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1.  Bacteria and Methanogens Differ along the Gastrointestinal Tract of Chinese Roe Deer (Capreolus pygargus) 
PLoS ONE  2014;9(12):e114513.
The current study provides the insight into the bacteria in the gastrointestinal tract (GIT) and methanogens presented in the rumen and cecum of the Chinese roe deer (Capreolus pygargus). The ruminal, ileal, cecal, and colonic contents, as well as feces, were obtained from each of the three, free-range, roe deer ingesting natural pasture after euthanasia. For the bacterial community, a total of 697,031 high-quality 16S rRNA gene sequences were generated using high-throughput sequencing, and assigned to 2,223 core operational taxonomic units (OTUs) (12 bacterial phyla and 87 genera). The phyla Firmicutes (51.2%) and Bacteroidetes (39.4%) were the dominant bacteria in the GIT of roe deer. However, the bacterial community in the rumen was significantly (P<0.01) different from the other sampled regions along the GIT. Secondly, Prevotella spp., Anaerovibrio spp., and unidentified bacteria within the families Veillonellaceae and Paraprevotellaceae were more abundant in the rumen than in the other regions. Unidentified bacteria within the family Enterobacteriaceae, Succinivibrio spp., and Desulfovibrio spp. were more predominant in the colon than in other regions. Unidentified bacteria within the family Ruminococcaceae, and Bacteroides spp. were more prevalent in the ileum, cecum and fecal pellets. For methanogens in the rumen and cecum, a total of 375,647 high quality 16S rRNA gene sequences were obtained and assigned to 113 core OTUs. Methanobrevibacter millerae was the dominant species accounting for 77.3±7.4 (S.E) % and 68.9±4.4 (S.E) % of total sequences in the rumen and cecum of roe deer, respectively. However, the abundance of Methanobrevibacter smithii was higher in the rumen than in the cecum (P = 0.004). These results revealed that there was intra variation in the bacterial community composition across the GIT of roe deer, and also showed that the methanogen community in the rumen differed from that in the cecum.
doi:10.1371/journal.pone.0114513
PMCID: PMC4260832  PMID: 25490208
2.  An Important Role for Mitochondrial Antiviral Signaling Protein in the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle 
Journal of Virology  2014;88(10):5778-5787.
ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) has been shown to be recognized by two families of pattern recognition receptors (PRRs), Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Here we show that MAVS and RIG-I (retinoic acid-inducible gene 1), an RLR family member, also have a role in suppressing KSHV replication and production. In the context of primary infection, we show that in cells with depleted levels of MAVS or RIG-I, KSHV transcription is increased, while beta interferon (IFN-β) induction is attenuated. We also observed that MAVS and RIG-I are critical during the process of reactivation. Depletion of MAVS and RIG-I prior to reactivation led to increased viral load and production of infectious virus. Finally, MAVS depletion in latent KSHV-infected B cells leads to increased viral gene transcription. Overall, this study suggests a role for MAVS and RIG-I signaling during different stages of the KSHV life cycle.
IMPORTANCE We show that RIG-I and its adaptor protein, MAVS, can sense KSHV infection and that these proteins can suppress KSHV replication following primary infection and/or viral reactivation.
doi:10.1128/JVI.03226-13
PMCID: PMC4019080  PMID: 24623417
3.  Duodenal Ferroportin Is Up-Regulated in Patients with Chronic Hepatitis C 
PLoS ONE  2014;9(10):e110658.
Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC.
doi:10.1371/journal.pone.0110658
PMCID: PMC4203811  PMID: 25330009
4.  Diffusion tensor tractography of the arcuate fasciculus in patients with brain tumors: Comparison between deterministic and probabilistic models 
Purpose
The purpose of this study was to compare the deterministic and probabilistic tracking methods of diffusion tensor white matter fiber tractography in patients with brain tumors.
Materials and Methods
We identified 29 patients with left brain tumors <2 cm from the arcuate fasciculus who underwent pre-operative language fMRI and DTI. The arcuate fasciculus was reconstructed using a deterministic Fiber Assignment by Continuous Tracking (FACT) algorithm and a probabilistic method based on an extended Monte Carlo Random Walk algorithm. Tracking was controlled using two ROIs corresponding to Broca’s and Wernicke’s areas. Tracts in tumoraffected hemispheres were examined for extension between Broca’s and Wernicke’s areas, anterior-posterior length and volume, and compared with the normal contralateral tracts.
Results
Probabilistic tracts displayed more complete anterior extension to Broca’s area than did FACT tracts on the tumor-affected and normal sides (p < 0.0001). The median length ratio for tumor: normal sides was greater for probabilistic tracts than FACT tracts (p < 0.0001). The median tract volume ratio for tumor: normal sides was also greater for probabilistic tracts than FACT tracts (p = 0.01).
Conclusion
Probabilistic tractography reconstructs the arcuate fasciculus more completely and performs better through areas of tumor and/or edema. The FACT algorithm tends to underestimate the anterior-most fibers of the arcuate fasciculus, which are crossed by primary motor fibers.
doi:10.4236/jbise.2013.62023
PMCID: PMC4199232  PMID: 25328583
Diffusion Tensor Imaging; DTI; Tractography; Probabilistic; FACT; Arcuate Fasciculus; Brain Tumors
5.  Total ionizing dose (TID) effects of γ ray radiation on switching behaviors of Ag/AlO x /Pt RRAM device 
Nanoscale Research Letters  2014;9(1):452.
The total ionizing dose (TID) effects of 60Co γ ray radiation on the resistive random access memory (RRAM) devices with the structure of Ag/AlO x /Pt were studied. The resistance in low resistance state (LRS), set voltage, and reset voltage are almost immune to radiation, whereas the initial resistance, resistance at high resistance state (HRS), and forming voltage were significantly impacted after radiation due to the radiation-induced holes. A novel hybrid filament model is proposed to explain the radiation effects, presuming that holes are co-operated with Ag ions to build filaments. In addition, the thermal coefficients of the resistivity in LRS can support this hybrid filament model. The Ag/AlO x /Pt RRAM devices exhibit radiation immunity to a TID up to 1 Mrad(Si) and are highly suitable for radiation-hard electronics applications.
doi:10.1186/1556-276X-9-452
PMCID: PMC4159639  PMID: 25246866
Total ionizing dose (TID) effects; γ ray radiation; RRAM; Hybrid filament model; Filament; Radiation-induced holes
6.  Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response 
Kidney international  2013;85(2):333-343.
The generation of reactive oxygen species plays a pivotal role in both acute and chronic glomerular injuries in patients with lupus nephritis. Since the transcription factor Nrf2 is a major regulator of the antioxidant response and is a primary cellular defense mechanism we sought to determine a role of Nrf2 in the progression of lupus nephritis. Pathological analyses of renal biopsies from patients with different types of lupus nephritis showed oxidative damage in the glomeruli, accompanied by an active Nrf2 antioxidant response. A murine lupus nephritis model using Nrf2+/+ and Nrf2−/− mice was established using pristine injection. In this model, Nrf2−/− mice suffered from greater renal damage and had more severe pathological alterations in the kidney. In addition, Nrf2+/+ mice showed ameliorative renal function when treated with sulforaphane, an Nrf2 inducer. Nrf2−/− mice had higher expression of TGFβ1, fibronectin and iNOS. In primary mouse mesangial cells, the nephritogenic monoclonal antibody R4A activated the NF-κB pathway and increased the level of reactive oxygen species, iNOS, TGFβ1 and fibronectin. Knockdown of Nrf2 expression aggravated all aforementioned responses induced by R4A. Thus, these results suggest that Nrf2 improves lupus nephritis by neutralizing reactive oxygen species and by negatively regulating the NF-κB and TGFβ1 signaling pathways.
doi:10.1038/ki.2013.343
PMCID: PMC3992978  PMID: 24025640
lupus nephritis; Nrf2; ROS; NF-κB; TGFβ1; iNOS
7.  Resveratrol, a Natural Antioxidant, Has a Protective Effect on Liver Injury Induced by Inorganic Arsenic Exposure 
BioMed Research International  2014;2014:617202.
Resveratrol (Rev) can ameliorate cytotoxic chemotherapy-induced toxicity and oxidative stress. Arsenic trioxide (As2O3) is a known cytotoxic environmental toxicant and a potent chemotherapeutic agent. However, the mechanisms by which resveratrol protects the liver against the cytotoxic effects of As2O3 are not known. Therefore, in the present study we investigated the mechanisms involved in the action of resveratrol using a cat model in which hepatotoxicity was induced by means of As2O3 treatment. We found that pretreatment with resveratrol, administered using a clinically comparable dose regimen, reversed changes in As2O3-induced morphological and liver parameters and resulted in a significant improvement in hepatic function. Resveratrol treatment also improved the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione and the retention of arsenic in liver tissue. These findings provide a better understanding of the mechanisms whereby resveratrol modulates As2O3-induced changes in liver function and tissue morphology. They also provide a stronger rationale for the clinical utilization of resveratrol for the reduction of As2O3-induced hepatotoxicity.
doi:10.1155/2014/617202
PMCID: PMC4132329  PMID: 25147808
8.  Co-occurrence of driver and passenger bacteria in human colorectal cancer 
Gut Pathogens  2014;6:26.
Background
Both genetic and epigenetic alterations have been reported to act as driving forces of tumorigenesis in colorectal cancer (CRC), but a growing body of evidence suggests that intestinal microbiota may be an aetiological factor in the initiation and progression of CRC. Recently, the “driver-passenger” model for CRC has connected these different factors, but little has been done to characterize the CRC gut microbiome.
Findings
Building on the driver-passenger model, we used 454 pyrosequencing of bacterial 16S rRNA genes associated with 10 normal, 10 adenoma, and 8 tumor biopsy samples, and found 7 potential driver bacterial genera and 12 potential passenger bacterial genera (7 being pro-inflammatory and 5 anti-inflammatory). Further analysis also showed certain co-expression patterns among different clusters of bacteria that may potentially be related to the promotion or progression of gut cancers.
Conclusions
The present findings provide preliminary experimental evidence supporting the proposition of bacterial “driver-passenger model” for CRC, and identified potentially novel microbial agents that may be connected to risk of CRC in a Han Chinese population.
doi:10.1186/1757-4749-6-26
PMCID: PMC4080773  PMID: 24995042
CRC; Driver bacteria; Passenger bacteria; Co-occurrence
9.  Long-term survival in patients with peripheral T-cell non-Hodgkin lymphomas after allogeneic hematopoietic stem cell transplantation 
Leukemia & lymphoma  2012;53(6):1124-1129.
Peripheral T-cell non-Hodgkin lymphomas (T-NHL) are rare diseases, with a worse prognosis compared to their B-cell counterparts. Allogeneic hematopoietic stem cell transplantation may have a role in the treatment of relapsed/refractory disease or high-risk histologies in the upfront setting. However, there is limited information on the efficacy of allogeneic transplantation for these diseases, as well as what factors may predict outcomes. We therefore performed a retrospective study of 34 patients who received an allogeneic transplant for the treatment of TNHL at a single center between January 1, 1992 and December 31, 2009. The median follow-up for survivors was 45 months (range 9-160 months). The two-year overall survival (OS) was 0.61 (95% CI: 0.43-0.75) with a plateau at twenty-eight months. Ki-67 expression ≤ 25% was predictive of improved OS (p < 0.01), and transplant in complete remission was predictive of a decreased cumulative incidence of events (p= 0.04). Three patients received DLI; and two patients demonstrated a response, supporting a graft-versus-lymphoma effect. These data demonstrate that allogeneic transplantation is a viable option for the treatment of T-NHL and merits prospective evaluation.
doi:10.3109/10428194.2011.645818
PMCID: PMC4054938  PMID: 22136377
Allogeneic HSCT; graft-versus-lymphoma effect; T-cell Non Hodgkin’s Lymphoma
10.  Real-Time Intraoperative CT Assessment of Quality of Permanent Interstitial Seed Implantation for Prostate Cancer 
Urology  2010;76(5):1138-1142.
Objectives
Evaluate real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions.
Methods
Twenty patients were evaluated intraoperatively with a mobile CBCT unit immediately after implantation while still anesthetized. The source-detector system is enclosed into a circular CT-like geometry with a bore that accommodates patients in the lithotomy position. After seed deposition, CBCT scans were obtained, Dosimetry was evaluated and compared to standard postimplantation CT-based assessment. In eight patients deposited seeds were localized in the intraoperative CBCT frame of reference and registered to the intraoperative transrectal ultrasound (TRUS) images. With this information, a second intraoperative plan was generated to ascertain if additional seeds were needed to achieve the planned prescription dose. Final dosimetry was compared with postimplantation scan assessment.
Results
Mean differences between dosimetric parameters from the intraoperative CBCT and post-implant CT scans were <0.5% for V100, D90, and V150 target values. Mean percentage differences for average urethral doses were not significantly different. Differences for D5 (maximum dose) of the urethra were <4%. The dose to 2 cc of the rectum differed by 10% on average. After fusion of implanted seed coordinates from the intraoperative CBCT scans onto the intraoperative TRUS images, dosimetric outcomes were similar to postimplantation CT dosimetric results.
Conclusions
Intraoperative CT-based dosimetric evaluation of prostate permanent seed implantation prior to anesthesia reversal is feasible and may avert misadministration of dose delivery. Dosimetric measurements based on the intraoperative CBCT scans are dependable and correlate well with postimplant diagnostic CT evaluation.
doi:10.1016/j.urology.2010.01.067
PMCID: PMC4049478  PMID: 20430423
Prostate; brachytherapy; dosimetry; image-guidance
11.  Dose Escalation for Prostate Cancer Radiotherapy: Predictors of Long-Term Biochemical Tumor Control and Distant Metastases–Free Survival Outcomes 
European urology  2011;60(6):1133-1139.
Background
Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients.
Objective
Identify predictors of biochemical tumor control and distant metastases–free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT.
Design, setting, and participants
This retrospective analysis comprised 2551 patients with clinical stages T1–T3 PCa. Median follow-up was 8 yr, extending >20 yr.
Intervention
Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo.
Measurements
A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed.
Results and limitations
Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels <70.2 Gy and 70.2–79.2 Gy were associated with 2.3-and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse– free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes.
Conclusions
Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.
doi:10.1016/j.eururo.2011.08.029
PMCID: PMC4037155  PMID: 21889832
12.  Comparison of Tumor Control and Toxicity Outcomes of High Dose Intensity-Modulated Radiotherapy and Brachytherapy for Patients with Favorable Risk Prostate Cancer 
Urology  2010;77(4):986-990.
Objectives
To compare long-term prostate-specific antigen relapse-free survival outcome and incidence of toxicity for low-risk prostate cancer treated with brachytherapy or intensity-modulated radiotherapy.
Methods
729 consecutive patients were treated with BRT (n=448; prescription dose, 144 Gy) and intensity-modulated radiotherapy alone (n=281; prescription dose, 81 Gy). Prostate-specific antigen relapse-free survival using nadir +2 definitions, and late toxicity using the National Cancer Institute's Common Terminology Criteria for Adverse Events.
Results
Seven-year prostate-specific antigen relapse-free survival for brachytherapy and intensity-modulated radiotherapy was 95% and 89% for low-risk patients (p=0.004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival even when adjusted for other variables. Incidence of metastatic disease between treatments was low for both treatment groups. Late grade 2 gastrointestinal toxicities were observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated radiotherapy groups, respectively (p=0.02). There were no significant differences between treatment groups for late grade ≥3 rectal complications (brachytherapy, 1.1%; intensity-modulated radiotherapy, 0%; p=0.19). Late grade 2 urinary toxicities were more often observed for brachytherapy than intensity-modulated radiotherapy (15.6% and 4.3%, respectively; p<0.0001). There were no significant differences between treatment groups for late grade 3 urinary toxicity (brachytherapy, 2.2%; intensity-modulated radiotherapy, 1.4%; p=0.62).
Conclusions
Among low risk prostate cancer patients, 7-year biochemical tumor control is superior for intraoperative-planning brachytherapy compared with high-dose intensity-modulated radiotherapy. While significant toxicities were minimal for both groups, modest but significant increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated radiotherapy.
doi:10.1016/j.urology.2010.07.539
PMCID: PMC4037156  PMID: 21195465
Low dose rate; Iodine-125; Prostate cancer; PSA-relapse–free survival; Brachytherapy; Toxicity
13.  Metformin and Prostate Cancer: Benefit for Development of Castration-resistant Disease and Prostate Cancer Mortality 
European urology  2012;63(4):709-716.
Background
In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC).
Objective
To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC.
Design, setting, and participants
Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States.
Intervention
Use of metformin in localized prostate cancer.
Outcome measurements and statistical analysis
Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer–specific mortality (PCSM), overall survival (OS), and development of CRPC.
Results and limitations
With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24–3.18]; p = 0.004), DMFS (adjusted HR: 3.68 [1.78–7.62]; p < 0.001), and PCSM (HR: 5.15 [1.53–17.35]; p = 0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83–119.89]; p = 0.01). The retrospective study design was the primary limitation of the study.
Conclusions
To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.
doi:10.1016/j.eururo.2012.12.004
PMCID: PMC4034673  PMID: 23287698
Diabetes; Metformin; Prostate cancer; Radiotherapy
14.  Phase 2 Study of Weekly Bortezomib in Mantle Cell and Follicular Lymphoma 
British journal of haematology  2009;146(6):652-655.
Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, p = 0.02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.
doi:10.1111/j.1365-2141.2009.07775.x
PMCID: PMC4035037  PMID: 19624539
Bortezomib; Follicular Lymphoma; Mantle cell Lymphoma; Non-Hodgkin Lymphoma; Proteasome inhibitor
15.  Adult Rhabdomyosarcoma Survival Improved with Treatment on Multimodality Protocols 
Purpose
Rhabdomyosarcoma (RMS) is a pediatric sarcoma rarely occurring in adults. For unknown reasons, adults with RMS have worse outcomes.
Methods
We analyzed data from all patients who presented to XXXXXXXX between 1990 and 2011 with RMS diagnosed at age 16 or older. 148 patients met study criteria. Ten were excluded for lack of adequate data.
Results
Median age was 28 yrs. Tumor histology was: embryonal 54%, alveolar 33%, pleomorphic 12%, and NOS 2%. The tumor site was unfavorable in 67% of patients. 33 patients (24%) were low risk, 61 (44%) intermediate risk, and 44 (32%) high risk. 46% were treated on or according to a prospective RMS protocol. Five-year overall survival (OS) was 45% for non-metastatic patients. Failure rates at 5 years for non-metastatic patients were 34% locally and 42% distantly. Among patients with non-metastatic disease (n=94), significant factors associated with OS were histology, site, risk group, age, and protocol treatment. On multivariate analysis, risk group and protocol treatment were significant after adjusting for age. Five-yr OS was 54% for protocol patients vs 36% for non-protocol patients.
Conclusions
Survival in non-metastatic adult patients was significantly improved for those treated on RMS protocols, most of which are now open to adults.
doi:10.1016/j.ijrobp.2012.12.016
PMCID: PMC3927967  PMID: 23414767
rhabdomyosarcoma; adolescents; adults; soft tissue sarcoma; age
16.  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
17.  Umbilical metastasis derived from early stage rectal cancer: a case report 
Background
Umbilical metastasis, also called Sister Mary Joseph’s nodule (SMJN), is defined as the umbilical nodule associated with advanced metastatic intra-abdominal and pelvic malignancies. A patient with umbilical metastasis has been deemed to have a poor prognosis. Rectal cancer presenting with a SMJN is a rare phenomenon, especially in the early stage and in middle-low rectal cancer.
Case presentation
We report a case of a 70-year-old male presenting with umbilical metastasis derived from rectal cancer (10 cm from the anal verge, T2N0).
Discussion and conclusion
For rectal cancer with umbilical metastasis, the exact metastatic routes as well as the criterion of diagnosis and treatments are not very clear. Here we review the literature on rectal cancer and SMJN to deepen the understanding of this disease.
doi:10.1186/1477-7819-12-82
PMCID: PMC3992153  PMID: 24708697
Rectal cancer; Umbilical metastasis; Sister Mary Joseph’s nodule (SMJN)
18.  Protective effect of resveratrol on arsenic trioxide-induced nephrotoxicity in rats 
Nutrition Research and Practice  2014;8(2):220-226.
BACKGROUD/OBEJECTIVES
Arsenic, which causes human carcinogenicity, is ubiquitous in the environment. This study was designed to evaluate modulation of arsenic induced cancer by resveratrol, a phytoalexin found in vegetal dietary sources that has antioxidant and chemopreventive properties, in arsenic trioxide (As2O3)-induced Male Wistar rats.
MATERIALS/METHODS
Adult rats received 3 mg/kg As2O3 (intravenous injection, iv.) on alternate days for 4 days. Resveratrol (8 mg/kg) was administered (iv.) 1 h before As2O3 treatment. The plasma and homogenization enzymes associated with oxidative stress of rat kidneys were measured, the kidneys were examined histologically and trace element contents were assessed.
RESULTS
Rats treated with As2O3 had significantly higher oxidative stress and kidney arsenic accumulation; however, pretreatment with resveratrol reversed these changes. In addition, prior to treatment with resveratrol resulted in lower blood urea nitrogen, creatinine and insignificant renal tubular epithelial cell necrosis. Furthermore, the presence of resveratrol preserved the selenium content (0.805 ± 0.059 µg/g) of kidneys in rats treated with As2O3. However, resveratrol had no effect on zinc level in the kidney relative to As2O3-treated groups.
CONCLUSIONS
Our data show that supplementation with resveratrol alleviated nephrotoxicity by improving antioxidant capacity and arsenic efflux. These findings suggest that resveratrol has the potential to protect against kidney damage in populations exposed to arsenic.
doi:10.4162/nrp.2014.8.2.220
PMCID: PMC3988513  PMID: 24741408
Arsenic; resveratrol; trace element; arsenic efflux
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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