patients (30.4 %) showed SD, and 14 patients (60.9 %) had PD. The PFS of the Oxaliplatin group and the Cisplatin group was 4.45 months (95 % CI 4.10–4.80) and 3.96 months (95 % CI 3.68–4.24) (P = 0.03), respectively. The median overall survival (OS) was 10.8 months (95 % CI 10.2–11.5) and 10.7 months (95 % CI 10.2–11.3) (P = 0.72), respectively. There was no statistically significant difference in the occurrence rate of grades 3 and 4 myelotoxicity between the two groups. However, there was a significant difference in the occurrence rate of grades 3 and 4 gastrointestinal reactions and peripheral neurotoxicity between the two groups (P < 0.05). A regime combining Pemetrexed and Oxaliplatin was marginally effective and well tolerated in patients with stage IIIb or IV lung adenocarcinoma who have received Erlotinib as second-line treatment.
doi:10.1007/s12032-013-0550-7
PMCID: PMC3667368  PMID: 23576138
Lung adenocarcinoma; Oxaliplatin; Pemetrexed; Erlotinib as second-line treatment
16.  Screening Chinese soybean genotypes for Agrobacterium-mediated genetic transformation suitability*  
The Agrobacterium-mediated transformation system is the most commonly used method in soybean transformation. Screening of soybean genotypes favorable for Agrobacterium-infection and tissue regeneration is the most important step to establish an efficient genetic transformation system. In this study, twenty soybean genotypes that originated from different soybean production regions in China were screened for transient infection, regeneration capacity, and stable transgenic efficiency. Three genotypes, Yuechun 04-5, Yuechun 03-3, and Tianlong 1, showed comparable stable transgenic efficiencies with that of the previously reported American genotypes Williams 82 and Jack in our experimental system. For the Tianlong 1, the average stable transformation efficiency is 4.59%, higher than that of control genotypes (Jack and Williams 82), which is enough for further genomic research and genetic engineering. While polymerase chain reaction (PCR), LibertyLink strips, and β-glucuronidase (GUS) staining assays were used to detect the insertion and expression of the transgene, leaves painted with 135 mg/L Basta could efficiently identify the transformants.
doi:10.1631/jzus.B1200278
PMCID: PMC3625525  PMID: 23549846
Soybean; Agrobacterium-mediated transformation; Genotypes; Stable transgenic efficiency
17.  Semi-automated, Quantitative Analysis of Retinal Ganglion Cell Morphology in Mice Selectively Expressing Yellow Fluorescent Protein 
Experimental eye research  2011;96(1):107-115.
The development of transgenic mouse lines that selectively label a subset of neurons provides unique opportunities to study detailed neuronal morphology and morphological changes under experimental conditions. In the present study, a mouse line in which a small number of retinal ganglion cells (RGCs) express yellow fluorescent protein (YFP) under control of the Thy-1 promoter was used (Feng et al., 2000). We characterized the number, distribution by retinal region and eccentricity of YFP-labeled RGCs using fluorescence microscopy and StereoInvestigator software (MicroBrightField, VT, USA). Then, we captured images of 4–6 YFP-expressing RGCs from each of 8 retinal regions by confocal microscopy, producing 3-dimensional and flattened data sets. A new semi-automated method to quantify the soma size, dendritic length and dendritic arbor complexity was developed using MetaMorph software (Molecular Devices, PA, USA). Our results show that YFP is expressed in 0.2% of all RGCs. Expression of YFP was not significantly different in central versus peripheral retina, but there were higher number of YFP expressing RGCs in the temporal quadrant than in the nasal. By confocal-based analysis, 58% of RGCs expressing YFP did so at a high level, with the remainder distributed in decreasing levels of brightness. Variability in detailed morphometric parameters was as great between two fellow retinas as in retinas from different mice. The analytic methods developed for this selective YFP expressing RGC model permit quantitative comparisons of parameters relevant to neuronal injury.
doi:10.1016/j.exer.2011.12.013
PMCID: PMC3419383  PMID: 22210127
mouse; retina; ganglion cell; glaucoma; optic nerve; neuropathy; yellow fluorescent protein
18.  Selenoprotein-Transgenic Chlamydomonas reinhardtii 
Nutrients  2013;5(3):624-636.
Selenium (Se) deficiency is associated with the occurrence of many diseases. However, excessive Se supplementation, especially with inorganic Se, can result in toxicity. Selenoproteins are the major forms of Se in vivo to exert its biological function. Expression of those selenoproteins, especially with the application of a newly developed system, is thus very important for studying the mechanism of Se in nutrition. The use of Chlamydomonas reinhardtii (C. reinhardtii) as a biological vector to express an heterogeneous protein is still at the initial stages of development. In order to investigate the possibility of using this system to express selenoproteins, human 15-KDa selenoprotein (Sep15), a small but widely distributed selenoprotein in mammals, was chosen for the expression platform test. Apart from the wild-type human Sep15 gene fragment, two Sep15 recombinants were constructed containing Sep15 open reading frame (ORF) and the selenocysteine insertion sequence (SECIS) element from either human Sep15 or C. reinhardtii selenoprotein W1, a highly expressed selenoprotein in this alga. Those Sep15-containing plasmids were transformed into C. reinhardtii CC-849 cells. Results showed that Sep15 fragments were successfully inserted into the nuclear genome and expressed Sep15 protein in the cells. The transgenic and wild-type algae demonstrated similar growth curves in low Se culture medium. To our knowledge, this is the first report on expressing human selenoprotein in green alga.
doi:10.3390/nu5030624
PMCID: PMC3705309  PMID: 23443677
15-KDa selenoprotein (Sep15); alga; Chlamydomonas reinhardtii (C. reinhardtii); selenium (Se); selenocysteine insertion sequence (SECIS)
19.  Automatic segmentation of the choroid in enhanced depth imaging optical coherence tomography images 
Biomedical Optics Express  2013;4(3):397-411.
Enhanced Depth Imaging (EDI) optical coherence tomography (OCT) provides high-definition cross-sectional images of the choroid in vivo, and hence is used in many clinical studies. However, the quantification of the choroid depends on the manual labelings of two boundaries, Bruch’s membrane and the choroidal-scleral interface. This labeling process is tedious and subjective of inter-observer differences, hence, automatic segmentation of the choroid layer is highly desirable. In this paper, we present a fast and accurate algorithm that could segment the choroid automatically. Bruch’s membrane is detected by searching the pixel with the biggest gradient value above the retinal pigment epithelium (RPE) and the choroidal-scleral interface is delineated by finding the shortest path of the graph formed by valley pixels using Dijkstra’s algorithm. The experiments comparing automatic segmentation results with the manual labelings are conducted on 45 EDI-OCT images and the average of Dice’s Coefficient is 90.5%, which shows good consistency of the algorithm with the manual labelings. The processing time for each image is about 1.25 seconds.
doi:10.1364/BOE.4.000397
PMCID: PMC3595084  PMID: 23504041
(100.0100) Image processing; (110.4500) Optical coherence tomography; (100.2960) Image analysis; (170.4470) Ophthalmology
20.  New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells 
The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex®, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9® and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
doi:10.1093/jmcb/mjs042
PMCID: PMC3570051  PMID: 22831834
prostate cancer stem cells; androgen receptor; combination therapy
21.  Combining the negative lymph nodes count with the ratio of positive and removed lymph nodes can better predict the postoperative survival in cervical cancer patients 
Background
To evaluate the impacts of the negative lymph nodes (NLNs) count on the prognostic prediction of the ratio of positive and removed lymph nodes (RPL) in cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RHPL).
Methods
The positive and negative lymph node counts were calculated for 609 postoperative cervical cancer patients. The 5-year survival rate (5-YSR) was examined according to clinicopathologic variables. Cox regression was used to identify independent prognostic factors.
Results
The NLNs count cutoffs were determined to be 10 and 25 with 5-YSR of 62.8% and 80.5%. The RPL of 13 patients who had the NLNs count of 10 or fewer was >20%. Among 242 patients who had 10 < NLNs count ≤ 25, 194 without positive nodes had the 5-YSR of 77.8%, 31 with 0% < RPL ≤ 5% had the 5-YSR of 3.2%, 15 with RPL > 20% had died when follow-up was completed. Among 354 patients who had NLNs count >25, 185 without positive nodes had the 5-YSR of 87.6%, 6 with 0% < RPL ≤ 5% had the 5-YSR of 25%, 15 with 5% < RPL ≤ 20% had the 5-YSR of 4.5%, and 2 with RPL >20% had died when follow-up was completed. Furthermore, stage, histologic grade and RPL were independently correlated with overall survival of cervical cancer patients after RHPL in the multivariate analysis.
Conclusions
RPL was an independent prognostic factor. The NLNs count is a key factor for improvement of survival prediction of RPL in cervical cancer.
doi:10.1186/1475-2867-13-6
PMCID: PMC3576300  PMID: 23374254
Cervical cancer; Lymph node; Pelvic lymphadenectomy; Prognosis
22.  Retinal Ganglion Cell Morphology after Optic Nerve Crush and Experimental Glaucoma 
Purpose.
To study sequential changes in retinal ganglion cell (RGC) morphology in mice after optic nerve crush and after induction of experimental glaucoma.
Methods.
Nerve crush or experimental glaucoma was induced in mice that selectively express yellow fluorescent protein (YFP) in RGCs. Mice were euthanized 1, 4, and 9 days after crush and 1, 3, and 6 weeks after induction of glaucoma by bead injection. All YFP-RGCs were identified in retinal whole mounts. Then confocal images of randomly selected RGCs were quantified for somal fluorescence brightness, soma size, neurite outgrowth, and dendritic complexity (Sholl analysis).
Results.
By 9 days after crush, 98% of RGC axons died and YFP-RGCs decreased by 64%. After 6 weeks of glaucoma, 31% of axons died, but there was no loss of YFP-RGC bodies. All crush retinas combined had significant decreases in neurite outgrowth parameters (P ≤ 0.036, generalized estimating equation [GEE] model) and dendritic complexity was lower than controls (P = 0.017, GEE model). There was no change in RGC soma area after crush. In combined glaucoma data, the RGC soma area was larger than control (P = 0.04, GEE model). At 3 weeks, glaucoma RGCs had significantly larger values for dendritic structure and complexity than controls (P = 0.044, GEE model), but no statistical difference was found at 6 weeks.
Conclusions.
After nerve crush, RGCs and axons died rapidly, and dendritic structure decreased moderately in remaining RGCs. Glaucoma caused an increase in RGC dendrite structure and soma size at 3 weeks.
Retinal ganglion cell morphology after optic nerve crush and experimental glaucoma.
doi:10.1167/iovs.12-9712
PMCID: PMC3630905  PMID: 22589442
23.  Cardioprotective Effects of 20(S)-Ginsenoside Rh2 against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo 
Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity. In vitro study on H9C2 cell line, as well as in vivo investigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.
doi:10.1155/2012/506214
PMCID: PMC3483725  PMID: 23125868
24.  Biomechanics of the Human Posterior Sclera: Age- and Glaucoma-Related Changes Measured Using Inflation Testing 
Purpose.
The objective of this study was to measure the biomechanical response of the human posterior sclera in vitro and to estimate the effects of age and glaucoma.
Methods.
Scleral specimens from 22 donors with no history of glaucoma and 11 donors with a history of glaucoma were excised 3 mm posterior to the equator and affixed to an inflation chamber. Optic nerve cross-sections were graded to determine the presence of axon loss. The time-dependent inflation response was measured in a series of pressure-controlled load–unload tests to 30 mm Hg and creep tests to 15 and 30 mm Hg. Circumferential and meridional strains were computed from the digital image correlation displacements, and midposterior stresses were determined from pressure and deformed geometry.
Results.
Among normal specimens, older age was predictive of a stiffer response and a thinner sclera. In the age group 75 to 93, diagnosed glaucoma eyes with axon damage were thicker than normal eyes. Both damaged and undamaged glaucoma eyes had a different strain response in the peripapillary sclera characterized by a stiffer meridional response. Undamaged glaucoma eyes had slower circumferential creep rates in the peripapillary sclera than normal eyes. Glaucoma eyes were not different from normal eyes in stresses and strains in the midposterior sclera.
Conclusions.
The observed differences in the biomechanical response of normal and glaucoma sclera may represent baseline properties that contribute to axon damage, or may be characteristics that result from glaucomatous disease.
This work represents the first characterization of the mechanical response of the human normal and glaucoma sclera under near physiological loading conditions. Older age was predictive of a stiffer response. Glaucoma eyes had a stiffer meridional response in the peripapillary sclera than normal eyes.
doi:10.1167/iovs.11-8009
PMCID: PMC3630906  PMID: 22395883
25.  Proteomic analysis of the effects of exogenous calcium on hypoxic-responsive proteins in cucumber roots 
Proteome Science  2012;10:42.
Background
Hypoxia acts as a plant stress factor, particularly in cucumbers plants under hydroponic culture. Calcium is involved in stress signal transmission and in the growth of plants. To determine the effect of exogenous calcium on hypoxic-responsive proteins in cucumber (Cucumis sativus L. cv. Jinchun No.2) roots, proteomic analysis was performed using two-dimensional electrophoresis (2-DE) and mass spectrometry.
Results
Cucumber roots were used to analyze the influence of hypoxia on plants. The expressions of 38 protein spots corresponding to enzymes were shown to change in response to hypoxia. Of these, 30 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/TOF MS analysis). The proteins were categorized according to functional groups, including glycolysis, the tricarboxylic acid (TCA) cycle, fermentative metabolism, nitrogen metabolism, energy metabolism, protein synthesis and defense against stress. Exogenous calcium appeared to alleviate hypoxic stress via these metabolic and physiological systems. Western blotting was used to analyze the accumulation of alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC); calcium further increased the expression of ADH and PDC under hypoxia. In addition, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the transcript levels of differentially expressed proteins.
Conclusions
Exogenous calcium enhanced the expression of enzymes involved in glycolysis, the TCA cycle, fermentative metabolism, nitrogen metabolism, and reactive oxygen species (ROS) defense in plants under hypoxia. Calcium appears to induce hypoxic tolerance of cucumber seedlings. These phenomena have prompted us to further investigate the mechanisms by which cucumbers respond to exogenous calcium under hypoxia.
doi:10.1186/1477-5956-10-42
PMCID: PMC3576256  PMID: 22788869
Cucumber; Calcium; Hypoxic stress; Proteomics

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