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1.  On-line monitoring of oxygen in Tubespin, a novel, small-scale disposable bioreactor 
Cytotechnology  2011;63(4):345-350.
A novel, optical sensor was fixed in a new type of disposable bioreactor, Tubespin, for the on-line (real-time) monitoring of dissolved oxygen concentrations during cell culture. The cell density, viability and volumetric mass transfer coefficient were also determined to further characterize the bioreactors. The kLa value of the Tubespin at standard conditions was 24.3 h−1, while that of a spinner flask was only 2.7 h−1. The maximum cell density in the Tubespin bioreactor reached 6 × 106 cells mL−1, which was two times higher than the cell density in a spinner flask. Furthermore, the dynamic dissolved oxygen level was maintained above 90% air-saturation in the Tubespin, while the value was only 1.9% in a spinner flask. These results demonstrate the competitive advantage of using the Tubespin system over spinner flasks for process optimization and scale-down studies of oxygen transfer and cell growth.
PMCID: PMC3140833  PMID: 21574065
Tubespin; Spinner flask; Dissolved oxygen; kLa
2.  Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24 
Acta Pharmacologica Sinica  2009;30(4):467-477.
The aim of this study was to creatively implement a novel chemo-gene-virotherapeutic strategy and further strengthen the antitumor effect in cancer cells by the combined use of ZD55-IL-24 and cisplatin.
ZD55-IL-24 is an oncolytic adenovirus that harbors interleukin 24 (IL-24), which has a strong antitumor effect and was identified and evaluated by PCR, RT-PCR, and Western blot analysis. Enhancement of cancer cell death using a combination of ZD55-IL-24 and cisplatin was assessed in several cancer cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cytopathic effect (CPE) assay. Apoptosis induction by treatment with ZD55-IL-24 and/or cisplatin was detected in BEL7404 and SMMC7721 by morphological evaluation, apoptotic cell staining, and flow cytometry analysis. In addition, negative effects on normal cells were evaluated in the L-02 cell line using the MTT assay, the CPE assay, morphological evaluation, apoptotic cell staining, and flow cytometry analysis.
The combination of ZD55-IL-24 and cisplatin, which is superior to ZD55-IL-24, cisplatin, and ZD55-EGFP, as well as ZD55-EGFP plus cisplatin, resulted in a significantly increased effect. Most importantly, conjugation of ZD55-IL-24 with cisplatin had toxic effects equal to that of cisplatin and did not have overlapping toxicities in normal cells.
This study showed that ZD55-IL-24 conjugated with cisplatin exhibited a remarkably increased cytotoxic and apoptosis-inducing effect in cancer cells and significantly reduced the toxicity in normal cells through the use of a reduced dose.
PMCID: PMC4002269  PMID: 19270721
cisplatin; MDA-7/IL-24; oncolytic adenovirus; apoptosis
3.  ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2 
Journal of cellular biochemistry  2014;115(8):1381-1391.
ARRY-334543 is a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters.
Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study.
Our results demonstrate that ARRY-334543 (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [125I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity towards ABCG2. Moreover, homology modeling predicted the binding conformation of ARRY-334543 at Arg482 centroid-based grid of ABCG2. However, ARRY-334543 at reversal concentration did not affect the expression level of ABCG2, AKT and ERK1/2 and regulate the re-localization of ABCG2.
We conclude that ARRY-334543 significantly reverses drug resistance mediated by ABCG2.
PMCID: PMC4086246  PMID: 24939447
ARRY-334543; ABCG2; Multidrug resistance; Tyrosine kinase inhibitor; Lung cancer
4.  Using SV119-Gold Nanocage Conjugates to Eradicate Cancer Stem Cells through a Combination of Photothermal and Chemo Therapies 
Advanced healthcare materials  2014;3(8):1283-1291.
Cancer stem cells (CSCs) are believed to be responsible for the long-term growth of a tumor, as well as its metastasis and recurrence after conventional therapies. Here we demonstrated that the sigma-2 receptor was over-expressed on the surface of breast CSCs, and thus could serve as a biomarker for the purpose of targeting. We were able to target breast CSCs with Au nanocages (AuNCs) by functionalizing their surfaces with SV119, a synthetic small molecule capable of binding to the sigma-2 receptor with high specificity. The interiors of the AuNCs could also be loaded with an anticancer drug to be selectively delivered to breast CSCs and released in a controllable fashion. Our results demonstrate that the SV119-AuNC conjugate can serve as a new platform to carry out photothermal and chemo therapies simultaneously, eradicating breast CSCs more effectively through a synergetic effect.
PMCID: PMC4134721  PMID: 24677807
cancer stem cells; gold nanocages; SV119; sigma-2 receptor; synergetic effect
5.  Unintentional drowning mortality, by age and body of water: an analysis of 60 countries 
Injury Prevention  2014;21(e1):e43-e50.
To examine unintentional drowning mortality by age and body of water across 60 countries, to provide a starting point for further in-depth investigations within individual countries.
The latest available three years of mortality data for each country were extracted from WHO Health Statistics and Information Services (updated at 13 November 2013). We calculated mortality rate of unintentional drowning by age group for each country. For countries using International Classification of Disease 10 (ICD-10) detailed 3 or 4 Character List, we further examined the body of water involved.
A huge variation in age-standardised mortality rate (deaths per 100 000 population) was noted, from 0.12 in Turkey to 9.19 in Guyana. Of the ten countries with the highest age-standardised mortality rate, six (Belarus, Lithuania, Latvia, Russia, Ukraine and Moldova) were in Eastern Europe and two (Kazakhstan and Kyrgyzstan) were in Central Asia. Some countries (Japan, Finland and Greece) had a relatively low rank in mortality rate among children aged 0–4 years, but had a high rank in mortality rate among older adults. On the contrary, South Africa and Colombia had a relatively high rank among children aged 0–4 years, but had a relatively low rank in mortality rate among older adults. With regard to body of water involved, the proportion involving a bathtub was extremely high in Japan (65%) followed by Canada (11%) and the USA (11%). Of the 13 634 drowning deaths involving bathtubs in Japan between 2009 and 2011, 12 038 (88%) were older adults aged 65 years or above. The percentage involving a swimming pool was high in the USA (18%), Australia (13%), and New Zealand (7%). The proportion involving natural water was high in Finland (93%), Panama (87%), and Lithuania (85%).
After considering the completeness of reporting and quality of classifying drowning deaths across countries, we conclude that drowning is a high-priority public health problem in Eastern Europe, Central Asia, Japan (older adults involving bathtubs), and the USA (involving swimming pools).
PMCID: PMC4501178  PMID: 24944343
6.  Phylogeny and differentiation of the St genome in Elymus L. sensu lato (Triticeae; Poaceae) based on one nuclear DNA and two chloroplast genes 
BMC Plant Biology  2015;15:179.
Hybridization and polyploidization can be major mechanisms for plant evolution and speciation. Thus, the process of polyploidization and evolutionary history of polyploids is of widespread interest. The species in Elymus L. sensu lato are allopolyploids that share a common St genome from Pseudoroegneria in different combinations with H, Y, P, and W genomes. But how the St genome evolved in the Elymus s. l. during the hybridization and polyploidization events remains unclear. We used nuclear and chloroplast DNA-based phylogenetic analyses to shed some light on this process.
The Maximum likelihood (ML) tree based on nuclear ribosomal internal transcribed spacer region (nrITS) data showed that the Pseudoroegneria, Hordeum and Agropyron species served as the St, H and P genome diploid ancestors, respectively, for the Elymus s. l. polyploids. The ML tree for the chloroplast genes (matK and the intergenic region of trnH-psbA) suggests that the Pseudoroegneria served as the maternal donor of the St genome for Elymus s. l. Furthermore, it suggested that Pseudoroegneria species from Central Asia and Europe were more ancient than those from North America. The molecular evolution in the St genome appeared to be non-random following the polyploidy event with a departure from the equilibrium neutral model due to a genetic bottleneck caused by recent polyploidization.
Our results suggest the ancient common maternal ancestral genome in Elymus s. l. is the St genome from Pseudoroegneria. The evolutionary differentiation of the St genome in Elymus s. l. after rise of this group may have multiple causes, including hybridization and polyploidization. They also suggest that E. tangutorum should be treated as C. dahurica var. tangutorum, and E. breviaristatus should be transferred into Campeiostachys. We hypothesized that the Elymus s. l. species origined in Central Asia and Europe, then spread to North America. Further study of intraspecific variation may help us evaluate our phylogenetic results in greater detail and with more certainty.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0517-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4499217  PMID: 26164196
Elymus s. l.; St genome; nr DNA; Chloroplast gene; Phylogeny; Molecular evolution
7.  When and why a colonoscopist should discontinue colonoscopy by himself? 
AIM: To investigate when and why a colonoscopist should discontinue incomplete colonoscopy by himself.
METHODS: In this cross-sectional study, 517 difficult colonoscope insertions (Grade C, Kudo’s difficulty classification) screened from 37800 colonoscopy insertions were collected from April 2004 to June 2014 by three 4th-level (Kudo’s classification) colonoscopists. The following common factors for the incomplete insertion were excluded: structural obstruction of the colon or rectum, insufficient colon cleansing, discontinuation due to patient’s discomfort or pain, severe colon disease with a perforation risk (e.g., severe ischemic colonopathy). All the excluded patients were re-scheduled if permission was obtained from the patients whose intubation had failed. If the repeat intubations were still a failure because of the difficult operative techniques, those patients were also included in this study. The patient’s age, sex, anesthesia and colonoscope type were recorded before colonoscopy. During the colonoscopic examination, the influencing factors of fixation, tortuosity, laxity and redundancy of the colon were assessed, and the insertion time (> 10 min or ≤ 10 min) were registered. The insertion time was analyzed by t-test, and other factors were analyzed by univariate and multivariate logistic regression.
RESULTS: Three hundred and twenty-two (62.3%) of the 517 insertions were complete in the colonoscope insertion into the ileocecum, but 195 (37.7%) failed in the insertion. Fixation, tortuosity, laxity or redundancy occurred during the colonoscopic examination. Multivariate logistic regression analysis revealed that fixation (OR = 0.06, 95%CI: 0.03-0.16, P < 0.001) and tortuosity (OR = 0.04, 95%CI: 0.02-0.08, P < 0.001) were significantly related to the insertion into the ileocecum in the left hemicolon; multivariate logistic regression analysis also revealed that fixation (OR = 0.16, 95%CI: 0.06-0.39, P < 0.001), tortuosity (OR 0.23, 95%CI: 0.13-0.43, P < 0.001), redundancy (OR = 0.12, 95%CI: 0.05-0.26, P < 0.001) and sex (OR = 0.35, 95%CI: 0.20-0.63, P < 0.001) were significantly related to the insertion into the ileocecum in the right hemicolon. Prolonged insertion time (> 10 min) was an unfavorable factor for the insertion into the ileocecum.
CONCLUSION: Colonoscopy should be discontinued if freedom of the colonoscope body’s insertion and rotation is completely lost, and the insertion time is prolonged over 30 min.
PMCID: PMC4491970  PMID: 26167083
Colonoscopy; Colonoscope insertion; Insertion technique
8.  Chemistry and pharmacology of the herb pair Flos Lonicerae japonicae-Forsythiae fructus 
Chinese Medicine  2015;10:16.
The Chinese medicine herb pair Flos Lonicerae japonicae (FLJ) and Forsythiae fructus (FF), is a representative heat-clearing (qing re) and detoxifying (jie du) combination that exhibits many pharmacological activities, including antibacterial, antiviral, antitumor, anti-inflammatory, and antioxidant effects. Extensive phytochemical studies have identified a series of bioactive compounds, such as chlorogenic acid from FLJ and forsythoside A from FF. This article provides a comprehensive review on the chemical and pharmacological principles of the traditional functions of FLJ-FF, and sheds light on further developments of this herb pair.
PMCID: PMC4497423  PMID: 26161134
9.  Evidence that the lung adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood 
The EML4-ALK fusion gene is more frequently found in younger, never smoking, lung cancer patients. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking lung cancer patients that are not exposed. We therefore hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene.
We compared the frequency of the EML4-ALK fusion gene among 197 never smoker lung cancer patients with and without a history of exposure to SHS during childhood at Mayo Clinic.
The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, while 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene.
The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood.
These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer.
PMCID: PMC4082445  PMID: 24755712
10.  Listeria monocytogenes antagonizes the human GTPase Cdc42 to promote bacterial spread 
Cellular microbiology  2014;16(7):1068-1079.
The bacterial pathogen Listeria monocytogenes uses actin-based motility to spread from infected human cells to surrounding healthy cells. Cell-cell spread involves the formation of thin extensions of the host plasma membrane (‘protrusions’) containing motile bacteria. In cultured enterocytes, the Listeria protein InlC promotes protrusion formation by binding and antagonizing the human scaffolding protein Tuba. Tuba is a known activator of the GTPase Cdc42. In this work, we demonstrate an important role for Cdc42 in controlling Listeria spread. Infection of the enterocyte cell line Caco-2 BBE1 induced a decrease in the level of Cdc42-GTP, indicating that Listeria downregulates this GTPase. Genetic data involving RNA interference indicated that bacterial impairment of Cdc42 may involve inhibition of Tuba. Experiments with dominant negative and constitutively activated alleles of Cdc42 demonstrated that the ability to inactivate Cdc42 is required for efficient protrusion formation by Listeria. Taken together, these findings indicate a novel mechanism of bacterial spread involving pathogen-induced downregulation of host Cdc42.
PMCID: PMC4186796  PMID: 24405483
11.  Antiproliferative effects of curcumin analog L49H37 in pancreatic stellate cells: a comparative study 
Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by a pronounced stromal reaction, which resists chemotherapeutics and effective tumor treatment. Pancreatic stellate cells (PSCs) are mainly responsible for this stromal reaction. Moreover, the cancer and stromal interaction seems to promote tumor proliferation. In this study, L49H37, a newly synthesized curcumin analog, was used as intervention to target the stromal compartment of pancreatic cancer.
In vitro cultures of human PSCs were exposed to curcumin and L49H37. Cell viability as well as growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and western blotting.
Curcumin and L49H37 effectively inhibited proliferation and induced apoptosis in PSCs. L49H37 was found to be more potent at a lower concentration than curcumin in the induction of apoptosis, as evidenced by cleaved poly (ADP-ribose) polymerase (PARP). The cells were retained in the G0/G1 phase of the cell cycle through the downregulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of extracellular signal regulated kinase ½ (ERK½).
The results indicate that curcumin analog L49H37 exhibits more potent inhibitory effects than curcumin itself at a lower concentration, which suggests that it may have a potential for further evaluation of its use against pancreatic adenocarcinoma, either as a single agent but, more probable, as part of a combination regimen.
PMCID: PMC4480178  PMID: 26129848
Pancreatic cancer; stroma; cleaved PARP; p21WAF1/Cip1
12.  Epidemiological investigation of 264 sporadic cases of ruptured cerebral aneurysm at a single institution in southwest China 
The purpose of this study was to investigate the epidemiology of sporadic ruptured cerebral aneurysm in the Chinese population.
We retrospectively analyzed the medical records of 264 consecutive Chinese patients admitted to the Affiliated Hospital of Zunyi Medical University of Guizhou Province in Southwest China between December 2012 and March 2015 for spontaneous subarachnoid hemorrhage due to a ruptured cerebral artery aneurysm.
The study population comprised 171 females and 93 males with a median age of 50 (range 5–76) years. The female to male ratio was 1.84:1. For both males and females, aneurysm rupture was most common in the 40–49-year age group (34.5%). Most of the ruptured aneurysms were in the size range of 2–5 mm (47.2%), followed by 5–10 mm (43.8%). Ruptured aneurysms occurred most often in the posterior communicating artery (36.6%) or the anterior communicating artery (25.7%). There were more cases of anterior communicating artery aneurysm on the left side (53 [Left side]/16 [Right side]=3.31, P>0.001) and slightly more cases of posterior communicating artery aneurysm on the right side (54 [Right side]/44[Left side]=1.23, P<0.05).
This study provides valuable information on the epidemiology of ruptured cerebral aneurysm in the Chinese population.
PMCID: PMC4494622  PMID: 26170673
cerebral aneurysm; rupture; subarachnoid hemorrhage; Chinese population; epidemiology
13.  Synthesis and evaluation of [18F]Exendin (9-39) as a potential biomarker to measure pancreatic beta-cell mass 
Nuclear medicine and biology  2011;39(2):167-176.
Glucagon-like peptide 1 (GLP-1) is released in response to food intake and plays an important role in maintaining blood glucose homeostasis. Exendin (9-39), a potent GLP-1R antagonist, has been labeled with In-111 for SPECT imaging. We report here the first radiosynthesis of [18F]exendin (9-39) ([18F]Ex(9-39)) and an evaluation of its potential as a biomarker for in vivo PET imaging of pancreatic β-cell mass (BCM) in rats.
F-18 label was introduced by conjugation of [18F]4-fluorobenzaldehyde with an Ex(9-39) derivative containing a 6-hydrazinonicotinyl group on the -amine of Lys27. PET imaging was carried out in Sprague-Dawley rats (5 control, 5 streptozotocin-induced diabetic) and BioBreeding-Diabetes Prone rats (3 at 7 wks, 3 at 12 wks) using HRRT following 0.187±0.084 mCi [18F]Ex(9-39) administration. Time activity curves were obtained from pancreas, liver and kidney. Pancreases were assayed for insulin content after the imaging study.
Site-specifically labeled [18F]Ex(9-39) was purified on a G15 open column with radiochemical and chemical purities >98%. PET imaging showed pancreatic SUV peaked at 10 min, and plateaued by 50 min to the end of scan (240 min). No correlations of pancreatic SUV with post-mortem measures of insulin content were seen.
[18F]Ex(9-39) was successfully prepared and used for PET imaging for the first time to measure pancreatic BCM. The results suggest that derivatization of the Lys27 residue might reduce binding affinity, as evidenced by the absence of specific binding. Exendin analogs radiolabeled at other sites may elucidate the active site required for binding.
PMCID: PMC4484741  PMID: 22033026
Glucagon-like peptide 1 (GLP-1); HYNIC; PET imaging; [18F]Exendin (9-39); pancreatic β-cell mass; diabetes
14.  Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPα Expression 
PLoS ONE  2015;10(6):e0131743.
Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein α (C/EBPα); such an increase is likely to promote the binding of C/EBPα to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy.
PMCID: PMC4486450  PMID: 26121644
15.  Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice 
PLoS Pathogens  2015;11(6):e1005001.
Human gamma herpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumors, particularly in in immune-compromised individuals. Due to the stringent host tropism, rodents are resistant to infection by human gamma herpesviruses, creating a significant barrier for the in vivo study of viral genes that contribute to tumorigenesis. The closely-related murine gamma herpesvirus 68 (γHV68) efficiently infects laboratory mouse strains and establishes robust persistent infection without causing apparent disease. Here, we report that a recombinant γHV68 carrying the KSHV G protein-coupled receptor (kGPCR) in place of its murine counterpart induces angiogenic tumors in infected mice. Although viral GPCRs are conserved in all gamma herpesviruses, kGPCR potently activated downstream signaling and induced tumor formation in nude mouse, whereas γHV68 GPCR failed to do so. Recombinant γHV68 carrying kGPCR demonstrated more robust lytic replication ex vivo than wild-type γHV68, although both viruses underwent similar acute and latent infection in vivo. Infection of immunosuppressed mice with γHV68 carrying kGPCR, but not wild-type γHV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi’s sarcoma. Immunohistochemistry staining identified abundant latently-infected cells and a small number of cells supporting lytic replication in tumor tissue. Thus, mouse infection with a recombinant γHV68 carrying kGPCR provides a useful small animal model for tumorigenesis induced by a human gamma herpesvirus gene in the setting of a natural course of infection.
Author Summary
Human gamma herpesviruses, including Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), are causatively linked to a spectrum of human oncogenic malignancies. Due to the stringent host restriction, rodents are generally not amenable to infection by EBV and KSHV. Murine gamma herpesvirus 68 (γHV68) is closely related to KSHV and EBV, although infection in mouse does not manifest apparent diseases. Here we developed a recombinant γHV68 that carries the KSHV G protein-coupled receptor, an important signaling molecule implicated in KSHV pathogenesis. Intriguingly, laboratory mice infected with this recombinant γHV68 developed angiogenic lesions that resembled human Kaposi’s sarcoma. This mouse infection with recombinant γHV68 carrying KSHV GPCR represents a useful model to investigate viral oncogenesis induced by human gamma herpesvirus in the context of viral infection.
PMCID: PMC4479558  PMID: 26107716
16.  Free-Breathing 3D Imaging of Right Ventricular Structure and Function Using Respiratory and Cardiac Self-Gated Cine MRI 
BioMed Research International  2015;2015:819102.
Providing a movie of the beating heart in a single prescribed plane, cine MRI has been widely used in clinical cardiac diagnosis, especially in the left ventricle (LV). Right ventricular (RV) morphology and function are also important for the diagnosis of cardiopulmonary diseases and serve as predictors for the long term outcome. The purpose of this study is to develop a self-gated free-breathing 3D imaging method for RV quantification and to evaluate its performance by comparing it with breath-hold 2D cine imaging in 7 healthy volunteers. Compared with 2D, the 3D RV functional measurements show a reduction of RV end-diastole volume (RVEDV) by 10%, increase of RV end-systole volume (RVESV) by 1.8%, reduction of RV systole volume (RVSV) by 21%, and reduction of RV ejection fraction (RVEF) by 12%. High correlations between the two techniques were found (RVEDV: 0.94; RVESV: 0.85; RVSV: 0.95; and RVEF: 0.89). Compared with 2D, the 3D image quality measurements show a small reduction in blood SNR, myocardium-blood CNR, myocardium contrast, and image sharpness. In conclusion, the proposed self-gated free-breathing 3D cardiac cine imaging technique provides comparable image quality and correlated functional measurements to those acquired with the multiple breath-hold 2D technique in RV.
PMCID: PMC4491385  PMID: 26185764
17.  The Insect Growth Regulator Pyriproxyfen Terminates Egg Diapause in the Asian Tiger Mosquito, Aedes albopictus 
PLoS ONE  2015;10(6):e0130499.
The Asian tiger mosquito, Aedes albopictus, is a highly invasive mosquito species that transmits chikungunya and dengue. This species overwinters as diapausing eggs in temperate climates. Early diapause termination may be a beneficial strategy for winter mosquito control; however, a mechanism to terminate the diapause process using chemicals is not known. We tested the hypothesis that a hormonal imbalance caused by the administration of juvenile hormone analog would terminate egg diapause in A. albopictus. We tested the insect growth regulator pyriproxyfen on all developmental stages to identify a susceptible stage for diapause termination. We found that pyriproxyfen treatment of mosquito eggs terminated embryonic diapause. The highest rates of diapause termination were recorded in newly deposited (78.9%) and fully embryonated (74.7%) eggs at 0.1 and 1 ppm, respectively. Hatching was completed earlier in newly deposited eggs (25–30 days) compared to fully embryonated eggs (71–80 days). The combined mortality from premature diapause termination and ovicidal activity was 98.2% in newly deposited and >98.9% in fully embryonated eggs at 1 ppm. The control diapause eggs did not hatch under diapausing conditions. Pyriproxyfen exposure to larvae, pupae and adults did not prevent the females from ovipositing diapausing eggs. There was no effect of pyriproxyfen on diapausing egg embryonic developmental time. We also observed mortality in diapausing eggs laid by females exposed to pyriproxyfen immediately after blood feeding. There was no mortality in eggs laid by females that survived larval and pupal exposures. In conclusion, diapausing eggs were the more susceptible to pyriproxyfen diapause termination compared to other life stages. This is the first report of diapause termination in A. albopictus with a juvenile hormone analog. We believe our findings will be useful in developing a new control strategy against overwintering mosquito populations.
PMCID: PMC4474921  PMID: 26090954
18.  MicroRNA-490-5p is a novel tumor suppressor targeting c-FOS in human bladder cancer 
Archives of Medical Science : AMS  2015;11(3):561-569.
Recent studies have demonstrated the critical roles of micro-RNAs in tumorigenesis and tumor progression. Here, we describe the regulation and function of miR-490-5p in bladder cancer.
Material and methods
Paired tissue samples were collected from bladder cancer patients (n = 20). Real-time PCR revealed that miR-490-5p expression was significantly down-regulated in human bladder cancer tissues and cells. Also there was an inverse relationship between the expression level of miR-490-5p and the pathological grade of bladder cancer. Western blotting was performed to detect the expression levels of c-FOS and TET1 in 6 matched tumor tissue samples and 4 bladder cell lines. Furthermore, to better understand the underlying mechanisms of miR-490-5p, we conducted gain and loss of function analysis by transfecting bladder cancer T24 cells with chemically synthesized miR-490-5p mimics and inhibitor, respectively.
We found that overexpression of miR-490-5p in T24 cells could inhibit cell proliferation and invasion and induce cell apoptosis. Conversely, suppression of miR-490-5p expression induced cell proliferation and invasion, while it inhibited cell apoptosis. In addition, our bioinformatics prediction and experimental data showed that c-FOS was a potential target of miR-490-5p. The expression level of c-FOS was significantly decreased after miR-490-5p overexpression and significantly increased after miR-490-5p suppression, indicating that c-FOS was a target of miR-490-5p.
These findings suggest that miR-490-5p is a novel tumor suppressor, contributing to the carcinogenesis of bladder cancer by targeting c-FOS.
PMCID: PMC4495152  PMID: 26170849
bladder cancer; miR-490-5p; tumor suppressor; c-FOS
19.  Single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery: a meta-analysis of randomised placebo-controlled studies 
BMJ Open  2015;5(6):e006815.
To evaluate the efficacy and safety of single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery.
Data sources and study eligibility criteria
A comprehensive literature search, using Medline (1966–2014), the Cochrane Central Register of Controlled Trials and Embase databases, was conducted to identify randomised placebo-controlled trials that used a combination of single-dose intra-articular bupivacaine and morphine for postoperative pain relief.
12 articles were included in this meta-analysis. The mean visual analogue scale (VAS) scores of the bupivacaine plus morphine group were significantly lower than those of the placebo group (weighted mean difference (WMD) −1.75; 95% CI −2.16 to −1.33; p<0.001). The VAS scores at the last follow-up time point (last VAS scores) of the bupivacaine plus morphine group were also significantly lower than those of the placebo group (WMD −1.46; 95% CI −1.63 to −1.29; p<0.001). The number of patients requiring supplementary analgesia was also significantly reduced (RR 0.60; 95% CI 0.39 to 0.93; p=0.02), while there was no significant difference in the time to first analgesic request (WMD 3.46; 95% CI −1.81 to 8.72; p=0.20) or short-term side effects (RR 1.67; 95% CI 0.65 to 4.26; p=0.29).
The administration of single-dose intra-articular bupivacaine plus morphine after knee arthroscopic surgery is effective for pain relief, and its short-term side effects remain similar to saline placebo.
PMCID: PMC4480015  PMID: 26078306
20.  The significance of membrane fluidity of feeder cell-derived substrates for maintenance of iPS cell stemness 
Scientific Reports  2015;5:11386.
The biological activity of cell-derived substrates to maintain undifferentiated murine-induced pluripotent stem (iPS) cells was correlated to membrane fluidity as a new parameter of cell culture substrates. Murine embryonic fibroblasts (MEFs) were employed as feeder cells and their membrane fluidity was tuned by chemical fixation using formaldehyde (FA). Membrane fluidity was evaluated by real-time single-molecule observations of green fluorescent protein-labeled epidermal growth factor receptors on chemically fixed MEFs. Biological activity was monitored by colony formation of iPS cells. Treatment with a low concentration of FA sustained the membrane fluidity and biological activity, which were comparable to those of mitomycin C-treated MEFs. The biological activity was further confirmed by sustained expression of alkaline phosphatase, SSEA-1, and other pluripotency markers in iPS cells after 3–5 days of culture on FA-fixed MEFs. Chemical fixation of feeder cells has several advantages such as providing ready-to-use culture substrates without contamination by proliferating feeder cells. Therefore, our results provide an important basis for the development of chemically fixed culture substrates for pluripotent stem cell culture as an alternative to conventional treatment by mitomycin C or x-ray irradiation.
PMCID: PMC4464345  PMID: 26065582
21.  Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways 
PLoS ONE  2015;10(6):e0129788.
It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.
PMCID: PMC4466396  PMID: 26070151
22.  Complete Genome Sequence of Agrobacterium tumefaciens Ach5 
Genome Announcements  2015;3(3):e00570-15.
Agrobacterium tumefaciens is a phytopathogenic bacterium that causes crown gall disease. The strain Ach5 was isolated from yarrow (Achillea ptarmica L.) and is the wild-type progenitor of other derived strains widely used for plant transformation. Here, we report the complete genome sequence of this bacterium.
PMCID: PMC4457062  PMID: 26044425
23.  Adjuvant intraoperative post-dissectional tumor bed chemotherapy—A novel approach in treating midgut neuroendocrine tumors 
Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. Even with skillful surgical dissection, macro and microscopic residual disease at the dissection site remains a possibility. We hypothesize these potential tumor residuals in mesenteric lymph node dissection beds can be eliminated safely by a local application of 5-fluorouracil (5-FU). We describe a novel technique invented by the author to treat these micro and macro residuals.
Retrospectively, charts of 62 consecutive midgut NET patients with boggy mesenteric lymphadenopathy who underwent cytoreductive debulking surgeries from 1/2007 to 12/2009 were reviewed. A total of 32 patients received an intraoperative application of 5-FU saturated gelfoam strips secured into the mesenteric defect following the extensive lymphadenectomy. A total of 30 untreated patients served as a control.
The 5-year survival after cytoreductive surgeries was 22/32 (68.8%) for the treated group, vs. 20/30 (66.7%) for the control. Six patients (6/32, 18.8%) among the study group required additional debulking surgeries, vs. 16 patients (16/30, 53.3%) in the control group. Upon reoperation, loco-regional recurrence was noted in 9 of the 16 patients (56.3%) in the control group, vs. only 2/6 (33.3%) of treated patients. Overall, local recurrence rate is 6.25% (2/32) in the treated group vs. 30% (9/30) in the control group. Post-op complication rates are similar in the two arms.
Intraoperative application of chemotherapy is a safe and effective adjuvant to reduce local recurrence and the need of reoperation by the tumoricidal or tumorstatic effects of 5-FU on any potential microscopic residual disease after extensive cytoreductive surgeries in advanced stage NET patients with mesenteric lymph node metastasis. It provides patients with sustained, slow releasing, high dose of 5-FU within the surgical bed with a negligible side effect profile. Further studies are required to evaluate its effect on long term survival.
PMCID: PMC4397243  PMID: 26029451
Midgut neuroendocrine tumors (NETs); intraoperative chemotherapy
24.  Involvement of the Ca2+ signaling pathway in osteoprotegerin inhibition of osteoclast differentiation and maturation 
Journal of Veterinary Science  2015;16(2):151-156.
The purpose of this study was to determine whether the Ca2+ signaling pathway is involved in the ability of osteoprotegerin (OPG) to inhibit osteoclast differentiation and maturation. RAW264.7 cells were incubated with macrophage colony-stimulating factor (M-CSF) + receptor activator of nuclear factor-κB ligand (RANKL) to stimulate osteoclastogenesis and then treated with different concentrations of OPG, an inhibitor of osteoclast differentiation. The intracellular Ca2+ concentration [Ca2+]i and phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the different treatment groups were measured by flow cytometry and Western blotting, respectively. The results confirmed that M-CSF + RANKL significantly increased [Ca2+]i and CaMKII phosphorylation in osteoclasts (p < 0.01), and that these effects were subsequently decreased by OPG treatment. Exposure to specific inhibitors of the Ca2+ signaling pathway revealed that these changes varied between the different OPG treatment groups. Findings from the present study indicated that the Ca2+ signaling pathway is involved in both the regulation of osteoclastogenesis as well as inhibition of osteoclast differentiation and activation by OPG.
PMCID: PMC4483497  PMID: 25549213
Ca2+ signaling pathway; osteoclast; osteoclastogenesis; osteoprotegerin
25.  New Anti-Inflammatory Cembranes from the Cultured Soft Coral Nephthea columnaris 
Marine Drugs  2015;13(6):3443-3453.
Two new cembranes, columnariols A (1) and B (2), were isolated from the cultured soft coral Nephthea columnaris. The structures of cembranes 1 and 2 were elucidated by spectroscopic methods. In the anti-inflammatory effects test, cembranes 1 and 2 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS and COX-2 protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Compound 1 exhibited moderate cytotoxicity toward LNCaP cells with an IC50 value of 9.80 μg/mL.
PMCID: PMC4483638  PMID: 26035022
Nephthea columnaris; cembrane; octocoral; antiinflammatory; iNOS; COX-2; cytotoxicity

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