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1.  Antiproliferative and apoptosis-inducing activity of schisandrin B against human glioma cells 
Cancer Cell International  2015;15(1):12.
Malignant glioma is the most devastating and aggressive tumour in the brain and is characterised by high morbidity, high mortality and extremely poor prognosis. The main purpose of the present study was to investigate the effects of schisandrin B (Sch B) on glioma cells both in vitro and in vivo and to explore the possible anticancer mechanism underlying Sch B-induced apoptosis and cell cycle arrest.
The anti-proliferative ability of Sch B on glioma cells were assessed by MTT and clony formation assays. Flow cytometric analysis was used to detect cell cycle changes. Apoptosis was determined by Hoechst 33342 staining and annexin V/PI double-staining assays. The mitochondrial membrane potential was detected by Rhodamine 123 staining. The in vivo efficacy of Sch B was measured using a U87 xenograft model in nude mice. The expressions of the apoptosis-related and cell cycle-related proteins were analysed by western blot. Student’s t-test was used to compare differences between treated groups and their controls.
We found that Sch B inhibited growth in a dose- and time-dependent manner as assessed by MTT assay. In U87 and U251 cells, the number of clones was strongly suppressed by Sch B. Flow cytometric analysis revealed that Sch B induced cell cycle arrest in glioma cells at the G0/G1 phase. In addition, Sch B induced glioma cell apoptosis and reduced mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanically, western blot analysis indicated that Sch B induced apoptosis by caspase-3, caspase-9, PARP, and Bcl-2 activation. Moreover, Sch B significantly inhibited tumour growth in vivo following the subcutaneous inoculation of U87 cells in athymic nude mice.
In summary, Sch B can reduce cell proliferation and induce apoptosis in glioma cells and has potential as a novel anti-tumour therapy to treat gliomas.
PMCID: PMC4326453
Glioma cells; Schisandrin B; Proliferation; Cell cycle; Apoptosis
2.  Novel Three-Component Rieske Non-Heme Iron Oxygenase System Catalyzing the N-Dealkylation of Chloroacetanilide Herbicides in Sphingomonads DC-6 and DC-2 
Applied and Environmental Microbiology  2014;80(16):5078-5085.
Sphingomonads DC-6 and DC-2 degrade the chloroacetanilide herbicides alachlor, acetochlor, and butachlor via N-dealkylation. In this study, we report a three-component Rieske non-heme iron oxygenase (RHO) system catalyzing the N-dealkylation of these herbicides. The oxygenase component gene cndA is located in a transposable element that is highly conserved in the two strains. CndA shares 24 to 42% amino acid sequence identities with the oxygenase components of some RHOs that catalyze N- or O-demethylation. Two putative [2Fe-2S] ferredoxin genes and one glutathione reductase (GR)-type reductase gene were retrieved from the genome of each strain. These genes were not located in the immediate vicinity of cndA. The four ferredoxins share 64 to 72% amino acid sequence identities to the ferredoxin component of dicamba O-demethylase (DMO), and the two reductases share 62 to 65% amino acid sequence identities to the reductase component of DMO. cndA, the four ferredoxin genes, and the two reductases genes were expressed in Escherichia coli, and the recombinant proteins were purified using Ni-affinity chromatography. The individual components or the components in pairs displayed no activity; the enzyme mixture showed N-dealkylase activities toward alachlor, acetochlor, and butachlor only when CndA-His6 was combined with one of the four ferredoxins and one of the two reductases, suggesting that the enzyme consists of three components, a homo-oligomer oxygenase, a [2Fe-2S] ferredoxin, and a GR-type reductase, and CndA has a low specificity for the electron transport component (ETC). The N-dealkylase utilizes NADH, but not NADPH, as the electron donor.
PMCID: PMC4135782  PMID: 24928877
3.  Seminar Report From the 2014 Taiwan Society of Inflammatory Bowel Disease (TSIBD) Spring Forum (May 24th, 2014): Crohn's Disease Versus Intestinal Tuberculosis Infection 
Intestinal Research  2015;13(1):6-10.
Since Taiwan is an endemic area for tuberculosis (TB), differential diagnosis between the intestinal TB and Crohn's disease is an important issue. The steering committee of Taiwan Society of Inflammatory Bowel Disease (TSIBD) has arranged a seminar accordingly on May 24th, 2014 and the different point of views by gastroenterologist, radiologist, pathologist and infectious disease specialist were suggested to help the proper diagnosis and management of these two diseases.
PMCID: PMC4316223
Crohn disease; Tuberculosis, intestine
4.  Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population 
World Journal of Gastroenterology : WJG  2014;20(47):17932-17940.
AIM: To study the prevalence and clinical biochemical, blood cell and metabolic features of lean-non-alcoholic fatty liver disease (lean-NAFLD) and its association with other diseases.
METHODS: Demographic, biochemical and blood examinations were conducted in all the subjects in this study. We classified the subjects into four groups according to their weight and NAFLD status: lean-control, lean-NAFLD [body mass index (BMI) < 24 kg/m2], overweight-obese control and overweight-obese NAFLD. One-way analysis of variance (ANOVA) was used to compare the means of continuous variables (age, BMI, blood pressure, glucose, lipid, insulin, liver enzymes and blood cell counts) and the χ2 test was used to compare the differences in frequency of categorical variables (sex, education, physical activity, smoking, alcohol consumption and prevalence of hypertension, hyperlipidemia, diabetes, metabolic syndrome central obesity and obesity). Both univariate and multivariate logistic regression models were adopted to calculate odds ratios (ORs) and predict hyperlipidemia, hypertension, diabetes and metabolic syndrome when we respectively set all controls, lean-control and overweight-obese-control as references. In multivariate logistic regression models, we adjusted potential confounding factors, including age, sex, smoking, alcohol consumption and physical activity.
RESULTS: The prevalence of NAFLD was very high in China. NAFLD patients were older, had a higher BMI, waist circumference, blood pressure, fasting blood glucose, insulin, blood lipid, liver enzymes and uric acid than the controls. Although lean-NAFLD patients had lower BMI and waist circumstance, they had significantly higher visceral adiposity index than overweight-obese controls. Lean-NAFLD patients had comparable triglyceride, cholesterin and low-density lipoprotein cholesterin to overweight-obese NAFLD patients. In blood cell examination, both lean and overweight-obese NAFLD was companied by higher white blood cell count, red blood cell count, hemoglobin and hematocrit value. All NAFLD patients were at risk of hyperlipidemia, hypertension, diabetes and metabolic syndrome (MetS). Lean-NAFLD was more strongly associated with diabetes (OR = 2.47, 95%CI: 1.14-5.35), hypertension (OR = 1.72, 95%CI: 1.00-2.96) and MetS (OR = 3.19, 95%CI: 1.17-4.05) than overweight-obese-NAFLD (only OR for MetS was meaningful: OR = 1.89, 95%CI: 1.29-2.77). NAFLD patients were more likely to have central obesity (OR = 1.97, 95%CI: 1.38-2.80), especially in lean groups (OR = 2.17, 95%CI: 1.17-4.05).
CONCLUSION: Lean-NAFLD has unique results in demographic, biochemical and blood examinations, and adds significant risk for diabetes, hypertension and MetS in lean individuals.
PMCID: PMC4273143  PMID: 25548491
Lean-non-alcoholic fatty liver disease; Metabolic disorder; Diabetes; Risk; Chinese
5.  Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy 
World Journal of Gastroenterology : WJG  2014;20(47):18013-18021.
AIM: To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy.
METHODS: In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pylori therapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots.
RESULTS: The pooled ORs for the eradication rates calculated by intention-to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I2 = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.
CONCLUSION: Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.
PMCID: PMC4273153  PMID: 25548501
Helicobacter pylori; Eradication; Probiotics; Meta-analysis; Adult
6.  Three species of Hitobia Kamura, 1992 (Araneae, Gnaphosidae) from south-west China 
ZooKeys  2014;25-34.
Two new species and one new record of the Hitobia are described from Gaoligong Mountains, Yunnan Province, China: Hitobia tengchong sp. n. (male), Hitobia hirtella sp. n. (male) and Hitobia makotoi Kamura, 2011. Distributional data and illustrations of body and copulatory organs are provided. The differences between the new species and their related species are discussed.
PMCID: PMC4284633  PMID: 25589867
Ground spider; south-east Asia
7.  Postoperative adjuvant transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond the Milan criteria: a retrospective analysis 
Objective: To clarify the value of postoperative adjuvant transcatheter arterial chemoembolization (TACE) for resectable multiple hepatocellular carcinoma beyond the Milan criteria. Background: Patients with multiple HCC have been shown to have a worse survival after a partial hepatectomy (PH) because of the high incidence of intrahepatic tumor recurrence. Postoperative adjuvant TACE is an optional strategy for HCC patients with a high recurrence risk. Its effects and range of applications are debatable. Methods: This retrospective study enrolled 135 HCC patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria, and those patients underwent a hepatectomy with/without postoperative adjuvant TACE from Jan. 2004 to Dec. 2008. The patients were divided to the PH cohort or the PH+TACE cohort. The prognosis measures were the disease-free survival (DFS) and overall survival (OS) from the date of treatment. Univariate and multivariate analyses were used to assess the prognostic factors associated with DFS and OS, using the Cox proportional hazards model. Results: The 1-, 2-, and 5-year DFS and OS for the PH+TACE group differed significantly from the PH group (p = 0.004, p = 0.002, respectively). Multivariate analysis revealed that the significant independent risk factors associated with the DFS and OS were postoperative TACE treatment (p = 0.002, p = 0.001, respectively) and the number of tumors (p = 0.006, p = 0.037, respectively). Conclusions: Our results show that postoperative adjuvant treatment resulted in delayed intrahepatic recurrence and better survival for patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria. Postoperative adjuvant TACE should be regarded as a common strategy for patients with resectable multiple HCC beyond the Milan criteria.
PMCID: PMC4300716  PMID: 25628953
TACE; multiple hepatocellular carcinoma; Milan criteria; recurrence; prognosis
8.  Identification of Genomic Alterations in Pancreatic Cancer Using Array-Based Comparative Genomic Hybridization 
PLoS ONE  2014;9(12):e114616.
Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer.
Materials and Methods
We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry.
Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3–q22.1 and 19q13.2 and homozygous deletions at 1p33–p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer.
These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers.
PMCID: PMC4263743  PMID: 25502777
9.  Deviation analysis of C2 translaminar screw placement assisted by a novel rapid prototyping drill template: a cadaveric study 
European Spine Journal  2013;22(12):2770-2776.
The goal of this study is to evaluate the accuracy of patient-specific CT-based rapid prototype drill templates for C2 translaminar screw insertion.
Volumetric CT scanning was performed in 32 cadaveric cervical spines. Using computer software, the authors constructed drill templates that fit onto the posterior surface of the C2 vertebrae with drill guides to match the slope of the patient’s lamina. Thirty-two physical templates were created from the computer models using a rapid prototyping machine. The drill templates were used to guide drilling of the lamina and post-operative CT images were obtained. The entry point and direction of the planned and inserted screws were measured and compared.
Sixty-four C2 translaminar screws were placed without violating the cortical bone of a single lamina. The bilateral average transverse angle of intended and actual screw for C2TLS was 56.60 ± 2.22°, 56.38 ± 2.51°, 56.65 ± 2.24°, 56.39 ± 2.45°. The bilateral mean coronal angle of the planned and actual screw for C2TLS was 0°, 0°, −0.07 ± 0.32°, 0.12 ± 0.57°. The average displacement of the entry point of the superior and inferior C2TLS in the x, y, z axis was 0.27 ± 0.85, 0.49 ± 1.46, −0.28 ± 0.69, 0.43 ± 0.88, 0.38 ± 1.51, 0.23 ± 0.64 mm.
The small deviations seen are likely due to human error in the form of small variations in the surgical technique and use of software to design the prototype. This technology improves the safety profile of this fixation technique and should be further studied in clinical applications.
PMCID: PMC3843787  PMID: 24005997
Rapid prototyping; Post–pre registration; Personalized drill template; Computer-assisted; C2 translaminar screws
10.  Rat Lung Response to PM2.5 Exposure under Different Cold Stresses 
Ambient particulate matters and temperature were reported to have additive effects over the respiratory disease hospital admissions and deaths. The purpose of this study is to discuss the interactive pulmonary toxicities of cold stress and fine particulate matter (PM2.5) exposure by estimating inflammation and oxidative stress responses. 48 Wistar male rats, matched by weight and age, were randomly assigned to six groups, which were treated with cold stress alone (0 °C, 10 °C, and 20 °C (Normal control)) and cold stresses plus PM2.5 exposures respectively. Cold stress alone groups were intratracheal instillation of 0.25 mL normal saline, while cold stress plus PM2.5 exposure groups were intratracheal instillation of 8 mg/0.25 mL PM2.5. These procedures were carried out for three times with an interval of 48 hours for each treatment. All rats were sacrificed after 48 hours of the third treatment. The bronchoalveolar lavage fluid (BALF) was collected for analyzing inflammatory cells and cytokines, and lung homogenate MDA was determined for oxidative stress estimation. Results showed higher level of total cell and neutrophil in the BALF of PM2.5 exposed groups (p < 0.05). Negative relationships between cold stress intensity and the level of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP) interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF were indicated in PM2.5 exposure groups. Exposure to cold stress alone caused significant increase of inflammatory cytokines and methane dicarboxylic aldehyde (MDA) and decline of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity only in 0 °C exposure group (p < 0.05). The two-way ANOVA found significant interactive effects between PM2.5 exposure and cold stress in the level of neutrophil, IL-6 and IL-8 and SOD activity (p < 0.05). These data demonstrated that inflammation and oxidative stress involved in the additive effect of PM2.5 exposure and cold stress on pulmonary toxicity, providing explanation for epidemiological studies on the health effect of ambient PM2.5 and cold stress.
PMCID: PMC4276653  PMID: 25514147
fine particulate matter (PM2.5); cold stress; inflammatory response; oxidative stress; rat lung
11.  Extensive calcifications in portal venous system in a patient with hepatocarcinoma 
World Journal of Gastroenterology : WJG  2014;20(43):16377-16380.
Calcification of the portal venous system is a rare entity that can be incidentally discovered during computed tomography (CT). We describe a case of extensive calcifications in the portal venous system in a middle-aged male patient with hepatocellular carcinoma (HCC). This patient presented with epigastric pain that had no obvious origin prior to admission. Laboratory examinations were positive for hepatitis B surface antigen and α-fetoprotein, and severe esophageal and gastric varices were detected during gastroscopy. Abdominal X-ray plain film showed well-defined linear and track-like calcification, with irregular margins directed along the course of the portal venous system. CT revealed extensive calcifications along the course of the portal, splenic, superior mesenteric and gastroesophageal veins. He underwent splenectomy 22 years ago due to splenomegaly and partial hepatectomy seven months before because of HCC of low-grade differentiation, confirmed by pathology. Finally, the patient was diagnosed with postoperative recurrent HCC and extensive portal venous system calcification after selective hepatic angiography under digital subtraction angiography.
PMCID: PMC4239534  PMID: 25473200
Portal vein; Calcification; Portal hypertension; Hepatocarcinoma; Hepatocellular carcinoma
12.  Positron Emission Tomography with [18F]FLT Revealed Sevoflurane-Induced Inhibition of Neural Progenitor Cell Expansion in vivo 
Neural progenitor cell expansion is critical for normal brain development and an appropriate response to injury. During the brain growth spurt, exposures to general anesthetics, which either block the N-methyl-d-aspartate receptor or enhance the γ-aminobutyric acid receptor type A can disturb neuronal transduction. This effect can be detrimental to brain development. Until now, the effects of anesthetic exposure on neural progenitor cell expansion in vivo had seldom been reported. Here, minimally invasive micro positron emission tomography (microPET) coupled with 3′-deoxy-3′ [18F] fluoro-l-thymidine ([18F]FLT) was utilized to assess the effects of sevoflurane exposure on neural progenitor cell proliferation. FLT, a thymidine analog, is taken up by proliferating cells and phosphorylated in the cytoplasm, leading to its intracellular trapping. Intracellular retention of [18F]FLT, thus, represents an observable in vivo marker of cell proliferation. Here, postnatal day 7 rats (n = 11/group) were exposed to 2.5% sevoflurane or room air for 9 h. For up to 2 weeks following the exposure, standard uptake values (SUVs) for [18F]-FLT in the hippocampal formation were significantly attenuated in the sevoflurane-exposed rats (p < 0.0001), suggesting decreased uptake and retention of [18F]FLT (decreased proliferation) in these regions. Four weeks following exposure, SUVs for [18F]FLT were comparable in the sevoflurane-exposed rats and in controls. Co-administration of 7-nitroindazole (30 mg/kg, n = 5), a selective inhibitor of neuronal nitric oxide synthase, significantly attenuated the SUVs for [18F]FLT in both the air-exposed (p = 0.00006) and sevoflurane-exposed rats (p = 0.0427) in the first week following the exposure. These findings suggested that microPET in couple with [18F]FLT as cell proliferation marker could be used as a non-invasive modality to monitor the sevoflurane-induced inhibition of neural progenitor cell proliferation in vivo.
PMCID: PMC4233913  PMID: 25452743
neural progenitor cell; positron emission tomography; [18F]FLT; sevoflurane; proliferation
13.  YAP Regulates Cell Proliferation, Migration, and Steroidogenesis in Adult Granulosa Cell Tumors 
Endocrine-related cancer  2014;21(2):297-310.
The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of ovary, excess production of estrogen, high frequency of recurrence and potential of malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild-type YAP or a constitutively active YAP mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in regulating GCT cell proliferation, migration and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT.
PMCID: PMC4222524  PMID: 24389730
Hippo/YAP pathway; granulosa cell tumor; cell proliferation; steroidogenesis; migration
14.  Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth 
Cell Research  2014;24(10):1164-1180.
An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.
PMCID: PMC4185347  PMID: 25223704
secreted microRNA; regulatory T cell; PTEN; microvesicle; immune evasion; tumor
15.  Safety and Efficacy of Adalimumab for Patients With Moderate to Severe Crohn's Disease: The Taiwan Society of Inflammatory Bowel Disease (TSIBD) Study 
Intestinal Research  2014;12(4):287-292.
Only moderate to severe Crohn's Disease (CD) patients without a satisfactory conventional therapy effect are eligible to get reimbursement from the National Health Insurance of Taiwan for using adalimumab. These are more stringent criteria than in many Western countries and Japan and Korea. We aim to explore the efficacy of using adalimumab in CD patients under such stringent criteria.
A retrospective analysis was conducted in nine medical centers in Taiwan and we collected the results of CD patients receiving adalimumab from Sep 2009 to Mar 2014. The clinical characteristics, response measured by CDAI (Crohn's Disease Activity Index), adverse events and survival status were recorded and analyzed. CR-70, CR-100, and CR-150 were defined as attaining a CDAI decrease of 70, 100 or 150 points compared with baseline.
A total of 103 CD patient records were used in this study. Sixty percent of these patients received combination therapy of adalimumab together with immunomodulators. CR-70 was 68.7%, 74.5% and 88.4% after week 4, 8 and 12 of treatment, respectively. The steroid-free rate, complications and survival were 47.6%, 9.7% and 99% of patients, respectively. In considering the mucosal healing, only 25% patients achieve mucosal healing after treatment for 6 to 12 months. Surgery was still needed in 16.5% of patients. Combination treatment of adalimumab with immunomodulators further decreased the level of CDAI at week 8 when compared with the monotherapy.
Even under the stringent criteria for using adalimumab, the response rate was comparable to those without stringent criteria.
PMCID: PMC4214955  PMID: 25374494
Crohn disease; Adalimumab; Efficacy; Safety
16.  Tamoxifen induces apoptosis through cancerous inhibitor of protein phosphatase 2A–dependent phospho-Akt inactivation in estrogen receptor–negative human breast cancer cells 
Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism.
In total, five ER-negative breast cancer cell lines (HCC-1937, MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3) were used for in vitro studies. Cellular apoptosis was examined by flow cytometry and Western blot analysis. Signal transduction pathways in cells were assessed by Western blot analysis. The in vivo efficacy of tamoxifen was tested in xenograft nude mice.
Tamoxifen induced significant apoptosis in MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3 cells, but not in HCC-1937 cells. Tamoxifen-induced apoptosis was associated with inhibition of cancerous inhibitor of protein phosphatase 2A (CIP2A) and phospho-Akt (p-Akt) in a dose-dependent manner. Ectopic expression of either CIP2A or Akt protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, tamoxifen increased protein phosphatase 2A (PP2A) activity, and tamoxifen-induced apoptosis was attenuated by the PP2A antagonist okadaic acid in the sensitive cell lines, but not in resistant HCC-1937 cells. Moreover, silencing CIP2A by small interfering RNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Furthermore, tamoxifen regulated CIP2A protein expression by downregulating CIP2A mRNA. Importantly, tamoxifen inhibited the in vivo growth of MDA-MB-468 xenograft tumors in association with CIP2A downregulation, whereas tamoxifen had no significant effect on CIP2A expression and anti-tumor growth in HCC-1937 tumors.
Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. Our data suggest a novel “off-target” mechanism of tamoxifen and suggest that CIP2A/PP2A/p-Akt signaling may be a feasible anti-cancer pathway.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0431-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4303112  PMID: 25228280
17.  In vivo ossification of a scaffold combining β-tricalcium phosphate and platelet-rich plasma 
Tricalcium phosphate (TCP) and platelet-rich plasma (PRP) are commonly used in bone tissue engineering. The aim of the present study was to investigate a composite that combined TCP with PRP and assess its effectiveness in the treatment of bone defects. Cavity-shaped bone defects were established on the tibiae of 27 beagle dogs, and were repaired by pure β-TCP with bone marrow stromal cells (BMSCs), β-TCP/PRP with BMSCs and autogenic ilium. The samples were harvested at 4, 8 and 12 weeks, and bone regeneration was evaluated using X-ray radiography, immunocytochemical staining of osteocalcin (OCN), hematoxylin and eosin staining and reverse transcription-polymerase chain reaction analyses. Biomechanical tests of the scaffolds were performed at the 12th week after scaffold implantation. When using pure β-TCP as a scaffold, the scaffold-bone interface was clear and no material adsorption and bone healing was observed. Substantial bone regeneration was observed when the tibial defects were restored using β-TCP/PRP and autogenic ilium. Furthermore, the mRNA expression levels of OCN, alkaline phosphatase and collagen type I α1 were significantly higher in the animals with β-TCP/PRP scaffolds at 8 and 12 weeks following implantation compared with those in the animals with the pure β-TCP scaffolds. The maximum load and compressive strength of the β-TCP/PRP scaffolds were similar to those of the autogenic ilium; however, they were significantly higher than those of the pure β-TCP scaffold. Thus, the β-TCP/PRP composite may be used as a potential scaffold to carry in vitro cultured BMSCs to treat bone defects.
PMCID: PMC4186334  PMID: 25289027
tricalcium phosphate; platelet-rich plasma; tissue engineering; bone defect; bone marrow stromal cells
18.  Metal-organic Frameworks as A Tunable Platform for Designing Functional Molecular Materials 
Journal of the American Chemical Society  2013;135(36):13222-13234.
Metal-organic frameworks (MOFs), also known as coordination polymers, represent an interesting class of crystalline molecular materials that are synthesized by combining metal-connecting points and bridging ligands. The modular nature of and mild conditions for MOF synthesis have permitted the rational structural design of numerous MOFs and the incorporation of various functionalities via constituent building blocks. The resulting designer MOFs have shown promise for applications in a number of areas, including gas storage/separation, nonlinear optics/ferroelectricity, catalysis, energy conversion/storage, chemical sensing, biomedical imaging, and drug delivery. The structure-property relationships of MOFs can also be readily established by taking advantage of the knowledge of their detailed atomic structures, which enables fine-tuning of their functionalities for desired applications. Through the combination of molecular synthesis and crystal engineering MOFs thus present an unprecedented opportunity for the rational and precise design of functional materials.
PMCID: PMC3800686  PMID: 23944646
19.  Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure–flow relation: The CARNet study 
Medical engineering & physics  2014;36(5):620-627.
Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n = 50 rest; n = 20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann–Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC > 0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.
PMCID: PMC4155942  PMID: 24725709
Cerebral autoregulation; Transfer function analysis; Method comparison; Standardisation
20.  A Probabilistic Model to Predict Clinical Phenotypic Traits from Genome Sequencing 
PLoS Computational Biology  2014;10(9):e1003825.
Genetic screening is becoming possible on an unprecedented scale. However, its utility remains controversial. Although most variant genotypes cannot be easily interpreted, many individuals nevertheless attempt to interpret their genetic information. Initiatives such as the Personal Genome Project (PGP) and Illumina's Understand Your Genome are sequencing thousands of adults, collecting phenotypic information and developing computational pipelines to identify the most important variant genotypes harbored by each individual. These pipelines consider database and allele frequency annotations and bioinformatics classifications. We propose that the next step will be to integrate these different sources of information to estimate the probability that a given individual has specific phenotypes of clinical interest. To this end, we have designed a Bayesian probabilistic model to predict the probability of dichotomous phenotypes. When applied to a cohort from PGP, predictions of Gilbert syndrome, Graves' disease, non-Hodgkin lymphoma, and various blood groups were accurate, as individuals manifesting the phenotype in question exhibited the highest, or among the highest, predicted probabilities. Thirty-eight PGP phenotypes (26%) were predicted with area-under-the-ROC curve (AUC)>0.7, and 23 (15.8%) of these were statistically significant, based on permutation tests. Moreover, in a Critical Assessment of Genome Interpretation (CAGI) blinded prediction experiment, the models were used to match 77 PGP genomes to phenotypic profiles, generating the most accurate prediction of 16 submissions, according to an independent assessor. Although the models are currently insufficiently accurate for diagnostic utility, we expect their performance to improve with growth of publicly available genomics data and model refinement by domain experts.
Author Summary
The Personal Genome Project (PGP) is an emerging community whose goal is to collect and publicly share genomes, environmental data, medical records, and clinical traits from tens of thousands of volunteers. This information may enable computer software to establish the relationships between patterns of alterations in human genomes and clinical phenotypic traits. We describe a novel, Bayesian mathematical model to predict such traits from genome sequence and population prevalence. The core of the model is a set of phenotypic penetrance estimates for aggregated genetic variants, which are learned without any information about particular individuals in a cohort of interest. We illustrate the model's utility in ranking individuals in the PGP cohort, according to their probability of having 146 phenotypes.
PMCID: PMC4154636  PMID: 25188385
21.  Discussing Occupy Wall Street on Twitter: Longitudinal Network Analysis of Equality, Emotion, and Stability of Public Discussion 
To evaluate the quality of public discussion about social movements on Twitter and to understand the structural features and evolution of longitudinal discussion networks, we analyze tweets about the Occupy Wall Street movement posted over the course of 16 days by investigating the relationship between inequality, emotion, and the stability of online discussion. The results reveal that (1) the discussion is highly unequal for both initiating discussions and receiving conversations; (2) the stability of the discussion is much higher for receivers than for initiators; (3) the inequality of online discussions moderates the stability of online discussions; and (4) on an individual level, there is no significant relationship between emotion and political discussion. The implications help evaluate the quality of public discussion, and to understand the relationship between online discussion and social movements.
PMCID: PMC3776622  PMID: 23656222
22.  Clearance of serum solutes by hemofiltration in dogs with severe heat stroke 
We have previously reported that hemofiltration (HF) may be an effective additional means of treating heat stroke when rapid cooling is not effective.
Dogs were assigned to a heat stroke (control) or heat stroke + hemofiltration (HF) group (n = 8 each group). After heat stroke induction, dogs in the HF group received HF for 3 h. Serum concentrations of interleukin (IL)-10, tumor necrosis factor (TNF)-α, IL-6, blood urea nitrogen (BUN) and creatinine were measured at baseline and 1, 2, and 3 h after heat stroke. Clearance rates of solutes were determined 1, 2, and 3 h after the start of HF.
Serum concentrations of all solutes tended to increase with time after heat stroke in the control group, but decreased (BUN, creatinine) or remained relatively unchanged (TNF-α, IL-6, IL-10) with time in the HF group. Concentrations of all solutes were significantly lower in the HF group compared with the control group at 2 and 3 h (P < 0.05). Clearance rates for small molecular weight solutes were high, while those for larger molecular weight solutes were low.
HF prevents heat stroke-induced increases in serum cytokine concentrations and is effective for clearing small molecular weight solutes from serum, but less effective for clearing larger molecular weight solutes, including TNF-α, IL-6, and IL-10.
PMCID: PMC4237957  PMID: 25145441
Clearance; Dogs; Heat stroke; Hemofiltration; Shock; Solute
23.  Drug Repositioning Discovery for Early- and Late-Stage Non-Small-Cell Lung Cancer 
BioMed Research International  2014;2014:193817.
Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC) is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.
PMCID: PMC4156989  PMID: 25210704
24.  A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy 
Oncology Letters  2014;8(5):2000-2006.
The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.
PMCID: PMC4186501  PMID: 25289086
dual-targeting; cyclic arginine-glycine-aspartic acid; transferrin; glioma
25.  Long-Term Outcomes after Dialysis-Requiring Acute Kidney Injury 
BioMed Research International  2014;2014:365186.
AKI-dialysis patients had a higher incidence of long-term ESRD and mortality than the patients without AKI. The patients who recovered from dialysis were associated with a lower incidence of long-term ESRD and mortality than in the patients who still required dialysis.
PMCID: PMC4145550  PMID: 25187902

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