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1.  Lead exposure in US worksites: A literature review and development of an occupational lead exposure database from the published literature 
Background
Retrospective exposure assessment of occupational lead exposure in population-based studies requires historical exposure information from many occupations and industries.
Methods
We reviewed published US exposure monitoring studies to identify lead exposure measurement data. We developed an occupational lead exposure database from the 175 identified papers containing 1,111 sets of lead concentration summary statistics (21% area air, 47% personal air, 32% blood). We also extracted ancillary exposure-related information, including job, industry, task/location, year collected, sampling strategy, control measures in place, and sampling and analytical methods.
Results
Measurements were published between 1940 and 2010 and represented 27 2-digit standardized industry classification codes. The majority of the measurements were related to lead-based paint work, joining or cutting metal using heat, primary and secondary metal manufacturing, and lead acid battery manufacturing.
Conclusions
This database can be used in future statistical analyses to characterize differences in lead exposure across time, jobs, and industries.
doi:10.1002/ajim.22448
PMCID: PMC4711746  PMID: 25968240
Lead; occupational exposure; exposure assessment; review; population-based studies
2.  Historical Occupational Trichloroethylene Air Concentrations Based on Inspection Measurements From Shanghai, China 
Annals of Occupational Hygiene  2014;59(1):62-78.
Purpose:
Trichloroethylene (TCE) is a carcinogen that has been linked to kidney cancer and possibly other cancer sites including non-Hodgkin lymphoma. Its use in China has increased since the early 1990s with China’s growing metal, electronic, and telecommunications industries. We examined historical occupational TCE air concentration patterns in a database of TCE inspection measurements collected in Shanghai, China to identify temporal trends and broad contrasts among occupations and industries.
Methods:
Using a database of 932 short-term, area TCE air inspection measurements collected in Shanghai worksites from 1968 through 2000 (median year 1986), we developed mixed-effects models to evaluate job-, industry-, and time-specific TCE air concentrations.
Results:
Models of TCE air concentrations from Shanghai work sites predicted that exposures decreased 5–10% per year between 1968 and 2000. Measurements collected near launderers and dry cleaners had the highest predicted geometric means (GM for 1986 = 150–190mg m−3). The majority (53%) of the measurements were collected in metal treatment jobs. In a model restricted to measurements in metal treatment jobs, predicted GMs for 1986 varied 35-fold across industries, from 11mg m−3 in ‘other metal products/repair’ industries to 390mg m–3 in ‘ships/aircrafts’ industries.
Conclusions:
TCE workplace air concentrations appeared to have dropped over time in Shanghai, China between 1968 and 2000. Understanding differences in TCE concentrations across time, occupations, and industries may assist future epidemiologic studies in China.
doi:10.1093/annhyg/meu066
PMCID: PMC4290627  PMID: 25180291
China; occupational exposures; population-based studies; statistical model; trichloroethylene
3.  Reliability and validity of expert assessment based on airborne and urinary measures of nickel and chromium exposure in the electroplating industry 
The reliability and validity of six experts’ exposure ratings were evaluated for 64 nickel-exposed and 72 chromium-exposed workers from six Shanghai electroplating plants based on airborne and urinary nickel and chromium measurements. Three industrial hygienists and three occupational physicians independently ranked the exposure intensity of each metal on an ordinal scale (1–4) for each worker's job in two rounds: the first round was based on responses to an occupational history questionnaire and the second round also included responses to an electroplating industry-specific questionnaire. Spearman correlation (rs) was used to compare each rating's validity to its corresponding subject-specific arithmetic mean of four airborne or four urinary measurements. Reliability was moderately-high (weighted kappa range=0.60–0.64). Validity was poor to moderate (rs= -0.37–0.46) for both airborne and urinary concentrations of both metals. For airborne nickel concentrations, validity differed by plant. For dichotomized metrics, sensitivity and specificity were higher based on urinary measurements (47–78%) than airborne measurements (16–50%). Few patterns were observed by metal, assessment round, or expert type. These results suggest that, for electroplating exposures, experts can achieve moderately-high agreement and (reasonably) distinguish between low and high exposures when reviewing responses to in-depth questionnaires used in population-based case-control studies.
doi:10.1038/jes.2014.22
PMCID: PMC4199939  PMID: 24736099
expert assessment; reliability; validity; nickel; chromium; electroplating industry
4.  Evaluating Temporal Trends from Occupational Lead Exposure Data Reported in the Published Literature Using Meta-Regression 
Annals of Occupational Hygiene  2014;58(9):1111-1125.
Objectives:
The published literature provides useful exposure measurements that can aid retrospective exposure assessment efforts, but the analysis of this data is challenging as it is usually reported as means, ranges, and measures of variability. We used mixed-effects meta-analysis regression models, which are commonly used to summarize health risks from multiple studies, to predict temporal trends of blood and air lead concentrations in multiple US industries from the published data while accounting for within- and between-study variability in exposure.
Methods:
We extracted the geometric mean (GM), geometric standard deviation (GSD), and number of measurements from journal articles reporting blood and personal air measurements from US worksites. When not reported, we derived the GM and GSD from other summary measures. Only industries with measurements in ≥2 time points and spanning ≥10 years were included in our analyses. Meta-regression models were developed separately for each industry and sample type. Each model used the log-transformed GM as the dependent variable and calendar year as the independent variable. It also incorporated a random intercept that weighted each study by a combination of the between- and within-study variances. The within-study variances were calculated as the squared log-transformed GSD divided by the number of measurements. Maximum likelihood estimation was used to obtain the regression parameters and between-study variances.
Results:
The blood measurement models predicted statistically significant declining trends of 2–11% per year in 8 of the 13 industries. The air measurement models predicted a statistically significant declining trend (3% per year) in only one of the seven industries; an increasing trend (7% per year) was also observed for one industry. Of the five industries that met our inclusion criteria for both air and blood, the exposure declines per year tended to be slightly greater based on blood measurements than on air measurements.
Conclusions:
Meta-analysis provides a useful tool for synthesizing occupational exposure data to examine exposure trends that can aid future retrospective exposure assessment. Data remained too sparse to account for other exposure predictors, such as job category or sampling strategy, but this limitation may be overcome by using additional data sources.
doi:10.1093/annhyg/meu061
PMCID: PMC4227532  PMID: 25193938
exposure; lead; meta-analysis; meta-regression; temporal trend
5.  Particulate Matter Exposure in a Police Station Located near a Highway 
People living or working near roadways have experienced an increase in cardiovascular or respiratory diseases due to vehicle emissions. Very few studies have focused on the PM exposure of highway police officers, particularly for the number concentration and size distribution of ultrafine particles (UFP). This study evaluated exposure concentrations of particulate matter (PM) in the Sinying police station near a highway located in Tainan, Taiwan, under different traffic volumes, traffic types, and shift times. We focused on periods when the wind blew from the highway toward the police station and when the wind speed was greater than or equal to 0.5 m/s. PM2.5, UFP, and PM-PAHs concentrations in the police station and an upwind reference station were measured. Results indicate that PM2.5, UFP, and PM-PAHs concentrations in the police station can be on average 1.13, 2.17, and 5.81 times more than the upwind reference station concentrations, respectively. The highest exposure level for PM2.5 and UFP was observed during the 12:00 PM–4:00 PM shift while the highest PAHs concentration was found in the 4:00 AM–8:00 AM shift. Thus, special attention needs to be given to protect police officers from exposure to high PM concentration.
doi:10.3390/ijerph121114541
PMCID: PMC4661666  PMID: 26580641
particulate matter; ultrafine particles; police station; highway
6.  VEGF, not VEGFR2, is associated with the angiogenesis effect of mini-TyrRS/mini-TrpRS in human umbilical vein endothelial cells in hypoxia 
Cytotechnology  2013;66(4):655-665.
The purpose of this study was to determine the relationship between VEGF and mini-TyrRS/mini-TrpRS in angiogenesis in hypoxic culture and to begin to comprehend their mechanism in angiogenesis. We designed a VEGF gene silencing assay by using lentivirus vectors, and then western blotting was used to determine the protein expression of VEGF, VEGFR2 and pVEGFR2 in three groups in hypoxic culture at 3, 6, 12, or 24 h: (1) untransfected human umbilical vein endothelial cells (HUVECs) (Control); (2) pGCSIL-GFP lentivirus vector-transduced HUVECs (Mock); and (3) pGCSIL-shVEGF lentivirus vector-transduced HUVECs (Experimental). We also detected the effects of mini-TyrRS/mini-TrpRS peptides on HUVEC proliferation, migration and tube formation after lentivirus vector transfection and VEGFR2 antibody injection. The results indicated that expression of the mini-TyrRS protein was increased, whereas that of mini-TrpRS was specifically decreased in hypoxic culture both in control and mock groups. However, this trend in protein levels of mini-TyrRS and mini-TrpRS was lost in the experimental group after transduction with the pGCSIL-shVEGF lentivirus vector. The protein expression of VEGF was increased in hypoxic culture both in control and mock groups. After transduction with the pGCSIL-shVEGF lentivirus vector, the protein level of VEGF was noticeably decreased in the experimental group; however, for VEGFR2, the results showed no significant difference in VEGFR2 protein expression in any of the groups. For pVEGFR2, we found a distinct trend from that seen with VEGF. The protein expression of pVEGFR2 was sharply increased in hypoxic culture in the three groups. The addition of mini-TyrRS significantly promoted proliferation, migration and tube formation of HUVECs, while mini-TrpRS inhibited these processes in both control and mock groups in hypoxic culture. However, these effects disappeared after transduction with the pGCSIL-shVEGF lentivirus vector in the experimental group, but no significant difference was observed after VEGFR2 antibody injection. The protein expression of VEGF is similar to that of mini-TyrRS in hypoxic culture and plays an important role in the mini-TyrRS/mini-TrpRS-stimulated proliferation, migration and tube formation of HUVECs in hypoxia. These results also suggest that the change in mini-TyrRS and mini-TrpRS expression in hypoxic culture is not related to VEGFR2 and that some other possible mechanisms, are involved in the phosphorylation of VEGFR2.
doi:10.1007/s10616-013-9619-6
PMCID: PMC4082773  PMID: 23896703
Mini-TyrRS; Mini-TrpRS; Angiogenesis; VEGF; VEGFR2; Hypoxia; HUVEC
7.  Systematically Extracting Metal- and Solvent-Related Occupational Information from Free-Text Responses to Lifetime Occupational History Questionnaires 
Annals of Occupational Hygiene  2014;58(5):612-624.
Objectives:
Lifetime occupational history (OH) questionnaires often use open-ended questions to capture detailed information about study participants’ jobs. Exposure assessors use this information, along with responses to job- and industry-specific questionnaires, to assign exposure estimates on a job-by-job basis. An alternative approach is to use information from the OH responses and the job- and industry-specific questionnaires to develop programmable decision rules for assigning exposures. As a first step in this process, we developed a systematic approach to extract the free-text OH responses and convert them into standardized variables that represented exposure scenarios.
Methods:
Our study population comprised 2408 subjects, reporting 11991 jobs, from a case–control study of renal cell carcinoma. Each subject completed a lifetime OH questionnaire that included verbatim responses, for each job, to open-ended questions including job title, main tasks and activities (task), tools and equipment used (tools), and chemicals and materials handled (chemicals). Based on a review of the literature, we identified exposure scenarios (occupations, industries, tasks/tools/chemicals) expected to involve possible exposure to chlorinated solvents, trichloroethylene (TCE) in particular, lead, and cadmium. We then used a SAS macro to review the information reported by study participants to identify jobs associated with each exposure scenario; this was done using previously coded standardized occupation and industry classification codes, and a priori lists of associated key words and phrases related to possibly exposed tasks, tools, and chemicals. Exposure variables representing the occupation, industry, and task/tool/chemicals exposure scenarios were added to the work history records of the study respondents. Our identification of possibly TCE-exposed scenarios in the OH responses was compared to an expert’s independently assigned probability ratings to evaluate whether we missed identifying possibly exposed jobs.
Results:
Our process added exposure variables for 52 occupation groups, 43 industry groups, and 46 task/tool/chemical scenarios to the data set of OH responses. Across all four agents, we identified possibly exposed task/tool/chemical exposure scenarios in 44–51% of the jobs in possibly exposed occupations. Possibly exposed task/tool/chemical exposure scenarios were found in a nontrivial 9–14% of the jobs not in possibly exposed occupations, suggesting that our process identified important information that would not be captured using occupation alone. Our extraction process was sensitive: for jobs where our extraction of OH responses identified no exposure scenarios and for which the sole source of information was the OH responses, only 0.1% were assessed as possibly exposed to TCE by the expert.
Conclusions:
Our systematic extraction of OH information found useful information in the task/chemicals/tools responses that was relatively easy to extract and that was not available from the occupational or industry information. The extracted variables can be used as inputs in the development of decision rules, especially for jobs where no additional information, such as job- and industry-specific questionnaires, is available.
doi:10.1093/annhyg/meu012
PMCID: PMC4053931  PMID: 24590110
cadmium; chlorinated solvents; exposure assessment methodology; lead
8.  Tackling the Cytotoxic Effect of a Marine Polycyclic Quinone-Type Metabolite: Halenaquinone Induces Molt 4 Cells Apoptosis via Oxidative Stress Combined with the Inhibition of HDAC and Topoisomerase Activities 
Marine Drugs  2015;13(5):3132-3153.
A marine polycyclic quinone-type metabolite, halenaquinone (HQ), was found to inhibit the proliferation of Molt 4, K562, MDA-MB-231 and DLD-1 cancer cell lines, with IC50 of 0.48, 0.18, 8.0 and 6.76 μg/mL, respectively. It exhibited the most potent activity against leukemia Molt 4 cells. Accumulating evidence showed that HQ may act as a potent protein kinase inhibitor in cancer therapy. To fully understand the mechanism of HQ, we further explored the precise molecular targets in leukemia Molt 4 cells. We found that the use of HQ increased apoptosis by 26.23%–70.27% and caused disruption of mitochondrial membrane potential (MMP) by 17.15%–53.25% in a dose-dependent manner, as demonstrated by Annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of Molt 4 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by HQ, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of HQ. The results of a cell-free system assay indicated that HQ could act as an HDAC and topoisomerase catalytic inhibitor through the inhibition of pan-HDAC and topoisomerase IIα expression, respectively. On the protein level, the expression of the anti-apoptotic proteins p-Akt, NFκB, HDAC and Bcl-2, as well as hexokinase II was inhibited by the use of HQ. On the other hand, the expression of the pro-apoptotic protein Bax, PARP cleavage, caspase activation and cytochrome c release were increased after HQ treatment. Taken together, our results suggested that the antileukemic effect of HQ is ROS-mediated mitochondrial apoptosis combined with the inhibitory effect on HDAC and topoisomerase activities.
doi:10.3390/md13053132
PMCID: PMC4446623  PMID: 26006712
halenaquinone; histone deacetylase (HDAC); mitochondria; reactive oxygen species (ROS); topoisomerase
9.  Hierarchical Clustering of Breast Cancer Methylomes Revealed Differentially Methylated and Expressed Breast Cancer Genes 
PLoS ONE  2015;10(2):e0118453.
Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs) and the hypomethylation of the megabase-sized partially methylated domains (PMDs) are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI) was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma) dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.
doi:10.1371/journal.pone.0118453
PMCID: PMC4338251  PMID: 25706888
10.  An Integrated Approach to Assess Exposure and Health-Risk from Polycyclic Aromatic Hydrocarbons (PAHs) in a Fastener Manufacturing Industry 
An integrated approach was developed to assess exposure and health-risk from polycyclic aromatic hydrocarbons (PAHs) contained in oil mists in a fastener manufacturing industry. One previously developed model and one new model were adopted for predicting oil mist exposure concentrations emitted from metal work fluid (MWF) and PAHs contained in MWF by using the fastener production rate (Pr) and cumulative fastener production rate (CPr) as predictors, respectively. By applying the annual Pr and CPr records to the above two models, long-term workplace PAH exposure concentrations were predicted. In addition, true exposure data was also collected from the field. The predicted and measured concentrations respectively served as the prior and likelihood distributions in the Bayesian decision analysis (BDA), and the resultant posterior distributions were used to determine the long-term exposure and health-risks posed on workers. Results show that long term exposures to PAHs would result in a 3.1%, 96.7%, and 73.4% chance of exceeding the PEL-TWA (0.2 mg/m3), action level (0.1 mg/m3), and acceptable health risk (10−3), respectively. In conclusion, preventive measures should be taken immediately to reduce workers’ PAH exposures.
doi:10.3390/ijerph110909578
PMCID: PMC4199036  PMID: 25226413
polycyclic aromatic hydrocarbons; oil mist; exposure assessment; health-risk assessment; metal work fluid
11.  Structure Elucidation and Cytotoxic Evaluation of New Polyacetylenes from a Marine Sponge Petrosia sp. 
The sponge Petrosia sp. yielded five polyacetylenic compounds (1–5), including two new polyacetylenes, petrosianynes A (1) and B (2). The structures of these compounds were elucidated by detailed spectroscopic analysis and by comparison with the physical and spectral data of related known analogues. Compounds 1–5 exhibited significant cytotoxic activity against a limited panel of cancer cell lines.
doi:10.3390/ijms150916511
PMCID: PMC4200862  PMID: 25238415
sponge; Petrosia; polyacetylene
12.  Higher blood pressure control rate in a real life management program provided by the community health service center in China 
BMC Public Health  2014;14:801.
Background
Community health service center (CHSC) in China is always regarded as a good facility of primary care, which plays an important role in chronic non-communicable disease management. This study aimed to investigate the blood pressure (BP) control rate in a real life CHSC-based management program and its determinants.
Methods
The study enrolled 3191 patients (mean age of 70 ± 10 years, 43% males) in a hypertension management program provided by the Yulin CHSC (Chengdu, China), which had been running for 9 years. Uncontrolled BP was defined as the systolic BP of ≥140 mmHg and/or the diastolic BP of ≥90 mmHg, and its associated factors were analyzed by using logistic regression.
Results
The duration of stay in the program was 33 ± 25 months. When compared with the BP at entry, the recent BP was significantly lowered (147 ± 17 vs. 133 ± 8 mmHg; 83 ± 11 vs. 75 ± 6 mmHg) and the BP control rate was dramatically increased (32 vs. 85%) (all p < 0.001). The age of >70 years [1.40 (odds ratio), 1.15-1.71 (95% confidence interval)], female gender (0.76, 0.63-0.93), longer stay of >33 months (0.77, 0.63-0.94), doctor in charge (0.97, 0.95-0.99), and the use of calcium channel blocker (1.35, 1.09-1.67) were significantly related to uncontrolled BP at the recent follow up (all p < 0.05).
Conclusions
This CHSC-run hypertension program provides an ideal platform of multi-intervention management, which is effective in achieving higher BP control rate in community patient population. However, the BP control status could be affected by age, gender and adherence of the patients, as well as practice behavior of the doctors.
doi:10.1186/1471-2458-14-801
PMCID: PMC4133080  PMID: 25098940
Hypertension; Blood pressure; Disease management; Public health; Community
13.  Comparison of Algorithm-based Estimates of Occupational Diesel Exhaust Exposure to Those of Multiple Independent Raters in a Population-based Case–Control Study 
Annals of Occupational Hygiene  2012;57(4):470-481.
Objectives:
Algorithm-based exposure assessments based on patterns in questionnaire responses and professional judgment can readily apply transparent exposure decision rules to thousands of jobs quickly. However, we need to better understand how algorithms compare to a one-by-one job review by an exposure assessor. We compared algorithm-based estimates of diesel exhaust exposure to those of three independent raters within the New England Bladder Cancer Study, a population-based case–control study, and identified conditions under which disparities occurred in the assessments of the algorithm and the raters.
Methods:
Occupational diesel exhaust exposure was assessed previously using an algorithm and a single rater for all 14 983 jobs reported by 2631 study participants during personal interviews conducted from 2001 to 2004. Two additional raters independently assessed a random subset of 324 jobs that were selected based on strata defined by the cross-tabulations of the algorithm and the first rater’s probability assessments for each job, oversampling their disagreements. The algorithm and each rater assessed the probability, intensity and frequency of occupational diesel exhaust exposure, as well as a confidence rating for each metric. Agreement among the raters, their aggregate rating (average of the three raters’ ratings) and the algorithm were evaluated using proportion of agreement, kappa and weighted kappa (κw). Agreement analyses on the subset used inverse probability weighting to extrapolate the subset to estimate agreement for all jobs. Classification and Regression Tree (CART) models were used to identify patterns in questionnaire responses that predicted disparities in exposure status (i.e., unexposed versus exposed) between the first rater and the algorithm-based estimates.
Results:
For the probability, intensity and frequency exposure metrics, moderate to moderately high agreement was observed among raters (κw = 0.50–0.76) and between the algorithm and the individual raters (κw = 0.58–0.81). For these metrics, the algorithm estimates had consistently higher agreement with the aggregate rating (κw = 0.82) than with the individual raters. For all metrics, the agreement between the algorithm and the aggregate ratings was highest for the unexposed category (90–93%) and was poor to moderate for the exposed categories (9–64%). Lower agreement was observed for jobs with a start year <1965 versus ≥1965. For the confidence metrics, the agreement was poor to moderate among raters (κw = 0.17–0.45) and between the algorithm and the individual raters (κw = 0.24–0.61). CART models identified patterns in the questionnaire responses that predicted a fair-to-moderate (33–89%) proportion of the disagreements between the raters’ and the algorithm estimates.
Discussion:
The agreement between any two raters was similar to the agreement between an algorithm-based approach and individual raters, providing additional support for using the more efficient and transparent algorithm-based approach. CART models identified some patterns in disagreements between the first rater and the algorithm. Given the absence of a gold standard for estimating exposure, these patterns can be reviewed by a team of exposure assessors to determine whether the algorithm should be revised for future studies.
doi:10.1093/annhyg/mes082
PMCID: PMC3629988  PMID: 23184256
case–control; diesel exhaust; expert judgement; exposure assessment
14.  Cracking the Cytotoxicity Code: Apoptotic Induction of 10-Acetylirciformonin B is Mediated through ROS Generation and Mitochondrial Dysfunction 
Marine Drugs  2014;12(5):3072-3090.
A marine furanoterpenoid derivative, 10-acetylirciformonin B (10AB), was found to inhibit the proliferation of leukemia, hepatoma, and colon cancer cell lines, with selective and significant potency against leukemia cells. It induced DNA damage and apoptosis in leukemia HL 60 cells. To fully understand the mechanism behind the 10AB apoptotic induction against HL 60 cells, we extended our previous findings and further explored the precise molecular targets of 10AB. We found that the use of 10AB increased apoptosis by 8.9%–87.6% and caused disruption of mitochondrial membrane potential (MMP) by 15.2%–95.2% in a dose-dependent manner, as demonstrated by annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of HL 60 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by 10AB, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of 10AB. The results of a cell-free system assay indicated that 10AB could act as a topoisomerase catalytic inhibitor through the inhibition of topoisomerase IIα. On the protein level, the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, caspase inhibitors XIAP and survivin, as well as hexokinase II were inhibited by the use of 10AB. On the other hand, the expression of the pro-apoptotic protein Bax was increased after 10AB treatment. Taken together, our results suggest that 10AB-induced apoptosis is mediated through the overproduction of ROS and the disruption of mitochondrial metabolism.
doi:10.3390/md12053072
PMCID: PMC4052332  PMID: 24857964
10-acetylirciformonin B; apoptosis; hexokinase; mitochondria; reactive oxygen species (ROS); topoisomerase
15.  Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway 
Marine Drugs  2013;11(9):3168-3185.
A dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway.
doi:10.3390/md11093168
PMCID: PMC3801119  PMID: 24065159
apoptosis; dibromotyrosine; mitochondrial dysfunction; oxidative stress; topoisomerase
16.  A fusion protein composed of receptor binding domain of vascular endothelial growth factor-A and constant region fragment of antibody: angiogenesis antagonistic activity 
Cytotechnology  2011;63(3):285-293.
Vascular endothelial growth factor (VEGF) promotes the growth of solid tumor mainly via VEGF receptor-1 and receptor-2, which are expressed preferentially in proliferating endothelial cells. Therefore, a strategy for simultaneous blockage of both VEGF receptors may have a useful therapeutic effect in tumor growth. In this study, we utilized a fusion protein which is composed of receptor binding domain of VEGF-A (RBDV) and the constant region fragment (Fc) of a human immunoglobulin G1 (IgG1), to interfere with the growth of human umbilical vein endothelial cells (HUVECs) via VEGF receptors. The results showed that RBDV-IgG1 Fc was able to bind with both VEGF receptor-1 and receptor-2. In addition, RBDV-IgG1 Fc could decrease VEGF-induced proliferation and tube formation among HUVECs. Moreover, the cytotoxic test showed RBDV-IgG1 Fc could also enhance the cytotoxic activity of human natural killing cells. The data are suggesting that the fusion protein, RBDV-IgG1 Fc, may have potential as an angiogenesis antagonist for future tumor therapy.
doi:10.1007/s10616-011-9340-2
PMCID: PMC3081053  PMID: 21461946
Vascular endothelial growth factor; Receptor binding domain of VEGF-A; Immunoglobulin; Fusion protein; Human umbilical vein endothelial cells
17.  Enhancement of anti-murine colon cancer immunity by fusion of a SARS fragment to a low-immunogenic carcinoembryonic antigen 
Background
It is widely understood that tumor cells express tumor-associated antigens (TAAs), of which many are usually in low immunogenicity; for example, carcinoembryonic antigen (CEA) is specifically expressed on human colon cancer cells and is viewed as a low-immunogenic TAA. How to activate host immunity against specific TAAs and to suppress tumor growth therefore becomes important in cancer therapy development.
Results
To enhance the immune efficiency of CEA in mice that received, we fused a partial CEA gene with exogenous SARS-CoV fragments. Oral vaccination of an attenuated Salmonella typhimurium strain transformed with plasmids encoding CEA-SARS-CoV fusion gene into BALB/c mice elicited significant increases in TNF-α and IL-10 in the serum. In addition, a smaller tumor volume was observed in CT26/CEA-bearing mice who received CEA-SARS-CoV gene therapy in comparison with those administered CEA alone.
Conclusion
The administration of fusing CEA-SARS-CoV fragments may provide a promising strategy for strengthening the anti-tumor efficacy against low-immunogenic endogenous tumor antigens.
doi:10.1186/1480-9222-14-2
PMCID: PMC3298716  PMID: 22304896
immunotherapy; tumor-derived peptide; tumor vaccine; low-immunogenicity
18.  Anodic Aluminum Oxide Membrane-Assisted Fabrication of β-In2S3 Nanowires 
Nanoscale Research Letters  2009;4(9):1059-1063.
In this study, β-In2S3 nanowires were first synthesized by sulfurizing the pure Indium (In) nanowires in an AAO membrane. As FE-SEM results, β-In2S3 nanowires are highly ordered, arranged tightly corresponding to the high porosity of the AAO membrane used. The diameter of the β-In2S3 nanowires is about 60 nm with the length of about 6–8 μm. Moreover, the aspect ratio of β-In2S3 nanowires is up to 117. An EDS analysis revealed the β-In2S3 nanowires with an atomic ratio of nearly S/In = 1.5. X-ray diffraction and corresponding selected area electron diffraction patterns demonstrated that the β-In2S3 nanowire is tetragonal polycrystalline. The direct band gap energy (Eg) is 2.40 eV from the optical measurement, and it is reasonable with literature.
doi:10.1007/s11671-009-9357-z
PMCID: PMC2894172  PMID: 20596400
Nanomaterials; In2S3; Nanowire; AAO
19.  Anodic Aluminum Oxide Membrane-Assisted Fabrication of β-In2S3Nanowires 
Nanoscale Research Letters  2009;4(9):1059-1063.
In this study, β-In2S3nanowires were first synthesized by sulfurizing the pure Indium (In) nanowires in an AAO membrane. As FE-SEM results, β-In2S3nanowires are highly ordered, arranged tightly corresponding to the high porosity of the AAO membrane used. The diameter of the β-In2S3nanowires is about 60 nm with the length of about 6–8 μm. Moreover, the aspect ratio of β-In2S3nanowires is up to 117. An EDS analysis revealed the β-In2S3nanowires with an atomic ratio of nearly S/In = 1.5. X-ray diffraction and corresponding selected area electron diffraction patterns demonstrated that the β-In2S3nanowire is tetragonal polycrystalline. The direct band gap energy (Eg) is 2.40 eV from the optical measurement, and it is reasonable with literature.
doi:10.1007/s11671-009-9357-z
PMCID: PMC2894172  PMID: 20596400
Nanomaterials; In2S3; Nanowire; AAO
20.  Synthesis and Characterization of Tin Disulfide (SnS2) Nanowires 
Nanoscale Research Letters  2009;4(7):694-698.
The ordered tin disulfide (SnS2) nanowire arrays were first fabricated by sulfurizing the Sn nanowires, which are embedded in the nanochannels of anodic aluminum oxide (AAO) template. SnS2 nanowire arrays are highly ordered and highly dense. X-ray diffraction (XRD) and corresponding selected area electron diffraction (SAED) patterns demonstrate the SnS2 nanowire is hexagonal polycrystalline. The study of UV/Visible/NIR absorption shows the SnS2 nanowire is a wide-band semiconductor with three band gap energies (3.3, 4.4, and 5.8 eV).
doi:10.1007/s11671-009-9299-5
PMCID: PMC2894233  PMID: 20596366
Nanomaterials; SnS2; Nanowire; AAO; Template
21.  Synthesis and Characterization of Tin Disulfide (SnS2) Nanowires 
Nanoscale Research Letters  2009;4(7):694-698.
The ordered tin disulfide (SnS2) nanowire arrays were first fabricated by sulfurizing the Sn nanowires, which are embedded in the nanochannels of anodic aluminum oxide (AAO) template. SnS2nanowire arrays are highly ordered and highly dense. X-ray diffraction (XRD) and corresponding selected area electron diffraction (SAED) patterns demonstrate the SnS2nanowire is hexagonal polycrystalline. The study of UV/Visible/NIR absorption shows the SnS2nanowire is a wide-band semiconductor with three band gap energies (3.3, 4.4, and 5.8 eV).
doi:10.1007/s11671-009-9299-5
PMCID: PMC2894233  PMID: 20596366
Nanomaterials; SnS2; Nanowire; AAO; Template
22.  Small interfering RNA knockdown of mini-TyrRS and mini-TrpRS effects angiogenesis in human umbilical vein endothelial cells in hypoxic culture 
Cytotechnology  2008;56(3):219-231.
Aim We studied the role of mini-TyrRS and mini-TrpRS in angiogenesis by using small interfering RNA-mediated mini-TyrRS/mini-TrpRS knockout in hypoxic culture of human umbilical vein endothelial cells. Methods SiRNA was used as the main method to inhibited the gene function. Silencing efficiency was assayed by real-time reverse transcription-polymerase chain reaction and western blotting. The angiogenic activity in vitro was evaluated by transwell migration assay and Matrigel-induced capillary tube formation in hypoxic culture. Cell proliferation was determined by crystal violet staining. Results The results showed that levels of the mini-TyrRS/mini-TrpRS gene and protein in mock transfection group and negative control group were higher, but noticeably decreased in experimental group. However, no significant difference was detected between mock transfection group and negative control group, but there was a statistically significant difference compared with experimental group. For mini-TyrRS-siRNA group, the cell migration, tube formation and the rate of cell proliferation were respectively inhibited by (47.4, 56.3, 65.4, 73.7%), (60.5, 69.1, 75.9, 83.6%) and (40.4, 56.2, 61.2, 68.0%). For mini-TrpRS-siRNA, were respectively increased by (18.0, 33.8, 45.1, 56.4%), (18.3, 31.2, 40.3, 45.7%) and (8.4, 26.4, 38.2, 46.6%). Conclusion These results indicated that angiogenesis is either stimulated by mini-TyrRS or inhibited by mini-TrpRS in matrigel models in hypoxic culture, raising the possibility that mini-TyrRS stimulates a common downstream signaling event. Thus, naturally occurring fragments of two proteins involved in translation, TyrRS and TrpRS, have opposing activity on endothelial cell angiogenesis in the matrigel assays. The opposing activities of the two tRNA synthetases suggest tight regulation of the balance between pro- and anti-angiogenic stimuli.
doi:10.1007/s10616-008-9151-2
PMCID: PMC2553632  PMID: 19002860
Mini-TyrRS; Mini-TrpRS; Hypoxia; Human umbilical vein endothelial cells; siRNA; Angiogenesis
23.  R497K polymorphism in epidermal growth factor receptor gene is associated with the risk of acute coronary syndrome 
BMC Medical Genetics  2008;9:74.
Background
Previous studies suggested that genetic polymorphisms in the epidermal growth factor receptor (EGFR) gene had been implicated in the susceptibility to some tumors and inflammatory diseases. EGFR has been recently implicated in vascular pathophysiological processes associated with excessive remodeling and atherosclerosis. Acute coronary syndrome (ACS) is a clinical manifestation of preceding atherosclerosis. Our purpose was to investigate the association of the EGFR polymorphism with the risk of ACS. In this context, we analyzed the HER-1 R497K and EGFR intron 1 (CA)n repeat polymorphisms in 191 patients with ACS and 210 age- and sex-matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and direct sequencing.
Results
There were significant differences in the genotype and allele distribution of R497K polymorphism of the EGFR gene between cases and controls. The Lys allele had a significantly increased risk of ACS compared with the Arg allele (adjusted OR = 1.49, 95% CI: 1.12–1.98, adjusted P = 0.006). However, no significant relationship between the number of (CA)n repeats of EGFR intron 1 (both alleles < 20 or any allele ≥ 20) and the risk of ACS was observed (adjusted OR = 0.97, 95% CI: 0.58–1.64, adjusted P = 0.911). Considering these two polymorphisms together, there was no statistically significant difference between the two groups.
Conclusion
R497K polymorphism of the EGFR gene is significantly associated with the risk of ACS. Our data suggests that R497K polymorphism may be used as a genetic susceptibility marker of the ACS.
doi:10.1186/1471-2350-9-74
PMCID: PMC2515827  PMID: 18664296

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