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1.  The efficacy of electroacupuncture for the treatment of simple female stress urinary incontinence - comparison with pelvic floor muscle training: study protocol for a multicenter randomized controlled trial 
Trials  2015;16:45.
Background
Previous research has shown that electroacupuncture therapy has a potential therapeutic effect for simple female stress urinary incontinence. In this study, pelvic floor muscle training, the first-line treatment for stress urinary incontinence in women based on meta-analysis of numerous randomized control trials and recommended by international clinical practice, is used as a control group to demonstrate whether electroacupuncture therapy is a better method for female stress urinary incontinence.
Methods/design
A randomized controlled trial has been designed to evaluate the therapeutic benefit of electroacupuncture for female stress urinary incontinence compared with pelvic floor muscle training. The safety of electroacupuncture and patient compliance will also be evaluated. Untoward reaction to the electroacupuncture, including a broken needle, fainting on acupuncture, or pain during acupuncture, will be recorded and the therapy will be stopped if an untoward reaction occurs. After we have received full ethical approval and patient consent, participants will be randomized to receive a series of 24 electroacupuncture or pelvic floor muscle training interventions. The frequency and amount of leakage will be measured as the primary outcome parameters. Secondary outcome parameters include the 1-hour pad test, the short-form of the International Consultation on Incontinence Questionnaire, patient subjective effectiveness evaluation, weekly usage of pad, and usage of specialty therapy for female stress urinary incontinence.
Discussion
This trial will help to determine whether electroacupuncture is a more effective treatment than pelvic floor muscle training for patients with female stress urinary incontinence.
Trial registration
ClinicalTrials.gov NCT01940432 (12 September 2013).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0560-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0560-1
PMCID: PMC4336724
Electroacupuncture; Female stress urinary incontinence; Pelvic floor muscle training
2.  Edwardsiella tarda-Induced Cytotoxicity Depends on Its Type III Secretion System and Flagellin 
Infection and Immunity  2014;82(8):3436-3445.
Many Gram-negative bacteria utilize a type III secretion system (T3SS) to translocate virulence proteins into host cells to cause diseases. In responding to infection, macrophages detect some of the translocated proteins to activate caspase-1-mediated cell death, called pyroptosis, and secretion of proinflammatory cytokines to control the infection. Edwardsiella tarda is a Gram-negative enteric pathogen that causes hemorrhagic septicemia in fish and both gastrointestinal and extraintestinal infections in humans. In this study, we report that the T3SS of E. tarda facilitates its survival and replication in murine bone marrow-derived macrophages, and E. tarda infection triggers pyroptosis of infected macrophages from mice and fish and increased secretion of the cytokine interleukin 1β in a T3SS-dependent manner. Deletion of the flagellin gene fliC of E. tarda results in decreased cytotoxicity for infected macrophages and does not attenuate its virulence in a fish model of infection, whereas upregulated expression of FliC in the fliC mutant strain reduces its virulence. We propose that the host controls E. tarda infection partially by detecting FliC translocated by the T3SS, whereas the bacteria downregulate the expression of FliC to evade innate immunity.
doi:10.1128/IAI.01065-13
PMCID: PMC4136207  PMID: 24891103
3.  Characterization of CaHsp70-1, a Pepper Heat-Shock Protein Gene in Response to Heat Stress and Some Regulation Exogenous Substances in Capsicum annuum L. 
Pepper (Capsicum annuum L.) is sensitive to heat stress (HS). Heat shock proteins 70 (Hsp70s) play a crucial role in protecting plant cells against HS and control varies characters in different plants. However, CaHsp70-1 gene was not well characterized in pepper. In this study, CaHsp70-1 was cloned from the pepper thermotolerant line R9, which encoded a protein of 652 amino acids, with a molecular weight of 71.54 kDa and an isoelectric point of 5.20. CaHsp70-1 belongs to the cytosolic Hsp70 subgroup, and best matched with tomato SlHsp70. CaHsp70-1 was highly induced in root, stem, leaf and flower in R9 with HS treatment (40 °C for 2 h). In both thermosensitive line B6 and thermotolerant line R9, CaHsp70-1 significantly increased after 0.5 h of HS (40 °C), and maintained in a higher level after 4 h HS. The expression of CaHsp70-1 induced by CaCl2, H2O2 and putrescine (Put) under HS were difference between B6 and R9 lines. The different expression patterns may be related to the differences in promoters of CaHsp70-1 from the two lines. These results suggest that CaHsp70-1 as a member of cytosolic Hsp70 subgroup, may be involved in HS defense response via a signal transduction pathway contained Ca2+, H2O2 and Put.
doi:10.3390/ijms151119741
PMCID: PMC4264136  PMID: 25356507
Capsicum annuum L.; CaHsp70-1; heat stress; gene expression
4.  EGF Potentiation of VEGF Production Is Cell Density Dependent in H292 EGFR Wild Type NSCLC Cell Line 
Non-small cell lung cancer (NSCLC) affects millions of patients each year worldwide. Existing therapies include epidermal growth factor receptor (EGFR) inhibition using small molecules or antibodies with good efficacy. Unfortunately, intrinsic and acquired resistance to EGFR therapy remains a persistent complication for disease treatment. A greater understanding of the role of EGFR in NSCLC etiology is crucial to improving patient outcomes. In this study, the role of EGFR in tumor angiogenesis was examined in H292 NSCLC cells under the pretense that confluent cells would exhibit a more angiogenic and growth-centered phenotype. Indeed, confluent H292 cells potentiated endothelial cell angiogenesis in co-culture models in an EGFR-dependent manner. While confluent H292 cells did not exhibit any change in EGFR protein expression, EGFR localization to the extracellular membrane was increased. EGFR membrane localization coincided with a comparable potentiation of maximal EGFR phosphorylation and was followed by a 3-fold increase in vascular endothelial growth factor A (VEGF-A) production as compared to subconfluent cells. EGFR-mediated VEGF-A production was determined to be dependent on signal transducer and activator of transcription 3 (STAT3) activation and not phosphoinositide 3-kinase (PI3K) signaling. These results identify unique cell density dependent phenotypes within a monoclonal NSCLC cell line and provide a potential mechanism of resistance to anti-EGFR therapy in metastatic NSCLC.
doi:10.3390/ijms151017686
PMCID: PMC4227184  PMID: 25272226
non-small cell lung cancer; vascular endothelial growth factor; epidermal growth factor receptor; cell density
5.  Pollution Characteristics and Possible Sources of Seldom Monitored Trace Elements in Surface Sediments Collected from Three Gorges Reservoir, China 
The Scientific World Journal  2014;2014:170639.
A geochemical study of Three Gorges Reservoir (TGR) sediments was carried out to analyze the concentrations, distribution, accumulation, and potential sources of the seldom monitored trace elements (SMTEs). The mean concentrations of Li, B, Be, Bi, V, Co, Ga, Sn, Sb, and Tl were 47.08, 2.47, 59.15, 0.50, 119.20, 17.83, 30.31, 3.25, 4.14, and 0.58 mg/kg, respectively. The concentrations of total SMTEs, together with their spatial distribution, showed that the SMTEs were mainly due to anthropogenic inputs in the region of TGR. The assessment by Geoaccumulation Index indicates that Tl, Be, V, Co, and Fe are at the unpolluted level; Bi, Li, Ga, and Sn were at the “uncontaminated to moderately contaminated” level. However, B was classified as “moderately contaminated” level and Sb was ranked as “strongly contaminated” level. The pollution level of the SMTEs is Sb > B > Bi > Li > Ga > Sn > Tl > Be > V > Co > Fe. The results of Correlation Analysis and Principal Component Analysis indicated Be, V, Co, Ga, Sn, Tl, Bi, and Fe in sediments have a natural source. B and Li were positively correlated with each other and mainly attributed into similar anthropogenic input. In addition, Sb has less relationship with other SMTEs, indicating that Sb has another kind of anthropogenic source.
doi:10.1155/2014/170639
PMCID: PMC4127282  PMID: 25136647
6.  Peroxisome proliferator-activated receptor δ (PPARδ) induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTor activation 
Cancer research  2013;73(14):4349-4361.
The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In the present study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathological changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to five months. Histopathological changes occurred concurrently with an increase in an inflammatory, invasive, metabolic and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning one week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTor signaling that were attenuated by treatment with the mTor inhibitor everolimus. Our findings are the first to demonstrate a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease.
doi:10.1158/0008-5472.CAN-13-0322
PMCID: PMC3723355  PMID: 23811944
PPARδ; transgenic; tumorigenesis; mTor; Plac1
7.  Platycodin D from Platycodonis Radix enhances the anti-proliferative effects of doxorubicin on breast cancer MCF-7 and MDA-MB-231 cells 
Chinese Medicine  2014;9:16.
Background
It has been demonstrated that platycodin D (PD) exhibits anti-cancer activities. This study aims to investigate the anti-proliferative effects of the combination of PD and doxorubicin (DOX) on human breast cancer cells (MCF-7 and MDA-MB-231 cells).
Methods
The anti-proliferative effects of different dosages of PD, DOX, and PD + DOX on MCF-7 and MDA-MB-231 cells were determined by the MTT assay. The 10 μM PD, 5 μM DOX, and 10 μM PD + 5 μM DOX induced-protein expression of apoptosis-related molecules on MCF-7 and MDA-MB-231 cells were detected by western blot. The 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX-induced mitochondrial membrane potential changes on MCF-7 and MDA-MB-231 cells were stained with JC-1 before visual determination. The intracellular accumulations of DOX, induced by 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX, were detected by flow cytometry.
Results
PD enhanced anti-cancer activities of DOX were observed in both MCF-7 and MDA-MB-231 cell lines. Compared with mono treatment, the combined treatment increased the protein expression of cleaved poly (ADP-ribose) polymerase and decreased the mitochondrial membrane potential. The combined treatment with PD did not obviously increase the accumulation of DOX in MCF-7 cells (1.66 ± 0.13 in DOX-treated group, and 1.69 ± 0.06 in PD + DOX-treated group, P = 0.76), but it significantly increased the accumulation of DOX in MDA-MB-231 cells (1.76 ± 0.17 in DOX-treated group, 2.09 ± 0.02 in PD + DOX-treated group, P = 0.027).
Conclusion
The combined treatment of DOX and PD exhibited stronger anti-proliferative effects on MCF-7 and MDA-MB-231 cells than DOX and PD treatment did.
doi:10.1186/1749-8546-9-16
PMCID: PMC4075934  PMID: 24982689
8.  Weekly Paclitaxel/Carboplatin/Trastuzumab Therapy Improves Pathologic Complete Remission in Aggressive HER2-Positive Breast Cancers, Especially in Luminal-B Subtype, Compared With a Once-Every-3-Weeks Schedule 
The Oncologist  2013;18(5):511-517.
The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab for HER2-positive, locally aggressive (stage IIB–IIIC) breast cancers were evaluated in this phase II trial. The results indicate that more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype.
Background.
The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab (PCarH) for HER2-positive, locally aggressive (stage IIB–IIIC) breast cancers were evaluated in this phase II trial.
Methods.
Patients were randomly assigned to receive either weekly (12 doses over 16 weeks) or once-every-3-weeks (4 doses over 12 weeks) treatment. The primary endpoint was pathologic complete remission (pCR) in the breast and axilla. To detect an assumed 35% pCR absolute difference between the two schedules, a minimum of 26 assessable patients in each group was required (two-sided α = 0.05, β = 0.2).
Results.
A total of 56 patients were enrolled (weekly group, n = 29; every-3-weeks group, n = 27). In the intent-to-treat analysis, pCR in the breast/axilla were found in 31 patients (55%; 95% confidence interval [CI]: 41%–69%). Compared with the every-3-weeks schedule, the weekly administration achieved higher pCR (41% vs. 69%; p = .03). After adjustment for clinical and pathological factors, the weekly administration was more effective than the every-3-weeks schedule, with hazard ratio of 0.3 (95% CI: 0.1–0.9; p = .03). Interestingly, weekly administration resulted in high pCR rates in both luminal-B (HER2-positive) and ERBB2+ tumors (67% vs. 71%; p = .78), whereas luminal-B (HER2-positive) tumors benefited less from the every-3-weeks schedule compared with the ERBB2+ tumors (21% vs. 62%, p = .03). These results remain after multivariate adjustment, showing weekly administration was more effective in the luminal-B (HER2-positive) subgroup (p = .02) but not in the ERBB2+ subgroup (p = .50).
Conclusion.
A more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype. Further studies to validate our findings are warranted.
doi:10.1634/theoncologist.2012-0057
PMCID: PMC3662841  PMID: 23635560
9.  Hepatoprotective effect of Cichorium intybus L., a traditional Uighur medicine, against carbon tetrachloride-induced hepatic fibrosis in rats 
AIM: To investigate the hepatoprotective effect of a Cichorium intybus L. extract (CIE) on CCl4-induced hepatic fibrosis in rats.
METHODS: Seventy-two male Wistar albino rats were randomly divided into six groups of twelve rats each. The normal control group was allowed free access to food and water. Liver injury was performed in the remaining five groups with an i.p. injection of a 1.0 mL/kg CCl4 and olive oil (2:3 v/v) mixture, twice weekly for 8 weeks. All rats, with the exception of the injury model group, were intragastrically (i.g.,) administered quantum satis (q.s.) dosages [CIE group: 6, 18, and 54 mg/kg, respectively; Fu Fang Bie Jia Ruan Gan Pian (FFBJRGP) group: 780 mg/kg]. The oral administration of different drugs was performed on the day before CCl4 administration and subsequently once per day for 8 wk. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) in the rat livers were measured. Histopathological changes in the liver were assessed for each group using HE staining and a Masson Trichrome examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was examined by immunohistochemical analysis.
RESULTS: CIE at oral doses of 6, 18, and 54 g/kg per day showed a significant hepatoprotective effect, especially at a dose of 54 g/kg per day. CIE doses reduced the levels of AST (149.04 ± 34.44, P < 0.01), ALT (100.72 ± 27.19, P < 0.01), HA (548.50 ± 65.09, P < 0.01), LN (28.69 ± 3.32, P < 0.01) and Hyp (263.33 ± 75.82, P < 0.01). With regards to hepatoprotective activity, the CIE dose of 54 g/kg per day produced the largest significant effect by increasing GSH (3.11 ± 0.81), SOD (269.98 ± 33.77, P < 0.01) and reducing MDA (2.76 ± 0.51, P < 0.01) levels in the liver. The expressions of TGF-β1 and α-SMA were measured by immunohistology and found to be significantly reduced by CIE in a dose-dependent manner.
CONCLUSION: CIE may effectively protect against CCl4-induced hepatic fibrosis in rats; thus, it is a promising anti-fibrotic therapeutic agent.
doi:10.3748/wjg.v20.i16.4753
PMCID: PMC4000513  PMID: 24782629
Cichorium intybus L. extract; Traditional Uighur medicine; Hepatic fibrosis; Carbon tetrachloride
10.  Heavy Metals Pollution and Pb Isotopic Signatures in Surface Sediments Collected from Bohai Bay, North China 
The Scientific World Journal  2014;2014:158796.
To investigate the characteristics and potential sources of heavy metals pollution, surface sediments collected from Bohai Bay, North China, were analyzed for the selected metals (Cd, Cr, Cu, Ni, Pb, and Zn). The Geoaccumulation Index was used to assess the level of heavy metal pollution. Pb isotopic compositions in sediments were also measured to effectively identify the potential Pb sources. The results showed that the average concentrations of Cd, Cr, Cu, Ni, Pb, and Zn were 0.15, 79.73, 28.70, 36.56, 25.63, and 72.83 mg/kg, respectively. The mean concentrations of the studied metals were slightly higher than the background values. However, the heavy metals concentrations in surface sediments in Bohai Bay were below the other important bays or estuaries in China. The assessment by Geoaccumulation Index indicated that Cr, Zn, and Cd were classified as “the unpolluted” level, while Ni, Cu, and Pb were ranked as “unpolluted to moderately polluted” level. The order of pollution level of heavy metals was: Pb > Ni > Cu > Cr > Zn > Cd. The Pb isotopic ratios in surface sediments varied from 1.159 to 1.185 for 206Pb/207Pb and from 2.456 to 2.482 for 208Pb/207Pb. Compared with Pb isotopic radios in other sources, Pb contaminations in the surface sediments of Bohai Bay may be controlled by the mix process of coal combustion, aerosol particles deposition, and natural sources.
doi:10.1155/2014/158796
PMCID: PMC4005065  PMID: 24982926
11.  Beneficial effects of natural Jeju groundwaters on lipid metabolism in high-fat diet-induced hyperlipidemic rats 
Nutrition Research and Practice  2014;8(2):165-171.
BACKGROUND
Groundwater is believed to possess many beneficial effects due to its natural source of various minerals. In this study, we examined the effects of natural Jeju groundwater S1 (Samdasoo™), S2 and S3 pumped up from different locations of Jeju Island, Korea, along with local tap water, on body weight gain, serum lipids and lipoproteins, and liver histopathology in high-fat diet-induced hyperlipidemic rats.
MATERIALS/METHODS
Rats were randomly and equally divided into 6 groups. Different water samples were supplied to the hyperlipidemic rats as their daily drinking water and the widely-used anti-hyperlipidemic drug simvastatin was used as a positive control. Body weight, serum lipids and lipoproteins were measured weekly. Liver weight, liver index and liver histopathology were examined after the execution of the rats.
RESULTS
After drinking Jeju groundwaters for two months, S2 but not S3 significantly reduced weight growth and serum triglycerides levels and increased high density lipoprotein-C (HDL-C) without affecting total cholesterol or LDL-C. S1 and particularly S2 significantly reduced the severity of liver hypertrophy and steatosis. All Groundwaters had much higher contents of vanadium (S3>S2>S1>>tap water) whereas S1 and S2 but not S3 markedly blocked autoxidation of ferrous ions.
CONCLUSION
Jeju Groundwater S1 and particularly S2 exhibit protective effects against hyperlipidemia and fatty liver and hypothesize that the beneficial effect of Jeju Groundwaters may be contributed from blockade of autoxidation of ferrous ions rather than their high contents of vanadium.
doi:10.4162/nrp.2014.8.2.165
PMCID: PMC3988505  PMID: 24741400
Jeju groundwaters; fatty liver; hyperlipidemia; vanadium; ferrous ion autoxidation
12.  The clinical value of the quantitative detection of four cancer-testis antigen genes in multiple myeloma 
Molecular Cancer  2014;13:25.
Background
Cancer-testis (CT) antigen genes might promote the progression of multiple myeloma (MM). CT antigens may act as diagnostic and prognostic markers in MM, but their expression levels and clinical implications in this disease are not fully understood. This study measured the expression levels of four CT antigen genes in Chinese patients with MM and explored their clinical implications.
Methods
Real-time quantitative polymerase chain reaction (qPCR) was used to quantify the expression of MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 mRNA in 256 bone marrow samples from 144 MM patients.
Results
In the newly diagnosed patients, the positive expression rates were 88.5% for MAGE-C1/CT7, 82.1% for MAGE-C2/CT10, 76.9% for MAGE-A3 and 25.6% for SSX-2. The expression levels and the number of co-expressed CT antigens correlated significantly with several clinical indicators, including the percentage of plasma cells infiltrating the bone marrow, abnormal chromosome karyotypes and the clinical course.
Conclusion
MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 expression levels provide potentially effective clinical indicators for the auxiliary diagnosis and monitoring of treatment efficacy in MM.
doi:10.1186/1476-4598-13-25
PMCID: PMC3922338  PMID: 24499297
Cancer-testis antigen gene; Multiple myeloma; Real-time quantitative polymerase chain reaction
13.  Clinical and laboratory characteristics of patients having amyloidogenic transthyretin deposition in osteoarthritic knee joints 
Objective: Our aim was to investigate clinical and laboratory characteristics of osteoarthritic patients who had amyloid deposition in their knee joints. Methods: Synovial membranes were obtained from 36 patients with knee osteoarthritis (OA) who underwent joint replacement surgery. From this sample, the diagnosis of amyloid was determined by Congo red staining, which demonstrated apple-green birefringence under a polarized microscope. All synovial membranes were immunohistochemically characterized for the expressions of amyloid immunoglobulin light chain (AL-κ and AL-λ), serum amyloid-A (SAA), amyloidogenic transthyretin (ATTR), and amyloidogenic β2-microglobulin (Aβ2M). Matrix-assisted laser desorption-ionizaton/time of flight mass spectrometry (MALDI-TOF MS) was used to analyze transthyretin (TTR) isoforms in the serum of each patient. Results: Nine cases (25%) were found to be amyloid-positive. Immunohistochemically, eight cases (88.9%) had ATTR deposition, and one sample (11.1%) was shown to be AL-κ-positive. MALDI-TOF MS identified that the TTR in the serum of the patients was unmodified wild-type TTR, TTR-Cys-S-S-Cys, and TTR-Cys-S-S-CysGly. The age at surgery and the disease duration were significantly higher in the ATTR-positive group than in the ATTR-negative group. Knee score and function score were significantly lower in the ATTR-positive group than in the ATTR-negative group. Conclusions: Amyloid deposition in synovial membranes of OA patients was found to be ATTR and AL-κ. TTR in the serum of the patients was unmodified wild-type TTR together with two isoforms. The high age at surgery, long disease duration, and a deteriorated knee function were associated with ATTR amyloid deposition in the osteoarthritic knee joints.
doi:10.1631/jzus.B1300046
PMCID: PMC3891123  PMID: 24390749
Amyloid; Immunoglobulin light chain; Matrix-assisted laser desorption-ionizaton/time of flight mass spectrometry (MALDI-TOF MS); Osteoarthritis; Transthyretin
14.  Molecular Phylogenetic Analysis of the Amiota taurusata Species Group within the Chinese Species, with Descriptions of Two New Species 
The relationships among six species of the Amiota taurusata Takada, Beppu, & Toda (Diptera: Drosophilidae) species group were investigated based on DNA sequence data of the mitochondrial NADH dehydrogenase subunit 2 (ND2) gene, using three species of the genus Amiota as outgroups. A mitochondrial gene, cytochrome c oxidase I (COI), can be used to discriminate between species of the taurusata group. Two new species are described from South China: A. protuberantis Shao et Chen, sp. nov. and A. shennongi Shao et Chen, sp. nov. A key to all the species of the taurusata group based on morphological characters is provided.
doi:10.1673/031.014.33
PMCID: PMC4206230  PMID: 25373180
cryptic species; drosophilid; East Asia; mtDNA; taxonomy
15.  Cathepsins mediate tumor metastasis 
Cathepsins are highly expressed in various human cancers, associated with tumor metastasis. It is superfamily, concluding A, B, C, D, E, F, G, H, L, K, O, S, V, and W family members. As a group of lysosomal proteinases or endopeptidases, each member has a different function, playing different roles in distinct tumorigenic processes such as proliferation, angiogenesis, metastasis, and invasion. Cathepsins belong to a diverse number of enzyme subtypes, including cysteine proteases, serine proteases and aspartic proteases. The contribution of cathepsins to invasion in human cancers is well documented, although the precise mechanisms by which cathepsins exert their effects are still not clear. In the present review, the role of cathepsin family members in cancer is discussed.
doi:10.4331/wjbc.v4.i4.91
PMCID: PMC3856311  PMID: 24340132
Cathepsin; Tumor; Metastasis; Mechanism
16.  Ganoderiol A-Enriched Extract Suppresses Migration and Adhesion of MDA-MB-231 Cells by Inhibiting FAK-SRC-Paxillin Cascade Pathway 
PLoS ONE  2013;8(10):e76620.
Cell adhesion, migration and invasion are critical steps for carcinogenesis and cancer metastasis. Ganoderma lucidum, also called Lingzhi in China, is a traditional Chinese medicine, which exhibits anti-proliferation, anti-inflammation and anti-metastasis properties. Herein, GAEE, G. lucidum extract mainly contains ganoderiol A (GA), dihydrogenated GA and GA isomer, was shown to inhibit the abilities of adhesion and migration, while have a slight influence on that of invasion in highly metastatic breast cancer MDA-MB-231 cells at non-toxic doses. Further investigation revealed that GAEE decreased the active forms of focal adhesion kinase (FAK) and disrupted the interaction between FAK and SRC, which lead to deactivating of paxillin. Moreover, GAEE treatment downregulated the expressions of RhoA, Rac1, and Cdc42, and decreased the interaction between neural Wiskott-Aldrich Syndrome protein (N-WASP) and Cdc42, which impair cell migration and actin assembly. To our knowledge, this is the first report to show that G.lucidum triterpenoids could suppress cell migration and adhesion through FAK-SRC-paxillin signaling pathway. Our study also suggests that GAEE may be a potential agent for treatment of breast cancer.
doi:10.1371/journal.pone.0076620
PMCID: PMC3812178  PMID: 24204647
17.  Impact of Three Oral Antidiabetic Drugs on Markers of β-Cell Function in Patients with Type 2 Diabetes: A Meta-Analysis 
PLoS ONE  2013;8(10):e76713.
Background
The effect of metformin, pioglitazone and sitagliptin on β-cell function in the treatment of type 2 diabetes is controversial. Therefore, we performed a systematic review and meta-analysis to obtain a better understanding in the β-cell effects of metformin, pioglitazone and sitagliptin.
Methods
We searched Pubmed and the Cochrane Center Register of Controlled Trials to identify relevant studies. Trials investigating effects of sitagliptin, metformin or pioglitazone on β-cell function were identified. The primary outcomes were homeostasis model assessment of β-cells (HOMA-β) and proinsulin/insulin ratio (PI/IR). Secondary outcome was hemoglobin A1c level. We used version 2 of the Comprehensive Meta Analysis software for all statistical analyses.
Results
Metformin monotherapy was more effective than sitagliptin in improving HOMA-β (18.01% (95% CI 11.09% to 24.94%) vs. 11.29% (95% CI 9.21% to 13.37%), P = 0.040) and more effective (−0.137 (95% CI −0.082 to −0.192)) than both sitagliptin (−0.064 (95% CI −0.036 to −0.092), P = 0.019) and pioglitazone (−0.068 (95% CI −0.044 to −0.093), P = 0.015) in decreasing PI/IR. Metformin and sitagliptin combined (40.23% (95%CI 32.30% to 48.16%)) were more effective than sitagliptin and pioglitazone (11.82% (95% CI 6.61% to 17.04%), P = 0.000) and pioglitazone and metformin(9.81% (95% CI 1.67% to 17.95%), P = 0.022) in improving HOMA-β and decreasing PI/IR (−0.177 (95% CI −0.118 to −0.237); −0.080 (95% CI −0.045 to −0.114), P = 0.007; −0.038 (95% CI, −0.005 to 0.071), P = 0.023).
Limitations
The included RCTs were of short duration (12–54 weeks). We could not determine long term effects on β-cells.
Conclusions
Metformin improves β-cell function more effectively than pioglitazone or sitagliptin in type 2 diabetes patients. Metformin and sitagliptin improved HOMA-β and PI/IR more than other combinations.
doi:10.1371/journal.pone.0076713
PMCID: PMC3808360  PMID: 24204660
18.  Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies 
Oncology Letters  2013;7(1):177-182.
Contemporary combined therapies that include the use of all-trans retinoic acid (ATRA) and arsenic compounds have reduced relapse rates from ~50 to <10% in acute promyelocytic leukemia (APL) patients, however relapse treatment remains controversial. Treatment outcomes in relapsed patients with APL previously treated with combined ATRA + arsenic compound therapy were investigated. A retrospective, observational study was conducted of 25 patients with APL (male to female ratio, 17:8; mean age, 36.4±10.3 years) exhibiting first-time relapse following combined ATRA + arsenic compound therapy. These patients were subsequently treated with secondary ATRA + arsenic compound therapy, salvage chemotherapy, monoclonal antibody therapy or intrathecal chemotherapy, between January 1994 and December 2010. The overall remission rate, duration of remission and toxic effects were assessed. Patient outcomes included mortality during secondary induction therapy (6/25, 24.0%); complete recovery from central nervous system (CNS) relapse following intrathecal chemotherapy (1/25, 4.0%); complete remission following ATRA + arsenic compound therapy (10/25, 40.0%), chemotherapy (3/25, 12.0%) and targeted therapy (1/25, 4.0%); and non-remission (NR) following ATRA + arsenic compound therapy (4/25, 16%). Four (16.0%) patients were subsequently treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), two of which remained disease-free at the end of the study period and two of which succumbed to the disease. Secondary bone marrow and CNS relapse occurred in 14 (56.0%) patients and one (4.0%) patient, respectively. ATRA + arsenic compound-based combination therapy was effective in re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds, producing low molecular remission rates and high risk of secondary relapse. Furthermore, investigation of early allo-HSCT is required to determine its potential as a therapeutic option for re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds.
doi:10.3892/ol.2013.1643
PMCID: PMC3861585  PMID: 24348844
acute promyelocytic leukemia; relapse; re-induction therapy; remission; all-trans retinoic acid; arsenic compound
19.  Maturation and Emigration of Single-Positive Thymocytes 
T lymphopoiesis in the thymus was thought to be completed once it reaches the single positive (SP) stage, a stage when T cells are “fully mature” and waiting to be exported at random or follow a “first-in-first-out” manner. Recent evidence, however, has revealed that the newly generated SP thymocytes undergo a multistage maturation program in the thymic medulla. Such maturation is followed by a tightly regulated emigration process and a further postthymic maturation of recent thymic emigrants (RTEs). This review summarizes recent progress in the late stage T cell development. The regulation of this developmental process is discussed.
doi:10.1155/2013/282870
PMCID: PMC3804360  PMID: 24187562
20.  The Psychological Impact of the SARS Epidemic on Hospital Employees in China: Exposure, Risk Perception, and Altruistic Acceptance of Risk 
Objective
We examined the psychological impact of the 2003 outbreak of severe acute respiratory syndrome (SARS) on hospital employees in Beijing, China.
Methods
In 2006, randomly selected employees (n = 549) of a hospital in Beijing were surveyed concerning their exposure to the 2003 SARS outbreak, and the ways in which the outbreak had affected their mental health.
Results
About 10% of the respondents had experienced high levels of posttraumatic stress (PTS) symptoms since the SARS outbreak. Respondents who had been quarantined, or worked in high-risk locations such as SARS wards, or had friends or close relatives who contracted SARS, were 2 to 3 times more likely to have high PTS symptom levels, than those without these exposures. Respondents’ perceptions of SARS-related risks were significantly positively associated with PTS symptom levels and partially mediated the effects of exposure. Altruistic acceptance of work-related risks was negatively related to PTS levels.
Conclusions
The psychological impact of stressful events related to an infectious disease outbreak may be mediated by peoples’ perceptions of those events; altruism may help to protect some health care workers against these negative impacts.
PMCID: PMC3780353  PMID: 19497162
severe acute respiratory syndrome; health care workers; posttraumatic stress; infectious disease outbreak; China
21.  Biofeedback Therapy Combined with Traditional Chinese Medicine Prescription Improves the Symptoms, Surface Myoelectricity, and Anal Canal Pressure of the Patients with Spleen Deficiency Constipation 
In order to observe the clinical therapeutic effects of Yiqi Kaimi Prescription and biofeedback therapy on treating constipation with deficiency of spleen qi, the 30 cases in the control group were given oral administration of Yiqi Kaimi Prescription, in combination with anus-lifting exercise; the 30 cases in the treatment group were given biofeedback therapy on the basis of the afore mentioned methods for the control group. The TCM symptom scores and anorectal pressures before and after treatment were observed and evaluated. There were significant differences in TCM symptom scores, anorectal pressure, and clinical recovery rate before and after treatment. In the treatment group, the total recovery rate was 86.66%, while in the control group it was 50%; there were significant differences between the two groups (P < 0.01). Yiqi Kaimi Prescription coupled with biofeedback therapy is clinically effective for treating constipation with deficiency of spleen qi, and thus this method is applicable for functional constipation with deficiency of spleen qi.
doi:10.1155/2013/830714
PMCID: PMC3745844  PMID: 23983805
22.  Abnormal Resting-State Activities and Functional Connectivities of the Anterior and the Posterior Cortexes in Medication-Naïve Patients with Obsessive-Compulsive Disorder 
PLoS ONE  2013;8(6):e67478.
Background
Obsessive-compulsive disorder (OCD) is a mental illness characterized by the loss of control. Because the cingulate cortex is believed to be important in executive functions, such as inhibition, we used functional magnetic resonance imaging (fMRI) techniques to examine whether and how activity and functional connectivity (FC) of the cingulate cortex were altered in drug-naïve OCD patients.
Methods
Twenty-three medication-naïve OCD patients and 23 well-matched healthy controls received fMRI scans in a resting state. Functional connectivities of the anterior cingulate (ACC) and the posterior cingulate (PCC) to the whole brain were analyzed using correlation analyses based on regions of interest (ROI) identified by the fractional amplitude of low-frequency fluctuation (fALFF). Independent Component Analysis (ICA) was used to identify the resting-state sub-networks.
Results
fALFF analysis found that regional activity was increased in the ACC and decreased in the PCC in OCD patients when compared to controls. FC of the ACC and the PCC also showed different patterns. The ACC and the PCC were found to belong to different resting-state sub-networks in ICA analysis and showed abnormal FC, as well as contrasting correlations with the severity of OCD symptoms.
Conclusions
Activity of the ACC and the PCC were increased and decreased, respectively, in the medication-naïve OCD patients compared to controls. Different patterns in FC were also found between the ACC and the PCC with respect to these two groups. These findings implied that the cardinal feature of OCD, the loss of control, may be attributed to abnormal activities and FC of the ACC and the PCC.
doi:10.1371/journal.pone.0067478
PMCID: PMC3696097  PMID: 23840714
23.  Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein 
Background
To investigate the ability of rESAT6 to identify different mycobacteria-sensitized guinea pigs and its safety in preclinical and phase I clinical study.
Material/Methods
Guinea pigs were sensitized with different Mycobacteria. After sensitization, all animals were intradermally injected with rESAT6 and either PPD or PPD-B. At 24 h after the injection, the erythema of the injection sites were measured using a double-blind method. For the preclinical safety study, different doses of rESAT6 and BSA were given 3 times intramuscularly to guinea pigs. On day 14 after the final immunization, the guinea pigs were intravenously injected with the same reagents in the hind legs and the allergic reactions were observed. A single-center, randomized, open phase I clinical trial was employed. The skin test was conducted in 32 healthy volunteers aged 19–65 years with 0.1 μg, 0.5 μg, and 1 μg rESAT6. Physical examination and laboratory tests were performed before and after the skin test and adverse reactions were monitored. The volunteers’ local and systemic adverse reactions and adverse events were recorded for 7 days.
Results
Positive PPD or PPD-B skin tests were observed in all Mycobacteria-sensitized guinea pigs; the diameters of erythema were all >10 mm. The rESAT6 protein induced a positive skin test result in the guinea pigs sensitized with MTB, M. bovis, M. africanum and M. kansasii; the diameters of erythema were 14.7±2.0, 9.3±3.8, 18.7±2.4, and 14.8±4.2 mm, respectively. A negative skin test result was detected in BCG-vaccinated and other NTM-sensitized guinea pigs. The rESAT6 caused no allergic symptoms, but many allergic reactions, such as cough, dyspnea, and even death, were observed in the guinea pigs who were administered BSA. During the phase I clinical trial, no adverse reactions were found in the 0.1 μg rESAT6 group, but in the 0.5 μg rESAT6 group 2 volunteers reported pain and 1 reported itching, and in the 1 μg rESAT6 group there was 1 case of pain, 1 case of itching, and 1 case of blister. No other local or systemic adverse reactions or events were reported.
Conclusions
The rESAT6 can differentiate effectively among MTB infection, BCG vaccination, and NTM infection and is safe in healthy volunteers.
doi:10.12659/MSMBR.883912
PMCID: PMC3659126  PMID: 23676766
phase I clinical trial; recombinant protein; skin test; latent M. tuberculosis infection
24.  The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis is Associated with an Anti-invasive and Anti-inflammatory Gene Signature 
Progesterone receptor (PR) antagonists are potent antitumor agents in carcinogen and progestin-dependent mammary tumorigenesis models through both PR and non-PR-mediated mechanisms. The PR antagonist mifepristone/RU486 has been used primarily as an abortifacient possessing high affinity for both the PR and glucocorticoid receptors (GR). To determine whether mifepristone would be effective as a chemopreventive agent, we assessed its effect on progestin/DMBA-induced mammary carcinogenesis in wild-type (WT) and estrogen receptor-α-positive (ER+) transgenic mice expressing the dominant-negative Pax8PPARγ (Pax8) fusion protein. Mifepristone administered at a dose of 2.5 mg significantly delayed mammary tumorigenesis in WT, but not in Pax8 mice, whereas, a three-fold higher dose almost completely blocked tumorigenesis in both WT and Pax8 mice. The sensitivity of WT mice to 2.5 mg mifepristone correlated with a expression profile of 79 genes in tumors, 52 of which exhibited the opposite response in Pax8 mice, and corresponded primarily to the down-regulation of genes associated with metabolism, inflammation and invasion. These results suggest that the chemopreventive activity of mifepristone in WT mice correlates with a specific gene expression signature that is associated with multiple nuclear receptor signaling pathways.
doi:10.1158/1940-6207.CAPR-11-0526
PMCID: PMC3437618  PMID: 22427346
25.  Random sparse sampling strategy using stochastic simulation and estimation for a population pharmacokinetic study 
The purpose of this study was to use the stochastic simulation and estimation method to evaluate the effects of sample size and the number of samples per individual on the model development and evaluation. The pharmacokinetic parameters and inter- and intra-individual variation were obtained from a population pharmacokinetic model of clinical trials of amlodipine. Stochastic simulation and estimation were performed to evaluate the efficiencies of different sparse sampling scenarios to estimate the compartment model. Simulated data were generated a 1000 times and three candidate models were used to fit the 1000 data sets. Fifty-five kinds of sparse sampling scenarios were investigated and compared. The results showed that, 60 samples with three points and 20 samples with five points are recommended, and the quantitative methodology of stochastic simulation and estimation is valuable for efficiently estimating the compartment model and can be used for other similar model development and evaluation approaches.
doi:10.1016/j.jsps.2013.01.010
PMCID: PMC3909756  PMID: 24493975
Amlodipine; Sparse sampling; Model estimation; Population pharmacokinetics

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