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1.  The Expression and Significance of Neuronal Iconic Proteins in Podocytes 
PLoS ONE  2014;9(4):e93999.
Growing evidence suggests that there are many common cell biological features shared by neurons and podocytes; however, the mechanism of podocyte foot process formation remains unclear. Comparing the mechanisms of process formation between two cell types should provide useful guidance from the progress of neuron research. Studies have shown that some mature proteins of podocytes, such as podocin, nephrin, and synaptopodin, were also expressed in neurons. In this study, using cell biological experiments and immunohistochemical techniques, we showed that some neuronal iconic molecules, such as Neuron-specific enolase, nestin and Neuron-specific nuclear protein, were also expressed in podocytes. We further inhibited the expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 by Small interfering RNA in cultured mouse podocytes and observed the significant morphological changes in treated podocytes. When podocytes were treated with Adriamycin, the protein expression of Neuron-specific enolase, nestin, synaptopodin and Ubiquitin carboxy terminal hydrolase-1 decreased over time. Meanwhile, the morphological changes in the podocytes were consistent with results of the Small interfering RNA treatment of these proteins. The data demonstrated that neuronal iconic proteins play important roles in maintaining and regulating the formation and function of podocyte processes.
doi:10.1371/journal.pone.0093999
PMCID: PMC3974844  PMID: 24699703
2.  High-Dose Chemo-Radiotherapy for Relapsed or Refractory Hodgkin Lymphoma and the Significance of Pre-transplant Functional Imaging 
British journal of haematology  2010;148(6):890-897.
We previously reported that three risk factors (RF): initial remission duration <1 year, active B symptoms, and extranodal disease predict outcome in relapsed or refractory Hodgkin lymphoma (HL). Our goal was to improve event-free survival (EFS) for patients with multiple RF and to determine if response to salvage therapy impacted outcome. We conducted a phase II intent-to-treat study of tailored salvage treatment: patients with 0 or 1 RF received standard-dose ifosfamide, carboplatin, and etoposide (ICE); patients with 2 RF received augmented ICE; patients with 3 RF received high-dose ICE with stem cell support. This was followed by evaluation with both computed tomography and functional imaging (FI); those with chemosensitive disease underwent high-dose chemoradiotherapy and autologous stem cell transplantation (ASCT). There was no treatment-related mortality. Compared to historical controls this therapy eliminated the difference in EFS between the 3 prognostic groups. Pre-ASCT FI predicted outcome; 4-year EFS rates was 33% vs. 77% for patients transplanted with positive vs negative FI respectively, p=0.00004, hazard ratio 4.61. Risk-adapted augmentation of salvage treatment in patients with HL is feasible and improves EFS in poorer-risk patients. Our data suggest that normalization of FI pre-ASCT predicts outcome, and should be the goal of salvage treatment.
doi:10.1111/j.1365-2141.2009.08037.x
PMCID: PMC3920913  PMID: 20085577
Hodgkin Lymphoma; HSCT; high-dose chemoradiotherapy
3.  Nephroprotective effect of astaxanthin against trivalent inorganic arsenic-induced renal injury in wistar rats 
Inorganic arsenic (iAs) is a toxic metalloid found ubiquitously in the environment. In humans, exposure to iAs can result in toxicity and cause toxicological manifestations. Arsenic trioxide (As2O3) has been used in the treatment for acute promyelocytic leukemia. The kidney is the critical target organ of trivalent inorganic As (iAsIII) toxicity. We examine if oral administration of astaxanthin (AST) has protective effects on nephrotoxicity and oxidative stress induced by As2O3 exposure (via intraperitoneal injection) in rats. Markers of renal function, histopathological changes, Na+-K+ ATPase, sulfydryl, oxidative stress, and As accumulation in kidneys were evaluated as indicators of As2O3 exposure. AST showed a significant protective effect against As2O3-induced nephrotoxicity. These results suggest that the mechanisms of action, by which AST reduces nephrotoxicity, may include antioxidant protection against oxidative injury and reduction of As accumulation. These findings might be of therapeutic benefit in humans or animals suffering from exposure to iAsIII from natural sources or cancer therapy.
doi:10.4162/nrp.2014.8.1.46
PMCID: PMC3944156  PMID: 24611105
Astaxanthin; trivalent inorganic arsenic; arsenic accumulation; nephrotoxicity; oxidative stress
4.  Expression of CXCR4 and breast cancer prognosis: a systematic review and meta-analysis 
BMC Cancer  2014;14:49.
Background
The chemokine receptor CXCR4 plays a significant role in biological processes, as well as in tumorigenesis and the progression of cancer, especially breast cancer. However, the clinical application of CXCR4 for breast cancer prognosis is still very limited. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the relationship between CXCR4 expression and the prognosis of breast cancer.
Methods
A comprehensive search strategy was used to search relevant literature in PubMed, MEDLINE and the ISI Web of Science. The correlation between CXCR4 expression and clinicopathological features and breast cancer prognosis was analyzed. This meta-analysis was carried out using Review Manager 4.2.
Result
Thirteen eligible studies consisting of 3865 participants were included. We found that breast cancers with CXCR4 expression were associated with lymph node status (pooled RR =1.20, 95% CI: 1.01-1.43, P<0.001) and distant metastasis (pooled RR =1.52, 95% CI: 1.17-1.98, P = 0.125). CXCR4 overexpression was significantly associated with disease free survival (DFS) (RR = 0.77, 95% CI = 0.70–0.86, P = 0.554) and overall survival (OS) (RR = 0.70, 95% CI = 0.59–0.83, P = 0.329). However, there was no significant association between CXCR4 expression and some clinical parameters of breast cancer, such as tumor category, ER status, PR status, or c-erbB-2 status.
Conclusion
Our meta-analysis showed that CXCR4 is an efficient prognostic factor for breast cancer. Overexpression of CXCR4 was significantly associated with lymph node status and distant metastasis and indicated poor overall and disease free survival.
doi:10.1186/1471-2407-14-49
PMCID: PMC3911796  PMID: 24475985
Breast cancer; CXCR4; Prognosis
5.  Prognostic Value and Clinicopathological Differences of HIFs in Colorectal Cancer: Evidence from Meta-Analysis 
PLoS ONE  2013;8(12):e80337.
Background
The prognostic value of HIFs in colorectal cancer was evaluated in a large number of studies, but the conclusions were inconclusive. Meanwhile, clinicopathologic differences of HIF-1α and HIF-2α were rarely compared in recent studies.
Methodology
Identical search strategies were used to search relevant literatures in the PubMed and Web of Science databases. The prognostic significances and clinicopathological differences of HIFs in CRC were analyzed.
Principal Findings
A total of 23studies comprising 2984 CRC patients met the inclusion criteria. The results indicated that overexpressed HIFs were significantly associated with increase of mortality risk, including overall survival (OS) (HR 2.06 95%CI 1.55–2.74) and disease free survival (HR 2.84, 95%CI 1.87–4.31). Subgroup analysis revealed that both overexpressed HIF-1α and HIF-2α had correlations with worse prognosis. The pooled HRs were 2.01 (95% CI: 1.55–2.6) and 2.07(95% CI: 1.01–4.26). Further subgroup analysis on HIF-1α was performed by study location, number of patients, quality score and cut-off value. The results showed that HIF-1α overexpression was significantly associated with poor OS, particularly in Asian countries (HR 2.3, 95% CI: 1.74–3.01), while not in European or other countries. In addition, overexpression of HIF-1α was closely related with these clinicopathological features, including Dukes' stages (OR 0.39, 95% CI: 0.17–0.89), UICC stages (OR 0.42 95% CI: 0.3–0.59), depth of invasion (OR 0.71, 95% CI: 0.51–0.99), lymphnode status (OR 0.49, 95% CI: 0.32–0.73) and metastasis (OR 0.29, 95% CI: 0.11–0.81). While overexpression of HIF-2α was only associated with grade of differentiation (OR 0.48, 95% CI: 0.29–0.81).
Conclusions
This study showed that both HIF-1α and HIF-2α overexpression were associated with an unfavorable prognosis. HIF-1α overexpression seemed to be associated with worse prognosis in Asian countries. Additionally, HIF-1α and HIF-2α indicated distinct clinicopathologic features.
doi:10.1371/journal.pone.0080337
PMCID: PMC3855620  PMID: 24324596
6.  The Protective Role of Resveratrol against Arsenic Trioxide-Induced Cardiotoxicity 
Arsenic trioxide (As2O3) shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Unfortunately, limiting the application of this effective agent to APL patients is severe cardiotoxicity. Resveratrol, the natural food-derived polyphenolic compound, is well known for its antioxidant properties and protects the cardiovascular system. But the potential role of resveratrol against As2O3 in heart via nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) is unclear. The present study evaluated the effects of pretreatment with resveratrol and As2O3 on oxidative stress and cardiac dysfunction in rat. In the present study, resveratrol decreased As2O3-induced reactive oxygen species generation, oxidative DNA damage, and pathological alterations. In addition, cardiac dysfunction parameters, intracellular calcium and arsenic accumulation, glutathione redox ratio, and cAMP deficiency levels were observed in As2O3-treated rats; these changes were attenuated by resveratrol. Furthermore, resveratrol significantly prohibited the downregulation of both Nrf2 and HO-1 gene expressions that were downregulated by As2O3, whereas resveratrol did not alter As2O3-induced nitric oxide formation. Thus, the protective role of resveratrol against As2O3-induced cardiotoxicity is implemented by the maintenance of redox homeostasis (Nrf2-HO-1 pathway) and facilitating arsenic efflux. Our findings suggest coadministration with resveratrol, and As2O3 might provide a novel therapeutic strategy for APL.
doi:10.1155/2013/407839
PMCID: PMC3847954  PMID: 24327821
7.  Comparison of the effectiveness of MRI Perfusion and Fluorine-18 FDG PET-CT for differentiating radiation injury from viable brain tumor 
Clinical imaging  2012;37(3):451-457.
Objectives
Differentiating radiation injury from viable tumor is important for optimizing patient care. Our aim was to directly compare the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) PET-CT and dynamic susceptibility-weighted contrast-enhanced (DSC) MR perfusion in differentiating radiation effects from tumor growth in patients with increased enhancement following radiotherapy for primary or secondary brain tumors.
Materials and Methods
We retrospectively identified 12 consecutive patients with primary and secondary brain tumors over a 1-year period that demonstrated indeterminate enhancing lesions after radiotherapy and that had undergone DSC MR perfusion, FDG PET-CT, and subsequent histopathologic diagnosis. The maximum SUV of the lesion (SUVlesion max), SUVratio (SUVlesion max/SUVnormal brain), maximum relative cerebral blood volume (rCBVmax), percentage of signal intensity recovery (PSR) and relative peak height (rPH) were calculated from the PET and MR perfusion studies. A prediction of tumor or radiation injury was made based on these variables while being blinded to the results of the surgical pathology.
Results
SUVratio had the highest predictive value (area under the curve = 0.943) for tumor progression, although this was not statistically better than any MR perfusion metric (area under the curve = 0.757–0.829).
Conclusions
This preliminary study suggests that FDG PET-CT and DSC MR perfusion may demonstrate similar effectiveness for distinguishing tumor growth from radiation injury. Assessment of the SUVratio may increase the sensitivity and specificity of FDG PET-CT for differentiating tumor and radiation injury. Further analysis is needed to help define which modality has greater predictive capabilities.
doi:10.1016/j.clinimag.2012.08.008
PMCID: PMC3789370  PMID: 23068052
Differentiating radiation injury and tumor; MRI perfusion versus FDG PET/CT; rCBVmax; PSR; rPH; SUVratio
8.  Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study 
BMC Genomics  2013;14:669.
Background
Elucidating gut microbiota among gallstone patients as well as the complex bacterial colonization of cholesterol gallstones may help in both the prediction and subsequent lowered risk of cholelithiasis. To this end, we studied the composition of bacterial communities of gut, bile, and gallstones from 29 gallstone patients as well as the gut of 38 normal individuals, examining and analyzing some 299, 217 bacterial 16S rRNA gene sequences from 120 samples.
Results
First, as compared with normal individuals, in gallstone patients there were significant (P < 0.001) increases of gut bacterial phylum Proteobacteria and decreases of three gut bacterial genera, Faecalibacterium, Lachnospira, and Roseburia. Second, about 70% of gut bacterial operational taxonomic units (OTUs) from gallstone patients were detectable in the biliary tract and bacteria diversity of biliary tract was significantly (P < 0.001) higher than that of gut. Third, analysis of the biliary tract core microbiome (represented by 106 bacteria OTUs) among gallstone patients showed that 33.96% (36/106) of constituents can be matched to known bacterial species (15 of which have publicly available genomes). A genome-wide search of MDR, BSH, bG, and phL genes purpotedly associated with the formation of cholesterol gallstones showed that all 15 species with known genomes (e.g., Propionibacterium acnes, Bacteroides vulgates, and Pseudomonas putida) contained at least contained one of the four genes. This finding could potentially provide underlying information needed to explain the association between biliary tract microbiota and the formation of cholesterol gallstones.
Conclusions
To the best of our knowledge, this is the first study to discover gut microbiota dysbiosis among gallstone patients, the presence of which may be a key contributor to the complex bacteria community assembly linked with the presence of cholesterol gallstones. Likewise, this study also provides the first large-scale glimpse of biliary tract microbiota potentially associated with cholesterol gallstones. Such a characterization of the biliary tract core microbiome has potentially important biological and medical implications regarding the role of bacteria in the formation cholesterol gallstones.
doi:10.1186/1471-2164-14-669
PMCID: PMC3851472  PMID: 24083370
Gut microbiota dysbiosis; Cholesterol gallstone; Bile; Bacterial colonization; Pyrosequencing
9.  Hypoxia-Inducible Factor and Vascular Endothelial Growth Factor Pathway for the Study of Hypoxia in a New Model of Otitis Media with Effusion 
Audiology & neuro-otology  2012;17(6):349-356.
The hypoxia-inducible factor and vascular endothelial growth factor (HIF-VEGF) pathway in hypoxic conditions of the middle ear due to dysfunction of the eustachian tube is still unknown, but it is considered as one pathogenetic mechanism in otitis media. This study was designed to investigate the possible involvement of the HIF-VEFG pathway in otitis media with effusion induced by dysfunction of the eustachian tube. We adopted a soft palate approach to obstruct the orifice of the eustachian tube to establish otitis media in a rat model. Auditory evoked brainstem response and tympanometry were used as hearing function tests, hypoxia-related factors were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of hypoxia-related proteins was detected by Western blot and immunostaining. The model of otitis media with effusion was successfully induced by cauterizing the orifice of the eustachian tube. RT-PCR showed up-regulation of hypoxia-related factors in cauterized ears. Western blot and immunostaining showed that the expression of hypoxia-related proteins in cauterized ears was increased. Hypoxia-induced vascular proliferation and an increase in permeability may be one pathogenetic mechanism of otitis media due to dysfunction of the eustachian tube.
doi:10.1159/000341163
PMCID: PMC3637049  PMID: 22907120
Animal model; Dysfunction; Eustachian tube; Hypoxia-inducible factor-1 α; Vascular endothelial growth factor
10.  Prognostic Value of CD166 Expression in Cancers of the Digestive System: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e70958.
Objective
Many studies have reported the prognostic predictive value of CD166 as a cancer stem cell marker in cancers of the digestive system; however, its predictive value remains controversial. Here, we investigate the correlation between CD166 positivity in digestive system cancers and clinicopathological features using meta-analysis.
Methods
A comprehensive search in PubMed and ISI Web of Science through March of 2013 was performed. Only articles containing CD166 antigen immunohistochemical staining in cancers of the digestive system were included,including pancreatic cancer, esophageal cancer, gastric cancer and colorectal cancer. Data comparing 3- and 5-year overall survival along with other clinicopathological features were collected.
Results
Nine studies with 2553 patients who met the inclusion criteria were included for the analysis. The median rate of CD166 immunohistochemical staining expression was 56% (25.4%–76.3%). In colorectal cancer specifically, the results of a fixed-effects model indicated that CD166-positive expression was an independent marker associated with a smaller tumor burden (T category; RR = 0.93, 95%, CI: 0.88–0.98) but worse spread to nearby lymph nodes (N category; RR = 1.17, 95% CI: 1.05–1.30). The 5-year overall survival rate was showed relationship with cytoplasmic positive staining of CD166 (RR = 1.47 95% 1.21–1.79), but no significant association was found in the pool or any other stratified analysis with 3- or 5- year overall survival rate.
Conclusion
Based on the published studies, different cellular location of CD166 has distinct prognostic value and cytoplasmic positive expression is associated with worse prognosis outcome. Besides, our results also find CD166 expression indicate advanced T category and N-positive status in colorectal cancer specifically.
doi:10.1371/journal.pone.0070958
PMCID: PMC3733726  PMID: 23940674
11.  Constraining the brachial plexus does not compromise regional control in oropharyngeal carcinoma 
Background
Accumulating evidence suggests that brachial plexopathy following head and neck cancer radiotherapy may be underreported and that this toxicity is associated with a dose–response. Our purpose was to determine whether the dose to the brachial plexus (BP) can be constrained, without compromising regional control.
Methods
The radiation plans of 324 patients with oropharyngeal carcinoma (OPC) treated with intensity-modulated radiation therapy (IMRT) were reviewed. We identified 42 patients (13%) with gross nodal disease <1 cm from the BP. Normal tissue constraints included a maximum dose of 66 Gy and a D05 of 60 Gy for the BP. These criteria took precedence over planning target volume (PTV) coverage of nodal disease near the BP.
Results
There was only one regional failure in the vicinity of the BP, salvaged with neck dissection (ND) and regional re-irradiation. There have been no reported episodes of brachial plexopathy to date.
Conclusions
In combined-modality therapy, including ND as salvage, regional control did not appear to be compromised by constraining the dose to the BP. This approach may improve the therapeutic ratio by reducing the long-term risk of brachial plexopathy.
doi:10.1186/1748-717X-8-173
PMCID: PMC3729584  PMID: 23835205
Brachial plexopathy; Intensity-modulated radiation therapy; Oropharyngeal carcinoma; Cisplatin; Cetuximab
12.  Interval censoring 
doi:10.1177/0962280209105023
PMCID: PMC3684949  PMID: 19654168
13.  Engineered External Guide Sequences Are Highly Effective in Inhibiting Gene Expression and Replication of Hepatitis B Virus in Cultured Cells 
PLoS ONE  2013;8(6):e65268.
External guide sequences (EGSs) are RNA molecules that consist of a sequence complementary to a target mRNA and recruit intracellular ribonuclease P (RNase P), a tRNA processing enzyme, for specific degradation of the target mRNA. We have previously used an in vitro selection procedure to generate EGS variants that efficiently induce human RNase P to cleave a target mRNA in vitro. In this study, we constructed EGSs from a variant to target the overlapping region of the S mRNA, pre-S/L mRNA, and pregenomic RNA (pgRNA) of hepatitis B virus (HBV), which are essential for viral replication and infection. The EGS variant was about 50-fold more efficient in inducing human RNase P to cleave the mRNA in vitro than the EGS derived from a natural tRNA. Following Salmonella-mediated gene delivery, the EGSs were expressed in cultured HBV-carrying cells. A reduction of about 97% and 75% in the level of HBV RNAs and proteins and an inhibition of about 6,000- and 130-fold in the levels of capsid-associated HBV DNA were observed in cells treated with Salmonella vectors carrying the expression cassette for the variant and the tRNA-derived EGS, respectively. Our study provides direct evidence that the EGS variant is more effective in blocking HBV gene expression and DNA replication than the tRNA-derived EGS. Furthermore, these results demonstrate the feasibility of developing Salmonella-mediated gene delivery of highly active EGS RNA variants as a novel approach for gene-targeting applications such as anti-HBV therapy.
doi:10.1371/journal.pone.0065268
PMCID: PMC3680410  PMID: 23776459
14.  β-catenin Overexpression in the Nucleus Predicts Progress Disease and Unfavourable Survival in Colorectal Cancer: A Meta-Analysis 
PLoS ONE  2013;8(5):e63854.
Background
β-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial.
Methodology
Identical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between β-catenin expression and clinicopathological features and prognosis was analyzed.
Principal Findings
A total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that β-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28–2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12–2.14; Z = 2.62; P = 0.009). However, there was no significant association between β-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88–1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of β-catenin in the nucleus indicated that β-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53–0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25–0.96, Z = 2.06, P = 0.039). β-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41–2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76–2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46–1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4–1.68, Z = 0.53, P = 0.594).
Conclusions
This study showed that β-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.
doi:10.1371/journal.pone.0063854
PMCID: PMC3663842  PMID: 23717499
15.  Toxicity and outcomes of thoracic re-irradiation using stereotactic body radiation therapy (SBRT) 
Background
Patients treated for a thoracic malignancy carry a significant risk of developing other lung lesions. Locoregional control of intrathoracic recurrences is challenging due to the impact of prior therapies on normal tissues. We examined the safety and efficacy of thoracic re-irradiation using high-precision image-guided stereotactic body radiation therapy (SBRT).
Methods
Records of 39 patients with prior intra-thoracic conventionally fractionated radiation therapy (RT) who underwent SBRT for a subsequent primary, recurrent or metastatic lung tumor from 11/2004 to 7/2011 were retrospectively reviewed.
Results
Median dose of prior RT was 61 Gy (range 30–80 Gy). Median biologically effective prescription dose (α/β = 10) (BED10) of SBRT was 70.4 Gy (range 42.6-180 Gy). With a median followup of 12.6 months among survivors, 1- and 2-year actuarial local progression-free survival (LPFS) were 77% and 64%, respectively. Median recurrence-free (RFS) and overall survival (OS) were 13.8 and 22.0 months, respectively. Patients without overlap of high-dose regions of the primary and re-irradiation plans were more likely to receive a BED10 ≥100 Gy, which was associated with higher LPFS (hazard ratio, [HR] = 0.18, p = 0.04), RFS ([HR] = 0.31, p = 0.038) and OS ([HR] = 0.25, p = 0.014). Grade 2 and 3 pulmonary toxicity was observed in 18% and 5% of patients, respectively. Other grade 2–4 toxicities included chest wall pain in 18%, fatigue in 15% and skin toxicity in 5%. No grade 5 events occurred.
Conclusions
SBRT can be safely and successfully administered to patients with prior thoracic RT. Dose reduction for cases with direct overlap of successive radiation fields results in acceptable re-treatment toxicity profile.
doi:10.1186/1748-717X-8-99
PMCID: PMC3651392  PMID: 23617949
Lung re-irradiation; SBRT; Pulmonary toxicity; BED
16.  miRNA-27b Targets Vascular Endothelial Growth Factor C to Inhibit Tumor Progression and Angiogenesis in Colorectal Cancer 
PLoS ONE  2013;8(4):e60687.
Colorectal cancer (CRC) is one of the most prevalent cancers globally and is one of the leading causes of cancer-related deaths due to therapy resistance and metastasis. Understanding the mechanism underlying colorectal carcinogenesis is essential for the diagnosis and treatment of CRC. microRNAs (miRNAs) can act as either oncogenes or tumor suppressors in many cancers. A tumor suppressor role for miR-27b has recently been reported in neuroblastoma, while no information about miR-27b in CRC is available. In this study, we demonstrated that miR-27b expression is decreased in most CRC tissues and determined that overexpression of miR-27b represses CRC cell proliferation, colony formation and tumor growth in vitro and in vivo. We identified vascular endothelial growth factor C (VEGFC) as a novel target gene of miR-27b and determined that miR-27b functioned as an inhibitor of tumor progression and angiogenesis through targeting VEGFC in CRC. We further determined that DNA hypermethylation of miR-27b CpG islands decreases miR-27b expression. In summary, an anti-tumor role for miR-27b and its novel target VEGFC in vivo could lead to tumor necrosis and provide a rationale for developing miR-27b as a therapeutic agent.
doi:10.1371/journal.pone.0060687
PMCID: PMC3625233  PMID: 23593282
17.  Time Course and Predictors for Cancer-Related Fatigue in a Series of Oropharyngeal Cancer Patients Treated with Chemoradiation Therapy 
The Oncologist  2012;17(4):569-576.
Cancer-related fatigue (CRF) is an underestimated phenomenon and is prevalent in head and neck cancer patients. Results on aspects of the time course of CRF and its correlation with pain as well as the impact of pain on CRF are discussed.
Learning Objectives
After completing this course, the reader will be able to: Discuss the incidence of cancer-related fatigue and the impact it has on cancer patients.Evaluate clinical correlates of cancer-related fatigue and describe possible interventions.Explain the time course of cancer-related fatigue before, during, and post-treatment and the effect treatment has on patients for years after treatment.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Cancer-related fatigue (CRF) is a highly prevalent and underestimated symptom in cancer patients. This study aims to analyze CRF solely in a cohort of oropharyngeal cancer patients who underwent treatment with radiotherapy (RT).
Methods.
In January 2008 to June 2010, 87 consecutive oropharyngeal carcinoma patients underwent definitive RT. Concurrent chemotherapy was used for 94% of patients. The median prescription dose to the planning target volume of the gross or clinical tumor volume was 70 Gy for definitive cases (n = 84) and 66 Gy for postoperative cases (n = 3), both delivered over 6.5 weeks. A normalized 12-point numeric rating scale assessed CRF from patient visits before, during, and after RT.
Results.
The median follow-up of living patients was 14 months. Fatigue peaked 1–2 weeks post-RT and remained higher than baseline for up to 2 years post-RT in 50% of patients. The average fatigue score at the time of completion of therapy or maximum thereafter up to 1 year post-RT was significantly worse than baseline. Patients who experienced pain had a trend toward significance with association for a higher maximum difference in fatigue from baseline. Karnofsky performance status score, weight change, and mood disorders did not correlate with CRF.
Conclusions.
Fatigue was a common treatment-related symptom in this uniform cohort of patients with oropharyngeal cancer. RT was highly correlated with worsening of CRF. Pain control has the potential to help mitigate CRF in patients experiencing pain, and will need to be confirmed using larger datasets.
doi:10.1634/theoncologist.2011-0437
PMCID: PMC3336831  PMID: 22398160
Oropharynx; Fatigue; Pain; Radiotherapy; Cancer; Chemotherapy; Head and neck; Pain
18.  Diversified pattern of the human colorectal cancer microbiome 
Gut Pathogens  2013;5:2.
Background
The aim of this study is to expand existing knowledge about the CRC-associated microbiome among Han Chinese, and to further discover the variation pattern of the human CRC microbiome across all population.
Findings
Using pyrosequencing-based molecular monitoring of bacterial 16S rRNA gene from eight tumor/normal tissue pairs of eight Chinese CRC patients, we analyzed and characterized the basic features of the CRC-associated microbiome. Firstly, we discovered an increasing diversity among tumor-associated bacterial communities. Secondly, in 50% of Chinese CRC patients, we found a significant increase of Roseburia (P = 0.017), and a concurrent decrease of both Microbacterium (P = 0.009) and Anoxybacillus (P = 0.009) in tumor tissue.
Conclusions
We discovered a novel CRC microbiome pattern in Chinese. Both the over-represented Roseburia bacteria at tumor sites and the over-represented Microbacterium and Anoxybacillus bacteria away from tumor sites were both closely related in Chinese CRC patients. Across several populations reported in this study and previously, we observed both common and distinctive patterns of human CRC microbiome’s association with a high-risk of CRC.
doi:10.1186/1757-4749-5-2
PMCID: PMC3599420  PMID: 23497613
Chinese; CRC; Microbiome; Pyrosequencing
19.  The Enigma of Myxofibrosarcoma of the Extremity 
Cancer  2011;118(2):518-527.
Background
The reported high rate of local recurrence (LR) in myxofibrosarcoma raises the question of whether this sarcoma histology should be considered radioresistant. We compared rates and patterns of LR of high-grade (HG) myxofibrosarcoma to HG leiomyosarcoma, chosen due to similarity in incidence and general treatment approach.
Methods
202 patients with primary non-metastatic extremity myxofibrosarcoma (n = 114) and leiomyosarcoma (n = 88) underwent limb-sparing surgery and were prospectively followed. All 202 patients had HG tumors; 138 (68%) received adjuvant radiotherapy.
Results
The groups were comparable in age, sex, and chemotherapy use. Compared with leiomyosarcoma, myxofibrosarcoma presented more frequently with tumors >5 cm (p < 0.001), deep location (p = 0.036), and upper extremity site (p = 0.015). In addition, rates of positive/close margins (p < 0.001) and use of RT (<0.001) were significantly higher in myxofibrosarcoma. The 5-year overall LR rate was not significantly different according to histology: 14.6% for myxofibrosarcoma, 13.2% for leiomyosarcoma (p = 0.594). The only predictor of LR for the whole cohort of patients was positive/close margins (p = 0.01). Of 17 myxofibrosarcoma LRs, 8 (47%) occurred out of field, vs 1 of 12 (8%) leiomyosarcoma LRs (p=0.04). Leiomyosarcoma more commonly recurred distantly (54.1 vs 24.3% at 5 years, p=0.014)
Conclusion
Despite more adverse clinical features, myxofibrosarcoma recurred less often distantly than leiomyosarcoma whereas the LR rate was comparable between the two groups, suggesting that adjuvant RT is effective in myxofibrosarcoma. Myxofibrosarcoma LRs more commonly occurred out of field. Reduction in radiation-field margins may not be advisable in myxofibrosarcoma.
doi:10.1002/cncr.26296
PMCID: PMC3360945  PMID: 21717447
soft tissue sarcoma; local recurrence; radiation; myxofibrosarcoma
20.  Renalase's Expression and Distribution in Renal Tissue and Cells 
PLoS ONE  2012;7(10):e46442.
To study renalase's expression and distribution in renal tissues and cells, renalase coded DNA vaccine was constructed, and anti-renalase monoclonal antibodies were produced using DNA immunization and hybridoma technique, followed by further investigation with immunological testing and western blotting to detect the expression and distribution of renalase among the renal tissue and cells. Anti-renalase monoclonal antibodies were successfully prepared by using DNA immunization technique. Further studies with anti-renalase monoclonal antibody showed that renalase expressed in glomeruli, tubule, mesangial cells, podocytes, renal tubule epithelial cells and its cells supernatant. Renalase is wildly expressed in kidney, including glomeruli, tubule, mesangial cells, podocytes and tubule epithelial cells, and may be secreted by tubule epithelial cells primarily.
doi:10.1371/journal.pone.0046442
PMCID: PMC3463591  PMID: 23056310
21.  MCAM is a novel metastasis marker and regulates spreading, apoptosis and invasion of ovarian cancer cells 
Tumour Biology  2012;33(5):1619-1628.
Melanoma cell adhesion molecule (MCAM) is a cell adhesion molecule that is abnormally expressed in a variety of tumours and is closely associated with tumour metastasis. The role of MCAM in ovarian cancer development has not been fully studied. In this study, through immunohistochemical staining of ovarian cancer tissue samples and RNA interference to silence MCAM in ovarian cancer cells, we examined the impact of MCAM on the biological functions of ovarian cancer cells and attempted to reveal the role of MCAM in ovarian cancer development. Our results showed that MCAM expression was particularly high in metastatic ovarian cancers compared with other pathological types of ovarian epithelial tissues. After MCAM silencing in the MCAM high-expression ovarian cancer cell line SKOV-3, the cell apoptosis was increased, whereas the cell spreading and invasion were significantly reduced, which may be related with dysregulation of small RhoGTPase (RhoA and Cdc42).These results suggest that MCAM expression in ovarian cancer is highly correlated with the metastatic potential of the cancer. MCAM is likely to participate in the regulation of the Rho signalling pathway to protect ovarian cancer cells from apoptosis and promote their malignant invasion and metastasis. Therefore, MCAM can be used not only as a molecular marker to determine the prognosis of ovarian cancer but also as a therapeutic target in metastatic ovarian cancer.
doi:10.1007/s13277-012-0417-0
PMCID: PMC3460169  PMID: 22610942
MCAM; Ovarian cancer; Spreading; Invasion; Apoptosis
22.  CORRELATION OF LOCAL FAILURE WITH MEASURES OF DOSE INSUFFICIENCY IN THE HIGH-DOSE SINGLE-FRACTION TREATMENT OF BONY METASTASES 
Purpose
In the setting of high-dose single-fraction image-guided radiotherapy of spine metastases, the delivered dose is hypothesized to be a significant factor in local control. We investigated the dependence of local control on measures of dose insufficiency.
Methods and Materials
The minimum doses received by the hottest 100%, 98%, and 95% (Dmin, D98, and D95) of the gross target volume (GTV) were computed for 91 consecutively treated lesions observed in 79 patients. Prescribed doses of 18–24 Gy were delivered in a single fraction. The spinal cord and cauda equina were constrained to a maximum dose of 12–14 Gy and 16 Gy, respectively. A rank-sum test was used to assess the differences between radiographic local failure and local control.
Results
With a median follow-up of 18 months, seven local failures have occurred. The distributions of GTV Dmin, D98, and D95 for treatments resulting in local failure were found to be statistically different from the corresponding distributions of the patient group as a whole. Taking no account of histology, p values calculated for Dmin, D98, and D95 were 0.004, 0.012, and 0.031, respectively. No correlations between local failure and target volume or between local failure and anatomic location were found.
Conclusions
The results indicate that Dmin, D98, and D95 may be important risk factors for local failure. No local failures in any histology were observed when Dmin was >15 Gy, suggesting that this metric may be an important predictor of local control.
doi:10.1016/j.ijrobp.2009.10.003
PMCID: PMC3319455  PMID: 20350795
Paraspinal metastasis; High-dose single-fraction radiotherapy; Local failure; Dose insufficiency
23.  Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma 
The Journal of Experimental Medicine  2011;208(9):1799-1807.
PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas.
New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.
doi:10.1084/jem.20110846
PMCID: PMC3171093  PMID: 21859846
24.  Outcomes for Patients Who Fail High Dose Chemoradiotherapy and Autologous Stem Cell Rescue for Relapsed and Primary Refractory Hodgkin Lymphoma 
British Journal of Haematology  2009;146(2):158-163.
Most patients with Hodgkin lymphoma (HL) are cured with first and second-line treatment; however for those who fail high dose chemoradiotherapy with autologous stem cell transplant (HDT-ASCT), outcome is unknown. This report is an analysis of patients with relapsed and primary refractory HL who were treated with HDT-ASCT and failed due to progression of disease (POD). Two hundred and two patients received HDT-ASCT at Memorial Sloan Kettering Cancer Center for relapsed or refractory HL between December 1994 and December 2005 and 71 failed due to POD. The median survival following HDT-ASCT failure was 25 months. Only 16 (23%) of the 71 patients are currently alive, 9 of whom are in remission. Multivariate analysis revealed two factors associated with poor outcome: relapse within 6 months of HDT-ASCT and primary refractory disease. The only factor associated with improved survival was the ability to receive a second transplant, in particular, reduced intensity allogeneic transplant (RIT). Novel therapies are needed for patients who fail HDT-ASCT, particularly those with primary refractory disease and those who relapse within 6 months of HDT-ASCT. Future studies should focus on prospectively evaluating RIT following HDT-ASCT failure in patients with remission duration from HDT-ASCT of greater than 6 months.
doi:10.1111/j.1365-2141.2009.07727.x
PMCID: PMC3278667  PMID: 19438504
25.  OTUB1 Overexpression in Mesangial Cells Is a Novel Regulator in the Pathogenesis of Glomerulonephritis through the Decrease of DCN Level 
PLoS ONE  2012;7(1):e29654.
Background
OTUB1 is a member of OTUs (Ovarian-tumor-domain-containing proteases), a deubiquitinating enzymes family (DUBs), which was shown as a proteasome-associated DUB to be involved in the proteins Ub-dependent degradation. It has been reported that OTUB1 was expressed in kidney tissue. But its concrete cellular location and function in the kidney remain unclear. Decorin (DCN) in mesangial cells (MC) is considered to be a potentially important factor for antagonizing glomerulonephritides, and its degradation is mediated by ubiquitination. The aim of this study is to investigate the role of OTUB1 expression in MC and its relationship with DCN during glomerulonephritis.
Methodology/Principal Findings
Using quantitative RT-PCR and Western blot, we demonstrated that OTUB1 mRNA and protein were constitutively expressed in cultured rat MC and found to be upregulated by the stimulation of IL-1β or ATS. OTUB1 overexpression was detected in the mesangial area of glomeruli in some immunocomplex mediated nephritides such as IgA nephropathy, acute diffuse proliferative glomerulonephritis and lupus nephritis by immunohistochemistry. The immunoprecipitation assay demonstrated that OTUB1 interacted with DCN. The overexpression of OTUB1 enhanced the ubiquitination and degradation of DCN in MC.
Conclusion/Significance
These data showed the inflammatory injury could up-regulate OTUB1 expression in MC, which might attribute the promoting effect of OTUB1 on glomerulonephritides to the decrease of DCN level.
doi:10.1371/journal.pone.0029654
PMCID: PMC3261153  PMID: 22279542

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