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1.  Value of 18F-FDG PET-CT in surveillance of postoperative colorectal cancer patients with various carcinoembryonic antigen concentrations 
AIM: To evaluate the value of positron emission tomography (PET)/computerized tomography (CT) in surveillance of colorectal cancer (CRC) patients with different carcinoembryonic antigen (CEA) concentrations.
METHODS: One hundred and six postoperative CRC patients who had suspected recurrence or metastasis and received fluorodeoxyglucose (FDG) PET/CT within one week were included in this study. The final diagnosis was confirmed by histological examination or clinical follow-up over at least six months.
RESULTS: The sensitivity, specificity, and accuracy of FDG PET/CT were 95.2%, 82.6%, and 92.5%, and 94.8%, 81.4% and 92.8%, respectively, in the case- and lesion-based analyses. The sensitivity and accuracy of FDG PET/CT significantly differed from CT in both analyses (χ2 = 8.186, P = 0.004; χ2 =6.201, P = 0.013; χ2 =13.445, P = 0.000; χ2 =11.194, P = 0.001). In the lesion-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT in the abnormal CEA group were 97.8%, 82.6%, and 95.6%, compared with 81.3%, 80%, and 80.6% for patients with normal CEA levels. In case-based analysis, the sensitivity, specificity, and accuracy of FDG PET/CT were 97.2%, 77.8%, and 95% in abnormal CEA group. Only in lesion-based analysis, the sensitivity and accuracy of FDG PET/CT in the abnormal CEA group were significantly superior to those in the normal CEA group (χ2 =6.432, P = 0.011; χ2 =7.837, P = 0.005). FDG PET/CT changed the management in 45.8% of patients with positive scans.
CONCLUSION: FDG PET/CT showed superior diagnostic value and is an advisable option in surveillance of postoperative CRC patients with a vague diagnosis.
doi:10.3748/wjg.v20.i21.6608
PMCID: PMC4047348  PMID: 24914384
Colorectal cancer; Carcinoembryonic antigen; Fluorodeoxyglucose positron emission tomography/computed tomography; Recurrence; Metastasis
2.  An Analysis of FMA Using Structural Self-Bisimilarity 
Journal of biomedical informatics  2013;46(3):497-505.
As ontologies are mostly manually created, they tend to contain errors and inconsistencies. In this paper, we present an automated computational method to audit symmetric concepts in ontologies by leveraging self-bisimilarity and linguistic structure in the concept names. Two concepts A and B are symmetric if concept B can be obtained from concept A by replacing a single modifier such as “left” with its symmetric modifier such as “right.” All possible local structural types for symmetric concept pairs are enumerated according to their local subsumption hierarchy, and the pairs are further classified into Non-Matches and Matches. To test the feasibility and validate the benefits of this method, we computed all the symmetric modifier pairs in the Foundational Model of Anatomy (FMA) and selected six of them for experimentation. 9893 Non-Matches and 221 abnormal Matches with potential errors were discovered by our algorithm. Manual evaluation by FMA domain experts on 176 selected Non-Matches and all the 221 abnormal Matches found 102 missing concepts and 40 misaligned concepts. Corrections for them have currently been implemented in the latest version of FMA. Our result demonstrates that self-bisimilarity can be a valuable method for ontology quality assurance, particularly in uncovering missing concepts and misaligned concepts. Our approach is computationally scalable and can be applied to other ontologies that are rich in symmetric concepts.
doi:10.1016/j.jbi.2013.03.005
PMCID: PMC3690136  PMID: 23557711
Ontology; FMA; Auditing; Bisimilarity; Symmetric concepts
3.  3-(2-Methyl-1,3-benzo­thia­zol-3-ium-3-yl)propane-1-sulfonate monohydrate 
In the title hydrated zwitterion, C11H13NO3S2·H2O, the N—C—C—C and C—C—C—S torsion angles in the side-chain are 171.06 (14) and 173.73 (12)°, respectively. In the crystal, inversion-related mol­ecules are π-stacked with an inter­planar separation of 3.3847 (2) Å. O—H⋯O hydrogen bonds link inversion-related mol­ecules with a pair of water mol­ecules to form R 4 2(8) rings. The closest S⋯S contact is 3.4051 (15) Å between inversion-related mol­ecules.
doi:10.1107/S1600536814011660
PMCID: PMC4051035  PMID: 24940284
4.  HNE catabolism and formation of HNE adducts are modulated by beta oxidation of fatty acids in the isolated rat heart 
We previously reported that a novel metabolic pathway functionally catabolizes 4-hydroxy-2-(E)-nonenal (HNE) via two parallel pathways, which rely heavily on β oxidation pathways. The hypothesis driving the present report is that perturbations of β oxidation will alter the catabolic disposal of HNE, favoring an increase in the concentrations of HNE and HNE modified proteins that may further exacerbate pathology. The current study employed Langendorff perfused hearts to investigate the impact of cardiac injury modeled by ischemia/reperfusion and, in a separate set of perfusions, the effects of elevated lipid (typically observed in obesity and type II diabetes) by perfusing with increased fatty acid concentrations (1 mM octanoate). During ischemia, HNE concentrations doubled and the glutathione-HNE adduct and 4-hydroxynonanoyl-CoA were increased by 7- and 10-fold, respectively. Under conditions of increased fatty acid, oxidation to 4-hydroxynonenoic acid was sustained, however, further catabolism through β oxidation was nearly abolished. The inhibition of HNE catabolism was not compensated by other disposal pathways of HNE, rather an increase in HNE-modified proteins was observed. Taken together, this study presents a mechanistic rationale for the accumulation of HNE and HNE-modified proteins in pathological conditions that involve alterations to β oxidation, such as myocardial ischemia, obesity and high fat diet induced diseases.
doi:10.1016/j.freeradbiomed.2013.01.005
PMCID: PMC3723455  PMID: 23328733
4-hydroxy-2(E)-nonenal; catabolism; fatty acid (β) oxidation; heart; lipid peroxidation; mass isotopomer
5.  Laparoscopic ligation of proximal splenic artery aneurysm with splenic function preservation 
Splenic artery aneurysm is one of the most common visceral aneurysms, and patients with this type of aneurysm often present without symptoms. However, when rupture occurs, it can be a catastrophic event. Although most of these aneurysms can be treated with percutaneous embolization, some located in uncommon parts of the splenic artery may make this approach impossible. We present a patient with an aneurysm in the proximal splenic artery, close to the celiac trunk, which was treated by laparoscopic ligation only, without resection of the aneurysm, and with long-term preservation of splenic function.
doi:10.3748/wjg.v20.i16.4835
PMCID: PMC4000525  PMID: 24782641
Laparoscopy; Splenic artery; Aneurysm; Laparoscopic ligation; Splenic function preservation
6.  Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: Pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate 
Chemical research in toxicology  2012;26(2):213-220.
We recently reported that levulinate (4-ketopentanoate) is converted in the liver to 4-hydroxypentanoate, a drug of abuse, and that the formation of 4-hydroxypentanoate is stimulated by ethanol oxidation. We also identified 3 parallel β-oxidation pathways by which levulinate and 4-hydroxypentanoate are catabolized to propionyl-CoA and acetyl-CoA. We now report that levulinate forms three seven-carbon cyclical CoA esters by processes starting with the elongation of levulinyl-CoA by acetyl-CoA to 3,6-diketoheptanoyl-CoA. The latter gamma-diketo CoA ester undergoes two parallel cyclization processes. One process yields a mixture of tautomers, i.e., cyclopentenyl- and cyclopentadienyl-acyl-CoAs. The second cyclization process yields a methyl-pyrrolyl-acetyl-CoA containing a nitrogen atom derived from the epsilon nitrogen of lysine, but without carbons from lysine. The cyclic CoA esters were identified in rat livers perfused with levulinate, and in livers and brains from rats gavaged with calcium levulinate ± ethanol. Lastly, 3,6-diketoheptanoyl-CoA, like 2,5-diketohexane, pyrrolates free lysine and, presumably, lysine residues from proteins. This may represent a new pathway for protein pyrrolation. The cyclic CoA esters and related pyrrolation processes may play a role in the toxic effects of 4-hydroxypentanoate.
doi:10.1021/tx3003643
PMCID: PMC3997259  PMID: 23171137
gamma diketones; CoA esters; lysine; pyrrolation; 4-hydroxypentanoate
7.  Radiation-induced malignant fibrous histiocytoma of the occipital: a case report 
Malignant fibrous histiocytoma (MFH) is a rare neoplasm exhibiting a propensity for aggressive clinical behavior. Effective treatment modality is surgical resection with wide margins, but its rate of recurrence and metastasis is still high. Early detection and complete excision of the tumor is necessary. A MFH of the occipital developed in a 51-year-old woman eight years after surgery and radiation for medulloblastoma of the cerebellar vermis. The secondary neoplasm arose at the site of tumor resection within the irradiated field, and was resected. The development of sarcomas is a recognized complication of radiation therapy. The final diagnosis after the operation was MFH. Radiation-induced sarcoma (RIS) is well known, but radiation-induced MFH is relatively rare in the head and neck region, especially in the occipital. The imaging findings are not diagnosis specific, but strict follow-up within the radiation field by computerized tomography (CT) and magnetic resonance imaging (MRI) and appreciation of the expected latency period may help in providing the diagnosis of RIS.
doi:10.1186/1477-7819-12-98
PMCID: PMC3999727  PMID: 24742094
Malignant fibrous histiocytoma; Radiation induced sarcoma; Occipital
8.  Therapeutic Effect of Jinzhen Oral Liquid for Hand Foot and Mouth Disease: A Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial 
PLoS ONE  2014;9(4):e94466.
Background
No specific antiviral agent against hand foot and mouth disease (HFMD) is available for clinical practice today.
Objective
To evaluate the efficacy and safety of Jinzhen oral solution in treating uncomplicated HFMD.
Methods
In this randomized, double-blind, placebo-controlled trial, 399 children aged 1 to 7 years with laboratory confirmed HFMD were randomized to receive Jinzhen oral liquid or placebo 3 times daily for 7 days with a 3-day follow-up. The primary outcomes were time to the first disappearance of oral ulcers and vesicles on hand or foot and time to the first normalization of temperature (fever clearance).
Results
There were 199 children enrolling into the Jinzhen group including 79 with fever and 200 into the placebo group including 93 with fever. Jinzhen reduced the time to the first disappearance of oral ulcers and vesicles on hand or foot to 4.9 days (95% CI, 4.6 to 5.2 days), compared with 5.7 days (95% CI, 5.4 to 6.0 days) in the placebo group (P = 0.0036). The median time of fever clearance was shorter in the 79 children who received Jinzhen (43.41 hrs, 95% CI, 37.05 to 49.76) than that in the 93 children who received placebo (54.92 hrs, 95% CI, 48.16 to 61.68) (P = 0.0161). Moreover, Jinzhen reduced the risk of symptoms by 28.5% compared with placebo (HR, 0.7150, 95% CI, 0.5719 to 0.8940, P = 0.0032). More importantly, treatment failure rate was significantly lower in the Jinzhen group (8.04%) compared with that in the placebo group (15.00%) (P = 0.0434). The incidence of serious adverse events did not differ significantly between the two groups (9 in Jinzhen group vs. 18 in placebo, P = 0.075).
Conclusions
Children with HFMD may benefit from Jinzhen oral liquid treatment as compared with placebo.
Trial Registration
Chinese Clinical Trial Registry (http://www.chictr.org/en/) ChiCTR-TRC-10000937
doi:10.1371/journal.pone.0094466
PMCID: PMC3983189  PMID: 24722423
9.  Comparison of the sagittal profiles among thoracic idiopathic scoliosis patients with different Cobb angles and growth potentials 
Background
Previous studies have demonstrated that pelvic incidence and sacral slope are significantly greater in idiopathic scoliosis patients compared with normal adolescents. However, whether these sagittal parameters are related to the progression of scoliosis remain unknown. The present was designed to determine the differences in the sagittal profiles among thoracic idiopathic scoliosis patients with different potentials for curve progression.
Methods
Ninety-seven outpatient idiopathic scoliosis patients enrolled from June 2008 to June 2011 were divided to three groups according to different Cobb angles and growth potentials: (1) non-progression of thoracic curve group, Risser sign of 5 and Cobb’s angle < 40°; (2) moderate progression of thoracic curve group, Risser sign of 5 and Cobb’s angle ≥ 40°; and (3) severe progression of thoracic curve group, Risser sign ≤ 3 and Cobb’s angle ≥ 40°. All patients underwent whole spinal anteroposterior and lateral X-ray in standing position, and the sagittal parameters were measured, including thoracic kyphosis, lumbar lordosis, sacral slope, pelvic incidence, and pelvic tilt.
Results
The average thoracic scoliosis Cobb’s angle in the non-progression group was significantly less than that in the moderate progression group (P < 0.01) and severe progression group (P < 0.01), but there was no statistical difference in the average thoracic scoliosis Cobb’s angle between the severe progression group and moderate progression group. The average thoracic kyphosis angle in the severe progression group (9° ± 4°) was significantly smaller than that in the non-progression group (18° ± 6°, P < 0.01) and moderate progression group (14° ± 5°, P < 0.05). No statistical differences were present in the average lumbar lordosis, sacral slope, pelvic incidence, and pelvic tilt among the three groups.
Conclusions
Thoracic hypokyphosis is strongly related with the curve progression in thoracic idiopathic scoliosis patients, but not pelvic sagittal profiles.
doi:10.1186/1749-799X-9-19
PMCID: PMC4012511  PMID: 24635839
Sagittal profiles; Idiopathic scoliosis; Thoracic kyphosis; Lumbar lordosis
10.  The prevalence of urethral and rectal Mycoplasma genitalium among men who have sex with men in China, a cross-sectional study 
BMC Public Health  2014;14:195.
Background
Although Mycoplasma genitalium (MG) is a common sexually transmitted infection (STI), very little information regarding the prevalence of MG among MSM (men who have sex with men) is available in China. The objective of this study was to determine the prevalence of MG among MSM in the city of Shenzhen, Guangdong Province, China, and to identify the potential risk factors associated with MG infection in this population.
Methods
Between January and May 2010, a total of 409 MSM were recruited in Shenzhen, Guangdong Province, China. An anonymous questionnaire was used to collect information regarding their sociological and sexual behaviors. In addition, their first-void urine (FVU) samples and rectal swabs were collected for PCR-based MG testing.
Results
Among the 406 FVU and 405 rectal swab samples were collected from 409 MSM, the overall MG prevalence was 8.1% (33/406, 95% CI 5.7%-10.6%), with a FVU positivity of 3.4% (95% CI 1.7%-5.4%) and a rectal positivity of 5.4% (95% CI 3.5%-7.7%). Using both univariate and multivariable logistic regression analyses, urethral MG infection was significantly associated with having more heterosexual behaviors (AOR 7.16, 95% CI 1.89-27.13), and with having unprotected anal intercourse in the past six months (AOR 4.80, 95% CI 1.40-16.47). Rectal MG infection was significantly associated with HIV infection based on univariate logistic regression analysis (OR = 4.49, 95% CI 1.18-17.12).
Conclusions
In this study, we investigated the prevalence of MG infection in the population of interest, as determined from both urethral and rectal specimen. We showed that MG was more prevalent in MSM who had bisexual behaviors compared to those who engaged only in homosexual behaviors. Further work is needed to establish the mode of MG transmission and to identify its role in HIV transmission. Meanwhile, more attention should be paid to MG infection among MSMs, and especially bisexual MSMs, which might have critical implications for effective HIV/STD control in China.
doi:10.1186/1471-2458-14-195
PMCID: PMC3938087  PMID: 24559387
Mycoplasma genitalium; Prevalence; MSM; China
11.  Extraskeletal myxoid chondrosarcoma: A report of two cases 
Oncology Letters  2014;7(4):1289-1291.
Extraskeletal myxoid chondrosarcoma (EMC) is a relatively rare but well-defined neoplasm. This report describes two patients, one with EMC of the buttock and one with EMC of the knee. The two cases presented with large lobed masses and long T1 and T2 signaling identified by magnetic resonance imaging (MRI). An enhanced MRI scan demonstrated enhancement of the tumors. The tumors were composed of strands or cords of oval and spindle cells embedded in abundant myxoid stroma. Pathology results confirmed EMC.
doi:10.3892/ol.2014.1884
PMCID: PMC3961448  PMID: 24944710
extraskeletal myxoid chondrosarcoma; buttock; knee
12.  Evaluation of a Novel Conjunctive Exploratory Navigation Interface for Consumer Health Information: A Crowdsourced Comparative Study 
Background
Numerous consumer health information websites have been developed to provide consumers access to health information. However, lookup search is insufficient for consumers to take full advantage of these rich public information resources. Exploratory search is considered a promising complementary mechanism, but its efficacy has never before been rigorously evaluated for consumer health information retrieval interfaces.
Objective
This study aims to (1) introduce a novel Conjunctive Exploratory Navigation Interface (CENI) for supporting effective consumer health information retrieval and navigation, and (2) evaluate the effectiveness of CENI through a search-interface comparative evaluation using crowdsourcing with Amazon Mechanical Turk (AMT).
Methods
We collected over 60,000 consumer health questions from NetWellness, one of the first consumer health websites to provide high-quality health information. We designed and developed a novel conjunctive exploratory navigation interface to explore NetWellness health questions with health topics as dynamic and searchable menus. To investigate the effectiveness of CENI, we developed a second interface with keyword-based search only. A crowdsourcing comparative study was carefully designed to compare three search modes of interest: (A) the topic-navigation-based CENI, (B) the keyword-based lookup interface, and (C) either the most commonly available lookup search interface with Google, or the resident advanced search offered by NetWellness. To compare the effectiveness of the three search modes, 9 search tasks were designed with relevant health questions from NetWellness. Each task included a rating of difficulty level and questions for validating the quality of answers. Ninety anonymous and unique AMT workers were recruited as participants.
Results
Repeated-measures ANOVA analysis of the data showed the search modes A, B, and C had statistically significant differences among their levels of difficulty (P<.001). Wilcoxon signed-rank test (one-tailed) between A and B showed that A was significantly easier than B (P<.001). Paired t tests (one-tailed) between A and C showed A was significantly easier than C (P<.001). Participant responses on the preferred search modes showed that 47.8% (43/90) participants preferred A, 25.6% (23/90) preferred B, 24.4% (22/90) preferred C. Participant comments on the preferred search modes indicated that CENI was easy to use, provided better organization of health questions by topics, allowed users to narrow down to the most relevant contents quickly, and supported the exploratory navigation by non-experts or those unsure how to initiate their search.
Conclusions
We presented a novel conjunctive exploratory navigation interface for consumer health information retrieval and navigation. Crowdsourcing permitted a carefully designed comparative search-interface evaluation to be completed in a timely and cost-effective manner with a relatively large number of participants recruited anonymously. Accounting for possible biases, our study has shown for the first time with crowdsourcing that the combination of exploratory navigation and lookup search is more effective than lookup search alone.
doi:10.2196/jmir.3111
PMCID: PMC3936301  PMID: 24513593
crowdsourcing; consumer health information; human computer interaction; information retrieval; search interfaces; comparative user evaluation
13.  Worldwide Susceptibility Rates of Neisseria gonorrhoeae Isolates to Cefixime and Cefpodoxime: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(1):e87849.
Background
Neisseria gonorrhoeae (NG) infection is a serious public health problem. The third-generation extended-spectrum cephalosporins (ESCs) have been used as the first-line treatment for NG infection for almost three decades. However, in recent years, treatment failures with the oral third-generation ESCs have been reported worldwide. This study aimed to estimate worldwide susceptibility rates of NG to cefixime and cefpodoxime by analyzing data from all relevant published studies.
Methodology/principal findings
Two researchers independently searched five databases to identify studies on susceptibilities of NG to cefixime and cefpodoxime published between January 1, 1984 and October 15, 2012. A fixed-effect model was used to perform group analysis, and a χ2 test was employed to make subgroup comparison. Publication bias was assessed with the Begg rank correlation test. The pooled susceptibility rate of NG isolates to cefixime was 99.8% (95% CI: 99.7%–99.8%). The cefixime susceptibility rate of NG isolates from men was significantly lower than that from patients without information of gender or from men and women; the susceptibility rate of NG isolates from Asia was significantly lower than that from other continents; and the susceptibility rate of NG isolates collected before or during 2003 was significantly higher than that after 2003. The pooled susceptibility rate of NG isolates to cefpodoxime was 92.8% (95% CI: 89.0%–95.3%), which was lower than that to cefixime (92.8% vs. 99.8%, χ2 = 951.809, P<0.01).
Conclusions
The susceptibility rate of NG isolates to cefixime varied with the gender of patients and geographical location from which NG isolates were collected, and declined with time. The reported lower susceptibility rate of NG isolates to cefixime and associated treatment failures, as well as the emergence of NG strains with cephalosporin resistance call for the more effective control of NG infection and the development of new antibiotics.
doi:10.1371/journal.pone.0087849
PMCID: PMC3909252  PMID: 24498212
14.  Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway 
Scientific Reports  2014;4:3840.
Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-κB pathway.
doi:10.1038/srep03840
PMCID: PMC3899591  PMID: 24452475
15.  First-Line Gemcitabine Plus Cisplatin in Nonsmall Cell Lung Cancer Patients 
Disease Markers  2014;2014:960458.
Aim. To evaluate the predictive value of RRM1, ERCCl, and BRCA1 expression in Chinese NSCLC patients treated with gemcitabine and cisplatin. Methods. Real-time fluorescent quantitative PCR was used to determine the RRM1, ERCC1, and BRCA1 mRNA expression levels of peripheral blood in late-stage NSCLC patients. The relationship between peripheral blood and mRNA expression in tumor tissues was analyzed further. Results. In terms of the tumor susceptibility to chemotherapy, the response rate in the low-RRM1-expression group was significantly greater than in the high-expression group (52.9% versus 5.9%, χ2 test, P = 0.007). Subjects with low peripheral blood RRM1 expression survived longer than those with high RRM1 expression (15.5 versus 12.0 months, logrank 3.980, P = 0.046). Linear correlations were observed between peripheral blood and tumor tissue expression levels for RRM1 (R2 = 0.045, P = 0.048) and BRCA1 (R2 = 0.021, P = 0.001). Conclusion. Our study demonstrates increased survival and superior efficacy of gemcitabine and cisplatin combination chemotherapy in the treatment of NSCLC patients with low peripheral blood RRM1 expression. The linear correlations of the relative expression of mRNA were observed between peripheral blood and tumor tissue expression levels for RRM1 and BRCA1. RRM1 gene expression may contribute to chemotherapy sensitivity and may be an indicator of survival. It was significant to individual chemotherapy of patients with advanced NSCLC who do not have sufficient tumor tissue.
doi:10.1155/2014/960458
PMCID: PMC3925578  PMID: 24591771
16.  Crowdsourcing Awareness: Exploration of the Ovarian Cancer Knowledge Gap through Amazon Mechanical Turk 
PLoS ONE  2014;9(1):e85508.
Background
Ovarian cancer is the most lethal gynecologic disease in the United States, with more women dying from this cancer than all gynecological cancers combined. Ovarian cancer has been termed the “silent killer” because some patients do not show clear symptoms at an early stage. Currently, there is a lack of approved and effective early diagnostic tools for ovarian cancer. There is also an apparent severe knowledge gap of ovarian cancer in general and of its indicative symptoms among both public and many health professionals. These factors have significantly contributed to the late stage diagnosis of most ovarian cancer patients (63% are diagnosed at Stage III or above), where the 5-year survival rate is less than 30%. The paucity of knowledge concerning ovarian cancer in the United States is unknown.
Methods
The present investigation examined current public awareness and knowledge about ovarian cancer. The study implemented design strategies to develop an unbiased survey with quality control measures, including the modern application of multiple statistical analyses. The survey assessed a reasonable proxy of the US population by crowdsourcing participants through the online task marketplace Amazon Mechanical Turk, at a highly condensed rate of cost and time compared to traditional recruitment methods.
Conclusion
Knowledge of ovarian cancer was compared to that of breast cancer using repeated measures, bias control and other quality control measures in the survey design. Analyses included multinomial logistic regression and categorical data analysis procedures such as correspondence analysis, among other statistics. We confirmed the relatively poor public knowledge of ovarian cancer among the US population. The simple, yet novel design should set an example for designing surveys to obtain quality data via Amazon Mechanical Turk with the associated analyses.
doi:10.1371/journal.pone.0085508
PMCID: PMC3899016  PMID: 24465580
17.  Autophagy Inhibition Contributes to the Synergistic Interaction between EGCG and Doxorubicin to Kill the Hepatoma Hep3B Cells 
PLoS ONE  2014;9(1):e85771.
(-)-Epigallocatechin-3-O-gallate(EGCG), the highest catechins from green tea, has promisingly been found to sensitize the efficacy of several chemotherapy agents like doxorubicin (DOX) in hepatocellular carcinoma (HCC) treatment. However, the detailed mechanisms by which EGCG augments the chemotherapeutic efficacy remain unclear. Herein, this study was designed to determine the synergistic impacts of EGCG and DOX on hepatoma cells and particularly to reveal whether the autophagic flux is involved in this combination strategy for the HCC. Electron microscopy and fluorescent microscopy confirmed that DOX significantly increased autophagic vesicles in hepatoma Hep3B cells. Western blot and trypan blue assay showed that the increasing autophagy flux by DOX impaired about 45% of DOX-induced cell death in these cells. Conversely, both qRT-PCR and western blotting showed that EGCG played dose-dependently inhibitory role in autophagy signaling, and that markedly promoted cellular growth inhibition. Amazingly, the combined treatment caused a synergistic effect with 40 to 60% increment on cell death and about 45% augmentation on apoptosis versus monotherapy pattern. The DOX-induced autophagy was abolished by this combination therapy. Rapamycin, an autophagic agonist, substantially impaired the anticancer effect of either DOX or combination with EGCG treatment. On the other hand, using small interference RNA targeting chloroquine autophagy-related gene Atg5 and beclin1 to inhibit autophagy signal, hepatoma cell death was dramatically enhanced. Furthermore, in the established subcutaneous Hep3B cells xenograft tumor model, about 25% reduction in tumor growth as well as 50% increment of apoptotic cells were found in combination therapy compared with DOX alone. In addition, immunohistochemistry analysis indicated that the suppressed tendency of autophagic hallmark microtubule-associated protein light chain 3 (LC3) expressions was consistent with thus combined usage in vitro. Taken together, the current study suggested that EGCG emerges as a chemotherapeutic augmenter and synergistically enhances DOX anticancer effects involving autophagy inhibition in HCC.
doi:10.1371/journal.pone.0085771
PMCID: PMC3897495  PMID: 24465696
18.  Single-stage combined anterior retropharyngeal and posterior approach for the resection and reconstruction of C2 metastatic tumors: A case report 
This study reports the case of a 44-year-old male who had experienced severe neck pain for one month and was diagnosed with a metastatic tumor of the left C2 vertebral body and the left transverse process. The tumor was distributed to layers A–D and sectors 3–7 according to the Weinstein-Boriani-Biagini classification, and was in Category IV according to the Harrington classification system. A conventional posterior cervical approach was used to resect the left transverse process and part of the tumor in a piecemeal fashion, and spinal instrumentation was also performed. Gelfoam and absorbable hemostatic gauze were placed ventrally to the left vertebral artery and the left C3 nerve root over the tumor bed to prevent their accidental injury in the subsequent anterior approach. A high anterior retropharyngeal approach was then used to resect the tumorous C2 vertebral body by corpectomy and to perform anterior reconstruction. Six months after the surgery, the patient remained pain free. Therefore, C2 metastatic tumor resection and spinal reconstruction can be fulfilled by a single-stage combined high anterior retropharyngeal and posterior approach.
doi:10.3892/etm.2014.1493
PMCID: PMC3961110  PMID: 24660034
upper cervical spine; surgery; surgical approach
19.  Small-cell extraskeletal osteosarcoma: case report and literature review 
Small-cell extraskeletal osteosarcoma is extremely rare and consists of sheets of small round cells with variable amounts of osteoid. This tumor is often difficult to diagnose when tissue samples do not include recognizable osteoid. Only four cases have been reported in English and none in Chinese. We report a typical case of small-cell extraskeletal osteosarcoma occurring in the left leg of a 40-year-old female. Laboratory results were within normal limits. Magnetic resonance imaging demonstrated a soft tissue mass measuring 36 mm × 18 mm in the medial lateral aspect of left limb. The initial histological findings led to a misdiagnosis because the first fine-needle biopsy was randomized and incomplete. However, an open surgical specimen showed recognizable osteoid, which enabled us to make a definitive diagnosis. We also present clinical, radiologic and pathologic features of this case.
PMCID: PMC3925930  PMID: 24551306
Small-cell extraskeletal osteosarcoma; osteosarcoma; soft tissue
20.  Deletion of Gpr128 results in weight loss and increased intestinal contraction frequency 
AIM: To generate a Gpr128 gene knockout mouse model and to investigate its phenotypes and the biological function of the Gpr128 gene.
METHODS: Bacterial artificial chromosome-retrieval methods were used for constructing the targeting vector. Using homologous recombination and microinjection technology, a Gpr128 knockout mouse model on a mixed 129/BL6 background was generated. The mice were genotyped by polymerase chain reaction (PCR) analysis of tail DNA and fed a standard laboratory chow diet. Animals of both sexes were used, and the phenotypes were assessed by histological, biochemical, molecular and physiological analyses. Semi-quantitative reverse transcription-PCR and Northern blotting were used to determine the tissue distribution of Gpr128 mRNA. Beginning at the age of 4 wk, body weights were recorded every 4 wk. Food, feces, blood and organ samples were collected to analyze food consumption, fecal quantity, organ weight and constituents of the blood and plasma. A Trendelenburg preparation was utilized to examine intestinal motility in wild-type (WT) and Gpr128-/- mice at the age of 8 and 32 wk.
RESULTS: Gpr128 mRNA was highly and exclusively detected in the intestinal tissues. Targeted deletion of Gpr128 in adult mice resulted in reduced body weight gain, and mutant mice exhibited an increased frequency of peristaltic contraction and slow wave potential of the small intestine. The Gpr128+/+ mice gained more weight on average than the Gpr128-/- mice since 24 wk, being 30.81 ± 2.84 g and 25.74 ± 4.50 g, respectively (n = 10, P < 0.01). The frequency of small intestinal peristaltic contraction was increased in Gpr128-/- mice. At the age of 8 wk, the frequency of peristalsis with an intraluminal pressure of 3 cmH2O was 6.6 ± 2.3 peristalsis/15 min in Gpr128-/- intestine (n = 5) vs 2.6 ± 1.7 peristalsis/15 min in WT intestine (n = 5, P < 0.05). At the age of 32 wk, the frequency of peristaltic contraction with an intraluminal pressure of 2 and 3 cmH2O was 4.6 ± 2.3 and 3.1 ± 0.8 peristalsis/15 min in WT mice (n = 8), whereas in Gpr128-/- mice (n = 8) the frequency of contraction was 8.3 ± 3.0 and 7.4 ± 3.1 peristalsis/15 min, respectively (2 cmH2O: P < 0.05 vs WT; 3 cmH2O: P < 0.01 vs WT). The frequency of slow wave potential in Gpr128-/- intestine (35.8 ± 4.3, 36.4 ± 4.2 and 37.1 ± 4.8/min with an intraluminal pressure of 1, 2 and 3 cmH2O, n = 8) was also higher than in WT intestine (30.6 ± 4.2, 31.4 ± 3.9 and 31.9 ± 4.5/min, n = 8, P < 0.05).
CONCLUSION: We have generated a mouse model with a targeted deletion of Gpr128 and found reduced body weight and increased intestinal contraction frequency in this animal model.
doi:10.3748/wjg.v20.i2.498
PMCID: PMC3923024  PMID: 24574718
G-protein-coupled receptors; Gpr128; Knockout mouse; Weight loss; Intestinal contraction frequency
21.  Significance of Interleukin-33 and Its Related Cytokines in Patients with Breast Cancers 
Interleukin-33 (IL-33) is a recently identified cytokine, an important member of the interleukin-1 family. IL-33 binds to its receptor ST2 to induce type 2 cytokines and exert both pro-inflammatory and protective functions in host defense and disease. Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. We detected the expression of IL-33 in tumor tissue, and IL-33 and its related cytokines in serum from BC patients. Using Luminex and immunohistochemistry methods, we found that serum levels of IL-33 were nearly twofold higher in patients with BC, compared to patients with benign breast diseases. In cancer tissues, expression of IL-33 was higher than matched normal breast tissues from the same patients, and was also associated with a well-differentiated phenotype, HER2 overexpression, more lymph nodes involvement, and a family history of malignant carcinoma. These results suggest that IL-33 may play an important role in the progress of BC and may be a useful biomarker for predicting the progress and metastasis of BC.
doi:10.3389/fimmu.2014.00141
PMCID: PMC3985005  PMID: 24778632
interleukin-33; ST2/ST2L; breast cancer; cytokines; immunosuppression
22.  Use of Indocyanine Green for Detecting the Sentinel Lymph Node in Breast Cancer Patients: From Preclinical Evaluation to Clinical Validation 
PLoS ONE  2013;8(12):e83927.
Assessment of the sentinel lymph node (SLN) in patients with early stage breast cancer is vital in selecting the appropriate surgical approach. However, the existing methods, including methylene blue and nuclides, possess low efficiency and effectiveness in mapping SLNs, and to a certain extent exert side effects during application. Indocyanine green (ICG), as a fluorescent dye, has been proved reliable usage in SLN detection by several other groups. In this paper, we introduce a novel surgical navigation system to detect SLN with ICG. This system contains two charge-coupled devices (CCD) to simultaneously capture real-time color and fluorescent video images through two different bands. During surgery, surgeons only need to follow the fluorescence display. In addition, the system saves data automatically during surgery enabling surgeons to find the registration point easily according to image recognition algorithms. To test our system, 5 mice and 10 rabbits were used for the preclinical setting and 22 breast cancer patients were utilized for the clinical evaluation in our experiments. The detection rate was 100% and an average of 2.7 SLNs was found in 22 patients. Our results show that the usage of our surgical navigation system with ICG to detect SLNs in breast cancer patients is technically feasible.
doi:10.1371/journal.pone.0083927
PMCID: PMC3865279  PMID: 24358319
23.  Using Isotopic Tools to Dissect and Quantitate Parallel Metabolic Pathways 
Journal of the American Chemical Society  2010;132(18):10.1021/ja100399m.
4-hydroxyacids are ubiquitous in human physiology. They are derived from the drugs of abuse γ-hydroxybutyrate (GHB), γ-hydroxypentanoate(GHP), in addition to the omnipresent lipid peroxidation product 4-Hydroxy-2-(E)-nonenal (4-HNE). Previously we reported that 4-hydroxyacids are catabolized through two parallel pathways. In this report we detail two isotopic tools that have allowed the dissection of this catabolic process, and illustrate how these tools can be used to quantify the relative flux down each pathway. We found that 4-hydroxynonanoate (a 4-hydroxyacid derived from 4-HNE) is primarly catabolized through a pathway that phosphorylates the C-4 hydroxyl and isomerizes it to a C-3 hydroxy compound, which is catabolized through β-oxidation.
doi:10.1021/ja100399m
PMCID: PMC3830949  PMID: 20408520
24.  Cloudwave: Distributed Processing of “Big Data” from Electrophysiological Recordings for Epilepsy Clinical Research Using Hadoop 
Epilepsy is the most common serious neurological disorder affecting 50–60 million persons worldwide. Multi-modal electrophysiological data, such as electroencephalography (EEG) and electrocardiography (EKG), are central to effective patient care and clinical research in epilepsy. Electrophysiological data is an example of clinical “big data” consisting of more than 100 multi-channel signals with recordings from each patient generating 5–10GB of data. Current approaches to store and analyze signal data using standalone tools, such as Nihon Kohden neurology software, are inadequate to meet the growing volume of data and the need for supporting multi-center collaborative studies with real time and interactive access. We introduce the Cloudwave platform in this paper that features a Web-based intuitive signal analysis interface integrated with a Hadoop-based data processing module implemented on clinical data stored in a “private cloud”. Cloudwave has been developed as part of the National Institute of Neurological Disorders and Strokes (NINDS) funded multi-center Prevention and Risk Identification of SUDEP Mortality (PRISM) project. The Cloudwave visualization interface provides real-time rendering of multi-modal signals with “montages” for EEG feature characterization over 2TB of patient data generated at the Case University Hospital Epilepsy Monitoring Unit. Results from performance evaluation of the Cloudwave Hadoop data processing module demonstrate one order of magnitude improvement in performance over 77GB of patient data. (Cloudwave project: http://prism.case.edu/prism/index.php/Cloudwave)
PMCID: PMC3900211  PMID: 24551370
25.  Hypothalamic Programming of Systemic Aging Involving IKKβ/NF-κB and GnRH 
Nature  2013;497(7448):211-216.
Summary
Aging is a result of gradual and overall functional deteriorations across the body; however, it is unknown if an individual tissue works to primarily mediate aging progress and lifespan control. Here we found that the hypothalamus is important for the development of whole-body aging in mice, and the underlying basis involves hypothalamic immunity mediated by IKKβ/NF-κB and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and lifespan extension are achieved in mice through preventing against aging-related hypothalamic or brain IKKβ/NF-κB activation. Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.
doi:10.1038/nature12143
PMCID: PMC3756938  PMID: 23636330
Hypothalamus; aging; lifespan; longevity; NF-κ; IKKβ; GnRH; mice

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