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1.  Effect of Menopausal Status on Carotid Intima-Media Thickness and Presence of Carotid Plaque in Chinese Women Generation Population 
Scientific Reports  2015;5:8076.
Menopause is an important physiological stage in women's life. The potential association of menopause with carotid intima-media thickness as well as with occurrence and stability of carotid plaque in Chinese female population is unclear. We conducted a population-based, cross-sectional study by recruiting 2,131 participants aged above 40 years from northeast of China. Carotid intima-media thickness (CIMT), presence of carotid plaque and its stability were evaluated by carotid duplex sonography. Among the participants, 1,133 (53.2%) were identified to be postmenopausal. After adjusting for potential confounding factors, presence of CIMT at 50th- 75th and ≥75th percentiles, carotid plaque and its unstable status were found to be significantly associated with the postmenopausal status (P < 0.001). When matched the participants by age, post-menopausal status was still associated with a higher risk of having unstable plaque. Moreover, our data show that postmenopausal status is a risk factor for intracranial arterial stenosis when compared with premenopausal status in the univariate analysis (OR = 1.314, P = 0.043), and such relationship is lost when the confounding factors are adjusted (OR = 0.828, P = 0.225). In conclusion, the vascular risk factors increase as the menopausal status changes. Compared with premenopausal status, postmenopausal status is associated with higher morbidity of CIMT, carotid plaque and its unstable status.
doi:10.1038/srep08076
PMCID: PMC4308700  PMID: 25627797
2.  Meningoencephalitis caused by Plesiomonas shigelloides in a Chinese neonate: case report and literature review 
The most usual presentation of Plesiomonas shigelloides infection is an acute gastroenteritis, and extraintestinal manifestations are extremely rare. We reported the first neonate with P. shigelloides meningoencephalitis in China and reviewed the twelve cases previously reported. Our report adds further awareness on Plesiomonas shigelloides meningoencephalitis in neonate and points out the importance of an early diagnosis and the use of sensitive antibiotics treatment to this fatal infection.
doi:10.1186/s13052-014-0107-1
PMCID: PMC4311455  PMID: 25599746
Neonate; Plesiomonas shigelloides; Meningitis; Meningoencephalitis
3.  Stem cells in gastric cancer 
Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Cancer stem cells (CSCs), which were first identified in acute myeloid leukemia and subsequently in a large array of solid tumors, play important roles in cancer initiation, dissemination and recurrence. CSCs are often transformed tissue-specific stem cells or de-differentiated transit amplifying progenitor cells. Several populations of multipotent gastric stem cells (GSCs) that reside in the stomach have been determined to regulate physiological tissue renewal and injury repair. These populations include the Villin+ and Lgr5+ GSCs in the antrum, the Troy+ chief cells in the corpus, and the Sox2+ GSCs that are found in both the antrum and the corpus. The disruption of tumor suppressors in Villin+ or Lgr5+ GSCs leads to GC in mouse models. In addition to residing GSCs, bone marrow-derived cells can initiate GC in a mouse model of chronic Helicobacter infection. Furthermore, expression of the cell surface markers CD133 or CD44 defines gastric CSCs in mouse models and in human primary GC tissues and cell lines. Targeted elimination of CSCs effectively reduces tumor size and grade in mouse models. In summary, the recent identification of normal GSCs and gastric CSCs has greatly improved our understanding of the molecular and cellular etiology of GC and will aid in the development of effective therapies to treat patients.
doi:10.3748/wjg.v21.i1.112
PMCID: PMC4284326  PMID: 25574084
Cancer stem cells; Gastric cancer; Lgr5; Villin; Troy; Sox2; CD133; CD44; E-cadherin
4.  Construction of a recombinant eukaryotic vector for a grass carp reovirus VP6 gene and its expression in vitro and in vivo 
VirusDisease  2013;25(1):69-77.
A recombinant plasmid expressing the VP6 inner capsid coding gene of grass carp reovirus (GCRV) was constructed and expressed in a Ctenopharyngodon idellus kidney (CIK) cell line and grass carps. The VP6 gene was amplified by RT-PCR, cloned into a pEGFP-N1 eukaryotic expression vector and transfected into CIK cells. Results from enhanced green fluorescent protein (EGFP) experiments and flow cytometry showed highest protein expression at 48 h. The immunoreactivity of fusion protein was confirmed using an indirect immunofluorescent assay. The specific binding between the fusion protein and polyclonal mouse GCRV VP6-specific antiserum indicated that the fusion protein was translated in vitro and had good immunogenicity. An antiviral activity assay showed that the virus titer was 100-fold lower in the GCRV VP6 expressed cells than in the pEGFP-N1 transfected cells. The expression levels of three immune genes in the head kidney of grass carps injected with the recombinant plasmid were used. Mx, TLR3 and IgM mRNA expression increased sharply at the 1st and 15th days post-injection (dpi). Specific antibodies were detected 30 days after vaccination. Neutralizing titers of the antibodies in vaccinated fish detected ranged from 160 to 320. Intramuscular injection of grass carps with 1 μg of pEGFP-N1-VP6 was found to provide strong protection against GCRV. These results suggested that the VP6 gene was a good candidate for the design of GCRV-DNA vaccines and to investigate the use of cytokines as co-stimulatory molecules.
doi:10.1007/s13337-013-0176-6
PMCID: PMC3889242  PMID: 24426312
Grass carp reovirus; GCRV VP6; Recombinant plasmid; Vaccine; Immunity
5.  Distributed Neural Networks of Tactile Working Memory 
Journal of physiology, Paris  2013;107(6):10.1016/j.jphysparis.2013.06.001.
Microelectrode recordings of cortical activity in primates performing working memory tasks reveal some cortical neurons exhibiting sustained or graded persistent elevations in firing rate during the period in which sensory information is actively maintained in short-term memory. These neurons are called “memory cells”. Imaging and transcranial magnetic stimulation studies indicate that memory cells may arise from distributed cortical networks. Depending on the sensory modality of the memorandum in working memory tasks, neurons exhibiting memory-correlated patterns of firing have been detected in different association cortices including prefrontal cortex, and primary sensory cortices as well.
Here we elaborate on neurophysiological experiments that lead to our understanding of the neuromechanisms of working memory, and mainly discuss findings on widely distributed cortical networks involved in tactile working memory.
doi:10.1016/j.jphysparis.2013.06.001
PMCID: PMC3844104  PMID: 23792021
6.  Genome-wide analysis of the Hsf family in soybean and functional identification of GmHsf-34 involvement in drought and heat stresses 
BMC Genomics  2014;15(1):1009.
Background
High temperature affects organism growth and metabolic activity. Heat shock transcription factors (Hsfs) are key regulators in heat shock response in eukaryotes and prokaryotes. Under high temperature conditions, Hsfs activate heat shock proteins (Hsps) by combining with heat stress elements (HSEs) in their promoters, leading to defense of heat stress. Since the first plant Hsf gene was identified in tomato, several plant Hsf family genes have been thoroughly characterized. Although soybean (Glycine max), an important oilseed crops, genome sequences have been available, the Hsf family genes in soybean have not been characterized accurately.
Result
We analyzed the Hsf genetic structures and protein function domains using the GSDS, Pfam, SMART, PredictNLS, and NetNES online tools. The genome scanning of dicots (soybean and Arabidopsis) and monocots (rice and maize) revealed that the whole-genome replication occurred twice in soybean evolution. The plant Hsfs were classified into 3 classes and 16 subclasses according to protein structure domains. The A8 and B3 subclasses existed only in dicots and the A9 and C2 occurred only in monocots. Thirty eight soybean Hsfs were systematically identified and grouped into 3 classes and 12 subclasses, and located on 15 soybean chromosomes. The promoter regions of the soybean Hsfs contained cis-elements that likely participate in drought, low temperature, and ABA stress responses. There were large differences among Hsfs based on transcriptional levels under the stress conditions. The transcriptional levels of the A1 and A2 subclass genes were extraordinarily high. In addition, differences in the expression levels occurred for each gene in the different organs and at the different developmental stages. Several genes were chosen to determine their subcellular localizations and functions. The subcellular localization results revealed that GmHsf-04, GmHsf-33, and GmHsf-34 were located in the nucleus. Overexpression of the GmHsf-34 gene improved the tolerances to drought and heat stresses in Arabidopsis plants.
Conclusions
This present investigation of the quantity, structural features, expression characteristics, subcellular localizations, and functional roles provides a scientific basis for further research on soybean Hsf functions.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1009) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-1009
PMCID: PMC4253008  PMID: 25416131
Hsfs; Genome-wide identification; Expression pattern; Subcellular localization; Functional identification; Soybean
7.  Healing time of incision infection after hepatobiliary surgery treated by needle-free incision suture closure 
World Journal of Gastroenterology : WJG  2014;20(42):15815-15819.
AIM: To compare the effectiveness of needle-free incision suture closure with butterfly tape and traditional secondary suturing techniques in treating incision infection.
METHODS: Two hundred and twenty-three patients with incision infection following hepatobiliary surgery at a tertiary hospital were randomly divided into three groups: 90 patients were closed by needle-free incision suture closure, which gradually closed the incision wound when drainage from incision infection was visibly decreased and healthy granulation tissues had grown; 79 patients were closed by butterfly bandage; another 54 patients were closed by traditional secondary suturing technique. Healing time of incision infection was calculated from the beginning of dressing change to the healing of the incision.
RESULTS: Healing time in the needle-free incision suture closure group (24.2 ± 7.2 d) was significantly shorter than that in the butterfly bandage group (33.3 ± 11.2 d) and the traditional secondary suturing group (36.2 ± 15.3 d) (P < 0.05). Healing time in the butterfly bandage group appeared to be slightly shorter than that in the secondary suture group, but the difference was not statistically significant (P > 0.05).
CONCLUSION: Needle-free incision suture closure could gradually close the infection wound at the same time of drainage and dressing change, thereby shortening the healing time.
doi:10.3748/wjg.v20.i42.15815
PMCID: PMC4229548  PMID: 25400467
Incision infection; Needle-free incision suture closure; Secondary suture; Drainage; Wound healing; Hepatobiliary surgery
8.  Notes on the genus Xenocerogria (Coleoptera, Tenebrionidae, Lagriini) from China 
ZooKeys  2014;93-108.
Three species of the genus Xenocerogria Merkl, 2007 have been recorded in China, Xenocerogria feai (Borchmann, 1911), Xenocerogria ignota (Borchmann, 1941) and Xenocerogria ruficollis (Borchmann, 1912). Xenocera xanthisma Chen, 2002 is proposed as a junior synonym of Xenocerogria ruficollis. Lectotype of Xenocerogria ignota is designated, and the species is transferred to the genus Lagria Fabricius, 1775. New Chinese province records of Xenocerogria ruficollis are provided.
doi:10.3897/zookeys.451.8478
PMCID: PMC4258622  PMID: 25493049
China; Lagriinae; lectotype designation; new synonym; redescription; Tenebrionidae; Xenocerogria
9.  Resting Heart Rate and Risk of Cardiovascular Diseases and All-Cause Death: The Kailuan Study 
PLoS ONE  2014;9(10):e110985.
Background
Resting heart rate (RHR) predicts both cardiovascular and noncardiovascular death in different populations. However, the results of the association between RHR and cardiovascular diseases (CVDs) are inconsistent, especially for each subtype of CVDs.
Objective
The aim of this study was to prospectively explore the relationship between RHR and CVDs including myocardial infarction (MI), ischemic stroke, and hemorrhagic stroke and all-cause death in a general population.
Methods
The Kailuan study is a prospective longitudinal cohort study on cardiovascular risk factors and cardiovascular or cerebrovascular events. Hazard ratio (HR) with 95% confidence intervals (CI) were calculated using Cox regression modeling.
Results
We analyzed 92,562 participants (18–98 years old) in the Kailuan Study. CVDs were developed in 1,903 people during follow-ups. In multivariate analysis with adjustment for major traditional cardiovascular risk factors, HRs of the highest quintile group compared with the lowest quintile group of RHR for all-cause CVDs, MI, any stroke, ischemic stroke, hemorrhagic stroke, and all-cause death were 1.03 (95% CI, 0.98–1.07), 1.10 (95% CI, 1.01–1.20), 1.01 (95% CI, 0.97–1.06), 1.02 (95% CI, 0.96–1.07), 1.01 (95% CI, 0.92–1.11) and 1.18, (95% CI, 1.13–1.23), respectively.
Conclusions
The elevated RHR was independently associated with the increased risk for MI and all-cause death, but not for all-cause CVDs, any stroke, ischemic stroke, nor hemorrhagic stroke. This indicates that the elevated RHR might be a risk marker for MI and all-cause death in general populations.
doi:10.1371/journal.pone.0110985
PMCID: PMC4208799  PMID: 25343354
10.  Comparison of the operation of arthroscopic tibial inlay and traditional tibial inlay for posterior cruciate ligament reconstruction 
Objective: To perform dual-bundle reconstruction of posterior cruciate ligament using full arthroscopic tibial inlay technology with self-designed tibia tunnel drilling system and to compare the effect of arthroscopic tibial inlay versus traditional technique for posterior cruciate ligament reconstruction. Material and methods: 32 patients were randomly divided into experiment group (improved tibial inlay, n = 17) and control group (traditional tibial inlay, n = 15). Self-designed tibia tunnel drill system was used to produce intraoperative deep-limited bone tunnel. During follow-up, the location of the bone block and the healing situation were checked by knee X-ray and spiral CT scan. Blood loss, operation time and nerve vascular injuries were evaluated. Results: Mean intraoperative blood loss was 123.53 ± 74.05 ml in the improved tibial inlay group compared with 332 ± 114.26 ml in the traditional tibial inlay group (t = 6.12, P < 0.05). Mean operation time was 235.27 ± 58.88 min in the improved tibial inlay group compared with 346.37 ± 59.67 min in the traditional tibial inlay group (t = 5.19, P < 0.05). Posterior drawer test were negative in 15 cases, slight positive in 2 with improved tibial inlay technique compared with 14 negative cases and 2 positive cases of traditional tibial Inlay technique. The X-ray and spiral CT scan showed the location of the bone block were perfect and healed well with the patent who received improved tibial inlay technology after 12 weeks postoperatively. Conclusion: Accurate depth-limited bone tunnel can be produced by the tibia tunnel drill system with minor trauma, less bleeding and reducing of nerves or vessels and the recent clinical effects of PCL reconstruction were pretty good.
PMCID: PMC4238543  PMID: 25419349
Posterior cruciate ligament; inlays; arthroscopy
11.  Splenosis mimicking an extramural duodenal mass: A case report 
Oncology Letters  2014;8(6):2811-2813.
Splenosis is a common disease, patients with splenosis are generally asymptomatic and therapy is not indicated. Splenosis is frequently observed in the abdomen and pelvic cavity and may mimic malignancy on imaging, often leading to unnecessary surgical intervention. The current study presents the case of a 55-year-old female patient, with a rare case of duodenal splenosis, who underwent unnecessary laparotomy due to a misdiagnosis of a malignant duodenal stromal tumor. Although splenosis was confirmed by intraoperative tissue biopsy, this mass was resected due to the lack of information with regard to this condition, an increased suspicion of progressive growth of the mass and chronic duodenal compression. The aim of this report is to raise the awareness of this entity in patients post-splenectomy, to avoid unnecessary surgery, particularly with an increased prevalence of patients with previous splenic trauma due to road traffic accidents. Therefore, the possibility of abdominal splenosis must be included in the differential diagnosis of patients with abdominal mass as the main clinical manifestation, where there is a history of splenic trauma or splenectomy and no other systemic symptoms. In the future noninvasive nuclear scintigraphy may serve as a suitable diagnostic approach for splenosis, thereby avoiding unnecessary laparotomies.
doi:10.3892/ol.2014.2609
PMCID: PMC4214512  PMID: 25364471
splenosis; splenectomy; malignancy; mass; biopsy
12.  Radioprotective effects of valproic acid, a histone deacetylase inhibitor, in the rat brain 
Biomedical Reports  2014;3(1):63-69.
Radiotherapy is commonly used in the treatment of brain tumors but can cause significant damage to surrounding normal brain. The radioprotective effects of valproic acid (VPA) on normal tissue in the rat brain were evaluated following irradiation. Male Wistar rats were used in the present study and 48 rats were randomly divided into four groups consisting of 12 rats each. The whole-brain irradiation (WBI) was delivered by X-ray and the rats received the following treatment once a day for 5 days. The control group (sham-exposed group) received sham irradiation plus physiological saline. The VPA group received sham irradiation plus 150 mg VPA/kg. The X-ray group received WBI plus physiological saline. The combined group received WBI plus 150 mg/kg intraperitoneally VPA. A total of 6 months post-irradiation, the rats were sacrificed and the brains were harvested. Cell apoptosis in the cortex was determined by immunohistochemistry 24 h post-irradiation using an antibody for protein caspase-3. Transmission electron microscope (TEM) analyses were used to assess the effects of VPA on the radioprotection of rat normal brain cells 6 months post-irradiation. The weights of the animals in the TEM group measured over the two weeks after the first injection of VPA were also observed. Histological findings demonstrated that apoptosis occurred on the cortex 1 day after treatment, peaking in the X-ray group. The cells of the combined group showed a moderate caspase-3 staining compared to the X-ray group. There was a trend towards a lower body weight of the X-ray group following irradiation compared to either no-irradiation or rats of the combined group, although there was no significant difference in the average weight between the combined group and irradiated rats. Mild swelling of the capillary endothelial cells in the irregular lumen was observed in the combined group, whereas the X-ray group showed a severe structural disorder. In conclusion, VPA supplementation during radiotherapy may be beneficial for radioprotection following WBI by reducing normal brain cell injury.
doi:10.3892/br.2014.367
PMCID: PMC4251104  PMID: 25469249
fractionated radiotherapy; valproic acid; brain injury; radioprotection
13.  Inhibition of beclin1 affects the chemotherapeutic sensitivity of osteosarcoma 
This study was conducted to explore the role of autophagy in cisplatin-resistant osteosarcoma. Cisplatin-resistant osteosarcoma cell line (MG63/DDP) was obtained from parental MG63 by treating cisplatin with an intermittent stepwise selection protocol. The autophagy in MG63/DDP and MG63 was fully analyzed by immunofluorescence and western blot analysis. Meanwhile, the autophagy and the sensitivity to cisplatin for MG63/DDP and MG63 after inhibition of beclin1 were analyzed in vitro and in vivo. Increased autophagy was observed in cisplatin resistant MG63/DDP cells and in the cisplatin-treated MG63 and MG63/DDP cells. Meanwhile, inhibition the beclin1 significantly inhibited the formation of autophagosome and resulted in the increase in the sensitivity to cisplatin for both MG63 and MG63/DDP cells in vitro and in vivo. In conclusion, autophagy is implicated in the cisplatin resistant osteosarcoma, and inhibition of beclin1 could be a target for improving osteosarcoma therapy.
PMCID: PMC4230152  PMID: 25400807
Cisplatin; osteosarcoma; autophagy; beclin1; MG63
14.  Handheld photoacoustic microscopy to detect melanoma depth in vivo 
Optics letters  2014;39(16):4731-4734.
We developed handheld photoacoustic microscopy (PAM) to detect melanoma and determine tumor depth in nude mice in vivo. Compared to our previous PAM system for melanoma imaging, a new light delivery mechanism is introduced to improve light penetration. We show that melanomas with 4.1 mm and 3.7 mm thicknesses can be successfully detected in phantom and in in vivo experiments, respectively. With its deep melanoma imaging ability and handheld design, this system can be tested for clinical melanoma diagnosis, prognosis, and surgical planning for patients at the bedside.
PMCID: PMC4160823  PMID: 25121860
15.  Near-infrared Optical-resolution Photoacoustic Microscopy 
Optics letters  2014;39(17):5192-5195.
Compared with visible light (380–700 nm), near-infrared light (700–1400 nm) undergoes weaker optical attenuation in biological tissue, thus it can penetrate deeper. Here, we demonstrate near-infrared optical-resolution photoacoustic microscopy (NIR-OR-PAM) with 1046 nm illumination. A penetration depth of 3.2 mm was achieved in chicken breast tissue ex vivo using optical fluence within the ANSI limit (100 mJ/cm2). Beyond ~0.6 mm deep in chicken breast tissue, NIR-OR-PAM has shown finer resolution than the visible counterpart with 570 nm illumination. The deep imaging capability of NIR-OR-PAM was validated in both the mouse ear and mouse brain. NIR-OR-PAM of possible lipid contrast was explored as well.
PMCID: PMC4161671  PMID: 25166107
16.  Relationship between C - Reactive Protein and Stroke: A Large Prospective Community Based Study 
PLoS ONE  2014;9(9):e107017.
Objective
Previous studies have suggested that C-reactive protein (CRP) was associated with risk of stroke. There were few studies in Asian population, or on stroke subtypes other than ischemic stroke. We thus investigated the relationship between CRP and the risks of all stroke and its subtypes in a Chinese adult population.
Methods
In the current study, we included 90,517 Chinese adults free of stroke and myocardial infarction at baseline (June 2006 to October 2007) in analyses. Strokes were classified as ischemic stroke (IS), intracranial heamorrhage (ICH) and subarachnoid heamorrhage (SAH). High-sensitivity CRP (hs-CRP) were categorized into three groups: <1 mg/L, 1 to 3 mg/L, and >3 mg/L. Cox proportional hazards regression was used to calculate the association between hs-CRP concentrations and all stroke, as well as its subtypes.
Results
During a median follow-up time of 49 months, we documented 1,472 incident stroke cases. Of which 1,049 (71.3%) were IS, 383 (26.0%) were ICH, and 40 (2.7%) were SAH. After multivariate adjustment, hs-CRP concentrations ≥1 mg/L were associated with increased risks of all stroke (hs-CRP 1–3 mg/L: hazard ratio (HR) 1.17, 95% confidential interval (CI) 1.03–1.33; hs-CRP>3 mg/L: HR 1.25, 95% CI 1.07–1.46) and IS (hs-CRP 1–3 mg/L: HR 1.17, 95% CI 1.01–1.36; hs-CRP>3 mg/L: HR 1.33, 95% CI 1.11–1.60), but not with ICH and SAH. Subgroup analyses showed that higher hs-CRP concentration was more prone to be a risk factor for all stroke and IS in non-fatal stroke, male and hypertensive participants.
Conclusion
We found that higher hs-CRP concentrations were associated with a higher risk of IS, particularly for non-fatal stroke, male and hypertensive subjects. In contrast, we did not observe significant associations between hs-CRP and ICH/SAH.
doi:10.1371/journal.pone.0107017
PMCID: PMC4156395  PMID: 25191699
17.  Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling 
The Journal of Cell Biology  2014;204(5):777-792.
Caveolae transduce mechanical stress into plasma membrane lipid alterations that disrupt Ras organization in an isoform-specific manner and modulate downstream signal transduction.
The molecular mechanisms whereby caveolae exert control over cellular signaling have to date remained elusive. We have therefore explored the role caveolae play in modulating Ras signaling. Lipidomic and gene array analyses revealed that caveolin-1 (CAV1) deficiency results in altered cellular lipid composition, and plasma membrane (PM) phosphatidylserine distribution. These changes correlated with increased K-Ras expression and extensive isoform-specific perturbation of Ras spatial organization: in CAV1-deficient cells K-RasG12V nanoclustering and MAPK activation were enhanced, whereas GTP-dependent lateral segregation of H-Ras was abolished resulting in compromised signal output from H-RasG12V nanoclusters. These changes in Ras nanoclustering were phenocopied by the down-regulation of Cavin1, another crucial caveolar structural component, and by acute loss of caveolae in response to increased osmotic pressure. Thus, we postulate that caveolae remotely regulate Ras nanoclustering and signal transduction by controlling PM organization. Similarly, caveolae transduce mechanical stress into PM lipid alterations that, in turn, modulate Ras PM organization.
doi:10.1083/jcb.201307055
PMCID: PMC3941050  PMID: 24567358
18.  Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters 
Molecular and Cellular Biology  2014;34(5):862-876.
Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters, however, has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions, indicating that Ras proteins engage in isoform-selective lipid sorting and accounting for different signal outputs from different Ras isoforms. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence, Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experimentation reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important previously unexplored opportunities for signal integration and signal processing.
doi:10.1128/MCB.01227-13
PMCID: PMC4023829  PMID: 24366544
19.  FGF2 and FGFR1 Signaling Regulate Functional Recovery Following Cuprizone Demyelination 
Neuroscience letters  2013;548:280-285.
In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 wk) or chronic (12 wk) demyelination. Plp/CreERT:Fgfr1fl/fl mice administered tamoxifen at 10 wks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination.
doi:10.1016/j.neulet.2013.05.010
PMCID: PMC3715376  PMID: 23684572
remyelination; corpus callosum; wheel activity; sociability; growth factor; multiple sclerosis; cuprizone
20.  A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs 
Scientific Reports  2014;4:6188.
Selective inhibition of function-specific β-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic β-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic β-GlcNAcase to against insect and bacterial chitinolytic β-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.
doi:10.1038/srep06188
PMCID: PMC4143770  PMID: 25155420
21.  miR-203 Suppresses the Proliferation and Migration and Promotes the Apoptosis of Lung Cancer Cells by Targeting SRC 
PLoS ONE  2014;9(8):e105570.
SRC, also known as proto-oncogene c-Src, is a non-receptor tyrosine kinase that plays an important role in cancer progression by promoting survival, angiogenesis, proliferation, and invasion pathways. In this study, we found that SRC protein levels were consistently upregulated in lung cancer tissues, but that SRC mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in SRC regulation. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for miRNAs that potentially target SRC. We identified specific targeting sites for miR-203 in the 3′-untranslated region (3′-UTR) of SRC. We then experimentally validated miR-203 as a direct regulator of SRC using cell transfection and luciferase assays and showed that miR-203 inhibited SRC expression and consequently triggered suppression of the SRC/Ras/ERK pathway. Finally, we demonstrated that the repression of SRC by miR-203 suppressed the proliferation and migration and promoted the apoptosis of lung cancer cells. In summary, this study provides the first clues regarding the role of miR-203 as a tumor suppressor in lung cancer cells through the inhibition of SRC translation.
doi:10.1371/journal.pone.0105570
PMCID: PMC4139332  PMID: 25140799
22.  The C-681G polymorphism of PPAR-γ gene is associated with susceptibility to non-alcoholic fatty liver disease 
Nonalcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of fatty acid in the liver, a common disease in the world. The research of single nucleotide polymorphisms (SNPs) provides a new approach for managing NAFLD. SNPs may increase or decrease the functions of the target genes and their encoding proteins. Peroxisome proliferator-activated receptor (PPAR) plays a key role in modulating metabolism of hepatic triglycerides and consequently magnitude of NAFLD. In this study, we investigated the effect of three SNPs in the PPAR-γ gene i.e. rs10865710 (C-681G), rs7649970 (C-689T) and rs1801282 (C34G, also termed Pro12Ala) on susceptibility to NAFLD. The participants were selected from our epidemiological survey. Totally 169 participants were enrolled in NAFLD group, and 699 healthy subjects were included as controls. PCR-RFLP was applied to detect the SNPs. The G allele frequency of rs10865710 in NAFLD group (41.1%) was significantly higher than that (34.8%) in controls (p = 0.03). Differences in other two loci (rs7649970 and rs1801282) were not statistically significant between the two groups (p > 0.05). This result was confirmed by haplotype analysis. The GCC haplotype (a set of 3 adjacent SNPs in linkage disequilibrium, corresponding to the three alleles of above polymorphisms in order) was a risk factor for the susceptibility to NAFLD (p = 0.03). This study has revealed that the G allele of rs10865710 in the PPAR-γ gene is associated with the increased susceptibility to NAFLD. Our findings may provide novel diagnostic biomarkers and therapeutic targets for NAFLD.
PMCID: PMC4126502  PMID: 22820754
gene; insulin resistance; non-alcoholic fatty liver disease; peroxisome proliferator-activated receptor-γ; polymorphism
23.  Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death 
Oncotarget  2014;5(15):6526-6539.
Microwave ablation (MWA) has been used as a classical hyperthermic ablation method for decades with the intention to induce direct killing of tumor cells or modulation of tumor architecture. The purpose of this study was to explore whether MWA induced tumor cell death could generate an immunogenic source of tumor antigens and elicit tumor-specific immune responses, taking an alternative antitumor effects. Three kinds of osteosarcoma cell lines, respectively derived from mice, rats and human, were selected as ablation models. In vitro and in situ tumor ablation were both performed to detect the “damage-associated molecular patterns” (DAMPs) exposure level. Active ablated products vaccination resulted in complete protection in both mouse and rat tumor-bearing models, which was mediated primarily by vaccine-elicited CD8+ T cells. These effector cells functioned by releasing IFN-γ and TNF-α in the presence of target cells, which may trigger FasL-directed cell apoptosis. These data suggest that MWA-processed osteosarcoma cells could be applied to generate specific antitumor effects, especially for in situ ablation. Hence, MWA could be used in combination with immunotherapy, especially for patients who have failed chemotherapy or who have limited treatment options.
PMCID: PMC4171648  PMID: 25153727
Immunogenic cell death; osteosarcoma; thermal therapy; microwave ablation; cytotoxic T cells
24.  microRNA-194 suppresses osteosarcoma cell proliferation and metastasis in vitro and in vivo by targeting CDH2 and IGF1R 
International Journal of Oncology  2014;45(4):1437-1449.
Studies have shown that miR-194 functions as a tumor suppressor and is associated with tumor growth and metastasis. We studied the effects of miR-194 in osteosarcoma and the possible mechanism by which miR-194 affected the survival, apoptosis and metastasis of osteosarcoma. Both human osteosarcoma cell lines SOSP-9607 and U2-OS were transfected with recombinant lentiviruses to regulate miR-194 expression. Overexpression of miR-194 partially inhibited the proliferation, migration, and invasion of osteosarcoma cells in vitro, as well as tumor growth and pulmonary metastasis of osteosarcoma cells in vivo. Potential miR-194 target genes were predicted using bioinformatics. Luciferase reporter assay, real-time quantitative PCR and western blotting confirmed that CDH2 (N-cadherin) and IGF1R were targets of miR-194. Using real-time quantitative PCR, we evaluated the expression of miR-194 and two miR-194 target genes, CDH2 and IGF1R in osteosarcoma samples from 107 patients and 99 formalin- or paraformalin-fixed paraffin-embedded tissues. The expressions of the target genes were also examined in osteosarcoma samples using immunohistochemistry. Overexpression of miR-194 inhibited tumor growth and metastasis of osteosarcoma probably by downregulating CDH2 and IGF1R. miR-194 may prove to be a promising therapeutic agent for osteosarcoma.
doi:10.3892/ijo.2014.2571
PMCID: PMC4151797  PMID: 25096247
osteosarcoma; miR-194; CDH2; IGF1R; metastasis; proliferation
25.  Resveratrol Inhibits Breast Cancer Stem-Like Cells and Induces Autophagy via Suppressing Wnt/β-Catenin Signaling Pathway 
PLoS ONE  2014;9(7):e102535.
Resveratrol, a natural polyphenolic compound, is abundantly found in plant foods and has been extensively studied for its anti-cancer properties. Given the important role of CSCs (Cancer Stem Cells) in breast tumorigenesis and progression, it is worth investigating the effects of resveratrol on CSCs. The article is an attempt to investigate the effects of resveratrol on breast CSCs. Resveratrol significantly inhibits the proliferation of BCSCs (breast cancer stem-like cells) isolated from MCF-7 and SUM159, and decreased the percentage of BCSCs population, consequently reduced the size and number of mammospheres in non-adherent spherical clusters. Accordingly, the injection of resveratrol (100 mg/kg/d) in NOD/SCID (nonobese diabetic/severe combined immunodeficient) mice effectively inhibited the growth of xenograft tumors and reduced BCSC population in tumor cells. After the reimplantation of primary tumor cells into the secondary mice for 30 d, all 6 control inoculations produced tumors, while tumor cells derived from resveratrol-treated mice only caused 1 tumor of 6 inoculations. Further studies by TEM (Transmission electron microscopy) analysis, GFP-LC3-II puncta formation assay and western blot for LC3-II, Beclin1 and Atg 7, showed that resveratrol induces autophagy in BCSCs. Moreover, resveratrol suppresses Wnt/β-catenin signaling pathway in BCSCs; over-expression of β-catenin by transfecting the plasmid markedly reduced resveratrol-induced cytotoxicity and autophagy in BCSCs. Our findings indicated that resveratrol inhibits BCSCs and induces autophagy via suppressing Wnt/β-catenin signaling pathway.
doi:10.1371/journal.pone.0102535
PMCID: PMC4113212  PMID: 25068516

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