PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (637)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
2.  Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia 
Hosgood, H. Dean | Wang, Wen-Chang | Hong, Yun-Chul | Wang, Jiu-Cun | Chen, Kexin | Chang, I-Shou | Chen, Chien-Jen | Lu, Daru | Yin, Zhihua | Wu, Chen | Zheng, Wei | Qian, Biyun | Park, Jae Yong | Kim, Yeul Hong | Chatterjee, Nilanjan | Chen, Ying | Chang, Gee-Chen | Hsiao, Chin-Fu | Yeager, Meredith | Tsai, Ying-Huang | Wei, Hu | Kim, Young Tae | Wu, Wei | Zhao, Zhenhong | Chow, Wong-Ho | Zhu, Xiaoling | Lo, Yen-Li | Sung, Sook Whan | Chen, Kuan-Yu | Yuenger, Jeff | Kim, Joo Hyun | Huang, Liming | Chen, Ying-Hsiang | Gao, Yu-Tang | Kim, Jin Hee | Huang, Ming-Shyan | Jung, Tae Hoon | Caporaso, Neil | Zhao, Xueying | Huan, Zhang | Yu, Dianke | Kim, Chang Ho | Su, Wu-Chou | Shu, Xiao-Ou | Kim, In-San | Bassig, Bryan | Chen, Yuh-Min | Cha, Sung Ick | Tan, Wen | Chen, Hongyan | Yang, Tsung-Ying | Sung, Jae Sook | Wang, Chih-Liang | Li, Xuelian | Park, Kyong Hwa | Yu, Chong-Jen | Ryu, Jeong-Seon | Xiang, Yongbing | Hutchinson, Amy | Kim, Jun Suk | Cai, Qiuyin | Landi, Maria Teresa | Lee, Kyoung-Mu | Hung, Jen-Yu | Park, Ju-Yeon | Tucker, Margaret | Lin, Chien-Chung | Ren, Yangwu | Perng, Reury-Perng | Chen, Chih-Yi | Jin, Li | Chen, Kun-Chieh | Li, Yao-Jen | Chiu, Yu-Fang | Tsai, Fang-Yu | Yang, Pan-Chyr | Fraumeni, Joseph F. | Seow, Adeline | Lin, Dongxin | Zhou, Baosen | Chanock, Stephen | Hsiung, Chao Agnes | Rothman, Nathaniel | Lan, Qing
Human genetics  2012;131(7):10.1007/s00439-012-1144-8.
A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10−12); however, this association did not achieve genome-wide significance (p < 10−7) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
doi:10.1007/s00439-012-1144-8
PMCID: PMC3875137  PMID: 22367405
3.  Antigenic Divergence of Bordetella pertussis Isolates in Taiwan 
Journal of Clinical Microbiology  2005;43(11):5457-5461.
In recent studies, antigenic divergence has been observed in Bordetella pertussis circulating isolates. We collected 80 Bordetella pertussis isolates in Taiwan from 1998 to 2004 and analyzed them using a combination of pulsed-field gel electrophoresis (PFGE) and sequencing of the ptxS1 and prn genes. The incidence of pertussis increases every 3 years, and most of the isolates prevalent since 1998 have expressed nonvaccine ptxS1A and prn2 alleles. Through PFGE analysis, all isolates could be classified into four major groups, and the incidence of these groups exhibited a correlation with the prn allele expressed by the isolates. We found that PFGE is more discriminative than gene sequencing, since it could divide the isolates expressing the prn2 allele into two groups: one group circulating from 1998 to 2001 and another group circulating from 2001 to 2004. The transition between the two groups in 2000 coincided with an outbreak of 326 cases. This research indicates that the antigenic divergence of B. pertussis circulating isolates has evolved over time in Taiwan. Such information will have implications for vaccine policy in Taiwan.
doi:10.1128/JCM.43.11.5457-5461.2005
PMCID: PMC1287815  PMID: 16272470
4.  MTA1 and MTA3 Regulate HIF1a Expression in Hypoxia-Treated Human Trophoblast Cell Line HTR8/Svneo 
Hypoxia plays an important role in placental trophoblast differentiation and function during early pregnancy. Hypoxia-inducible factor 1 alpha (HIF1a) is known to regulate cellular adaption to hypoxic conditions. However, our current understanding of the role of HIF1a in trophoblast physiology is far from complete. Metastasis Associated Protein 1 and 3 (MTA1 and MTA3) are components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin remodeling complex, and are highly expressed in term placental trophoblasts. However, the role of MTA1 and MTA3 in the hypoxic placental environment of early pregnancy is unknown. In the present study, we examined the association among MTA1, MTA3 and HIF1a expression under hypoxic conditions in trophoblasts both in vivo and in vitro. We first investigated the localization of MTA1 and MTA3 with HIF1a expression in the placental trophoblast of 1st trimester placenta via immunohistochemistry. Our data reveals that under physiologically hypoxic environment, MTA1 and MTA3 along with HIF1a are highly expressed by villous trophoblasts. Next, we investigated the effect of hypoxia on these genes in vitro using the first trimester-derived HTR8/SVneo cell line and observed up-regulation of MTA1 and MTA3 as well as HIF1a protein following hypoxia treatment. To investigate the direct effect of MTA1 and MTA3 upon HIF1a, we over-expressed MTA1 and MTA3 genes in HTR8/SVneo cells respectively and examined protein levels of HIF1a via Western blot as well as HIF1a target gene expression using a luciferase assay driven by a hypoxia-response element promoter (HRE-luciferase). We found that over-expressions of MTA1 and MTA3 up-regulate both HIF1a protein level and HRE-luciferase activity under hypoxic condition. In summary, both MTA1 and MTA3 are induced by hypoxia and up-regulate HIF1a expression and HIF1a target gene expression in trophoblasts. These data suggest that MTA1 and MTA3 play critical roles in trophoblast function and differentiation during early pregnancy.
PMCID: PMC4332396
Chromatin remodeling; Trophoblast; Hypoxia
5.  The NFKB1 polymorphism (rs4648068) is associated with the cell proliferation and motility in gastric cancer 
BMC Gastroenterology  2015;15:21.
Background
We have demonstrated previously that NFKB1 single nucleotide polymorphism (SNP) rs4648068 GG homozygote was associated with the increased risk of gastric cancer in Chinese Han population. In this study, we constructed the recombinant plasmid pGL3-AA, pGL3-GG, pGL3-AA-NFKB and pGL3-GG-NFKB to investigate the function of rs4648068 by cell biology experiments.
Methods
Quantitative real-time PCR was used to detect NFKB1 SNP rs4648068 genotype in the patients with gastric cancer. Anti-NF-κB1 p50 polyclonal antibodies were used for immunohistochemical analysis of the tissue specimens. The subsection of NFKB1 containing the promoter site and adjacent three consecutive exons were obtained by PCR technique and subcloned into the vector pGL3-Basic. Dual-Luciferase reporter assay was used to detect the transcriptional activity of the constructed promoter. Effects of transcription factor NFKB1 on C/EBPβ expression were determined by chromatin immunoprecipitation and Western analysis. Furthermore, proliferation and invasion ability of the transduced cell were also measured and compared.
Results
Intensive staining for p50 expression was observed in the tissues of GG genotype patients, compared with those of GA group and AA genotype patients. The transcriptional activity of rs4648068 (A > G) by dual-Luciferase reporter assay suggested that the luciferase activity of homozygote group (pGL3-GG) was greater than that of the control (pGL3-AA), especially at the stimulation of LPS. We found that the luciferase activity was also influenced by pGL3-GG levels. The effects of NFKB1 rs4648068 were enhanced by rs4648065 on the transduced cells. The interaction between NFKB1 promoter nucleotide sequence and C/EBPβ was regulated by the functional SNP rs4648068 in SGC-7901 cells. Our data indicated that the transduction of pGL3 expression plasmid pGL3-GG-NFKB improved the proliferation and motility of gastric cancer cells. Correspondingly, the homozygote GG of SNP rs4648068 strengthened the transcriptional activity of NFKB1 and influenced the cell biological activity.
Conclusion
The transcriptional activity of NFKB1 was associated with SNP rs4648068, and this functional SNP site has the important effects on cell proliferation and motility.
doi:10.1186/s12876-015-0243-0
PMCID: PMC4331381
NFKB1; Polymorphism; Gastric cancer; Susceptibility; Single nucleotide polymorphism
6.  Unequally Distributed Psychological Assets: Are There Social Disparities in Optimism, Life Satisfaction, and Positive Affect? 
PLoS ONE  2015;10(2):e0118066.
Socioeconomic status is associated with health disparities, but underlying psychosocial mechanisms have not been fully identified. Dispositional optimism may be a psychosocial process linking socioeconomic status with health. We hypothesized that lower optimism would be associated with greater social disadvantage and poorer social mobility. We also investigated whether life satisfaction and positive affect showed similar patterns. Participants from the Midlife in the United States study self-reported their optimism, satisfaction, positive affect, and socioeconomic status (gender, race/ethnicity, education, occupational class and prestige, income). Social disparities in optimism were evident. Optimistic individuals tended to be white and highly educated, had an educated parent, belonged to higher occupational classes with more prestige, and had higher incomes. Findings were generally similar for satisfaction, but not positive affect. Greater optimism and satisfaction were also associated with educational achievement across generations. Optimism and life satisfaction are consistently linked with socioeconomic advantage and may be one conduit by which social disparities influence health.
doi:10.1371/journal.pone.0118066
PMCID: PMC4324648  PMID: 25671665
7.  Transgenic Mouse Models for Alcohol Metabolism, Toxicity and Cancer 
Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol metabolizing enzymes and GSH synthesizing enzymes and their relevance to alcohol research.
doi:10.1007/978-3-319-09614-8_22
PMCID: PMC4323349  PMID: 25427919
8.  Optimal Optic Nerve Sheath Diameter Threshold for the Identification of Elevated Opening Pressure on Lumbar Puncture in a Chinese Population 
PLoS ONE  2015;10(2):e0117939.
Ultrasonography of the optic nerve sheath diameter (ONSD) is a non-invasive and rapid method that might be helpful in the identification of increased intracranial pressure (ICP). The use of an ONSD greater than 5 mm on ultrasound as an indicator of increased ICP in a Caucasian population has been studied. However, the cut-off point of this predictor in Chinese patients has not been established. Thus, we conducted this study to identify the ONSD criterion for the detection of elevated opening pressure on lumbar puncture (LP) in a Chinese population and to investigate the influencing factors. This study was a blind cross-sectional study. Patients who presented with suspected increased ICP were included. The opening pressure on LP of each participant was confirmed. We analyzed the clinical differences between the groups of patients with abnormal and normal opening pressures on LP. A receiver operating characteristic curve was constructed to determine the ONSD cut-off point for the identification of abnormal opening pressure on LP. In total, 279 patients were recruited, and 101 patients presented with elevated opening pressure on LP. ONSD was a significant independent predictor of elevated opening pressure on LP (p<0.001). However, no statistical significance was observed regarding the factors that might have affected this relationship including gender, age, body mass index, waistline, head circumference, hypertension and pathological subtype. The ONSD cut-off point for the identification of elevated opening pressure on LP was 4.1 mm; this cut-off yielded a sensitivity of 95% and a specificity of 92%. ONSD is a strong and accurate predictor of elevated opening pressure on LP. The cut-off point of this predictor in a Chinese population was remarkably lower than that found in a Caucasian population. Thus, ethnic differences should be noted when using the ONSD as an indicator of increased ICP.
doi:10.1371/journal.pone.0117939
PMCID: PMC4322040  PMID: 25664663
9.  GATA Transcription Factors in Pregnancy 
GATA transcription factors are Zinc finger members which perform a variety of important functions within the 3-germ layers as well as in extra embryonic endoderm during embryonic development. Distinct roles for GATA transcription factors have previously been identified in hematopoietic, the cardiac vascular system, the central neural system, as well as respiratory and intestinal systems. However, the role of GATA transcription factors in trophoblast lineage and placental development is far more complete. This review focuses on the roles of GATA transcription factors during pregnancy: the establishment of trophoblast lineage, trophoectoderm maintenance, trophoblast differentiation and the pathogenesis of placenta-related diseases of pregnancy.
PMCID: PMC4319706
GATA transcription factors; Trophoblast; Pregnancy
10.  Emergence of human-like H3N2 influenza viruses in pet dogs in Guangxi, China 
Virology Journal  2015;12:10.
Background
After the 1968 H3N2 pandemic emerged in humans, H3N2 influenza viruses continuously circulated and evolved in nature. An H3N2 variant was circulating in humans in the 1990s and subsequently introduced into the pig population in the 2000s. This virus gradually became the main subtype of swine influenza virus worldwide. However, there were no reports of infections in dogs with this virus.
Findings
In 2013, 35 nasal swabs from pet dogs were positive for Influenza A virus by RT-PCR. Two viruses were isolated and genetically characterized. In the phylogenetic trees of all gene segments, two H3N2 canine isolates clustered with Moscow/10/99 and most H3N2 swine influenza viruses. These results indicated that two H3N2 CIVs possessed high homology with human/swine influenza viruses, which at the same time exhibited some amino acid substitutions in NA, polymerase basic protein 1 (PB1), and nucleoprotein (NP), which probably were related to the interspecies transmission.
Conclusions
These two viruses share the highest homology with swine H3N2, Moscow/99-like viruses, which indicated that these viruses might originate from swine viruses.
doi:10.1186/s12985-015-0243-2
PMCID: PMC4324672  PMID: 25645259
Pet dogs; H3N2 subtype; Human-like influenza viruses
11.  Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Involved in Inflammation by Negatively Regulating the NF-κB Pathway 
Scientific Reports  2015;5:8133.
Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.
doi:10.1038/srep08133
PMCID: PMC4313098  PMID: 25640174
12.  The Role of CYP2E1 in Alcohol Metabolism and Sensitivity in the Central Nervous System 
Sub-cellular biochemistry  2013;67:235-247.
Ethanol consumption has effects on the central nervous system (CNS), manifesting as motor incoordination, sleep induction (hypnosis), anxiety, amnesia, and the reinforcement or aversion of alcohol consumption. Acetaldehyde (the direct metabolite of ethanol oxidation) contributes to many aspects of the behavioral effects of ethanol. Given acetaldehyde cannot pass through the blood brain barrier, its concentration in the CNS is primarily determined by local production from ethanol. Catalase and cytochrome P450 2E1(CYP2E1) represent the major enzymes in the CNS that catalyze ethanol oxidation. CYP2E1 is expressed abundantly within the microsomes of certain brain cells and is localized to particular brain regions. This chapter focuses on the discussion of CYP2E1 in ethanol metabolism in the CNS, covering topics including how it is regulated, where it is expressed and how it influences sensitivity to ethanol in the brain.
doi:10.1007/978-94-007-5881-0_8
PMCID: PMC4314297  PMID: 23400924
13.  The Clinical Significance and Risk Factors of Solitary Lymph Node Metastasis in Gastric Cancer 
PLoS ONE  2015;10(1):e0114939.
Aims
To assess the clinical significance and risk factors of solitary lymph node metastasis (SLM) in gastric carcinoma and establish a more accurate method to evaluate the possibility of lymph node metastasis (LM).
Methods
A total of 385 patients with gastric carcinoma who underwent D2 lymphadenectomy at the Cancer Center of Sun Yat-Sen University were included in this research. Then we used a group of data from Sun Yat-sen University Gastrointestinal Hospital (SYSUGIH) to validate the accuracy of our developed method. The χ2 test, Kaplan–Meier analysis, log-rank test, COX model, and discriminate analysis were used to analyze the data with SPSS13.0.
Results
We found that the LM number and pathological T staging were independent prognostic risk factors. CEA grading, LN status by CT, and T staging by CT were independent risk factors for LM in gastric carcinoma. In addition, we developed the equation Y = -5.0 + X1 + 1.8X3 + 0.7X4 (X1 = CEA grading, X3 = LN status by CT, X4 = T staging by CT) to evaluate the situation of LM. The data from SYSUGIH shows this equation has a better accuracy compared with CT.
Conclusions
SLM is an independent risk factor in gastric cancer. And there was no survival difference between the skip metastasis group and the other SLM group (P = 0.659). It is inappropriate for the patient with SLM doing a standard D2 lymphadenectomy, due to the fact that LM rarely occurs in the splenic artery, splenic hilum. The risk factors for LM include CEA grading, LN status by CT, and T staging by CT. And we can use Y = -5.0 + X1 + 1.8X3 + 0.7X4 (X1, CEA grading, X3 = LN status by CT, X4 = T staging by CT, the critical value is 0.3) to estimate the possibility of LM, which has a better accuracy compared with CT.
doi:10.1371/journal.pone.0114939
PMCID: PMC4310611  PMID: 25633364
14.  Complete Genome Sequence of Vibrio alginolyticus ATCC 17749T 
Genome Announcements  2015;3(1):e01500-14.
Vibrio alginolyticus is a Gram-negative halophilic bacterium and has been recognized as an opportunistic pathogen in both humans and marine animals. It is the causative agent of food-borne diseases, such as gastroenteritis, and it invades through wounds in predisposed individuals. In this study, we present the completed genome of V. alginolyticus ATCC 17749T through high-throughput sequencing.
doi:10.1128/genomeA.01500-14
PMCID: PMC4319515  PMID: 25635021
15.  Application of the C3-Binding Motif of Streptococcal Pyrogenic Exotoxin B to Protect Mice from Invasive Group A Streptococcal Infection 
PLoS ONE  2015;10(1):e0117268.
Group A streptococcus (GAS) is an important human pathogen that produces several extracellular exotoxins to facilitate invasion and infection. Streptococcal pyrogenic exotoxin B (SPE B) has been demonstrated to be an important virulence factor of GAS. Our previous studies indicate that SPE B cleaves complement 3 (C3) and inhibits the activation of complement pathways. In this study, we constructed and expressed recombinant fragments of SPE B to examine the C3-binding site of SPE B. Using enzyme-linked immunosorbent assays and pull-down assays, we found that the C-terminal domain, containing amino-acid residues 345–398, of SPE B was the major binding site of human serum C3. We further identified a major, Ala376-Pro398, and a minor C3-binding motif, Gly346-Gly360, that both mediated the binding of C3 complement. Immunization with the C3-binding motifs protected mice against challenge with a lethal dose of non-invasive M49 strain GAS but not invasive M1 strains. To achieve higher efficiency against invasive M1 GAS infection, a combination of synthetic peptides derived from C-terminal epitope of streptolysin S (SLSpp) and from the major C3-binding motif of SPE B (PP6, Ala376-Pro398) was used to elicit specific immune response to those two important streptococcal exotoxins. Death rates and the severity of skin lesions decreased significantly in PP6/SLSpp-immunized mice that were infected with invasive M1 strains of GAS. These results indicate a combination of the C3-binding motif of SPE B and the protective epitope of SLS could be used as a subunit vaccine against invasive M1 strains group A streptococcal infection.
doi:10.1371/journal.pone.0117268
PMCID: PMC4309557  PMID: 25629609
16.  Multivariate analysis of risk factors for predicting supplementary posterior instrumentation after anterolateral decompression and instrumentation in treating thoracolumbar burst fractures 
Background
Although anterolateral decompression and instrumentation has several advantages in treating thoracolumbar burst fractures, the risk factors for supplementary posterior instrumentation are still unclear.
Methods
We retrospectively reviewed 238 patients who underwent anterolateral decompression and instrumentation for single-level thoracolumbar burst fractures from January 2010 and March 2012. The influences of several potential risk factors that might affect supplementary posterior instrumentation were assessed using univariate and multivariate analyses.
Results
Twenty seven patients who developed worsening back pain without neurological deterioration after the anterolateral approach treatment need further posterior instrumentation fixation. The univariate analysis showed that age, disruption of the posterior longitudinal ligament complex (PLC), and fracture level were the risk factors for supplementary posterior instrumentation. However, age and integrity of the PLC were the independent risk factors for supplementary posterior instrumentation by multivariate analyses.
Conclusions
Supplemental posterior instrumentation was necessary in 11.3% of cases following anterolateral decompression and instrumentation in the present study. Older age and disruption of the PLC were the independent risk factors in prediction of supplementary posterior instrumentation in treating thoracolumbar burst fractures.
doi:10.1186/s13018-015-0155-2
PMCID: PMC4314733  PMID: 25627918
Thoracolumbar burst fracture; Anterolateral decompression; Posterior instrumentation; Multivariate analysis; Risk factors
17.  Swelling/Floating Capability and Drug Release Characterizations of Gastroretentive Drug Delivery System Based on a Combination of Hydroxyethyl Cellulose and Sodium Carboxymethyl Cellulose 
PLoS ONE  2015;10(1):e0116914.
The aim of this study was to characterize the swelling and floating behaviors of gastroretentive drug delivery system (GRDDS) composed of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) and to optimize HEC/NaCMC GRDDS to incorporate three model drugs with different solubilities (metformin, ciprofloxacin, and esomeprazole). Various ratios of NaCMC to HEC were formulated, and their swelling and floating behaviors were characterized. Influences of media containing various NaCl concentrations on the swelling and floating behaviors and drug solubility were also characterized. Finally, release profiles of the three model drugs from GRDDS formulation (F1-4) and formulation (F1-1) were examined. Results demonstrated when the GRDDS tablets were tested in simulated gastric solution, the degree of swelling at 6 h was decreased for each formulation that contained NaCMC in comparison to those in de-ionized water (DIW). Of note, floating duration was enhanced when in simulated gastric solution compared to DIW. Further, the hydration of tablets was found to be retarded as the NaCl concentration in the medium increased resulting in smaller gel layers and swelling sizes. Dissolution profiles of the three model drugs in media containing various concentrations of NaCl showed that the addition of NaCl to the media affected the solubility of the drugs, and also their gelling behaviors, resulting in different mechanisms for controlling a drug’s release. The release mechanism of the freely water-soluble drug, metformin, was mainly diffusion-controlled, while those of the water-soluble drug, ciprofloxacin, and the slightly water-soluble drug, esomeprazole, were mainly anomalous diffusion. Overall results showed that the developed GRDDS composed of HEC 250HHX and NaCMC of 450 cps possessed proper swelling extents and desired floating periods with sustained-release characteristics.
doi:10.1371/journal.pone.0116914
PMCID: PMC4305323  PMID: 25617891
18.  Evolutionary analysis of rubella viruses in mainland China during 2010–2012: endemic circulation of genotype 1E and introductions of genotype 2B 
Scientific Reports  2015;5:7999.
Rubella remains a significant burden in mainland China. In this report, 667 viruses collected in 24 of 31 provinces of mainland China during 2010–2012 were sequenced and analyzed, significantly extending previous reports on limited numbers of viruses collected before 2010. Only viruses of genotypes 1E and 2B were found. Genotype 1E viruses were found in all 24 provinces. Genotype 1E viruses were likely introduced into mainland China around 1997 and endemic transmission of primarily one lineage became established. Viruses reported here from 2010–2012 are largely in a single cluster within this lineage. Genotype 2B viruses were rarely detected in China prior to 2010. This report documents a previously undetected 2B lineage, which likely became endemic in eastern provinces of China between 2010 and 2012. Bayesian analyses were performed to estimate the evolutionary rates and dates of appearance of the genotype 1E and 2B viral linages in China. A skyline plot of viral population diversity did not provide evidence of reduction of diversity as a result of vaccination, but should be useful as a baseline for such reductions as vaccination programs for rubella become widespread in mainland China.
doi:10.1038/srep07999
PMCID: PMC4303870  PMID: 25613734
19.  Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment 
BioMed Research International  2015;2015:354143.
In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1) is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT) and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.
doi:10.1155/2015/354143
PMCID: PMC4317583
20.  The Association between NQO1 Pro187Ser Polymorphism and Bladder Cancer Susceptibility: A Meta-Analysis of 15 Studies 
PLoS ONE  2015;10(1):e0116500.
Background
NAD(P)H:quinone oxidoreductase 1 (NQO1), an obligate two-electron reductase, plays an important role in reducing reactive quinones to less reactive and less toxic hydroquinones. Genetic variations in NQO1 gene that impede its enzyme function may be considered as putative risk factor for cancer. Numerous studies have been performed to investigate the association between NQO1 Pro187Ser polymorphism and bladder cancer risk; nevertheless, the results remain controversial.
Methods
We indentified eligible publications from PubMed, Embase and CBM databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the strength of the associations. False-positive report probability (FPRP) analysis was also performed for all statistically significant findings.
Results
We collected a total of 15 studies including 4298 cases and 4275 controls in the final meta-analysis. Overall, the NQO1 187Ser carriers were associated with an increased bladder cancer risk (homozygous: OR = 1.43, 95% CI = 1.08-1.90; recessive: OR = 1.33, 95% CI = 1.03-1.72; dominant: OR = 1.19, 95% CI = 1.04-1.37, and allele comparing: OR = 1.18, 95% CI = 1.06-1.33). Stratification analyses showed a statistically significant association among Asians (homozygous: OR = 1.82, 95% CI = 1.39-2.38; recessive: OR = 1.52, 95% CI = 1.20-1.93, dominant: OR = 1.40, 95% CI = 1.05-1.88, and allele comparing: OR = 1.35, 95% CI = 1.15-1.58), never smokers (homozygous: OR = 2.30, 95% CI = 1.14-4.65; heterozygous: OR = 2.26, 95% CI = 1.43-3.56; dominant model: OR = 1.59, 95% CI = 1.14-2.21, and allele comparing: OR = 1.72, 95% CI = 1.27-2.33), hospital-based studies (homozygous: OR = 1.46, 95% CI = 1.09-1.94; recessive: OR = 1.32, 95% CI = 1.02-1.69; dominant: OR = 1.28, 95% CI = 1.05-1.56, and allele comparing: OR = 1.24, 95% CI = 1.07-1.43), studies with genotyping performed by PCR-RFLP under all genetic models, and studies with minor allele frequency >0.30 (homozygous: OR = 1.69, 95% CI = 1.25-2.27; recessive: OR = 1.46, 95% CI = 1.10-1.95, and allele comparing: OR = 1.25, 95% CI = 1.04-1.51), respectively.
Conclusions
Despite some limitations, our meta-analysis provides sufficient evidence that NQO1 Pro187Ser polymorphism may contribute to bladder cancer risk. These findings need further validation in well-designed prospective studies with larger sample size and different ethnicities, especially for Asians.
doi:10.1371/journal.pone.0116500
PMCID: PMC4300190  PMID: 25602258
21.  Candida albicans OPI1 Regulates Filamentous Growth and Virulence in Vaginal Infections, but Not Inositol Biosynthesis 
PLoS ONE  2015;10(1):e0116974.
ScOpi1p is a well-characterized transcriptional repressor and master regulator of inositol and phospholipid biosynthetic genes in the baker’s yeast Saccharomyces cerevisiae. An ortholog has been shown to perform a similar function in the pathogenic fungus Candida glabrata, but with the distinction that CgOpi1p is essential for growth in this organism. However, in the more distantly related yeast Yarrowia lipolytica, the OPI1 homolog was not found to regulate inositol biosynthesis, but alkane oxidation. In Candida albicans, the most common cause of human candidiasis, its Opi1p homolog, CaOpi1p, has been shown to complement a S. cerevisiae opi1∆ mutant for inositol biosynthesis regulation when heterologously expressed, suggesting it might serve a similar role in this pathogen. This was tested in the pathogen directly in this report by disrupting the OPI1 homolog and examining its phenotypes. It was discovered that the OPI1 homolog does not regulate INO1 expression in C. albicans, but it does control SAP2 expression in response to bovine serum albumin containing media. Meanwhile, we found that CaOpi1 represses filamentous growth at lower temperatures (30°C) on agar, but not in liquid media. Although, the mutant does not affect virulence in a mouse model of systemic infection, it does affect virulence in a rat model of vaginitis. This may be because Opi1p regulates expression of the SAP2 protease, which is required for rat vaginal infections.
doi:10.1371/journal.pone.0116974
PMCID: PMC4300220  PMID: 25602740
22.  Stability and toxicity of empty or gene-loaded lipopolysaccharide-amine nanopolymersomes 
Successful in vivo gene delivery mediated by nonviral vectors requires efficient extracellular and intracellular gene delivery, but few studies have given attention to the former. That is why numerous gene delivery systems have succeeded in vitro, while the expected clinical success has not come about. To realize efficient extracellular gene delivery, the stability of vectors and/or their complexes with genes in body fluids is first required, which prevents loaded genes from premature unloading and degradation. Furthermore, the storage stability of vectors under common conditions is important for their widespread applications. Lipopolysaccharide-amine nanopolymersomes (NPs), a gene vector developed by our group recently, have higher than 95% in vitro transfection efficiency in mesenchymal stem cells when delivering pEGFP, and induce significant angiogenesis in zebrafish when delivering plasmid encoding vascular endothelial growth factor deoxyribonucleic acid (pVEGF). To reveal their extracellular delivery ability and storage stability, in this study their stability in various simulant physiological environments and storage conditions was systematically studied by monitoring their changes in disassembly, size, zeta potential, and transfection efficiency. Additionally, damage to the mitochondria of mesenchymal stem cells was evaluated. Results show that NPs and plasmid deoxyribonucleic acid (pDNA)-loaded NPs (pNPs) have acceptable stability against dilution, anions, salts, pH, enzyme, and serum, presumably assuring their efficient extracellular delivery in vivo. Moreover, both the lyophilized NPs at room temperature and NP/pNP solution at 4°C have high storage stability, and pNPs show low damage to the mitochondria. The acceptable stability of NPs combined with compatibility and efficient gene transfection highlight their huge potential in the clinic as a gene delivery vector.
doi:10.2147/IJN.S74156
PMCID: PMC4298338  PMID: 25609964
nanopolymersomes; extracellular delivery stability; storage stability; toxicity; polyethyleneimine; alginate; cholesterol; mesenchymal stem cells
23.  X13CMS: Global Tracking of Isotopic Labels in Untargeted Metabolomics 
Analytical Chemistry  2014;86(3):1632-1639.
Studies of isotopically labeled compounds have been fundamental to understanding metabolic pathways and fluxes. They have traditionally, however, been used in conjunction with targeted analyses that identify and quantify a limited number of labeled downstream metabolites. Here we describe an alternative workflow that leverages recent advances in untargeted metabolomic technologies to track the fates of isotopically labeled metabolites in a global, unbiased manner. This untargeted approach can be applied to discover novel biochemical pathways and characterize changes in the fates of labeled metabolites as a function of altered biological conditions such as disease. To facilitate the data analysis, we introduce X13CMS, an extension of the widely used mass spectrometry-based metabolomic software package XCMS. X13CMS uses the XCMS platform to detect metabolite peaks and perform retention-time alignment in liquid chromatography/mass spectrometry (LC/MS) data. With the use of the XCMS output, the program then identifies isotopologue groups that correspond to isotopically labeled compounds. The retrieval of these groups is done without any a priori knowledge besides the following input parameters: (i) the mass difference between the unlabeled and labeled isotopes, (ii) the mass accuracy of the instrument used in the analysis, and (iii) the estimated retention-time reproducibility of the chromatographic method. Despite its name, X13CMS can be used to track any isotopic label. Additionally, it detects differential labeling patterns in biological samples collected from parallel control and experimental conditions. We validated the ability of X13CMS to accurately retrieve labeled metabolites from complex biological matrices both with targeted LC/MS/MS analysis of a subset of the hits identified by the program and with labeled standards spiked into cell extracts. We demonstrate the full functionality of X13CMS with an analysis of cultured rat astrocytes treated with uniformly labeled (U-)13C-glucose during lipopolysaccharide (LPS) challenge. Our results show that out of 223 isotopologue groups enriched from U-13C-glucose, 95 have statistically significant differential labeling patterns in astrocytes challenged with LPS compared to unchallenged control cells. Only two of these groups overlap with the 32 differentially regulated peaks identified by XCMS, indicating that X13CMS uncovers different and complementary information from untargeted metabolomic studies. Like XCMS, X13CMS is implemented in R. It is available from our laboratory website at http://pattilab.wustl.edu/x13cms.php.
doi:10.1021/ac403384n
PMCID: PMC3982964  PMID: 24397582
24.  Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets 
Cell metabolism  2013;19(1):135-145.
SUMMARY
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β-cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. We identified a cluster of miRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β-cells and dramatically down-regulated in islets from T2DM organ donors. The down-regulation of this locus strongly correlates with hyper-methylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1 that cause increased β-cell apoptosis upon over-expression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.
doi:10.1016/j.cmet.2013.11.016
PMCID: PMC3932527  PMID: 24374217
25.  Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry 
Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to somatic fumarate hydratase mutation. Germline mutations account for the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulates in affected cells with formation of S-(2-succino)-cysteine, which can be detected with polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells, but not in normal tissues or tumors unassociated with Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth muscle tumors were prospectively analyzed for features suggesting Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding 9 cases. Germline genetic testing for fumarate hydratase mutations was performed in 3 cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemistry was performed with controls from a tissue microarray [leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)]. Of the 9 study cases, 4 had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of 3 tested patients had germline fumarate hydratase mutations. Only 1 leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for germline fumarate hydratase mutation or the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible Hereditary Leiomyomatosis and Renal Cell Carcinoma.
doi:10.1038/modpathol.2013.215
PMCID: PMC4048336  PMID: 24309325
uterine leiomyomas; fumarate hydratase; HLRCC (hereditary leiomyomatosis and renal cell carcinoma syndrome); S-(2-succino)-cysteine; succination

Results 1-25 (637)