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1.  The adhesion of mussel foot protein-3 to TiO2 surfaces: the effect of pH 
Biomacromolecules  2013;14(4):1072-1077.
The underwater adhesion of marine mussels relies on mussel foot proteins (mfps) rich in the catecholic amino acid 3, 4-dihydroxyphenylalanine (Dopa). As a side-chain, Dopa is capable of strong bidentate interactions with a variety of surfaces, including many minerals and metal oxides. Titanium is among the most widely used medical implant material and quickly forms a TiO2 passivation layer under physiological conditions. Understanding the binding mechanism of Dopa to TiO2 surfaces is therefore of considerable theoretical and practical interest. Using a surface forces apparatus, we explored the force-distance profiles and adhesion energies of mussel foot protein 3 (mfp-3) to TiO2 surfaces at three different pHs (pH3, 5.5 and 7.5). At pH3, mfp-3 showed the strongest adhesion force on TiO2, with an adhesion energy of ~ −7.0 mJ/m2. Increasing the pH gives rise to two opposing effects: (1) increased oxidation of Dopa, thus decreasing availability for the Dopa-mediated adhesion, and (2) increased bidentate Dopa-Ti coordination, leading to the further stabilization of the Dopa group and thus an increasing of adhesion force. Both effects were reflected in the resonance-enhanced Raman spectra obtained at the three deposition pHs. The two competing effects give rise to a higher adhesion force of mfp-3 on TiO2 surface at pH 7.5 than at pH 5.5. Our results suggest that Dopa-containing proteins and synthetic polymers have great potential as coating materials for medical implant materials, particularly if redox activity can be controlled.
PMCID: PMC3635841  PMID: 23452271
2.  Acupuncture for Essential Hypertension: A Meta-Analysis of Randomized Sham-Controlled Clinical Trials 
Background. Acupuncture is frequently advocated as an adjunct treatment for essential hypertension. The aim of this review was to assess its adjunct effectiveness in treating hypertension. Methods. We searched PubMed, the Cochrane Library, EMBASE, and the Chinese databases Sino-Med, CNKI, WanFang, and VIP through November, 2012, for eligible randomized controlled trials that compared acupuncture with sham acupuncture. Outcome measures were changes in diastolic (DBP) and systolic blood pressure (SBP). Results. A total of 4 randomized controlled trials were included. We found no evidence of an improvement with the fact that acupuncture relative to sham acupuncture in SBP change (n = 386; mean difference = −3.80 mmHg, 95% CI = −10.03–2.44 mmHg; I2 = 99%), and an insignificant improvement in DBP change (n = 386; mean difference = −2.82 mmHg, 95% CI = −5.22–(−0.43) mmHg; I2 = 97%). In subgroup analyses, acupuncture significantly improved both SBP and DBP in patients taking antihypertensive medications. Only minor acupuncture-related adverse events were reported. Conclusions. Our results are consistent with acupuncture significantly lowers blood pressure in patients taking antihypertensive medications. We did not find that acupuncture without antihypertensive medications significantly improves blood pressure in those hypertensive patients.
PMCID: PMC3960742  PMID: 24723957
3.  Immunomodulation and the quorum sensing molecule 3-oxo-C12-homoserine lactone: The importance of chemical scaffolding for probe development† 
As a guide for chemical probe design, focused analogue synthetic studies were undertaken upon the lactone ring of 3-oxo-C12-homoserine lactone. We have concluded that hydrolytic instability of the heterocyclic ring is pivotal for its ability to modulate immune signaling and probe preparation was aligned with these findings.
PMCID: PMC3566768  PMID: 23328974
4.  Expression of IGFBP-6 in a proliferative vitreoretinopathy rat model and its effects on retinal pigment epithelial cell proliferation and migration 
To investigate the expression of insulin-like growth factor binding protein-6 (IGFBP-6) in a proliferative vitreoretinopathy (PVR) model and its effects on proliferation and migration in retinal pigment epithelial (RPE) cells.
A PVR Wistar rat model was established by the intravitreal injection of RPE-J cells combined with platelet-rich plasma (PRP). The expression levels of IGFBP-6 were tested by ELISA. ARPE-19 cell proliferation was evaluated by the MTS method, and cell migration was evaluated by wound healing assays.
The success rate of the PVR model was 89.3% (25/28). IGFBP-6 was expressed at higher levels in the vitreous, serum and retina of rats experiencing advanced PVR (grade 3) than in the control group (vitreous: 152.80±15.08ng/mL vs 105.44±24.81ng/mL, P>0.05; serum: 93.48±9.27ng/mL vs 80.59±5.20ng/mL, P<0.05; retina: 3.02±0.38ng/mg vs 2.05±0.53ng/mg, P<0.05). In vitro, IGFBP-6 (500ng/mL) inhibited the IGF-II (50ng/mL) induced ARPE-19 cell proliferation (OD value at 24h: from 1.38±0.05 to 1.30±0.02; 48h: from 1.44±0.06 to 1.35±0.05). However, it did not affect basal or VEGF-, TGF-β- and PDGF-induced cell proliferation. IGFBP-6 (500ng/mL) reduced the IGF-II (50ng/mL)-induced would healing rate [24h: from (43.91±3.85)% to (29.76±2.49)%; 48 h: from (66.09±1.67)% to (59.88±3.43)%].
Concentrations of IGFBP-6 increased in the vitreous, serum, and retinas only in advanced PVR in vivo. IGFBP-6 also inhibited IGF-II-induced cell proliferation in a not dose or time dependent manner and migration. IGFBP-6 participates in the development of PVR and might play a protective role in PVR.
PMCID: PMC3949454  PMID: 24634859
insulin-like growth factor binding protein-6; proliferative vitreoretinopathy; retinal pigment epithelial cells
5.  Prediction of Early Response to Chemotherapy in Lung Cancer by Using Diffusion-Weighted MR Imaging 
The Scientific World Journal  2014;2014:135841.
Purpose. To determine whether change of apparent diffusion coefficient (ADC) value could predict early response to chemotherapy in lung cancer. Materials and Methods. Twenty-five patients with advanced non-small cell lung cancer underwent chest MR imaging including DWI before and at the end of the first cycle of chemotherapy. The tumor's mean ADC value and diameters on MR images were calculated and compared. The grouping reference was based on serial CT scans according to Response Evaluation Criteria in Solid Tumors. Logistic regression was applied to assess treatment response prediction ability of ADC value and diameters. Results. The change of ADC value in partial response group was higher than that in stable disease group (P = 0.004). ROC curve showed that ADC value could predict treatment response with 100% sensitivity, 64.71% specificity, 57.14% positive predictive value, 100% negative predictive value, and 82.7% accuracy. The area under the curve for combination of ADC value and longest diameter change was higher than any parameter alone (P ≤ 0.01). Conclusions. The change of ADC value may be a sensitive indicator to predict early response to chemotherapy in lung cancer. Prediction ability could be improved by combining the change of ADC value and longest diameter.
PMCID: PMC3943194
6.  Cell cycle–related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients 
Carcinogenesis  2012;34(2):299-306.
Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle–related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle–related genes and 31 DNA repair–related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan–Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5×10–4). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16–6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.
PMCID: PMC3564440  PMID: 23125224
7.  E3 Ubiquitin Ligase CHIP and NBR1-Mediated Selective Autophagy Protect Additively against Proteotoxicity in Plant Stress Responses 
PLoS Genetics  2014;10(1):e1004116.
Plant stress responses require both protective measures that reduce or restore stress-inflicted damage to cellular structures and mechanisms that efficiently remove damaged and toxic macromolecules, such as misfolded and damaged proteins. We have recently reported that NBR1, the first identified plant autophagy adaptor with a ubiquitin-association domain, plays a critical role in plant stress tolerance by targeting stress-induced, ubiquitinated protein aggregates for degradation by autophagy. Here we report a comprehensive genetic analysis of CHIP, a chaperone-associated E3 ubiquitin ligase from Arabidopsis thaliana implicated in mediating degradation of nonnative proteins by 26S proteasomes. We isolated two chip knockout mutants and discovered that they had the same phenotypes as the nbr1 mutants with compromised tolerance to heat, oxidative and salt stresses and increased accumulation of insoluble proteins under heat stress. To determine their functional interactions, we generated chip nbr1 double mutants and found them to be further compromised in stress tolerance and in clearance of stress-induced protein aggregates, indicating additive roles of CHIP and NBR1. Furthermore, stress-induced protein aggregates were still ubiquitinated in the chip mutants. Through proteomic profiling, we systemically identified heat-induced protein aggregates in the chip and nbr1 single and double mutants. These experiments revealed that highly aggregate-prone proteins such as Rubisco activase and catalases preferentially accumulated in the nbr1 mutant while a number of light-harvesting complex proteins accumulated at high levels in the chip mutant after a relatively short period of heat stress. With extended heat stress, aggregates for a large number of intracellular proteins accumulated in both chip and nbr1 mutants and, to a greater extent, in the chip nbr1 double mutant. Based on these results, we propose that CHIP and NBR1 mediate two distinct but complementary anti-proteotoxic pathways and protein's propensity to aggregate under stress conditions is one of the critical factors for pathway selection of protein degradation.
Author Summary
Environmental stresses such as heat cause generation of misfolded and damaged proteins, which are highly toxic and must be efficiently removed. In plants, NBR1, the first isolated autophagy receptor with an ubiquitin-association domain, plays a critical role in plant stress tolerance by targeting ubiquitinated protein aggregates under stress conditions for degradation by autophagy. To study how stress-induced misfolded and damaged proteins are detected and ubiquitinated in plant cells, we analyzed the chaperone-associated E3 ubiquitin ligase CHIP from Arabidopsis thaliana for its role in protection against proteotoxicity in plant stress responses. Disruption of Arabidopsis CHIP caused increased sensitivity to a spectrum of abiotic stresses as found in the Arabidopsis nbr1 mutants. Disruption of both Arabidopsis CHIP and NBR1 further compromised plant stress tolerance, indicating that their roles are additive. Furthermore, in the chip nbr1 double mutant, compromised heat tolerance was associated with increased accumulation of insoluble proteins derived mostly from heat-sensitive but biologically important proteins such as Rubisco activase, catalases and proteins required for protein synthesis and folding. Importantly, stress-induced protein aggregates were still highly ubiquitinated in the chip mutants. These results strongly suggest that CHIP and NBR1 function in two distinct but complementary anti-proteotoxic pathways in plant stress responses.
PMCID: PMC3907298  PMID: 24497840
8.  Genome sequence of Anopheles sinensis provides insight into genetics basis of mosquito competence for malaria parasites 
BMC Genomics  2014;15:42.
Anopheles sinensis is an important mosquito vector of Plasmodium vivax, which is the most frequent and widely distributed cause of recurring malaria throughout Asia, and particularly in China, Korea, and Japan.
We performed 454 next-generation sequencing and obtained a draft sequence of A. sinensis assembled into scaffolds spanning 220.8 million base pairs. Analysis of this genome sequence, we observed expansion and contraction of several immune-related gene families in anopheline relative to culicine mosquito species. These differences suggest that species-specific immune responses to Plasmodium invasion underpin the biological differences in susceptibility to Plasmodium infection that characterize these two mosquito subfamilies.
The A. sinensis genome produced in this study, provides an important resource for analyzing the genetic basis of susceptibility and resistance of mosquitoes to Plasmodium parasites research which will ultimately facilitate the design of urgently needed interventions against this debilitating mosquito-borne disease.
PMCID: PMC3901762  PMID: 24438588
Genome; Anopheles sinensis; Malaria
9.  Desmoplastic small round cell tumor: a case report and review of the literature 
Desmoplastic small round cell tumor is a rare malignant tumor that has a poor prognosis. It affects predominantly young males. In the current report, a 14-year-old male patient was admitted to the hospital for evaluation of abdominal distension, and abdominal pain. Imaging examination revealed a high prevalence of multiple intraperitoneal and liver parenchymal cystic and solid tumors. After an explorative surgery, the pathological findings confirmed the presentation of desmoplastic small round cell tumor. Diagnosis of desmoplastic small round cell tumor could easily have been overlooked since there was no specific evidence for this condition available in the clinical and imaging examinations. In the present study, ultrasound examination detected solid cystic masses, which suggested the presence of necrosis and hemorrhage. Immunohistochemistry and cytogenetic studies confirmed the diagnosis of desmoplastic small round cell tumor in this patient.
PMCID: PMC3976550  PMID: 24410799
Desmoplastic small round cell tumor; Imaging; Pathology
10.  Hydrophobic enhancement of Dopa-mediated adhesion in a mussel foot protein 
Dopa (3,4-dihydroxyphenylalanine) is recognized as a key chemical signature of mussel adhesion and has been adopted into diverse synthetic polymer systems. Dopa’s notorious susceptibility to oxidation, however, poses significant challenges to the practical translation of mussel adhesion. Using a Surface Forces Apparatus to investigate the adhesion of Mfp3 (mussel foot protein 3) slow, a hydrophobic protein variant of the Mfp3 family in the plaque, we have discovered a subtle molecular strategy correlated with hydrophobicity that appears to compensate for Dopa instability. At pH 3, where Dopa is stable, Mfp3 slow like Mfp3 fast adhesion to mica is directly proportional to the mol% of Dopa present in the protein. At pH 5.5 and 7.5, however, loss of adhesion in Mfp3 slow was less than half that occurring in Mfp3 fast, purportedly because Dopa in Mfp3 slow is less prone to oxidation. Indeed, cyclic voltammetry showed that the oxidation potential of Dopa in Mfp3 slow is significantly higher than in Mfp3 fast at pH 7.5. A much greater difference between the two variants was revealed in the interaction energy of two symmetric Mfp3 slow films (Ead = −3 mJ/m2). This energy corresponds to the energy of protein cohesion which is notable for its reversibility and pH-independence. Exploitation of aromatic hydrophobic sequences to protect Dopa against oxidation as well as to mediate hydrophobic and H-bonding interactions between proteins provides new insights for developing effective artificial underwater adhesives.
PMCID: PMC3587158  PMID: 23214725
11.  Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips 
Epigenetics  2013;8(1):34-43.
Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.
PMCID: PMC3549879  PMID: 23208076
genome-wide; DNA methylation; alterations; hepatocellular carcinoma; 450K BeadChips
12.  RBOH1-dependent H2O2 production and subsequent activation of MPK1/2 play an important role in acclimation-induced cross-tolerance in tomato 
Journal of Experimental Botany  2013;65(2):595-607.
H2O2 and mitogen-activated protein kinase (MAPK) cascades play important functions in plant stress responses, but their roles in acclimation response remain unclear. This study examined the functions of H2O2 and MPK1/2 in acclimation-induced cross-tolerance in tomato plants. Mild cold, paraquat, and drought as acclimation stimuli enhanced tolerance to more severe subsequent chilling, photooxidative, and drought stresses. Acclimation-induced cross-tolerance was associated with increased transcript levels of RBOH1 and stress- and defence-related genes, elevated apoplastic H2O2 accumulation, increased activity of NADPH oxidase and antioxidant enzymes, reduced glutathione redox state, and activation of MPK1/2 in tomato. Virus-induced gene silencing of RBOH1, MPK1, and MPK2 or MPK1/2 all compromised acclimation-induced cross-tolerance and associated stress responses. Taken together, these results strongly suggest that acclimation-induced cross-tolerance is largely attributed to RBOH1-dependent H2O2 production at the apoplast, which may subsequently activate MPK1/2 to induce stress responses.
PMCID: PMC3904713  PMID: 24323505
Cross-tolerance; hydrogen peroxide; mitogen-activated protein kinase; reactive oxygen species; Respiratory burst oxidase homologue 1; signal transduction; Solanum lycopersicum.
13.  Bayesian Network Analysis Reveals Alterations to Default Mode Network Connectivity in Individuals at Risk for Alzheimer's Disease 
PLoS ONE  2013;8(12):e82104.
Alzheimer's disease (AD) is associated with abnormal functioning of the default mode network (DMN). Functional connectivity (FC) changes to the DMN have been found in patients with amnestic mild cognitive impairment (aMCI), which is the prodromal stage of AD. However, whether or not aMCI also alters the effective connectivity (EC) of the DMN remains unknown. We employed a combined group independent component analysis (ICA) and Bayesian network (BN) learning approach to resting-state functional MRI (fMRI) data from 17 aMCI patients and 17 controls, in order to establish the EC pattern of DMN, and to evaluate changes occurring in aMCI. BN analysis demonstrated heterogeneous regional convergence degree across DMN regions, which were organized into two closely interacting subsystems. Compared to controls, the aMCI group showed altered directed connectivity weights between DMN regions in the fronto-parietal, temporo-frontal, and temporo-parietal pathways. The aMCI group also exhibited altered regional convergence degree in the right inferior parietal lobule. Moreover, we found EC changes in DMN regions in aMCI were correlated with regional FC levels, and the connectivity metrics were associated with patients' cognitive performance. This study provides novel sights into our understanding of the functional architecture of the DMN and adds to a growing body of work demonstrating the importance of the DMN as a mechanism of aMCI.
PMCID: PMC3855765  PMID: 24324753
14.  Papillary thyroid carcinoma with massive metastasis in the uterine corpus: a case report 
BMC Cancer  2013;13:551.
Distant metastases stemming from a papillary thyroid carcinoma (PTC) are quite rare. Here we report an exceptional case of PTC presenting with cervical lymphatic and uterine metastases. This is the first case report of a PTC with uterine involvement.
Case presentation
A 60-year-old Chinese woman came to our hospital complaining of discomfort in the throat that she had been experiencing for about half a month. PTC and cervical lymphatic metastasis were diagnosed after ultrasound examinations. A massive heterogeneous mass was found beside the uterus during the pre-operative checkup and a diagnosis of ovarian carcinoma was suspected after a thorough case discussion. However, it proved to be a metastasis from the PTC as determined by pathological and immunohistochemical examinations after the operation. The patient declined further treatments. She was followed for 22 months with no sign of recurrence detected.
In this report, an unusual case of PTC was presented. The patient had not only regional lymphatic metastasis, but also had a massive metastasis in the uterine corpus, which was initially misdiagnosed as ovarian carcinoma. This case is of interest because of its rarity and exceptionally good prognosis. The reason for the misdiagnosis was attributed to overlooking the possibility of a distant metastasis coming from a PTC. This case raises the issue that completing an iodine-131 scan before operating on patients with PTC may be warranted.
PMCID: PMC3870965  PMID: 24252387
Papillary thyroid carcinoma; Metastasis; Ultrasound; Uterine
15.  The Genome Database for Rosaceae (GDR): year 10 update 
Nucleic Acids Research  2013;42(D1):D1237-D1244.
The Genome Database for Rosaceae (GDR, http:/, the long-standing central repository and data mining resource for Rosaceae research, has been enhanced with new genomic, genetic and breeding data, and improved functionality. Whole genome sequences of apple, peach and strawberry are available to browse or download with a range of annotations, including gene model predictions, aligned transcripts, repetitive elements, polymorphisms, mapped genetic markers, mapped NCBI Rosaceae genes, gene homologs and association of InterPro protein domains, GO terms and Kyoto Encyclopedia of Genes and Genomes pathway terms. Annotated sequences can be queried using search interfaces and visualized using GBrowse. New expressed sequence tag unigene sets are available for major genera, and Pathway data are available through FragariaCyc, AppleCyc and PeachCyc databases. Synteny among the three sequenced genomes can be viewed using GBrowse_Syn. New markers, genetic maps and extensively curated qualitative/Mendelian and quantitative trait loci are available. Phenotype and genotype data from breeding projects and genetic diversity projects are also included. Improved search pages are available for marker, trait locus, genetic diversity and publication data. New search tools for breeders enable selection comparison and assistance with breeding decision making.
PMCID: PMC3965003  PMID: 24225320
16.  CottonGen: a genomics, genetics and breeding database for cotton research 
Nucleic Acids Research  2013;42(D1):D1229-D1236.
CottonGen ( is a curated and integrated web-based relational database providing access to publicly available genomic, genetic and breeding data for cotton. CottonGen supercedes CottonDB and the Cotton Marker Database, with enhanced tools for easier data sharing, mining, visualization and data retrieval of cotton research data. CottonGen contains annotated whole genome sequences, unigenes from expressed sequence tags (ESTs), markers, trait loci, genetic maps, genes, taxonomy, germplasm, publications and communication resources for the cotton community. Annotated whole genome sequences of Gossypium raimondii are available with aligned genetic markers and transcripts. These whole genome data can be accessed through genome pages, search tools and GBrowse, a popular genome browser. Most of the published cotton genetic maps can be viewed and compared using CMap, a comparative map viewer, and are searchable via map search tools. Search tools also exist for markers, quantitative trait loci (QTLs), germplasm, publications and trait evaluation data. CottonGen also provides online analysis tools such as NCBI BLAST and Batch BLAST.
PMCID: PMC3964939  PMID: 24203703
17.  Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma 
Epigenetics  2012;7(11):1230-1237.
Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
PMCID: PMC3499324  PMID: 22976466
HCC; genome-wide; host gene; microRNA; DNA methylation
18.  The Value of Ultrasound in Detecting Extra-Axillary Regional Node Involvement in Patients With Advanced Breast Cancer 
The Oncologist  2012;17(11):1402-1408.
The role of regional ultrasound in providing clinically relevant information was evaluated in the assessment of regional lymphatics for accurate staging and treatment of breast cancer patients. Regional ultrasound was found to be beneficial in initial staging evaluations.
Learning Objectives
After completing this course, the reader will be able to: Describe the ways in which regional ultrasound has contributed to more accurate staging in a population of locally advanced breast cancer patients.Explain how regional nodal information leads to changes in radiation therapy portals and total doses.Discuss the role of regional ultrasound in reflecting a truer level of disease burden in locally advanced breast cancer patients before therapies, including neoadjuvant chemotherapy, may limit knowledge of disease extent and consequently affect radiation treatment planning.
This article is available for continuing medical education credit at
Assessment of the regional lymphatics is important for accurate staging and treatment of breast cancer patients. We sought to determine the role of regional ultrasound in providing clinically relevant information. We retrospectively analyzed data from patients who were treated curatively in 1996–2006 at The University of Texas MD Anderson Cancer Center for clinical stage III breast cancer. We compared differences in regional lymph node staging based on ultrasound versus mammography and physical examination in the 865 of 1,200 patients who had external-beam radiation as part of their treatment and regional ultrasound studies as part of their initial evaluation. Ultrasound uniquely identified additional lymph node involvement beyond the level I or II axilla in 37% of the patients (325 of 865), leading to a change in clinical nodal stage. Ninety-one percent of these abnormalities that could be biopsied (266 or 293) were confirmed to contain disease. The sites of additional regional nodal disease were: infraclavicular disease, 32% (275 of 865); supraclavicular disease, 16% (140 of 865); and internal mammary disease, 11% (98 of 865). All patients with involvement in the extra-axillary regional nodal basins received a radiation boost to the involved areas ≥10 Gy. Thus, over one third of patients with advanced breast cancer had their radiation plan altered by the ultrasound findings. Regional ultrasound evaluation in patients with advanced breast cancer commonly revealed abnormalities within and beyond the axilla, which changed the clinical stage of disease and the radiation treatment strategy. Therefore, regional ultrasound is beneficial in the initial staging evaluation for such patients.
PMCID: PMC3500360  PMID: 22982581
Regional ultrasound; Breast cancer; Staging; Locally advanced
19.  Limited Proteolysis Via Millisecond Digestions in Protease-Modified Membranes 
Analytical chemistry  2012;84(19):8357-8363.
Sequential adsorption of poly(styrene sulfonate) (PSS) and proteases in porous nylon yields enzymatic membrane reactors for limited protein digestion. Although a high local enzyme density (~30 mg/cm3) and small pore diameters in the membrane lead to digestion in < 1 s, the low membrane thickness (170 μm) affords control over residence times at the ms level to limit digestion. Apomyoglobin digestion demonstrates that peptide lengths increase as the residence time in the membrane decreases. Moreover, electron transfer dissociation (ETD) tandem mass spectrometry (MS/MS) on a large myoglobin proteolytic peptide (8 kD) provides a resolution of 1–2 amino acids. Under denaturing conditions, limited membrane digestion of bovine serum albumin (BSA) and subsequent ESI-Orbitrap MS analysis reveal large peptides (3 kD–10 kD) that increase the sequence coverage from 53 % (2-s digestion) to 82 % (0.05-s digestion). With this approach we also performed membrane-based limited proteolysis of a large Arabidopsis GTPase, ROOT HAIR DEFECTIVE 3 (RHD3), and showed suitable probing for labile regions near the C-terminus to suggest what protein reconstruction might make RHD3 more suitable for crystallization.
PMCID: PMC3683959  PMID: 22950601
20.  Intraoperative Blood Loss Independently Predicts Survival and Recurrence after Resection of Colorectal Cancer Liver Metastasis 
PLoS ONE  2013;8(10):e76125.
Although numerous prognostic factors have been reported for colorectal cancer liver metastasis (CRLM), few studies have reported intraoperative blood loss (IBL) effects on clinical outcome after CRLM resection.
We retrospectively evaluated the clinical and histopathological characteristics of 139 patients who underwent liver resection for CRLM. The IBL cutoff volume was calculated using receiver operating characteristic curves. Overall survival (OS) and recurrence free survival (RFS) were assessed using the Kaplan–Meier and Cox regression methods.
All patients underwent curative resection. The median follow up period was 25.0 months (range, 2.1–88.8). Body mass index (BMI) and CRLM number and tumor size were associated with increased IBL. BMI (P=0.01; 95% CI = 1.3–8.5) and IBL (P<0.01; 95% CI = 1.6–12.5) were independent OSOs predictors. Five factors, including IBL (P=0.02; 95% CI = 1.1–4.1), were significantly related to RFS via multivariate Cox regression analysis. In addition, OSOs and RFS significantly decreased with increasing IBL volumes. The 5-year OSOs of patients with IBL≤250, 250–500, and >500mL were 71%, 33%, and 0%, respectively (P<0.01). RFS of patients within three IBL volumes at the end of the first year were 67%, 38%, and 18%, respectively (P<0.01).
IBL during CRLM resection is an independent predictor of long term survival and tumor recurrence, and its prognostic value was confirmed by a dose–response relationship.
PMCID: PMC3788029  PMID: 24098431
21.  The Role of Hydrogen Peroxide and Nitric Oxide in the Induction of Plant-Encoded RNA-Dependent RNA Polymerase 1 in the Basal Defense against Tobacco Mosaic Virus 
PLoS ONE  2013;8(9):e76090.
Plant RNA-dependent RNA Polymerase 1 (RDR1) is an important element of the RNA silencing pathway in the plant defense against viruses. RDR1 expression can be elicited by viral infection and salicylic acid (SA), but the mechanisms of signaling during this process remains undefined. The involvement of hydrogen peroxide (H2O2) and nitric oxide (NO) in RDR1 induction in the compatible interactions between Tobacco mosaic tobamovirus (TMV) and Nicotiana tabacum, Nicotiana benthamiana, and Arabidopsis thaliana was examined. TMV inoculation onto the lower leaves of N. tabacum induced the rapid accumulation of H2O2 and NO followed by the increased accumulation of RDR1 transcripts in the non-inoculated upper leaves. Pretreatment with exogenous H2O2 and NO on upper leaf led to increased RDR1 expression and systemic TMV resistance. Conversely, dimethylthiourea (an H2O2 scavenger) and 2-(4-carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (an NO scavenger) partly blocked TMV- and SA-induced RDR1 expression and increased TMV susceptibility, whereas pretreatment with exogenous H2O2 and NO failed to diminish TMV infection in N. benthamiana plants with naturally occurring RDR1 loss-of-function. Furthermore, in N. tabacum and A. thaliana, TMV-induced H2O2 accumulation was NO-dependent, whereas NO generation was not affected by H2O2. These results suggest that, in response to TMV infection, H2O2 acts downstream of NO to mediate induction of RDR1, which plays a critical role in strengthening RNA silencing to restrict systemic viral infection.
PMCID: PMC3786905  PMID: 24098767
22.  Hospital-Based Colorectal Cancer Survival Trend of Different Tumor Locations from 1960s to 2000s 
PLoS ONE  2013;8(9):e73528.
Our aim is to explore the trend of association between the survival rates of colorectal cancer (CRC) and the different clinical characteristics in patients registered from 1960s to 2000s. We hypothesized that the survival rate of CRC increases over time and varies according to anatomic subsites.
Information from a total of 4558 stage T(1-4)N(1-2)M0 CRC patients registered from 1960s to 2008 were analyzed. The association of CRC overall survival with age, gender, tumor locations, time, histopathology types, pathology grades, no. of examined lymph nodes, the T stage, and the N stage was analyzed. The assessment of the influence of prognostic factors on patient survival was performed using Cox’s proportional hazard regression models.
From 1960 to 2008, the studied CRC patients included 2625 (57.6%) and 1933 (42.4%) males and females, respectively. These included 1896 (41.6%) colon cancers, and 2662 (58.4%) rectum cancers. The 5-year survival rate was 49%, 58%, 58%, 70%, and 77% for the time duration of 1960s, 1970s, 1980s, 1990s and 2000s, respectively. An increased 5-year survival rate was observed in the colon cancer and rectum cancer patients. Patients older than 60 years of age were more likely to develop colonic cancer (sigmoid) than rectum cancer (49.2% vs. 39.9%). The Cox regression model showed that only rectum cancer survival was related to time duration.
The overall survival and 5-year survival rates showed an increase from the 1960s to 2000s. There is a trend of rightward shift of tumor location in CRC patients.
PMCID: PMC3772028  PMID: 24069202
23.  Association between TYMS Expression and Efficacy of Pemetrexed–Based Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis 
PLoS ONE  2013;8(9):e74284.
The predictive value of thymidylate synthase (TYMS) to sensitivity to pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is controversial. We conducted a meta-analysis of all relevant published data to assess the association of TYMS expression with the clinical outcomes of pemetrexed-based regimen in advanced NSCLC.
Patients and Methods
We conducted an electronic search using using PubMed, Embase, OVID and Cochrane Library databases and manual search. Pooled odds ratio (OR) for the response rate and hazard ratio (HR) for the overall survival and progression free survival were calculated using the software Revman 5.0.
There were 11 studies (n=798) met our criteria for evaluation. Response rate to pemetrexed-based regimen was significantly higher in patients with low/negative TYMS (OR=2.96, 95%CI [1.81, 4.86] P<0.0001). Patients with low/negative TYMS who were treated with pemetrexed-based regimen had longer progression free survival (HR 0.50, 95%CI [0.41, 0.61] P <0.00001) and overall survival (HR 0.41, 95%CI [0.22, 0.78] P=0.007) than those with high/positive TYMS.
Low/negative TYMS expression was significantly associated with higher response rate, longer median survival and longer progression free survival for advanced NSCLC patients receiving pemtrexed-based chemotherapy. Hence, TYMS may be a potential predictor of sensitivity to pemtrexed-based chemotherapy in advanced NSCLC. Large scale prospective clinical trials are still warranted.
PMCID: PMC3769376  PMID: 24040222
24.  Correction: Transcriptome Analysis of Acyl-Homoserine Lactone-Based Quorum Sensing Regulation in Yersinia pestis 
PLoS ONE  2013;8(9):10.1371/annotation/3f0e8e82-1db8-45fe-a700-c64ede3e3c61.
PMCID: PMC3812340  PMID: 24205403
25.  Early Growth Response Protein-1 Promoter-Mediated Synergistic Antitumor Effect of hTERTC27 Gene Therapy and 5-Flurorouracil on Nasopharyngeal Carcinoma 
hTERTC27 is a newly constructed polypeptide that can induce telomere dysfunction. To study the synergistic antitumor effects of the hTERTC27 polypeptide driven by the early growth response protein-1 (Egr-1) promoter and chemotherapeutic 5-flurorouracil (5-FU) on nasopharyngeal carcinoma, a series of in vitro and in vivo experiments were performed. The results showed that hTERTC27 expression was significantly increased up to 7.21-folds by the 5-FU-activated Egr-1 promoter in C666-1 cells. Overexpressed hTERTC27 made the cells more sensitive to 5-FU, and additionally, inhibited cell proliferation about 20.41%. Combinational therapy of overexpressed hTERTC27 driven by the 5-FU-activated Egr-1 promoter and 5-FU synergistically inhibited cell proliferation and promoted apoptosis of C666-1 cells for about 4.75-fold and 1.76-fold in comparison with a sole therapy of hTERTC27 or 5-FU in vitro. In vivo experiments showed that overexpressed hTERTC27 driven by 5-FU-activated Egr-1 promoter and 5-FU synergistically reduced tumor volume, tumor weight, and local infiltration, which may be relative to tumor cell apoptosis. These results suggest that combinational therapy of overexpressed hTERTC27, which is driven by the 5-FU-activated Egr-1 promoter, and 5-FU may provide a novel approach to treat nasopharyngeal cancer.
PMCID: PMC3432866  PMID: 22947087
5-FU; Egr-1; hTERTC27; nasopharyngeal carcinoma; gene therapy

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