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1.  Proteomic Study of Differential Protein Expression in Mouse Lung Tissues after Aerosolized Ricin Poisoning 
Ricin is one of the most poisonous natural toxins from plants and is classified as a Class B biological threat pathogen by the Centers for Disease Control and Prevention (CDC) of U.S.A. Ricin exposure can occur through oral or aerosol routes. Ricin poisoning has a rapid onset and a short incubation period. There is no effective treatment for ricin poisoning. In this study, an aerosolized ricin-exposed mouse model was developed and the pathology was investigated. The protein expression profile in the ricin-poisoned mouse lung tissue was analyzed using proteomic techniques to determine the proteins that were closely related to the toxicity of ricin. 2D gel electrophoresis, mass spectrometry and subsequent biological functional analysis revealed that six proteins including Apoa1 apolipoprotein, Ywhaz 14-3-3 protein, Prdx6 Uncharacterized Protein, Selenium-binding protein 1, HMGB1, and DPYL-2, were highly related to ricin poisoning.
doi:10.3390/ijms15057281
PMCID: PMC4057672  PMID: 24786090
ricin; aerosol; lung injury; proteomics
2.  Biocompatible and Photostable AIE Dots with Red Emission for In Vivo Two-Photon Bioimaging 
Scientific Reports  2014;4:4279.
Bioimaging systems with cytocompatibility, photostability, red fluorescence, and optical nonlinearity are in great demand. Herein we report such a bioimaging system. Integration of tetraphenylethene (T), triphenylamine (T), and fumaronitrile (F) units yielded adduct TTF with aggregation-induced emission (AIE). Nanodots of the AIE fluorogen with efficient red emission were fabricated by encapsulating TTF with phospholipid. The AIE dots enabled three-dimensional dynamic imaging with high resolution in blood vessels of mouse brain under two-photon excitation.
doi:10.1038/srep04279
PMCID: PMC3955920  PMID: 24632722
3.  Influenza A(H1N1)pdm09 Virus Infection in Giant Pandas, China 
Emerging Infectious Diseases  2014;20(3):480-483.
We confirmed infection with influenza A(H1N1)pdm09 in giant pandas in China during 2009 by using virus isolation and serologic analysis methods. This finding extends the host range of influenza viruses and indicates a need for increased surveillance for and control of influenza viruses among giant pandas.
doi:10.3201/eid2003.131531
PMCID: PMC3944863  PMID: 24565026
giant pandas; pandemic; H1N1; influenza A virus; influenza A(H1N1)pdm09; serologic analysis; influenza; viruses; China; Ailuropoda melanoleuca; respiratory infections
4.  Over-expression of miR-98 in FFPE tissues might serve as a valuable source for biomarker discovery in breast cancer patients 
The miR-98 is thought to be associated with various cancers. This study was to evaluate the potential predictive value of miR-98 expression in formalin-fixed paraffin-embedded tissue of breast cancer patients. The expression levels of miR-98 were examined in 98 breast cancer patients and 40 cancer-free controls using real-time quantitative PCR. The comparison of miR-98 expression levels between patient and control was performed using the Mann-Whitney test. The miR-98 showed higher expression levels in breast cancer patients compared with cancer free controls (p<0.01). The expression levels of miR-98 were highly correlated with miR24/93/378 in breast cancer patients. The miR-98 exhibited great capability of discriminating between cancer patients and controls by the Receiver-operator characteristic (ROC) curve analysis. The miR-98 was found highly correlated with breast cancer by Univariable logistic regression analysis. These results suggest that over-expression of miR-98 in formalin-fixed paraffin-embedded tissues might serve as a valuable source for biomarker discovery in breast cancer patients.
PMCID: PMC3971322  PMID: 24696733
Biomarkers; miR-98; breast cancer; miRNA; cancer
5.  SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival 
Purpose
We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed proteins in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when compared to matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival.
Experimental Design
To test our hypothesis we first analyzed the protein expression of SLC1A5 used in archival lung cancer tissues by immunohistochemictry (IHC) and immunoblotting (N=98), and cell lines (N=36). To examine SLC1A5 involvement in a.a transportation, we performed kinetic analysis of Gln uptake in lung cancer cell lines in the presence and absence of a pharmacological inhibitor of SLC1A5, gamma-L-Glutamyl-p-Nitroanilide (GPNA). Finally we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell cycle progression and growth signaling pathways of 5 lung cancer cell lines.
Results
Our results demonstrate that 1) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC) and 50% of neuroendocrine tumors, 2) SLC1A5 is located at the cytoplasmic membrane, is significantly associated with SCC histology and male gender, and 3) 68% of Gln is transported in a Na+ -dependent manner, 50% of which is attributed to SLC1A5 activity, 4) pharmacological and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR- signaling.
Conclusions
These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells metabolism, growth and survival.
doi:10.1158/1078-0432.CCR-12-2334
PMCID: PMC3697078  PMID: 23213057
Biomarkers; glutamine; transporters; lung cancer
6.  Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice 
There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming.
doi:10.1172/JCI70291
PMCID: PMC3904614  PMID: 24401276
7.  Efficacy analysis of three-year subcutaneous SQ-standardized specific immunotherapy in house dust mite-allergic children with asthma 
The present study aimed to evaluate the efficacy of three-year subcutaneous SQ-standardized specific immunotherapy (SCIT) in house dust mite (HDM)-allergic children with asthma. Ninety children with allergic asthma to HDMs, with or without allergic rhinitis, were randomly divided into two groups, the treatment group and the control group. The treatment group received SCIT combined with standardized glucocorticoid management and the control group received standardized glucocorticoid management alone for a period of three years. The mean daily dose of inhaled corticosteroids (ICSs), a four-week diary recording the symptom scores of asthma, peak expiratory flow (PEF) measurements, skin prick test results and serum immunoglobulin E (IgE) levels were assessed prior to treatment and following one, two and three years of treatment. The median dose of ICS was reduced in the treatment group after two and three years of treatment compared with that of the control group. After three years of treatment, the discontinuation percentage of ICS in the treatment group was higher than that in the control group. The treatment group demonstrated significantly reduced daytime and night-time asthmatic symptom scores, increased PEF values and reduced serum IgE levels after two and three years of treatment compared with those in the control group (P<0.05). In conclusion, three-year SCIT treatment combined with ICS is an effective immunotherapy for children with allergic asthma and resulted in a reduction of the required ICS dose.
doi:10.3892/etm.2014.1469
PMCID: PMC3919950  PMID: 24520258
SQ-standardized specific immunotherapy; inhaled corticosteroids; asthma; house dust mite; children
8.  No Association of Genetic Variants in BDNF With Major Depression: A Meta- and Gene-Based Analysis 
Major depressive disorder (MDD) is a complex psychiatric condition with strong genetic predisposition. The association of MDD with genetic polymorphisms, such as Val66Met (rs6265), in the brain derived neurotrophic factor (BDNF), have been reported in many studies and the results were conflicting. In this study, we performed a systematic literature search and conducted random-effects meta-analysis to evaluate genetic variants in BDNF with MDD. A gene-based analysis was also conducted to investigate the cumulative effects of genetic polymorphisms in BDNF. A total of 28 studies from 26 published articles were included in our analysis. Meta-analysis yielded an estimated odds ratio (OR) of 0.96 (95% CI: 0.89–1.05; P= 0.402) for Val66Met (rs6265), 0.83 (95% CI: 0.67–1.04; P= 0.103) for 11757C/G, 1.16 (95% CI: 0.74–1.82; P= 0.527) for 270T/C, 1.03 (95% CI: 0.18–5.75; P= 0.974) for 712A/G and 0.98 (95% CI: 0.85–1.14; P= 0.831) for rs988748. The gene-based analysis indicated that BDNF is not associated with MDD (P>0.21). Our updated meta- and novel gene-based analyses provide no evidence of the association of BDNF with major depression.
doi:10.1002/ajmg.b.32122
PMCID: PMC3725128  PMID: 23184535
major depressive disorder; BDNF; polymorphism; meta-analysis; gene-based analysis
9.  Intraductal papillary neoplasm of the bile duct 
Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma that is characterized by intraductal growth and better outcomes compared with common cholangiocarcinoma. IPNBs are mainly found in patients from Far Eastern areas, where hepatolithiasis and clonorchiasis are endemic. According to the immunohistochemical profiles of the mucin core proteins, IPNBs are classified into four types: pancreaticobiliary, intestinal, gastric, and oncocytic. Approximately 40%-80% of IPNBs contain a component of invasive carcinoma or tubular or mucinous adenocarcinoma, suggesting that IPNB is a disease with high potential for malignancy. It is difficult to make an accurate preoperative diagnosis because of IPNB’s low incidence and the lack of specificity in its clinical manifestation. The most common abnormal preoperative imaging findings of IPNB are intraductal masses and the involvement of bile duct dilation. Simultaneous proximal and distal bile duct dilation can be detected in some cases, which has diagnostic significance. Cholangiography and cholangioscopy are needed to confirm the pathology and demonstrate the extent of the lesions. However, pathologic diagnosis by biopsy cannot reflect the actual stage in many cases because different foci may be of different stages and because mixed pathologic findings may exist in the same lesion. Surgical resection is the major treatment. Systematic cholangioscopy with staged biopsies and frozen sections is recommended during resection to ensure that no minor tumors are left and that curative resection is achieved. Staging, histologic subtype, curative resection and lymph node metastasis are factors affecting long-term survival.
doi:10.3748/wjg.v19.i46.8595
PMCID: PMC3870504  PMID: 24379576
Intraductal neoplasm; Papillary cholangiocarcinoma; Biliary papillomatosis; Mucinous; Prognosis
10.  An Anti-Human Thymocyte Globulin-Based Reduced-Intensity Conditioning Regimen Is Associated with a Higher Quality of Life and Lower Organ Toxicity without Affecting Lymphocyte Reconstitution 
PLoS ONE  2013;8(9):e73755.
Reduced-intensity (RIT) conditioning regimens are gaining increased attention as a result of their advantages and efficacy. However, no data are available regarding whether these regimens improve patient quality of life (QoL). In our study, health-related QoL (HRQoL) was retrospectively assessed in 111 patients with hematological malignancies. Analysis of the Quality of Life Questionnaire indicated that 35 of the RIT patients were able to perform their normal work and returned to their baseline levels of function 2 to 3 months after transplantation. In the myeloablative (MA) group, only 24 patients were able to resume work, and these patients returned to their baseline levels of function 6 to 8 months after transplantation (68.6% vs. 40.0%, P = 0.004). Grade III–IV organ toxicity occurred in 20% of the RIT patients and in 52% of the MA patients (P = 0.001), and the cumulative incidences of grades III–IV acute graft-versus-host disease (GVHD) were 13.7% and 35.0% in RIT and MA patients, respectively (P = 0.015). In conclusion, the RIT conditioning regimens were well tolerated by the patients, with a low incidence of transplant-related mortality (TRM) and serious acute GVHD. In addition, these regimens minimized procedure-related toxicity, improved QoL and did not influence lymphocyte reconstitution; however, OS was similar for both regimens because the relapse rate was relatively increased in the RIT groups.
doi:10.1371/journal.pone.0073755
PMCID: PMC3767797  PMID: 24040055
11.  Hepatic Parenchymal Changes following Transcatheter Embolization and Chemoembolization in a Rabbit Tumor Model 
PLoS ONE  2013;8(8):e70757.
Objective
To compare the effects of transcatheter arterial chemoembolization (TACE) with transcatheter arterial embolization (TAE) on liver function, hepatic damage, and hepatic fibrogenesis in a rabbit tumor model.
Materials and Methods
Thirty-nine New Zealand white rabbits implanted with VX2 tumors in the left liver lobes were randomly divided into three groups: TAE, TACE, and control group. In the TAE group (n = 15), polyvinyl alcohol particles (PVAs) were used for left hepatic artery embolization. In the TACE group (n = 15), the tumors were treated with left hepatic arterial infusions of a suspension of 10-hydroxycamptothecin and lipiodol, followed by embolization with PVAs. In the control group (n = 9), the animals received sham treatment with distilled water. Serum and liver samples were collected at 6 hours, 3 days and 7 days after treatment. Liver damage was measured using a liver function test and histological analyses. Liver fibrogenesis and hepatic stellate cell (HSC) activation were evaluated using Sirius Red and anti-alpha-smooth muscle actin (α-SMA) immunohistochemical stains.
Results
TACE caused liver injury with greater increases in serum alanine aminotransferase and aspartate aminotransferase levels on day 3 (P<0.05). Histological analyses revealed increased hepatic necrosis in adjacent non-tumorous liver tissue from day 3 compared to the TAE group (Suzuki score of 2.33±1.29 versus 1.13±1.18, P = 0.001). HSC activation and proliferation were significantly increased in the TACE group compared to the control group at 3 and 7 days after treatment (0.074±0.014 vs. 0.010±0.006, and 0.088±0.023 vs. 0.017±0.009, P<0.05). Sirius Red staining demonstrated a statistically significant increase in collagen deposition in the livers in the TACE group 7 days after embolization compared to the control group (0.118±0.012 vs. 0.060±0.017, P = 0.05).
Conclusion
The results of this animal study revealed that TACE induced prominent hepatocellular damage and hepatic fibrogenesis, which compromised liver function and may be responsible for chronic liver decompensation.
doi:10.1371/journal.pone.0070757
PMCID: PMC3743795  PMID: 23967098
12.  Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis 
The European respiratory journal  2011;39(5):1171-1180.
Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis.
pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression.
Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues.
pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.
doi:10.1183/09031936.00184410
PMCID: PMC3717253  PMID: 21965228
Differentiation; lung adenocarcinoma; lung pre-invasive lesions; polymeric immunoglobulin receptor; proliferation
13.  Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development 
Science translational medicine  2010;2(26):26ra25.
Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.
doi:10.1126/scitranslmed.3000251
PMCID: PMC3694402  PMID: 20375364
14.  Detection of Murine Toxoplasmosis Using Magnetic Bead-Based Serum Peptide Profiling by MALDI-TOF MS 
Abstract
Establishment of a rapid, highly specific, and accurate method for diagnosis of Toxoplasma gondii infection is essential to control and prevent zoonotic toxoplasmosis. In this study, a novel diagnostic strategy using magnetic bead-based serum peptide profiling by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was developed. The serum peptides (samples I, II, and III) from T. gondii RH strain-infected mice at days 3, 6, and 9 post-infection (p.i.), and healthy mice were enriched by the optimized magnetic bead-based hydrophobic interaction (MB-HIC8). The mass spectrograms were acquired by MALDI-TOF MS, and analyzed by ClinProTools bioinformatics software from Bruker Daltonics. The diagnostic models from T. gondii RH-infected serum peptide profiling of samples I, II, and III were produced by genetic algorithms, and verified by cross-validation. The sample II model could correctly recognize T. gondii RH strain infection in mice at days 3, 6, and 9 p.i. with a sensitivity of 91.1% and a specificity of 96.7%., and also detect T. gondii ME49 strain-infected serum samples at days 3, 6, 9, and 12 p.i. with a sensitivity of 91.7%. The results of the present study suggest that serum peptide profiling by MALDI-TOF MS is a novel potential tool for the clinical diagnosis of acute T. gondii infection.
doi:10.1089/vbz.2011.0742
PMCID: PMC3366097  PMID: 22448678
MALDI-TOF MS; Mice; Serum peptide profiling; Toxoplasmosis
15.  Comparison of two different double-plate fixation methods with olecranon osteotomy for intercondylar fractures of the distal humeri of young adults 
Although several studies have demonstrated good results with open reduction and internal fixation of intercondylar fractures of the distal humerus, few have specifically addressed the results of such surgical fixation in young adults. The purpose of this study was to compare the clinical outcomes in patients with intercondylar fractures of the distal humerus treated using two different double-plating methods. Twenty-five patients with distal humeral fractures classified as type C according to the Association for Osteosynthesis/Association for the Study of Internal Fixation (AO/ASIF) classification system, who were admitted to the Second Hospital Affiliated to Anhui Medical University (Hefei, China) from October 2008 to October 2011, were included in the study. The patients were treated with two different double-plate fixation and olecranon osteotomy methods. Thirteen patients were treated by perpendicular plating (group I) and twelve patients by Y-shaped double-plating in the coronal plane (group II). All the patients were followed up for 12–38 months, with an average of 19.2±7.1 months in group I and 18.3±4.0 months in group II. All the osteotomies and fractures had healed by the final follow-up. Complications developed in 4 patients in group I and 3 patients in group II. According to the Mayo Elbow Performance Scores (MEPS), 84.6% of patients in group I and 83.3% in group II had excellent or good scores. No significant differences were identified between the clinical outcomes of the two plating methods. The olecranon osteotomy approach with double-plate fixation is a good choice for the surgical treatment of type C intercondylar fractures in young adult distal humeri. The two plating methods provide solid fixation, permit early rehabilitation and result in satisfactory clinical outcomes.
doi:10.3892/etm.2013.1102
PMCID: PMC3735874  PMID: 23935736
intercondylar fracture; distal humerus; double plate; internal fixation
16.  Genetic variants in FTO associated with metabolic syndrome: a meta- and gene-based analysis 
Molecular Biology Reports  2011;39(5):5691-5698.
The objective of this study was to examine the effect of genetic variants in fat mass and obesity associated (FTO) gene on metabolic syndrome (MetS). A systematic literature search was performed and random-effects meta-analysis was used to evaluate genetic variants in FTO with MetS. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in FTO. A total of 18 studies from 13 published papers were included in our analysis. Random-effects meta-analysis yielded an estimated odds ratio of 1.19 (95% CI 1.12–1.27; P = 1.38 × 10−7) for rs9939609, 1.19 (95% CI 1.05–1.35; P = 0.008) for rs8050136, and 1.89 (95% CI 1.20–2.96; P = 0.006) for rs1421085. The gene-based analysis indicated that FTO is strongly associated with MetS (P < 10−5). This association remains after excluding rs9939609, a SNP that was frequently reported to have strong association with obesity and MetS. In this study, we concluded that the FTO gene may play a critical role in leading to MetS. Targeting this gene may provide novel therapeutic strategies for the prevention and treatment of metabolic syndrome.
doi:10.1007/s11033-011-1377-y
PMCID: PMC3381863  PMID: 22189543
Metabolic syndrome; FTO; Polymorphism; Meta-analysis; Gene-based analysis
17.  The Complete Chloroplast Genome Sequence of the Medicinal Plant Salvia miltiorrhiza 
PLoS ONE  2013;8(2):e57607.
Salvia miltiorrhiza is an important medicinal plant with great economic and medicinal value. The complete chloroplast (cp) genome sequence of Salvia miltiorrhiza, the first sequenced member of the Lamiaceae family, is reported here. The genome is 151,328 bp in length and exhibits a typical quadripartite structure of the large (LSC, 82,695 bp) and small (SSC, 17,555 bp) single-copy regions, separated by a pair of inverted repeats (IRs, 25,539 bp). It contains 114 unique genes, including 80 protein-coding genes, 30 tRNAs and four rRNAs. The genome structure, gene order, GC content and codon usage are similar to the typical angiosperm cp genomes. Four forward, three inverted and seven tandem repeats were detected in the Salvia miltiorrhiza cp genome. Simple sequence repeat (SSR) analysis among the 30 asterid cp genomes revealed that most SSRs are AT-rich, which contribute to the overall AT richness of these cp genomes. Additionally, fewer SSRs are distributed in the protein-coding sequences compared to the non-coding regions, indicating an uneven distribution of SSRs within the cp genomes. Entire cp genome comparison of Salvia miltiorrhiza and three other Lamiales cp genomes showed a high degree of sequence similarity and a relatively high divergence of intergenic spacers. Sequence divergence analysis discovered the ten most divergent and ten most conserved genes as well as their length variation, which will be helpful for phylogenetic studies in asterids. Our analysis also supports that both regional and functional constraints affect gene sequence evolution. Further, phylogenetic analysis demonstrated a sister relationship between Salvia miltiorrhiza and Sesamum indicum. The complete cp genome sequence of Salvia miltiorrhiza reported in this paper will facilitate population, phylogenetic and cp genetic engineering studies of this medicinal plant.
doi:10.1371/journal.pone.0057607
PMCID: PMC3584094  PMID: 23460883
18.  Cell Budding from Normal Appearing Epithelia: A Predictor of Colorectal Cancer Metastasis? 
Background: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC.
Novel findings: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or “budding” of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker.
New hypothesis: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as “seeds” to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation.
doi:10.7150/ijbs.5441
PMCID: PMC3555151  PMID: 23355797
Lymphocyte infiltration; tumor capsule; tumor invasion; tumor metastasis; stem cell.
19.  Tumor-Infiltrating Immune Cells: Triggers for Tumor Capsule Disruption and Tumor Progression? 
Background: Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC).
Materials and Methods: Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging.
Results: Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination.
Conclusions: Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis.
doi:10.7150/ijms.5798
PMCID: PMC3607233  PMID: 23532368
Colorectal cancer; tumor capsule; tumor invasion; metastasis, lymphocyte aggregates.
20.  FastUniq: A Fast De Novo Duplicates Removal Tool for Paired Short Reads 
PLoS ONE  2012;7(12):e52249.
The presence of duplicates introduced by PCR amplification is a major issue in paired short reads from next-generation sequencing platforms. These duplicates might have a serious impact on research applications, such as scaffolding in whole-genome sequencing and discovering large-scale genome variations, and are usually removed. We present FastUniq as a fast de novo tool for removal of duplicates in paired short reads. FastUniq identifies duplicates by comparing sequences between read pairs and does not require complete genome sequences as prerequisites. FastUniq is capable of simultaneously handling reads with different lengths and results in highly efficient running time, which increases linearly at an average speed of 87 million reads per 10 minutes. FastUniq is freely available at http://sourceforge.net/projects/fastuniq/.
doi:10.1371/journal.pone.0052249
PMCID: PMC3527383  PMID: 23284954
21.  Over-expression of mitochondrial antiviral signaling protein inhibits coxsackievirus B3 infection by enhancing type-I interferons production 
Virology Journal  2012;9:312.
Background
Recent studies have revealed that Mitochondrial Antiviral Signaling (MAVS) protein plays an essential role in the inhibition of viral infection through type I interferon (IFN) pathway. It has been shown that 3C (pro) cysteine protease of coxsackievirus B3 (CVB3) cleaves MAVS to inhibit type I IFNs induction. Other workers also found that MAVS knock-out mice suffered CVB3 susceptibility and severe histopathological change. Accordingly,our experiments were designed to explore the protection of over-expressing MAVS against CVB3 infection and the possible mechanism.
Results
In this study, HeLa cells (transfected with MAVS constructs pre- or post- exposure to CVB3) were used to analyze the function of exogenous MAVS on CVB3 infection. The results revealed that though CVB3 infection induced production of type I IFNs, viral replication and cell death were not effectively inhibited. Similarly, exogenous MAVS increased type I IFNs moderately. Morever, we observed robust production of type I IFNs in CVB3 post-infected HeLa cells thereby successfully inhibiting CVB3 infection, as well formation of cytopathic effect (CPE) and cell death. Finally, introduction of exogenous MAVS into CVB3 pre-infected cells also restricted viral infection efficiently by greatly up-regulating IFNs.
Conclusions
In summary, exogenous MAVS effectively prevents and controls CVB3 infection by modulating and promoting the production of type I IFNs. The IFNs level in MAVS over-expressing cells is still tightly regulated by CVB3 infection. Thus, the factors that up-regulate MAVS might be an alternative prescription in CVB3-related syndromes by enhancing IFNs production.
doi:10.1186/1743-422X-9-312
PMCID: PMC3546859  PMID: 23249700
Mitochondrial antiviral signaling protein; Coxsackievirus B3; Interferon; Antiviral response
22.  An innovative approach for the characterization of the isoforms of a monoclonal antibody product 
mAbs  2011;3(6):505-512.
Protein biopharmaceuticals, such as monoclonal antibodies (mAbs) are widely used for the prevention and treatment of various diseases. The complex and lengthy upstream and downstream production methods of the antibodies make them susceptible to physical and chemical modifications. Several IgG1 immunoglobulins are used as medical agents for the treatment of colon, breast and head and neck cancers, and at least four to eight isoforms exist in the products. The regulatory agencies understand the complex nature of the antibody molecules and allow the manufactures to set their own specifications for lot release, provided the safety and efficacy of the products are established in animal models prior to clinical trials. During the manufacture of a mAb product, we observed lot-to-lot variability in the isoform content and, although the variability is within the set specifications for lot release, made attempts to gain mechanistic insight by isolating and characterizing the individual isoforms. Matrix-assisted laser desorption/ionization (MALDI) and liquid chromatography (LC)/mass spectrometry (MS)/MS analyses of the isolated isoforms indicate that this variability is caused by sialic acid content, as well as truncation of C-terminal lysine of the individual isoforms. Sialidase and carboxypeptidase treatment of the product confirm the observations made by MALDI and LC/MS/MS.
doi:10.4161/mabs.3.6.18090
PMCID: PMC3242836  PMID: 22123057
IgG1; isoforms; charge heterogeneity; monoclonal antibody; glycosylation; silaic acid
23.  MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11 
Oncotarget  2012;3(11):1370-1385.
Angiogenesis and invasion are essential processes for solid tumor growth and dissemination. The tumor development process can be dependent on the activation of a series of signaling pathways, including growth factor-activated pathways. MicroRNAs have been shown to be critical for tumorigenesis, but their roles in cancer angiogenesis, invasion and other signaling pathways important for tumor development are still unclear in the context of tumor biology. We investigated the role of microRNA miR-98 in regulating tumor growth, invasion, and angiogenesis using a highly aggressive breast cancer model in vitro and in vitro. We found that the expression of miR-98 inhibited breast cancer cell proliferation, survival, tumor growth, invasion, and angiogenesis. Conversely, inhibition of endogenous miR-98 promoted cell proliferation, survival, tumor growth, invasion, and angiogenesis. It appeared that miR-98 inhibited angiogenesis by modulating endothelial cell activities including cell spreading, cell invasion and tubule formation. Interestingly, miR-98 reduced the expression of ALK4 and MMP11, both of which were potential targets of miR-98. Transfection of an anti-miR-98 construct increased the expression of both targets. We confirmed that mir-98 targeted the 3'-untranslated regions of ALK4 and MMP11. Finally, ALK4- and MMP11-specific siRNAs inhibited breast cancer cell proliferation, survival, and angiogenesis. Rescue experiments with ALK4 and MMP11 constructs reversed the anti-proliferative, anti-invasive and anti-angiogenic effects of miR-98. Our findings define a regulatory role of miR-98 in tumor angiogenesis and invasion through repressed ALK4 and MMP11 expression.
PMCID: PMC3717799  PMID: 23211491
microRNA; miR-98; angiogenesis; tumorigenesis; invasion
24.  The Early Stage Adjacent Disc Degeneration after Percutaneous Vertebroplasty and Kyphoplasty in The Treatment of Osteoporotic VCFs 
PLoS ONE  2012;7(10):e46323.
Background
The purpose of this paper is to determine the early incidence of disc de- generation adjacent to the vertebral body of osteoporotic fracture treated with percutaneous vertebroplasty or balloon kyphoplasty and whether adjacent disc degeneration is accelerated by this two procedures.
Methods
182 patients with painful vertebral compression fractures were treated. A total of 97 patients were enrolled in this prospective study. 97 patients with a mean age of 65.3 years were classified into control group and surgical treatment group of non-random. 35 patients were in contol group and 62 patients who were performed percutaneous vertebroplasty or balloon kyphoplasty in treatment group. X-ray and Magnetic resonance imaging were done at the first and final visit. The grade of disc degeneration above the fractured vertebral was confirmed by evaluation of bony oedema in the fat suppressed sequences and T2-weighted image of magnetic resonance imaging. The height of degenerative disc was measured on X-ray film.
Results
All patients were followed up two years after the first visit and the follow-up rate was 90.7% (88/97). The incidence of degeneration of adjacent disc above the fractured vertebral was 29.0% (9/31) in control group and 52.6% (30/57) in treatment group. It presented a statistically significant difference between two groups about the incidence of adjacent disc degeneration (P = 0.033). The percentage of adjacent disc height reduction in control group was 13.5% and 17.6% in treatment group. Statistically significant difference of VAS score and ODI was not found between the first evaluation postoperatively and the final follow-up in treatment group (P>0.05).
Conclusions
Disc degeneration adjacent to the fractured vertebral is accelerated by VP and BK procedures in the early stage, but clinical outcomes has not been weakened even in the presence of accelerated disc degeneration.
doi:10.1371/journal.pone.0046323
PMCID: PMC3466231  PMID: 23056283
25.  U2AF1 Mutations in Chinese Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome 
PLoS ONE  2012;7(9):e45760.
Somatic mutations of U2AF1 gene have recently been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we analyzed the frequency and clinical impact of U2AF1 mutations in a cohort of 452 Chinese patients with myeloid neoplasms. Mutations in U2AF1 were found in 2.5% (7/275) of AML and 6.3% (6/96) of MDS patients, but in none of 81 CML. All mutations were heterozygous missense mutations affecting codon S34 or Q157. There was no significant association of U2AF1 mutation with blood parameters, FAB subtypes, karyotypes and other gene mutations in AML. The overall survival (OS) of AML patients with U2AF1 mutation (median 3 months) was shorter than those without mutation (median 7 months) (P = 0.035). No difference in the OS was observed between MDS patients with and without U2AF1 mutations. Our data show that U2AF1 mutation is a recurrent event at a low frequency in AML and MDS.
doi:10.1371/journal.pone.0045760
PMCID: PMC3446943  PMID: 23029227

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