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1.  Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma 
Neuro-Oncology  2013;15(7):853-864.
CD163 is a 130-kDa transmembrane protein expressed in human monocytes and macrophages, and the aberrant expression of CD163 in breast and colorectal cancer associated with patients' poor prognosis was reported. Here, we analyzed the expression of CD163 in meningioma, a common intracranial tumor, and its molecular mechanism in association with meningioma progression.
First, we performed immunohistochemical analysis using 50 human meningioma specimens. Next, we established CD163-overexpressing human meningioma cell lines and investigated its roles in tumor progression in vitro and in vivo.
Immunohistochemically, 26 of 50 human meningioma specimens (52.0%) were positive for CD163 in tumor cells, including benign grade I (48.5%) and grade II (71.4%) cases. Furthermore, CD163 expression was correlated with histological atypical parameters that directly predict the prognosis of meningioma. CD163-overexpressing meningioma cells showed significant suppression of apoptosis and accelerated tumor growth in nude mice. In addition, unexpected splenomegaly affiliated with the xenograft predicted tumor-derived granulocyte colony-stimulating factor (G-CSF) production, which was confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay.
To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma.
PMCID: PMC3688010  PMID: 23539121
apoptosis; CD163; G-CSF; malignancy; meningioma
2.  Bisphenol A and Phthalates and Endometriosis, The ENDO Study 
Fertility and sterility  2013;100(1):162-169.e2.
To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis.
Matched cohort design.
14 clinical centers in Salt Lake City, Utah or San Francisco, California, 2007–2009.
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, while the population cohort comprised 131 women matched on age and residence.
Main Outcome Measure(s)
Surgically visualized or pelvic magnetic resonance imaging (MRI) diagnosed endometriosis in the two cohorts, respectively.
Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index and creatinine. In the population cohort, six phthalate metabolites (mBP, mCMHP, mECPP, mEHP, mEHHP, and mEOHP) were significantly associated with approximately a twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (mOP; OR=1.38; 95% CI 1.10, 1.72), or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis (mEHP; OR=1.35; 95% CI 1.03, 1.78).
Select phthalates were associated with higher odds of an endometriosis diagnosis for women with MRI diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.
PMCID: PMC3700684  PMID: 23579005
Bisphenol A; endometriosis; endocrine disrupting chemicals; epidemiology; phthalates
3.  IFN-γ and TNF-α Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFκB Signaling 
Stem cells (Dayton, Ohio)  2013;31(7):1383-1395.
An inflammatory microenvironment may cause organ degenerative diseases and malignant tumors. However, the precise mechanisms of inflammation-induced diseases are not fully understood. Here we show that the proinflammatory cytokines interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) synergistically impair self-renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor κB (NFκB)–mediated activation of Mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-γ and TNF-α result in significantly increased susceptibility to malignant transformation in MSCs through NFκB–mediated upregulation of the oncogenes c-Fos and c-Myc. Depletion of either IFN-γ or TNF-α in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFκB–mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN-γ and TNF-α, results in blockage of MSC deficiency and tumorigenesis by inhibition of NF-κB/SMAD7 and NFκB/c-FOS and c-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-γ and TNF-α, synergistically induce MSC deficiency via NFκB/SMAD7 signaling and tumorigenesis via NFκB–mediated oncogene activation.
PMCID: PMC3706580  PMID: 23553791
Mesenchymal stem cells; Stem cell-microenvironment interactions; Differentiation; Cancer; Cytokines
4.  Study Design Considerations for Evaluating Efficacy of Systemic Pre-Exposure Prophylaxis Interventions 
The development of interventions for systemic Pre-Exposure Prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration’s (FDA) approval of Emtricitabine/Tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention.
Possible designs for a PrEP Phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules.
Non-inferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the three PrEP trials demonstrating efficacy of FTC/TDF. However these HIV endpoint trials may require extremely large numbers of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on prior placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (i.e. women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting.
Following FDA approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
PMCID: PMC3725298  PMID: 23764624
Pre-exposure Prophylaxis; Non-inferiority; efficacy; phase 3; clinical trials; adherence
5.  An epigenomic approach to therapy for tamoxifen-resistant breast cancer 
Cell Research  2014;24(7):809-819.
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.
PMCID: PMC4085766  PMID: 24874954
epigenomic; tamoxifen; breast cancer
6.  Differentially Expressed Plasma MicroRNAs and the Potential Regulatory Function of Let-7b in Chronic Thromboembolic Pulmonary Hypertension 
PLoS ONE  2014;9(6):e101055.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.
PMCID: PMC4076206  PMID: 24978044
7.  Emerging Applications of Metabolomics in Studying Chemopreventive Phytochemicals 
The AAPS Journal  2013;15(4):941-950.
Phytochemicals from diet and herbal medicines are under intensive investigation for their potential use as chemopreventive agents to block and suppress carcinogenesis. Chemical diversity of phytochemicals, together with complex metabolic interactions between phytochemicals and biological system, can overwhelm the capacity of traditional analytical platforms, and thus pose major challenges in studying chemopreventive phytochemicals. Recent progresses in metabolomics have transformed it to become a robust systems biology tool, suitable for examining both chemical and biochemical events that contribute to the cancer prevention activities of plant preparations or their bioactive components. This review aims to discuss the technical platform of metabolomics and its existing and potential applications in chemoprevention research, including identifying bioactive phytochemicals in plant extracts, monitoring phytochemical exposure in humans, elucidating biotransformation pathways of phytochemicals, and characterizing the effects of phytochemicals on endogenous metabolism and cancer metabolism.
PMCID: PMC3787217  PMID: 23794098
chemoprevention; metabolism; metabolomics; phytochemical
8.  RNA-seq analyses of multiple meristems of soybean: novel and alternative transcripts, evolutionary and functional implications 
BMC Plant Biology  2014;14:169.
Soybean is one of the most important crops, providing large amounts of dietary proteins and edible oil, and is also an excellent model for studying evolution of duplicated genes. However, relative to the model plants Arabidopsis and rice, the present knowledge about soybean transcriptome is quite limited.
In this study, we employed RNA-seq to investigate transcriptomes of 11 soybean tissues, for genome-wide discovery of truly expressed genes, and novel and alternative transcripts, as well as analyses of conservation and divergence of duplicated genes and their functional implications. We detected a total of 54,132 high-confidence expressed genes, and identified 6,718 novel transcriptional regions with a mean length of 372 bp. We also provided strong evidence for alternative splicing (AS) events for ~15.9% of the genes with two or more exons. Among them, 1,834 genes exhibited stage-dependent AS, and 202 genes had tissue-biased exon-skipping events. We further defined the conservation and divergence in expression patterns between duplicated gene pairs from recent whole genome duplications (WGDs); differentially expressed genes, tissue preferentially expressed genes, transcription factors and specific gene family members were identified for shoot apical meristem and flower development.
Our results significantly improved soybean gene annotation, and also provide valuable resources for functional genomics and studies of the evolution of duplicated genes from WGDs in soybean.
PMCID: PMC4070088  PMID: 24939556
Soybean; RNA-seq; Transcriptome; Novel transcriptional regions; Alternative splicing; Meristem; Transcription factors
9.  Bare-Bones Teaching-Learning-Based Optimization 
The Scientific World Journal  2014;2014:136920.
Teaching-learning-based optimization (TLBO) algorithm which simulates the teaching-learning process of the class room is one of the recently proposed swarm intelligent (SI) algorithms. In this paper, a new TLBO variant called bare-bones teaching-learning-based optimization (BBTLBO) is presented to solve the global optimization problems. In this method, each learner of teacher phase employs an interactive learning strategy, which is the hybridization of the learning strategy of teacher phase in the standard TLBO and Gaussian sampling learning based on neighborhood search, and each learner of learner phase employs the learning strategy of learner phase in the standard TLBO or the new neighborhood search strategy. To verify the performance of our approaches, 20 benchmark functions and two real-world problems are utilized. Conducted experiments can been observed that the BBTLBO performs significantly better than, or at least comparable to, TLBO and some existing bare-bones algorithms. The results indicate that the proposed algorithm is competitive to some other optimization algorithms.
PMCID: PMC4071861
10.  Feleucins: Novel Bombinin Precursor-Encoded Nonapeptide Amides from the Skin Secretion of Bombina variegata 
BioMed Research International  2014;2014:671362.
The first amphibian skin antimicrobial peptide (AMP) to be identified was named bombinin, reflecting its origin from the skin of the European yellow-bellied toad (Bombina variegata). Bombinins and their related peptides, the bombinin Hs, were subsequently reported from other bombinid toads. Molecular cloning of bombinin-encoding cDNAs from skin found that bombinins and bombinin Hs were coencoded on the same precursor proteins. Here, we report the molecular cloning of two novel cDNAs from a skin secretion-derived cDNA library of B. variegata whose open-reading frames each encode a novel bombinin (GIGGALLNVGKVALKGLAKGLAEHFANamide) and a C-terminally located single copy of a novel nonapeptide (FLGLLGGLLamide or FLGLIGSLLamide). These novel nonapeptides were named feleucin-BV1 and feleucin-BV2, respectively. The novel bombinin exhibited 89% identity to homologues from the toads, B. microdeladigitora and B. maxima. The feleucins exhibited no identity with any amphibian AMP archived in databases. Synthetic feleucins exhibited a weak activity against Staphylococcus aureus (128–256 mg/L) but feleucin-BV1 exhibited a synergistic action with the novel bombinin. The present report clearly demonstrates that the skin secretions of bombinid toads continue to represent a source of peptides of novel structure that could provide templates for the design of therapeutics.
PMCID: PMC4070539
11.  Structural Insights into SraP-Mediated Staphylococcus aureus Adhesion to Host Cells 
PLoS Pathogens  2014;10(6):e1004169.
Staphylococcus aureus, a Gram-positive bacterium causes a number of devastating human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. S. aureus SraP, a surface-exposed serine-rich repeat glycoprotein (SRRP), is required for the pathogenesis of human infective endocarditis via its ligand-binding region (BR) adhering to human platelets. It remains unclear how SraP interacts with human host. Here we report the 2.05 Å crystal structure of the BR of SraP, revealing an extended rod-like architecture of four discrete modules. The N-terminal legume lectin-like module specifically binds to N-acetylneuraminic acid. The second module adopts a β-grasp fold similar to Ig-binding proteins, whereas the last two tandem repetitive modules resemble eukaryotic cadherins but differ in calcium coordination pattern. Under the conditions tested, small-angle X-ray scattering and molecular dynamic simulation indicated that the three C-terminal modules function as a relatively rigid stem to extend the N-terminal lectin module outwards. Structure-guided mutagenesis analyses, in addition to a recently identified trisaccharide ligand of SraP, enabled us to elucidate that SraP binding to sialylated receptors promotes S. aureus adhesion to and invasion into host epithelial cells. Our findings have thus provided novel structural and functional insights into the SraP-mediated host-pathogen interaction of S. aureus.
Author Summary
Staphylococcus aureus is an important pathogen that causes a range of human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. The increasing resistance of S. aureus to most of the current antibiotics emphasizes the need to develop new approaches to control staphylococcal infections. As a surface-exposed serine-rich repeat glycoprotein (SRRP), S. aureus SraP is involved in the pathogenesis of infective endocarditis via its ligand-binding region (BR) adhering to human platelets. However, little is known about how SraP interacts with its host receptor(s). Through structural and functional analyses of the BR domain, we have discovered a specific binding of SraP to N-acetylneuraminic acid (Neu5Ac), in agreement with a recent report of the trisaccharide ligand of SraP. Further mutagenesis analysis showed that SraP binding to Neu5Ac and the trisaccharide promotes S. aureus adhesion to and invasion into host epithelial cells. These findings increase our knowledge of surface protein mediated interaction of S. aureus with host epithelial cells.
PMCID: PMC4047093  PMID: 24901708
12.  B and N isolate-doped graphitic carbon nanosheets from nitrogen-containing ion-exchanged resins for enhanced oxygen reduction 
Scientific Reports  2014;4:5184.
B,N-codoped carbon nanostructures (BNCS) can serve as alternative low-cost metal-free electrocatalysts for oxygen reduction reactions (ORR). However, the compensation effect between the p- (B atoms) and n-type (N atoms) dopants would make the covalent boron-nitride (BN) easily formed during the synthesis of BNCS, leading to a unsatisfactory ORR activity. Therefore, it has been challenging to develop facile and rapid synthetic strategies for highly active BNCS without forming the direct covalent BN. Here, a facile method is developed to prepare B and N isolate-doped graphitic nanosheets (BNGS) by using iron species for saving N element and simultaneous doping the B element from nitrogen-containing ion-exchanged resins (NR). The resulting BNGS exhibits much more onset potential (Eonset) compared with the B-doped graphitic carbon nanosheets (BGS), N-doped graphitic carbon nanosheets (NGS), as well as B,N-codoped disorder carbon (BNC). Moreover, the BNGS shows well methanol tolerance propery and excellent stability (a minimal loss of activity after 5,000 potential cycles) compared to that of commercial Pt/C catalyst. The goog performance for BNGS towards ORR is attributed to the synergistic effect between B and N, and the well electrons transport property of graphitic carbon in BNGS.
PMCID: PMC4046170  PMID: 24898033
13.  Increased Incidence of Benign Pancreatic Pathology following Pancreaticoduodenectomy for Presumed Malignancy over 10 Years despite Increased Use of Endoscopic Ultrasound 
Despite using imaging studies, tissue sampling, and serologic tests about 5–10% of surgeries done for presumed pancreatic malignancies will have benign findings on final pathology. Endoscopic ultrasound (EUS) is used with increasing frequency to study pancreatic masses. The aim of this study is to examine the effect of EUS on prevalence of benign diseases undergoing Whipple over the last decade. Patients who underwent Whipple procedure for presumed malignancy at Emory University Hospital from 1998 to 2011 were selected. Demographic data, history of smoking and drinking, history of diabetes and pancreatitis, imaging data, pathology reports, and tumor markers were extracted. 878 patients were found. 95 (10.82%) patients had benign disease. Prevalence of benign finding had increased over the recent years despite using more EUS. Logistic regression models showed that abdominal pain (OR: 5.829, 95% CI 2.681–12.674, P ≤ 0.001) and alcohol abuse (OR: 3.221, CI 95%: 1.362–7.261, P: 0.002) were predictors of benign diseases. Jaundice (OR: 0.221, 95% CI: 0.084–0.58, P: 0.002), mass (OR: 0.145, 95% CI: 0.043–0.485, P: 0.008), and ductal dilation (OR: 0.297, 95% CI 0.134–0.657, P: 0.003) were associated with malignancy. Use of imaging studies, ERCP, and EUS has not decreased the percentage of benign findings after surgery for presumed pancreatic malignancy.
PMCID: PMC4068051
14.  Histone Deacetylase HDAC4 Promotes Gastric Cancer SGC-7901 Cells Progression via p21 Repression 
PLoS ONE  2014;9(6):e98894.
Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5′-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer.
PMCID: PMC4045860  PMID: 24896240
16.  Quercitrin Protects Skin from UVB-induced Oxidative Damage 
Exposure of the skin to ultraviolet B (UVB) radiation causes oxidative damage to skin, resulting in sunburn, photoaging, and skin cancer. It is generally believed that the skin damage induced by UV irradiation is a consequence of generation of reactive oxygen species (ROS). Recently, there is an increased interest in the use of natural products as chemopreventive agents for non-melanoma skin cancer (NMSC) due to their antioxidants and anti-inflammatory properties. Quercitrin, glycosylated form of quercetin, is the most common flavonoid in nature with antioxidant properties. The present study investigated the possible beneficial effects of quercitrin to inhibit UVB irradiation-induced oxidative damage in vitro and in vivo. Our results showed that quercitrin decreased ROS generation induced by UVB irradiation in JB6 cells. Quercitrin restored catalase expression and GSH/GSSG ratio reduced by UVB exposure, two major antioxidant enzymes, leading to reductions of oxidative DNA damage and apoptosis and protection of the skin from inflammation caused by UVB exposure. The present study demonstrated that quercitrin functions as an antioxidant against UVB irradiation-induced oxidative damage to skin.
PMCID: PMC3700335  PMID: 23545178
ultraviolet B; quercitrin; antioxidant; reactive oxygen species; oxidative damage; apoptosis; inflammation
17.  Early clinical effects of the Dynesys system plus transfacet decompression through the Wiltse approach for the treatment of lumbar degenerative diseases 
This study investigated early clinical effects of Dynesys system plus transfacet decompression through the Wiltse approach in treating lumbar degenerative diseases.
37 patients with lumbar degenerative disease were treated with the Dynesys system plus transfacet decompression through the Wiltse approach.
Results showed that all patients healed from surgery without severe complications. The average follow-up time was 20 months (9–36 months). Visual Analogue Scale and Oswestry Disability Index scores decreased significantly after surgery and at the final follow-up. There was a significant difference in the height of the intervertebral space and intervertebral range of motion (ROM) at the stabilized segment, but no significant changes were seen at the adjacent segments. X-ray scans showed no instability, internal fixation loosening, breakage, or distortion in the follow-up.
The Dynesys system plus transfacet decompression through the Wiltse approach is a therapeutic option for mild lumbar degenerative disease. This method can retain the structure of the lumbar posterior complex and the motion of the fixed segment, reduce the incidence of low back pain, and decompress the nerve root.
PMCID: PMC4043541  PMID: 24859831
Lumbar Degenerative Disease; Wiltse Approach; Dynesys; Osteoarthritis; Spine; Decompression; Surgical
18.  The Sub-Classification of Amnestic Mild Cognitive Impairment Using MRI-Based Cortical Thickness Measures 
Background: Amnestic mild cognitive impairment (aMCI) is considered to be the transitional stage between healthy aging and Alzheimer’s disease (AD). Moreover, aMCI individuals with additional impairment in one or more non-memory cognitive domains are at higher risk of conversion to AD. Hence accurate identification of the sub-types of aMCI would enable earlier detection of individuals progressing to AD.
Methods: We examine the group differences in cortical thickness between single-domain and multiple-domain sub-types of aMCI, and as well as with respect to age-matched controls in a well-balanced cohort from the Sydney Memory and Aging Study. In addition, the diagnostic value of cortical thickness in the sub-classification of aMCI as well as from normal controls using support vector machine (SVM) classifier is evaluated, using a novel cross-validation technique that can handle class-imbalance.
Results: This study revealed an increased, as well as a wider spread, of cortical thinning in multiple-domain aMCI compared to single-domain aMCI. The best performances of the classifier for the pairs (1) single-domain aMCI and normal controls, (2) multiple-domain aMCI and normal controls, and (3) single and multiple-domain aMCI were AUC = 0.52, 0.66, and 0.54, respectively. The accuracy of the classifier for the three pairs was just over 50% exhibiting low specificity (44–60%) and similar sensitivity (53–68%).
Conclusion: Analysis of group differences added evidence to the hypothesis that multiple-domain aMCI is a later stage of AD compared to single-domain aMCI. The classification results show that discrimination among single, multiple-domain sub-types of aMCI and normal controls is limited using baseline cortical thickness measures.
PMCID: PMC4033252  PMID: 24904520
amnestic; mild cognitive impairment; subtype; cortical thickness; classification; early detection; Alzheimer
19.  mzGroupAnalyzer-Predicting Pathways and Novel Chemical Structures from Untargeted High-Throughput Metabolomics Data 
PLoS ONE  2014;9(5):e96188.
The metabolome is a highly dynamic entity and the final readout of the genotype x environment x phenotype (GxExP) relationship of an organism. Monitoring metabolite dynamics over time thus theoretically encrypts the whole range of possible chemical and biochemical transformations of small molecules involved in metabolism. The bottleneck is, however, the sheer number of unidentified structures in these samples. This represents the next challenge for metabolomics technology and is comparable with genome sequencing 30 years ago. At the same time it is impossible to handle the amount of data involved in a metabolomics analysis manually. Algorithms are therefore imperative to allow for automated m/z feature extraction and subsequent structure or pathway assignment. Here we provide an automated pathway inference strategy comprising measurements of metabolome time series using LC- MS with high resolution and high mass accuracy. An algorithm was developed, called mzGroupAnalyzer, to automatically explore the metabolome for the detection of metabolite transformations caused by biochemical or chemical modifications. Pathways are extracted directly from the data and putative novel structures can be identified. The detected m/z features can be mapped on a van Krevelen diagram according to their H/C and O/C ratios for pattern recognition and to visualize oxidative processes and biochemical transformations. This method was applied to Arabidopsis thaliana treated simultaneously with cold and high light. Due to a protective antioxidant response the plants turn from green to purple color via the accumulation of flavonoid structures. The detection of potential biochemical pathways resulted in 15 putatively new compounds involved in the flavonoid-pathway. These compounds were further validated by product ion spectra from the same data. The mzGroupAnalyzer is implemented in the graphical user interface (GUI) of the metabolomics toolbox COVAIN (Sun & Weckwerth, 2012, Metabolomics 8: 81–93). The strategy can be extended to any biological system.
PMCID: PMC4028198  PMID: 24846183
20.  Expression of fibroblast specific protein-1 in pleural tuberculosis and its clinical biological significance 
Fibroblast specific protein-1 (S100A4) is related with many fibrotic diseases, but its role in the pathogenesis of pleural fibrosis has not been fully elucidated. Then we aim to investigate the expression and effect of fibroblast specific protein-1 (S100A4) in pleural tuberculosis and, subsequently, pleural fibrosis.
The expression of S100A4 in pleura was examined in 30 patients with pleural tuberculosis and 5 control (disease-free) patients by immunohistochemistry using the streptavidin-peroxidase (S-P) conjugated method.
The expression of S100A4 in pleura was mainly distributed in the nucleus and cytoplasm of fibroblasts and vascular endothelial cells, and the positive rate was 90.0% (27 out of 30 patients with pleural tuberculosis). There were no expressions of S100A4 in the control group. In the pleura of all 30 patients with pleural tuberculosis, S100A4 had a higher expression in the two- to eight-week duration of the disease.
S100A4 plays an important role in the phenotypic transformation of pleural mesothelial cells and the development of pleural fibrosis.
PMCID: PMC4038721  PMID: 24885536
Pleural tuberculosis; Fibroblast specific protein-1; Pleural mesothelial cells; Pleural fibrosis
21.  Epithelial-Mesenchymal Transition During Oncogenic Transformation Induced by Hexavalent Chromium Involves Reactive Oxygen Species-Dependent Mechanisms in Lung Epithelial Cells 
Hexavalent Chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial–mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhanced binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention.
PMCID: PMC3664092  PMID: 23518002
Hexavalent Chromium; Oncogenic transformation; Epithelial-Mesenchymal Transition; Histone; cancer signaling; epithelial cells
22.  Three-Class Differential Diagnosis among Alzheimer Disease, Frontotemporal Dementia, and Controls 
Biomarkers derived from brain magnetic resonance (MR) imaging have promise in being able to assist in the clinical diagnosis of brain pathologies. These have been used in many studies in which the goal has been to distinguish between pathologies such as Alzheimer’s disease and healthy aging. However, other dementias, in particular, frontotemporal dementia, also present overlapping pathological brain morphometry patterns. Hence, a classifier that can discriminate morphometric features from a brain MRI from the three classes of normal aging, Alzheimer’s disease (AD), and frontotemporal dementia (FTD) would offer considerable utility in aiding in correct group identification. Compared to the conventional use of multiple pair-wise binary classifiers that learn to discriminate between two classes at each stage, we propose a single three-way classification system that can discriminate between three classes at the same time. We present a novel classifier that is able to perform a three-class discrimination test for discriminating among AD, FTD, and normal controls (NC) using volumes, shape invariants, and local displacements (three features) of hippocampi and lateral ventricles (two structures times two hemispheres individually) obtained from brain MR images. In order to quantify its utility in correct discrimination, we optimize the three-class classifier on a training set and evaluate its performance using a separate test set. This is a novel, first-of-its-kind comparative study of multiple individual biomarkers in a three-class setting. Our results demonstrate that local atrophy features in lateral ventricles offer the potential to be a biomarker in discriminating among AD, FTD, and NC in a three-class setting for individual patient classification.
PMCID: PMC4026692  PMID: 24860545
differential diagnosis; Alzheimer; frontotemporal disease; multi-class; ventricle
23.  Identification and functional characterization of bidirectional gene pairs and their intergenic regions in maize 
BMC Genomics  2014;15(1):338.
Bidirectional gene pairs exist as a specific form of gene organization in microorganisms and mammals as well as in model plant species, such as Arabidopsis and rice. Little is known about bidirectional gene pairs in maize, which has a large genome and is one of the most important grain crops.
We conducted a genome-wide search in maize using genome sequencing results from the inbred line B73. In total, 1696 bidirectional transcript pairs were identified using a modified search model. We functionally characterized the promoter activity of the intergenic regions of most of the bidirectional transcript pairs that were expressed in embryos using a maize embryo transient expression system. A comparative study of bidirectional gene pairs performed for three monocot (Zea mays, Sorghum bicolor and Oryza sativa) and two dicot (Arabidopsis thaliana and Glycine max) plant genomes showed that bidirectional gene pairs were abundant in the five plant species. Orthologous bidirectional gene pairs were clearly distinguishable between the monocot and dicot species although the total numbers of orthologous bidirectional genes were similar. Analysis of the gene pairs using the Blast2GO software suite showed that the molecular functions (MF), cellular components (CC), and biological processes (BP) associated with the bidirectional transcripts were similar among the five plant species.
The evolutionary analysis of the function and structure of orthologous bidirectional gene pairs in various plant species revealed a potential pathway of their origin, which may be required for the evolution of a new species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-338) contains supplementary material, which is available to authorized users.
PMCID: PMC4035068  PMID: 24886269
Genome-wide; Bidirectional gene pair; Bidirectional promoter; Maize
24.  Feasibility and Safety of ALVAC-HIV vCP1521 Vaccine in HIV- exposed Infants in Uganda: Results from the First HIV Vaccine Trial in Infants in Africa 
The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) for prevention mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from Phase I, randomized, double blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV-1-infected women in Uganda are reported.
HIV exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8 and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination, and days 1 and 2 post-vaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA PCR.
From October 2006 to May 2007, 60 infants (48 vaccine, 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by Diptheria, Polio, Hepatitis B and Heamophilus influenzae type B and measles vaccination were similar in the two arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine, 1 placebo) and one in vaccine arm at 2 weeks of age].
The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high quality infant HIV vaccine trials is achievable in Africa.
PMCID: PMC3625520  PMID: 23221981
HIV vaccine; ALVAC; infants; Africa; breast milk transmission
25.  Development of a DNA Microarray Method for Detection and Identification of All 15 Distinct O-Antigen Forms of Legionella pneumophila 
Applied and Environmental Microbiology  2013;79(21):6647-6654.
Legionella is ubiquitous in many environments. At least 50 species and 70 serogroups of the Gram-negative bacterium have been identified. Of the 50 species, 20 are pathogenic, and Legionella pneumophila is responsible for the great majority (approximately 90%) of the Legionnaires' disease cases that occur. Furthermore, of the 15 L. pneumophila serogroups identified, O1 alone causes more than 84% of the Legionnaires' disease cases that occur worldwide. Rapid and reliable assays for the detection and identification of L. pneumophila in water, environmental, and clinical samples are in great demand. L. pneumophila bacteria are traditionally identified by their O antigens by immunological methods. We have recently developed an O serogroup-specific DNA microarray for the detection of all 15 distinct O-antigen forms of L. pneumophila, including serogroups O1 to O15. A total of 35 strains were used to verify the specificity of the microarray, including 15 L. pneumophila O-antigen standard reference strains and seven L. pneumophila clinical isolates as target strains, seven reference strains of other non-pneumophila Legionella species as closely related strains, and six non-Legionella bacterial species as nonrelated strains. The detection sensitivity was 1 ng of genomic DNA or 0.4 CFU/ml in water samples with filter enrichment and plate culturing. This study demonstrated that the microarray allows specific, sensitive, and reproducible detection of L. pneumophila serogroups. To the best of our knowledge, this is the first report of a microarray serotyping method for all 15 distinct O-antigen forms of L. pneumophila.
PMCID: PMC3811488  PMID: 23974134

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