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1.  DNA Methylation in Cosmc Promoter Region and Aberrantly Glycosylated IgA1 Associated with Pediatric IgA Nephropathy 
PLoS ONE  2015;10(2):e0112305.
IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. Elevation of aberrantly glycosylated IgA1 is a key feature of it. The expression of the specific molecular chaperone of core1ß1, 3galactosyl transferase (Cosmc) is known to be reduced in IgAN. We aimed to investigate whether the methylation of CpG islands of Cosmc gene promoter region could act as a possible mechanism responsible for down-regulation of Cosmc and related higher secretion of aberrantly glycosylated IgA1in lymphocytes from children with IgA nephropathy. Three groups were included: IgAN children (n = 26), other renal diseases (n = 11) and healthy children (n = 13). B-lymphocytes were isolated and cultured, treated or not with IL-4 or 5-Aza-2’-deoxycytidine (AZA). The levels of DNA methylation of Cosmc promotor region were not significantly different between the lymphocytes of the three children populations (P = 0.113), but there were significant differences between IgAN lymphocytes and lymphocytes of the other two children populations after IL-4 (P<0.0001) or AZA (P<0.0001). Cosmc mRNA expression was low in IgAN lymphocytes compared to the other two groups (P<0.0001). The level of aberrantly glycosylated IgA1 was markedly higher in IgAN group compared to the other groups (P<0.0001). After treatment with IL-4, the levels of Cosmc DNA methylation and aberrantly glycosylated IgA1 in IgAN lymphocytes were remarkably higher than the other two groups (P<0.0001) with more markedly decreased Cosmc mRNA content (P<0.0001). After treatment with AZA, the levels in IgAN lymphocytes were decreased, but was still remarkably higher than the other two groups (P<0.0001), while Cosmc mRNA content in IgAN lymphocytes were more markedly increased than the other two groups (P<0.0001). The alteration of DNA methylation by IL-4 or AZA specifically correlates in IgAN lymphocytes with alterations in Cosmc mRNA expression and with the level of aberrantly glycosylated IgA1 (r = −0.948, r = 0. 707). Our results suggested that hypermethylation of Cosmc promoter region could be a key mechanism for the reduction of Cosmc mRNA expression in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.
doi:10.1371/journal.pone.0112305
PMCID: PMC4315396  PMID: 25647400
2.  Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation 
Nature  2014;517(7532):89-93.
Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/β-dependent antiviral immunity in mice1–4. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases5. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi–Goutières syndrome and spondyloenchondrodysplasia6–9.We further show that an absence of intracellular ISG15 in the patients’ cells prevents the accumulation of USP1810,11, a potent negative regulator of IFN-α/β signalling, resulting in the enhancement and amplification of IFN-α/β responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/β immunity. In humans, intracellular ISG15 is IFN-α/β-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-α/β and prevention of IFN-α/β-dependent autoinflammation.
doi:10.1038/nature13801
PMCID: PMC4303590  PMID: 25307056
3.  A rare case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis caused by a novel dominant mutation in CACNA1S: features and prognosis after adrenalectomy 
BMC Urology  2014;14(1):96.
Background
Acute hypokalaemic paralysis is characterised by acute flaccid muscle weakness and has a complex aetiological spectrum. Herein we report, for the first time, a case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis type I resulting from a novel dominant mutation in CACNA1S. We present the clinical features and prognosis after adrenalectomy in this case.
Case presentation
A 43-year-old Han Chinese male presented with severe hypokalaemic paralysis that remitted after taking oral potassium. The patient had suffered from periodic attacks of hypokalaemic paralysis for more than 20 years. A computed tomography (CT) scan of the abdomen showed a nodular mass on the left adrenal gland, although laboratory examination revealed the patient had not developed primary aldosteronism. The patient underwent a left adrenalectomy 4 days after admission, and the pathological examination further confirmed a 1.1 cm benign nodule at the periphery of the adrenal gland. Three months after the adrenalectomy, a paralytic attack recurred and the patient asked for assistance from the Department of Medical Genetics. His family history showed that two uncles, one brother, and a nephew also had a history of periodic paralysis, although their symptoms were milder. The patient’s CACNA1S and SCN4A genes were sequenced, and a novel missense mutation, c.1582C > T (p.Arg528Cys), in CACNA1S was detected. Detection of the mutation in five adult male family members, including three with periodic paralysis and two with no history of the disease, indicated that this mutation caused hypokalaemic periodic paralysis type I in his family. Follow-up 2 years after adrenalectomy showed that the serum potassium concentration was increased between paralyses and the number and severity of paralytic attacks were significantly decreased.
Conclusion
We identified a novel dominant mutation, c.1582C > T (p.Arg528Cys), in CACNA1S that causes hypokalaemic periodic paralysis. The therapeutic effect of adrenalectomy indicated that unilateral adrenal hyperplasia might make paralytic attacks more serious and more frequent by decreasing serum potassium. This finding suggests that the surgical removal of hyperplastic tissues might relieve the symptoms of patients with severe hypokalaemic paralysis caused by other incurable diseases, even if the adrenal lesion does not cause primary aldosteronism.
doi:10.1186/1471-2490-14-96
PMCID: PMC4259161  PMID: 25430699
Unilateral adrenal hyperplasia; Hypokalaemic periodic paralysis; CACNA1S; Adrenalectomy
4.  Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis 
Molecular Cancer  2014;13(1):254.
Background
The epithelial-to-mesenchymal transition (EMT) process results in a loss of cell-cell adhesion, increased cell mobility, and is crucial for enabling the metastasis of cancer cells. Recently, the enzyme SIRT1 has been implicated in a variety of physiological processes; however, its role in regulating oral cancer metastasis and EMT is not fully elucidated. Here, we propose a mechanism by which the enzyme sirtuin1 (SIRT1) regulates the EMT process in oral cancer by deacetylating Smad4 and repressing the effect of TGF-β signaling on matrix metalloproteinase-7 (MMP7).
Methods
The roles of SIRT1 in tumor cell migration/invasion and metastasis to the lungs were investigated using the Boyden chamber assay and orthotopic injections, respectively. RNA interference was used to knockdown either SIRT1 or Smad4 expression in oral squamous cell carcinoma (OSCC) cell lines. Immunoblotting, zymographic assays, and co-immunoprecipitation were used to examine the effects of SIRT1 overexpression on MMP7 expression and activity, as well as on SIRT1/ Smad4 interaction.
Results
We found that compared with normal human oral keratinocytes (HOKs), SIRT1 was underexpressed in OSCC cells, and also in oral cancer tissues obtained from 14 of 21 OSCC patients compared with expression in their matched normal tissues. Overexpression of SIRT1 inhibited migration of OSCC cells in vitro, as well as their metastasis to the lung in vivo. Furthermore, up-regulation of SIRT1 in metastatic OSCCs significantly inhibited the migration and invasion abilities of OSCC cells, while concomitantly increasing the expression of E-cadherin, and decreasing the expressions of mesenchymal markers. We also identified Smad4, a TGF-β-activated transcription factor, as a direct target protein for SIRT1. Overexpression of SIRT1 in OSCC cells led to decreased levels of acetylated Smad4, and inhibition of TGF-β-induced signaling. By associating and deacetylating Smad4, SIRT1 enzyme can influence MMP7 expression, MMP enzyme activity, and consequently, cell migration, invasion, and tumor metastasis in OSCCs.
Conclusions
These findings provide a valuable insight into the potential role of the SIRT1 enzyme in regulating cell migration and invasion in oral squamous cell carcinoma. Our findings suggest the SIRT1/Smad4/MMP7 pathway as a target for oral cancer driven by EMT.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-254) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-4598-13-254
PMCID: PMC4258025  PMID: 25424420
Sirtuin 1; Epithelial-to-mesenchymal transition; Migration; Metastasis; Matrix metalloproteinase-7; Oral squamous cell carcinoma
5.  Molecular Mechanisms of Thoracic Aortic Dissection 
The Journal of surgical research  2013;184(2):907-924.
Thoracic aortic dissection (TAD) is a highly lethal vascular disease. In many patients with TAD, the aorta progressively dilates and ultimately ruptures. Dissection formation, progression, and rupture cannot be reliably prevented pharmacologically because the molecular mechanisms of aortic wall degeneration are poorly understood. The key histopathologic feature of TAD is medial degeneration, a process characterized by smooth muscle cell depletion and extracellular matrix degradation. These structural changes have a profound impact on the functional properties of the aortic wall and can result from excessive protease-mediated destruction of the extracellular matrix, altered signaling pathways, and altered gene expression. Review of the literature reveals differences in the processes that lead to ascending versus descending and sporadic versus hereditary TAD. These differences add to the complexity of this disease. Although tremendous progress has been made in diagnosing and treating TAD, a better understanding of the molecular, cellular, and genetic mechanisms that cause this disease is necessary to developing more effective preventative and therapeutic treatment strategies.
doi:10.1016/j.jss.2013.06.007
PMCID: PMC3788606  PMID: 23856125
aortic dissection; media; degeneration; aneurysm
6.  PathoScope 2.0: a complete computational framework for strain identification in environmental or clinical sequencing samples 
Microbiome  2014;2:33.
Background
Recent innovations in sequencing technologies have provided researchers with the ability to rapidly characterize the microbial content of an environmental or clinical sample with unprecedented resolution. These approaches are producing a wealth of information that is providing novel insights into the microbial ecology of the environment and human health. However, these sequencing-based approaches produce large and complex datasets that require efficient and sensitive computational analysis workflows. Many recent tools for analyzing metagenomic-sequencing data have emerged, however, these approaches often suffer from issues of specificity, efficiency, and typically do not include a complete metagenomic analysis framework.
Results
We present PathoScope 2.0, a complete bioinformatics framework for rapidly and accurately quantifying the proportions of reads from individual microbial strains present in metagenomic sequencing data from environmental or clinical samples. The pipeline performs all necessary computational analysis steps; including reference genome library extraction and indexing, read quality control and alignment, strain identification, and summarization and annotation of results. We rigorously evaluated PathoScope 2.0 using simulated data and data from the 2011 outbreak of Shiga-toxigenic Escherichia coli O104:H4.
Conclusions
The results show that PathoScope 2.0 is a complete, highly sensitive, and efficient approach for metagenomic analysis that outperforms alternative approaches in scope, speed, and accuracy. The PathoScope 2.0 pipeline software is freely available for download at: http://sourceforge.net/projects/pathoscope/.
doi:10.1186/2049-2618-2-33
PMCID: PMC4164323  PMID: 25225611
7.  Involvement of p53 Mutation and Mismatch Repair Proteins Dysregulation in NNK-Induced Malignant Transformation of Human Bronchial Epithelial Cells 
BioMed Research International  2014;2014:920275.
Genome integrity is essential for normal cellular functions and cell survival. Its instability can cause genetic aberrations and is considered as a hallmark of most cancers. To investigate the carcinogenesis process induced by tobacco-specific carcinogen NNK, we studied the dynamic changes of two important protectors of genome integrity, p53 and MMR system, in malignant transformation of human bronchial epithelial cells after NNK exposure. Our results showed that the expression of MLH1, one of the important MMR proteins, was decreased early and maintained the downregulation during the transformation in a histone modification involved and DNA methylation-independent manner. Another MMR protein PMS2 also displayed a declined expression while being in a later stage of transformation. Moreover, we conducted p53 mutation analysis and revealed a mutation at codon 273 which led to the replacement of arginine by histidine. With the mutation, DNA damage-induced activation of p53 was significantly impaired. We further reintroduced the wild-type p53 into the transformed cells, and the malignant proliferation can be abrogated by inducing cell cycle arrest and apoptosis. These findings indicate that p53 and MMR system play an important role in the initiation and progression of NNK-induced transformation, and p53 could be a potential therapeutic target for tobacco-related cancers.
doi:10.1155/2014/920275
PMCID: PMC4151862  PMID: 25215298
8.  Epithelial and stromal expression of miRNAs during prostate cancer progression 
Global microRNA (miRNA) profile may predict prostate cancer (PCa) behaviors. In this study, we examined global miRNA expression by miRNA profiling as well as specific miRNA expression levels in PCa epithelium and stroma by in situ hybridization (ISH) and correlated with various clinicopathological features. We first performed comprehensive miRNA profiling on 27 macrodissected cases of PCa by miRNA microarray. A total of 299 miRNAs were significantly dysregulated in high grade and advanced stage PCa. We demonstrated that PCa can be readily classified into high grade/stage and low-grade/stage groups by its global miRNA expression profile. Next, we examined the expression of several selected dysregulated miRNAs, including let-7c, miR-21, miR-27a, miR-30c, and miR-219, in PCa by ISH. The levels of miRNA expression in epithelial and stromal cells were scored semiquantitatively and compared with clinicopathological features, including age, race, Gleason score, stage, PSA recurrence, metastasis, hormone resistance and survival. We found that the expression of miR-30c and miR-219 were significantly down-regulated in PCa. miR-21 and miR-30c were significantly down-regulated in PCa in African Americans compared to Caucasian Americans. In addition, down-regulation of let-7c, miR-21, miR-30c, and miR-219 are associated with metastatic disease. Furthermore, down-regulation of miR-30c and let-7c are significantly associated with androgen-dependent PCa. In PCa stromal cells, let-7c downregulation is significantly associated with extraprostatic extension. Our data suggest that selected miRNAs may serve as potential biomarkers to predict cancer progression.
PMCID: PMC4113495  PMID: 25075250
miRNA; prostate cancer progression
9.  Full-Genome Analysis of Influenza A(H7N9) Virus from Shanghai, China, 2014 
Genome Announcements  2014;2(3):e00578-14.
We analyzed the complete genome sequence of the A/Shanghai/01/2014 (H7N9) strain, which will provide a better understanding of the evolution of influenza A(H7N9) virus.
doi:10.1128/genomeA.00578-14
PMCID: PMC4064026  PMID: 24948761
10.  3D Face Recognition Based on Multiple Keypoint Descriptors and Sparse Representation 
PLoS ONE  2014;9(6):e100120.
Recent years have witnessed a growing interest in developing methods for 3D face recognition. However, 3D scans often suffer from the problems of missing parts, large facial expressions, and occlusions. To be useful in real-world applications, a 3D face recognition approach should be able to handle these challenges. In this paper, we propose a novel general approach to deal with the 3D face recognition problem by making use of multiple keypoint descriptors (MKD) and the sparse representation-based classification (SRC). We call the proposed method 3DMKDSRC for short. Specifically, with 3DMKDSRC, each 3D face scan is represented as a set of descriptor vectors extracted from keypoints by meshSIFT. Descriptor vectors of gallery samples form the gallery dictionary. Given a probe 3D face scan, its descriptors are extracted at first and then its identity can be determined by using a multitask SRC. The proposed 3DMKDSRC approach does not require the pre-alignment between two face scans and is quite robust to the problems of missing data, occlusions and expressions. Its superiority over the other leading 3D face recognition schemes has been corroborated by extensive experiments conducted on three benchmark databases, Bosphorus, GavabDB, and FRGC2.0. The Matlab source code for 3DMKDSRC and the related evaluation results are publicly available at http://sse.tongji.edu.cn/linzhang/3dmkdsrcface/3dmkdsrc.htm.
doi:10.1371/journal.pone.0100120
PMCID: PMC4062431  PMID: 24940876
11.  Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis 
BMC Cancer  2014;14:442.
Background
Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis.
Methods
SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo.
Results
We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA.
Conclusions
Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.
doi:10.1186/1471-2407-14-442
PMCID: PMC4067087  PMID: 24931737
Extracellular signal-related kinase; Invasion; Metastasis; Oral cancer; Src-homology 2 domain-containing tyrosine phosphatase 2
12.  Clinical Value of 99Tcm-MDP SPECT Bone Scintigraphy in the Diagnosis of Unilateral Condylar Hyperplasia 
The Scientific World Journal  2014;2014:256256.
Purpose. To investigate the clinical value of 99Tcm-MDP SPECT for the diagnosis of unilateral condylar hyperplasia (UCH). Methods. One hundred forty-nine patients who underwent mandibular 99Tcm-MDP SPECT between January 2009 and December 2012 were studied, including 105 cases that were clinically suspected of UCH and 44 comparable cases without UCH as a control group. Results. Increased bone activity was observed in the affected condyles for all UCH patients. In the UCH group, the relative percentage uptake on the affected side was 59% (SD ± 4.3%), significantly higher than the 41% (SD ± 4.1%) uptake on the contralateral side (P<0.001). Similarly, the condyle/skull ratio was significantly higher for the affected side (1.66 ± 0.63) than for the contralateral side (1.34 ± 0.34, P < 0.01. No significant difference was found in the control group between the left and right condyles. Values for the sensitivity (95%), specificity (61%), positive (84.4%) and negative (84.6%) predictive values, and accuracy (84.5%) for 99Tcm-MDP SPECT in the diagnosis of UCH were calculated. However, for the hyperplastic condyle, no correlation was observed between the thickness of each cartilage layer and the relative uptake in the SPECT image. Conclusion. 99Tcm-MDP SPECT is accurate for diagnosing UCH and can provide a reference for treatment options.
doi:10.1155/2014/256256
PMCID: PMC4037566  PMID: 24901015
13.  Glycation of Apoprotein A-I Is Associated With Coronary Artery Plaque Progression in Type 2 Diabetic Patients 
Diabetes Care  2013;36(5):1312-1320.
OBJECTIVE
To investigate whether glycation level of apoprotein (apo)A-I is associated with coronary artery disease (CAD) and plaque progression in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Among 375 consecutive type 2 diabetic patients undergoing quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), 82 patients with nonsignificant stenosis (luminal diameter narrowing <30% [group I]) and 190 patients with significant CAD (luminal diameter stenosis ≥70% [group II]) were included for analysis of apoA-I glycation level and serum activity of lecithin: cholesterol acyltransferase (LCAT). The control group had 136 healthy subjects. At the 1-year follow-up, angiography and IVUS were repeated mainly in group II patients for plaque progression assessment.
RESULTS
Relative intensity of apoA-I glycation by densitometry was increased, and serum LCAT activity was decreased stepwise across groups control, I, and II. These two measurements were associated with the number of diseased coronary arteries and extent index in group II. During 1-year follow-up, QCA detected 45 patients with plaque progression in 159 subjects, and IVUS found 38 patients with plaque progression in 127 subjects. Baseline relative intensity of apoA-I glycation was significantly increased in patients with plaque progression compared with those without, with values associated with changes in QCA and IVUS measurements. Multivariable regression analysis revealed that baseline relative intensity of apoA-I glycation was an independent determinant of CAD and plaque progression in type 2 diabetic patients.
CONCLUSIONS
ApoA-I glycation level is associated with the severity of CAD and coronary artery plaque progression in type 2 diabetic patients.
doi:10.2337/dc12-1411
PMCID: PMC3631856  PMID: 23230102
14.  3D Ear Identification Based on Sparse Representation 
PLoS ONE  2014;9(4):e95506.
Biometrics based personal authentication is an effective way for automatically recognizing, with a high confidence, a person’s identity. Recently, 3D ear shape has attracted tremendous interests in research field due to its richness of feature and ease of acquisition. However, the existing ICP (Iterative Closet Point)-based 3D ear matching methods prevalent in the literature are not quite efficient to cope with the one-to-many identification case. In this paper, we aim to fill this gap by proposing a novel effective fully automatic 3D ear identification system. We at first propose an accurate and efficient template-based ear detection method. By utilizing such a method, the extracted ear regions are represented in a common canonical coordinate system determined by the ear contour template, which facilitates much the following stages of feature extraction and classification. For each extracted 3D ear, a feature vector is generated as its representation by making use of a PCA-based local feature descriptor. At the stage of classification, we resort to the sparse representation based classification approach, which actually solves an l1-minimization problem. To the best of our knowledge, this is the first work introducing the sparse representation framework into the field of 3D ear identification. Extensive experiments conducted on a benchmark dataset corroborate the effectiveness and efficiency of the proposed approach. The associated Matlab source code and the evaluation results have been made publicly online available at http://sse.tongji.edu.cn/linzhang/ear/srcear/srcear.htm.
doi:10.1371/journal.pone.0095506
PMCID: PMC3989323  PMID: 24740247
15.  High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma 
Background
The expression of 5-hydroxymethylcytosine (5-hmC) and isocitrate dehydrogenase 2 (IDH2) is frequently downregulated in numerous cancers. 5-hmC and IDH2 expression in hepatocellular carcinoma (HCC) has yet to be determined.
Methods
The immunohistochemical expression of 5-hmC and IDH2 were analyzed in tissue microarrays containing samples from 646 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of 5-hmC and IDH2 were evaluated by Cox regression and Kaplan-Meier analyses.
Results
We discovered that low 5-hmC and IDH2 expression was associated with malignant behaviors. Low 5-hmC or IDH2 expression alone and combined 5-hmC and IDH2 expression were associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that 5-hmC or IDH2 and 5-hmC/IDH2 were independent prognostic indicators for OS and time to recurrence (TTR), which was confirmed in an independent validation cohort.
Conclusions
5-hmC and IDH2 correlate with less aggressive tumor behavior in HCC. When 5-hmC and IDH2 are considered together, they serve as a prognostic marker in patients with surgically resected HCCs.
doi:10.1186/1756-9966-33-32
PMCID: PMC4081660  PMID: 24716838
5-hydroxymethylcytosine; Isocitrate dehydrogenase 2; Hepatocellular carcinoma; Immunohistochemistry; Prognosis
16.  Androgen receptor coactivators that inhibit prostate cancer growth 
It is well documented that androgen receptor (AR), a steroid hormone receptor, is important for prostate cancer (PCa) growth. Conversely, however, there is increasing evidence that activation of AR by androgens can also lead to growth suppression in prostate cells. AR mediated transcription is regulated by a number of different transcriptional coactivators. Changes in expression level or cellular localization of specific coactivators may play a crucial role in this switch between proliferative and anti- proliferative processes regulated by AR target gene programs. In this review, we discuss the expression and function of several AR coactivators exhibiting growth suppressive function in PCa, including ARA70/ELE1/NCOA4, androgen receptor coactivator p44/MEP50/WDR77, TBLR1, and ART-27. In luciferase reporter assays, they all have been shown to activate AR mediated transcriptional activation. ARA70 exists in two forms, the full length nuclear ARA70α and internally spliced cytoplasmic ARA70β. For p44 and TBLR1, we identified nuclear and cytoplasmic forms with distinct expression and function. In comparison of their expression (ARA70α, p44, TBLR1 and ART-27) in prostate, these coactivators are expressed in the nucleus of benign prostate epithelial cells while they are more predominantly expressed in cytoplasmic form (ARA70β, cytoplasmic p44 and TBLR1) in PCa. Consistent with their nuclear expression in benign prostate, the nuclear form of these coactivators inhibit PCa growth targeting a subset of AR target genes. In contrast, the cytoplasmic versions of these proteins enhance PCa growth and invasion. Interestingly, first characterized as an AR coactivator in luciferase assays, ART-27 functions as corepressor for endogenous AR target genes. Importantly, the growth inhibitions by these nuclear proteins are androgen-dependent processes and the regulation of invasion is androgen-independent. Understanding the molecular switches involved in the transition from AR dependent growth promotion to growth suppression and dysregulation of these coactivator proteins promoting androgen-independent invasion may lead to identification of novel therapeutic targets for PCa.
PMCID: PMC4219292  PMID: 25374906
Androgen receptor; coactivator; growth inhibition; prostate cancer
17.  HGCS: an online tool for prioritizing disease-causing gene variants by biological distance 
BMC Genomics  2014;15:256.
Background
Identifying the genotypes underlying human disease phenotypes is a fundamental step in human genetics and medicine. High-throughput genomic technologies provide thousands of genetic variants per individual. The causal genes of a specific phenotype are usually expected to be functionally close to each other. According to this hypothesis, candidate genes are picked from high-throughput data on the basis of their biological proximity to core genes — genes already known to be responsible for the phenotype. There is currently no effective gene-centric online interface for this purpose.
Results
We describe here the human gene connectome server (HGCS), a powerful, easy-to-use interactive online tool enabling researchers to prioritize any list of genes according to their biological proximity to core genes associated with the phenotype of interest. We also make available an updated and extended version for all human gene-specific connectomes. The HGCS is freely available to noncommercial users from: http://hgc.rockefeller.edu/.
Conclusions
The HGCS should help investigators from diverse fields to identify new disease-causing candidate genes more effectively, via a user-friendly online interface.
doi:10.1186/1471-2164-15-256
PMCID: PMC4051124  PMID: 24694260
18.  The Proteome of TLR3-stimulated human immortalized fibroblasts; implications for susceptibility to herpes simplex encephalitis 
Background
Inborn errors in the Toll like receptor 3 (TLR3)-Interferon (IFN) type I and III pathway have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE-susceptibility. Moreover, many patients do not display any TLR3-related fibroblastic phenotype.
Objective
This suggests the study of other signalling pathways downstream of TLR3 and/or other independent pathways which may contribute to HSE susceptibility.
Methods
We have used the stable isotope labelling of amino acids in cell culture (SILAC) proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation.
Results
Cells from healthy controls were compared to cells from a patient with a known genetic aetiology of HSE (UNC93B−/−) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2 (SOD2). The HSE patients show clear differences in functional response networks when compared to healthy patients and also when compared to each other.
Conclusions
The present study delineates a number of novel proteins, TLR3-related pathways and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal SOD2 as a potential therapeutic target for amelioration of the neurological sequelae caused by HSE.
doi:10.1016/j.jaci.2013.01.008
PMCID: PMC3640632  PMID: 23434283
Herpes simplex encephalitis (HSE); SILAC; proteomics; mass spectrometry; fibroblast; herpes simplex virus 1 (HSV-1); TLR3; interferon (IFN)
19.  AKT2 Confers Protection Against Aortic Aneurysms and Dissections 
Circulation research  2012;112(4):618-632.
Rationale
Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown.
Objective
In this study, we examined the role of AKT2 in protecting the aorta from developing AAD.
Methods and Results
AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II (AngII), these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. Additionally, AngII-infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase (MMP)-9 and reduced expression of tissue inhibitor of metalloproteinase (TIMP)-1. In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 (FOXO1) to the MMP-9 and TIMP-1 promoters.
Conclusions
Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.
doi:10.1161/CIRCRESAHA.112.300735
PMCID: PMC3586338  PMID: 23250987
Aortic aneurysm and dissection; AKT; FOXO1; MMP-9; TIMP-1
20.  ADAMTS-1 and ADAMTS-4 levels are Elevated in Thoracic Aortic Aneurysms and Dissections 
The Annals of thoracic surgery  2012;95(2):570-577.
Background
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently identified family of extracellular metalloproteinases that has been shown to participate in tissue destruction. We hypothesized that ADAMTS-1 and ADAMTS-4 expression is increased in aortic tissues from patients with thoracic aortic aneurysms and dissections.
Methods
We examined ADAMTS-1 and ADAMTS-4 expression in human descending thoracic aortic aneurysms (n=14), chronic descending thoracic aortic dissections (n=16), and descending thoracic aortas from age-matched control organ donors (n=12). In these tissues, we also evaluated the degradation of versican, a proteoglycan substrate of ADAMTS-1 and ADAMTS-4. In cultured macrophages, we examined whether ADAMTS-4 functions in macrophage infiltration by using a transwell assay.
Results
ADAMTS-1 and ADAMTS-4 protein and mRNA expression was significantly higher in thoracic aortic aneurysm and dissection tissues than in control aortic tissues. Double immunofluorescence staining showed the expression of ADAMTS-1 and ADAMTS-4 in smooth muscle cells and macrophages. Consistent with the upregulation of ADAMTS-1 and ADAMTS-4 in thoracic aortic aneurysm and dissection tissues, versican was degraded significantly more in these tissues than in control aortic tissues. In cultured macrophages, transforming growth factor-β increased ADAMTS-4 protein levels and induced macrophage invasion; knocking down ADAMTS-4 reduced cell invasion.
Conclusions
Increased expression of ADAMTS proteins may promote thoracic aortic aneurysm progression by degrading versican and facilitating macrophage invasion.
doi:10.1016/j.athoracsur.2012.10.084
PMCID: PMC3593585  PMID: 23245439
Aneurysm (thoracic aortic); inflammatory cells (macrophages); inflammatory mediators (metalloproteinases); pathology (aorta); vascular science (pathology)
21.  TLR3 immunity to infection in mice and humans 
Current opinion in immunology  2013;25(1):19-33.
TLR3 is a receptor for dsRNA, which is generated during most viral infections. However, other cellular processes may also produce dsRNA and there are other receptors for dsRNA. The role of TLR3 in protective immunity to viruses has been investigated in mice and humans with genetically impaired TLR3 responses. TLR3-deficient mice responded to experimental challenge with 16 different viruses in various ways. They were susceptible to eight viruses, normally resistant to three other viruses, and their survival rates were higher than those of wild-type mice following infection with four other viruses. Conflicting results were obtained for the other virus tested. These data are difficult to understand in terms of a simple pattern based on virus structure or tissue tropism. Surprisingly, the known human patients with inborn errors of the TLR3 pathway have remained healthy or developed encephalitis in the course of natural primary infection with HSV-1. These patients display no clear susceptibility to other infections, including viral infections, such as other forms of viral encephalitis and other HSV-1 diseases in particular. This restricted susceptibility to viruses seems to result from impaired TLR3-dependent IFN-α/β production by central nervous system (CNS)-resident non-hematopoietic cells infected with HSV-1. These studies neatly illustrate the value of combining genetic studies of experimental infections in mice and natural infections in humans, to elucidate the biological function of host molecules in protective immunity.
doi:10.1016/j.coi.2012.11.001
PMCID: PMC3594520  PMID: 23290562
22.  Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma 
Oncotarget  2014;5(4):882-893.
Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.
PMCID: PMC4011590  PMID: 24658464
Glioblastoma; DRD2; EGFR; mitogenic signaling
23.  Olive Leaf Extract Attenuates Obesity in High-Fat Diet-Fed Mice by Modulating the Expression of Molecules Involved in Adipogenesis and Thermogenesis 
The present study aimed to investigate whether olive leaf extract (OLE) prevents high-fat diet (HFD)-induced obesity in mice and to explore the underlying mechanisms. Mice were randomly divided into groups that received a chow diet (CD), HFD, or 0.15% OLE-supplemented diet (OLD) for 8 weeks. OLD-fed mice showed significantly reduced body weight gain, visceral fat-pad weights, and plasma lipid levels as compared with HFD-fed mice. OLE significantly reversed the HFD-induced upregulation of WNT10b- and galanin-mediated signaling molecules and key adipogenic genes (PPARγ, C/EBPα, CD36, FAS, and leptin) in the epididymal adipose tissue of HFD-fed mice. Furthermore, the HFD-induced downregulation of thermogenic genes involved in uncoupled respiration (SIRT1, PGC1α, and UCP1) and mitochondrial biogenesis (TFAM, NRF-1, and COX2) was also significantly reversed by OLE. These results suggest that OLE exerts beneficial effects against obesity by regulating the expression of genes involved in adipogenesis and thermogenesis in the visceral adipose tissue of HFD-fed mice.
doi:10.1155/2014/971890
PMCID: PMC3927866  PMID: 24624222
24.  The Reaction of Bone to Tumor Growth From Human Breast Cancer Cells in a Rat Spine Single Metastasis Model 
Spine  2011;36(7):497-504.
Study Design
In vivo experiments to develop a rat spine single metastasis model by using human breast cancer cells.
Objective
To study the survival and tumorigenesis of the human breast cancer cells after transplantation to vertebral body (VB) by intraosseous injection as a model for therapeutic studies of spine metastatic tumor.
Summary of Background Data
VBs are the most common bones involved in the metastases of breast cancer. To develop experimental therapeutics requires an appropriate animal model. Moreover, it is also important to establish accurate and sensitive detection methods for the evaluation.
Methods
MDA-MB-231 human breast cancer cells were injected into 3-week-old female athymic rats. The tumorigenesis was assayed with quantitative in vivo bioluminescence (IVIS), microcomputed tomography (micro-CT), quantitative CT (qCT), micro position emission tomography (micro-PET), and histologic studies.
Results
A spine single metastasis model of human breast cancer was successfully developed in rats. The IVIS signal intensity from the cancer cells increased after 2 weeks. Signal from the tumor in spine can be detected by micro-PET at day 1. The signal intensity decreased after 1 week and then recovered and continually increased afterwards. Bone destruction was demonstrated in the qCT and micro-CT images. However, both qCT and micro-CT found that the bone density in the cancer cell-injected VB increased before the appearance of osteolysis. The growth of tumor and the reaction of bone in the VB were observed simultaneously by histology.
Conclusion
A spine single metastasis model was developed by injection of human breast cancer cells into the VB of athymic rats. This is the first report of quantitative evaluation with micro-PET in a spine metastasis model. In addition, the detection of osteogenesis after the introduction of MDA-MB-231 cells in vivo is a novel observation.
doi:10.1097/BRS.0b013e3181d8906f
PMCID: PMC3897243  PMID: 21422981
breast cancer; animal model; spine tumor; metastasis; positron emission tomography
25.  EVER2 Deficiency is Associated with Mild T-cell Abnormalities 
Journal of clinical immunology  2012;33(1):14-21.
Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4+ and CD8+ T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4+ and effector memory CD8+ T cells, a bias of the TCR Vαβ and Vγδ repertoires and an increase of skin-homing CD4+ T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both.
doi:10.1007/s10875-012-9749-1
PMCID: PMC3733103  PMID: 22903682
Epidermodysplasia verruciformis; EVER; immune deficiencies; Tcells

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