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1.  Measurement of Fetal Abdominal and Subscapular Subcutaneous Tissue Thickness during Pregnancy to Predict Macrosomia: A Pilot Study 
PLoS ONE  2014;9(3):e93077.
This study assessed the growth trends and reference ranges of the ultrasound parameters, fetal abdominal subcutaneous tissue thickness (ASTT) and subscapular subcutaneous tissue thickness (SSTT), in the last two trimesters of normal pregnancy in a Chinese population. We recruited 744 healthy women with singleton pregnancies. The ASTT and SSTT were evaluated at different times between 21 and 36 weeks of gestation. The correlations between these parameters and fetal gestational weeks were assessed using linear regression analysis. Both ASTT and SSTT increased with gestation, and both parameters showed a strong correlation with gestation (ASTT vs. GA, R2 = 0.792; P<0.0001; SSTT vs. GA, R2 = 0.302; P<0.0001). Time-specific reference ranges, including 5th, 50th and 95th percentiles and means ± SD, were constructed for ASTT and SSTT. These results provide a preliminary reference range to evaluate whether fetal development and maternal metabolic health is normal or not in a Chinese population.
doi:10.1371/journal.pone.0093077
PMCID: PMC3968095  PMID: 24675769
2.  Diagnostic and prognostic value of minor elevated cardiac troponin levels for percutaneous coronary intervention-related myocardial injury: a prospective, single-center and double-blind study 
Journal of Biomedical Research  2014;28(2):98-107.
Abstract
Cardiac troponin-I (cTnI) and -T (cTnT) are sensitive and specific markers of myocardial injury. However, the role of increased cTnI and cTnT in percutaneous coronary intervention (PCI)-related myocardial injury remains controversial. In this prospective, single-center and double-blind study, we aimed to determine the diagnostic and prognostic value of cTnI as well as cTnT (cTns) in PCI-related myocardial injury in a Chinese population. A total of 1,008 patients with stable angina pectoris and non-ST-segment elevation acute coronary syndrome were recruited. The levels of cTnI and cTnT were examined before and after PCI. All patients were followed up for 26±9 months to observe the incidence of major adverse cardiac events (MACEs). Our results showed that post-PCI cTnI and/or cTnT levels were increased to more than the 99th percentile upper reference limit (URL) in 133 (13.2%) patients, among which 22 (2.2%) were more than 5 × 99th percentile URL. By univariate analysis, an elevation in cTns after PCI was not an independent predictor of increased MACEs, HR 1.35 (P  =  0.33, 95%CI: 0.74–2.46). In conclusion, our data demonstrate that the incidence of PCI-related myocardial injury is not common in a Chinese population and minor elevated cTns levels may not be a sensitive prognostic marker for MACEs.
doi:10.7555/JBR.28.20130124
PMCID: PMC3968280
percutaneous coronary intervention (PCI); troponins; PCI-related myocardial injury; major adverse cardiac events; diagnosis; prognosis
3.  1H-Nuclear magnetic resonance-based metabolomic analysis of brain in mice with nicotine treatment 
BMC Neuroscience  2014;15:32.
Background
Nicotine is rapidly absorbed from cigarette smoke and therefore induces a number of chronic illnesses with the widespread use of tobacco products. Studies have shown a few cerebral metabolites modified by nicotine; however, endogenous metabolic profiling in brain has not been well explored.
Results
H NMR-based on metabonomics was applied to investigate the endogenous metabolic profiling of brain hippocampus, nucleus acumens (NAc), prefrontal cortex (PFC) and striatum. We found that nicotine significantly increased CPP in mice, and some specific cerebral metabolites differentially changed in nicotine-treated mice. These modified metabolites included glutamate, acetylcholine, tryptamine, glucose, lactate, creatine, 3-hydroxybutyrate and nicotinamide-adenine dinucleotide (NAD), which was closely associated with neurotransmitter and energy source. Additionally, glutathione and taurine in hippocampus and striatum, phosphocholine in PFC and glycerol in NAc were significantly modified by nicotine, implying the dysregulation of anti-oxidative stress response and membrane metabolism.
Conclusions
Nicotine induces significant metabonomic alterations in brain, which are involved in neurotransmitter disturbance, energy metabolism dysregulation, anti-oxidation and membrane function disruptions, as well as amino acid metabolism imbalance. These findings provide a new insight into rewarding effects of nicotine and the underlying mechanism.
doi:10.1186/1471-2202-15-32
PMCID: PMC3936859  PMID: 24558969
Metabolomics; Nicotine; Metabolite; NMR; Place preference
4.  Concurrent Middle Cerebral Artery Occlusion and Intra-arterial Drug Infusion via Ipsilateral Common Carotid Artery Catheter in the Rat 
Journal of neuroscience methods  2012;213(1):63-69.
Pre-clinical development of therapy for acute ischemic stroke requires robust animal models; the rodent middle cerebral artery occlusion (MCAo) model using a nylon filament inserted into the internal carotid artery is the most popular. Drug screening requires targeted delivery of test substance in a controlled manner. To address these needs, we developed a novel method for delivering substances directly into the ischemic brain during MCAo in the awake rat. An indwelling catheter is placed in the common carotid artery ipsilateral to the occlusion at the time of the surgical placement of the occluding filament. The internal and common carotid arteries are left patent to allow superfusion anterograde. The surgeries can be completed quickly to allow rapid recovery from anesthesia; tests substances can be infused at any given time for any given duration. To simulate clinical scenarios, the occluding filament can be removed minutes or hours later (reperfusion) followed by therapeutic infusions. By delivering drug intra-arterially to the target tissue, “first pass” loss in the liver is reduced and drug effects are concentrated in the ischemic zone. To validate our method, rats were infused with Evans blue dye either intra-arterially or intravenously during a 4 hour MCAo. After a 30 minute reperfusion period, the dye was extracted from each hemisphere and quantitated with a spectrophotometer. Significantly more dye was measured in the ischemic hemispheres that received the dye intra-arterially.
doi:10.1016/j.jneumeth.2012.12.004
PMCID: PMC3570629  PMID: 23261656
Cerebral ischemia; stroke; middle cerebral artery occlusion; intraluminal filament; drug delivery
5.  An integrated clinico-metabolomic model improves prediction of death in sepsis 
Science translational medicine  2013;5(195):195ra95.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
doi:10.1126/scitranslmed.3005893
PMCID: PMC3924586  PMID: 23884467
6.  PHLPP1 gene deletion protects the brain from ischemic injury 
A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2 hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7±2.7% versus 22.9±3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia.
doi:10.1038/jcbfm.2012.150
PMCID: PMC3564187  PMID: 23072745
Akt; ischemia; middle cerebral artery occlusion (MCAO); PH domain leucine-rich repeat protein phosphatase (PHLPP); stroke
7.  The Effects of Geometry on Skin Penetration and Failure of Polymer Microneedles 
Microneedles are small-scale devices that may be used for drug delivery and biosensing. In this study, the forces required for mechanical failure, the modes of mechanical failure, as well as the mechanisms for microneedle penetration into porcine skin were examined. Microneedles produced from the acrylate-based polymer e-Shell 200 using an indirect rapid prototyping approach involving two-photon polymerization and poly(dimethylsiloxane) micromolding were found to possess sufficient strength for penetration of porcine skin. The failure forces were an order of magnitude greater than the forces necessary for full insertion into the skin. Bending was the most common form of failure; an increasing aspect ratio and a decreasing tip diameter were associated with lower failure forces. Video captured during skin penetration revealed that microneedle penetration into the skin occurred by means of a series of insertions and not by means of a single insertion event. Images obtained during and after skin penetration confirmed microneedle penetration of skin as well as transdermal delivery of lucifer yellow dye. These findings shed insight into the mechanisms of microneedle penetration and failure, facilitating design improvements for polymer microneedles.
doi:10.1080/01694243.2012.705101
PMCID: PMC3610923  PMID: 23543070
microneedle; micromolding; acrylate-based polymer; porcine skin
8.  Bioactive Cembranoids, Sarcocrassocolides P–R, from the Dongsha Atoll Soft Coral Sarcophyton crassocaule 
Marine Drugs  2014;12(2):840-850.
New cembranoids, sarcocrassocolides P–R (1–3) and four known compounds (4–7) were isolated from the soft coral Sarcophyton crassocaule. The structures of the metabolites were determined by extensive spectroscopic analysis. Compounds 3–5 and 7 were shown to exhibit cytotoxicity toward a limited panel of cancer cell lines and all compounds 1–7 displayed potent in vitro anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells by inhibiting the expression of inducible nitric oxide synthase (iNOS) protein. Compound 7 also showed significant activity in reducing the accumulation of cyclooxygenase-2 (COX-2) protein in the same macrophage cells.
doi:10.3390/md12020840
PMCID: PMC3944518  PMID: 24477285
soft coral; Sarcophyton crassocaule; cytotoxic activity; anti-inflammatory activity
9.  Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level 
PLoS ONE  2014;9(1):e87040.
Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. 1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.
doi:10.1371/journal.pone.0087040
PMCID: PMC3904956  PMID: 24489831
10.  miR-200b as a prognostic factor in breast cancer targets multiple members of RAB family 
Background
miR-200b has been reported to be a tumor suppressor and a promising therapeutic target in cancer. miR-200b has been associated with epithelial-mesenchymal transition and chemo-resistance in cancer. The aim of this study is to investigate the expression of miR-200b, its prognostic roles and its potential targets in breast cancer.
Methods
qRT-PCR was used to detect miR-200b expression in breast cancer tissues and cell lines. In situ hybridization of miR-200b on tissue microarray including 134 breast cancer samples was used to evaluate its prognostic role. Novel targets of miR-200b in breast cancer were predicted and confirmed by luciferase reporter assay and western bloting. Immunohistochemical staining was used for protein detection. The biological effects of miR-200b in breast cancer cells were further confirmed by ectopic expression of its mimics followed by MTT assay and invasion test.
Results
miR-200b was downregulated in breast cancer tissues and cell lines and its low-expression correlated with poor outcome in breast cancer patients. Members of RAB family, RAB21, RAB23, RAB18 and RAB3B were predicted to be the targets of miR-200b. The luciferase reporter assay was performed to certificate this prediction. The expressions of RAB21, RAB23, RAB18 and RAB3B were suppressed by transfection of miR-200b in breast cancer cells. Over-expression of miR-200b or knock-down of RAB21, RAB23, RAB18 and RAB3B inhibited breast cancer cell proliferation and invasion in vitro.
Conclusions
Our study provides evidence that miR-200b is a prognostic factor in breast cancer targeting multiple members of RAB family. MiR-200b could be a potential therapeutic target in breast cancer.
doi:10.1186/1479-5876-12-17
PMCID: PMC3898994  PMID: 24447584
miR-200b; RAB family; Breast cancer; Prognosis
11.  The Strain at Bone-Implant Interface Determines the Effect of Spinopelvic Reconstruction following Total Sacrectomy: A Strain Gauge Analysis in Various Spinopelvic Constructs 
PLoS ONE  2014;9(1):e85298.
Purpose
There is still some controversy regarding the optimal biomechanical concept for spinopelvic stabilization following total sacrectomy for malignancy. Strains at specific anatomical sites at pelvis/sacrum and implants interfaces have been poorly investigated. Herein, we compared and analyzed the strains applied at key points at the bone-implant interface in four different spinopelvic constructs following total sacrectomy; consequently, we defined a balanced architecture for spinopelvic fusion in that situation.
Methods
Six human cadaveric specimens, from second lumbar vertebra to proximal femur, were used to compare the partial strains at specific sites in a total sacrectomy model. Test constructs included: (1) intact pelvis (control), (2) sacral-rod reconstruction (SRR), (3) bilateral fibular flap reconstruction (BFFR), (4) four-rods reconstruction (FRR), and (5) improved compound reconstruction (ICR). Strains were measured by bonded strain gauges onto the surface of three specific sites (pubic rami, arcuate lines, and posterior spinal rods) under a 500 N axial load.
Results
ICR caused lower strains at specific sites and, moreover, on stress distribution and symmetry, compared to the other three constructs. Strains at pubic rami and arcuate lines following BFFR were lower than those following SRR, but higher at the posterior spinal rod construct. The different modes of strain distribution reflected different patient’s parameter-related conditions. FRR model showed the highest strains at all sites because of the lack of an anterior bracing frame.
Conclusions
The findings of this investigation suggest that both anterior bracing frame and the four-rods load dispersion provide significant load sharing. Additionally, these two constructs decrease the peak strains at bone-implant interface, thus determining the theoretical surgical technique to achieve optimal stress dispersion and balance for spinopelvic reconstruction in early postoperative period following total sacrectomy.
doi:10.1371/journal.pone.0085298
PMCID: PMC3891848  PMID: 24454839
12.  C1q-like Factor, a Target of miR-430, Regulates Primordial Germ Cell Development in Early Embryos of Carassius auratus 
C1q-like is a significant maternal factor of TNF/C1q super-family, and the abundant protein has been observed in both mature eggs of Carassius auratus and Carassius auratus gibelio, but its biological function in early embryo development has remained unclear. In this study, we firstly revealed a high level of maternal C1q-like transcript existence only in mature eggs of Carassius auratus, whereas no any maternal C1q-like transcript was observed in that of Carassius auratus gibelio. During embryonic development, the C1q-like zygotic expression begins around cardiopalmus stage in embryos of both Carassius auratus and Carassius auratus gibelio. Then, we examined the biological role of C1q-like by morpholino-mediated knockdown in early embryo development. Knockdown of CaOC1q resulted in a significant reduction of primordial germ cells (PGCs) in Carassius auratus, as shown by whole mount in situ hybridization with vasa-specific RNA probe, fluorescence immunostaining of vasa protein, and GFP imaging of the GFP-nanos1-3'UTR mRNA reporter. In vitro and in vivo evidence indicated that a microRNA, miR-430 could repress the C1q-like expression and PGC development. These data suggest that C1q-like should be a direct target of miR-430 and play an essential role in PGC development of Carassius auratus.
doi:10.7150/ijbs.7490
PMCID: PMC3879587  PMID: 24391447
C1q-like; microRNA; miR-430; knockdown; primordial germ cell; early embryogenesis
13.  CDK inhibitor p57Kip2 is negatively regulated by COP9 signalosome subunit 6 
Cell Cycle  2012;11(24):4633-4641.
Subunit 6 of the COP9 signalosome complex, CSN6, is known to be critical to the regulation of the MDM2-p53 axis for cell proliferation and anti-apoptosis, but its many targets remain unclear. Here we show that p57Kip2 is a target of CSN6, and that CSN6 is a negative regulator of p57Kip2. CSN6 associates with p57Kip2, and its overexpression can decrease the steady-state expression of p57Kip2; accordingly, CSN6 deficiency leads to p57Kip2 stabilization. Mechanistic studies show that CSN6 associates with p57Kip2 and Skp2, a component of the E3 ligase, which, in turn, facilitates Skp2-mediated protein ubiquitination of p57Kip2. Loss of Skp2 compromised CSN6-mediated p57Kip2 destabilization, suggesting collaboration between Skp2 and CSN6 in degradation of p57Kip2. CSN6’s negative impact on p57Kip2 elevation translates into cell growth promotion, cell cycle deregulation and potentiated transformational activity. Significantly, univariate Kaplan-Meier analysis of tumor samples demonstrates that high CSN6 expression or low p57 expression is associated with poor overall survival. These data suggest that CSN6 is an important negative regulator of p57Kip2, and that overexpression of CSN6 in many types of cancer could lead to decreased expression of p57Kip2 and result in promoted cancer cell growth.
doi:10.4161/cc.22887
PMCID: PMC3562308  PMID: 23187808
COP9; CSN6; Skp2; cell cycle; p57
15.  Inhibition of Elongation Factor-2 Kinase Augments the Antitumor Activity of Temozolomide against Glioma 
PLoS ONE  2013;8(11):e81345.
Background
Glioblastoma multiforme (GBM), the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ) is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ.
Methodology/Principal Findings
Using RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and in vitro and in vivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ.
Conclusions/Significance
These findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma.
doi:10.1371/journal.pone.0081345
PMCID: PMC3841121  PMID: 24303044
16.  Deep Learning with Hierarchical Convolutional Factor Analysis 
Unsupervised multi-layered (“deep”) models are considered for general data, with a particular focus on imagery. The model is represented using a hierarchical convolutional factor-analysis construction, with sparse factor loadings and scores. The computation of layer-dependent model parameters is implemented within a Bayesian setting, employing a Gibbs sampler and variational Bayesian (VB) analysis, that explicitly exploit the convolutional nature of the expansion. In order to address large-scale and streaming data, an online version of VB is also developed. The number of basis functions or dictionary elements at each layer is inferred from the data, based on a beta-Bernoulli implementation of the Indian buffet process. Example results are presented for several image-processing applications, with comparisons to related models in the literature.
doi:10.1109/TPAMI.2013.19
PMCID: PMC3683114  PMID: 23787342
17.  Superimposed traumatic brain injury modulates vasomotor responses in third-order vessels after hemorrhagic shock 
Background
Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of death in trauma. Recent studies suggest that TBI may influence physiological responses to acute blood loss. This study was designed to assess to what extent superimposed TBI may modulate physiologic vasomotor responses in third-order blood vessels in the context of HS.
Methods
We have combined two established experimental models of pressure-controlled hemorrhagic shock (HS; MAP 50 mmHg/60 min) and TBI (lateral fluid percussion (LFP)) to assess vasomotor responses and microcirculatory changes in third-order vessels by intravital microscopy in a spinotrapezius muscle preparation. 23 male Sprague–Dawley rats (260–320 g) were randomly assigned to experimental groups: i) Sham, ii) HS, iii) TBI + HS, subjected to impact or sham operation, and assessed.
Results
HS led to a significant decrease in arteriolar diameters by 20% to baseline (p < 0.01). In TBI + HS this vasoconstriction was less pronounced (5%, non-significant). At completed and at 60 minutes of resuscitation arteriolar diameters had recovered to pre-injury baseline values. Assessment of venular diameters revealed similar results. Arteriolar and venular RBC velocity and blood flow decreased sharply to < 20% of baseline in HS and TBI + HS (p < 0.01). Immediately after and at 60 minutes of resuscitation, an overshoot in arterial RBC velocity (140% of baseline) and blood flow (134.2%) was observed in TBI + HS.
Conclusion
Superimposed TBI modulated arteriolar and venular responses to HS in third-order vessels in a spinotrapezius muscle preparation. Further research is necessary to precisely define the role of TBI on the microcirculation in tissues vulnerable to HS.
doi:10.1186/1757-7241-21-77
PMCID: PMC3843561  PMID: 24257108
Trauma; Hemorrhagic shock; Lateral fluid percussion; Brain injury; Spinotrapezius muscle; Third order vessels; Vasomotor response; Microcirculation
18.  Beneficial Effects of Schisandrin B on the Cardiac Function in Mice Model of Myocardial Infarction 
PLoS ONE  2013;8(11):e79418.
The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.
doi:10.1371/journal.pone.0079418
PMCID: PMC3832629  PMID: 24260217
19.  C/EBP homologous protein deficiency aggravates acute pancreatitis and associated lung injury 
AIM: To investigate the pathophysiological role of C/EBP homologous protein (CHOP) in severe acute pancreatitis and associated lung injury.
METHODS: A severe acute pancreatitis model was induced with 6 injections of cerulein (Cn, 50 μg/kg) at 1-h intervals, then intraperitoneal injection of lipopolysaccharide (LPS, 7.5 mg/kg) in CHOP-deficient (Chop-/-) mice and wild-type (WT) mice. Animals were sacrificed under anesthesia, 3 h or 18 h after LPS injection. Serum amylase, lipase, and cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)-α], pathological changes, acute lung injury, and apoptosis in the pancreas were evaluated. Serum amylase and lipase activities were detected using a medical automatic chemical analyzer. Enzyme-linked immunosorbent assay kits were used to evaluate TNF-α and IL-6 levels in mouse serum and lung tissue homogenates. Apoptotic cells in sections of pancreatic tissues were determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) analysis. The mouse carotid arteries were cannulated and arterial blood samples were collected for PaO2 analysis. The oxygenation index was expressed as PaO2/FiO2.
RESULTS: Administration of Cn and LPS for 9 and 24 h induced severe acute pancreatitis in Chop-/- and WT mice. When comparing Chop-/- mice and WT mice, we observed that CHOP-deficient mice had greater increases in serum TNF-α (214.40 ± 19.52 pg/mL vs 150.40 ± 16.70 pg/mL; P = 0.037), amylase (4236.40 ± 646.32 U/L vs 2535.30 ± 81.83 U/L; P = 0.041), lipase (1678.20 ± 170.57 U/L vs 1046.21 ± 35.37 U/L; P = 0.008), and IL-6 (2054.44 ± 293.81 pg/mL vs 1316.10 ± 108.74 pg/mL; P = 0.046) than WT mice. The histopathological changes in the pancreases and lungs, decreased PaO2/FiO2 ratio, and increased TNF-α and IL-6 levels in the lungs were greater in Chop-/- mice than in WT mice (pancreas: Chop-/- vs WT mice, hemorrhage, P = 0.005; edema, P = 0.005; inflammatory cells infiltration, P = 0.005; total scores, P = 0.006; lung: hemorrhage, P = 0.017; edema, P = 0.017; congestion, P = 0.017; neutrophil infiltration, P = 0.005, total scores, P = 0.001; PaO2/FiO2 ratio: 393 ± 17.65 vs 453.8, P = 0.041; TNF-α: P = 0.043; IL-6, P = 0.040). Results from TUNEL analysis indicated increased acinar cell apoptosis in mice following the induction of acute pancreatitis. However, Chop-/- mice displayed significantly reduced pancreatic apoptosis compared with the WT mice (201.50 ± 31.43 vs 367.00 ± 47.88, P = 0.016).
CONCLUSION: These results suggest that CHOP can exert protective effects against acute pancreatitis and limit the spread of inflammatory damage to the lungs.
doi:10.3748/wjg.v19.i41.7097
PMCID: PMC3819545  PMID: 24222953
C/EBP homologous protein; Acute pancreatitis, Lung injury; Cytokines; Apoptosis
20.  Magnetic endoscopic imaging vs standard colonoscopy: Meta-analysis of randomized controlled trials 
AIM: To assess the theoretical advantages of magnetic endoscope imaging (MEI) over standard colonoscopies (SCs) and to compare their efficacies.
METHODS: Electronic databases, including PubMed, EMBASE, the Cochrane library and the Science Citation Index, were searched to retrieve relevant trials. In addition, abstracts from papers presented at professional meetings and the reference lists of retrieved articles were reviewed to identify additional studies. The meta-analyses were performed using RevMan 5.1. A random effect model with the Mantel-Haenszel method was used for pooling dichotomous and continuous data. A sensitivity analysis was performed by excluding the trials with a small number of patients and by excluding the trials performed by inexperienced providers.
RESULTS: Eight randomized controlled trials (RCTs), including 2967 patients, were included in the meta-analysis to compare cecal intubation rates and times, sedation dose, abdominal pain scores and the use of ancillary maneuvers between MEI and SC. The overall OR was 1.92 (95%CI: 1.13-3.27, eight RCTs), as indicated by the cecal intubation rate of MEI compared with SC, but MEI did not have any distinct advantage over SC for cecal intubation time (MD = -0.07, 95%CI: -0.16-0.02; three RCTs). MEI did not generally result in lower pain scores. Outcomes were also analyzed for the two subgroups based on the endoscopists’ experience level to evaluate cecal intubation rates. MEI presented better outcomes for non-experienced colonoscopists than experienced colonoscopists.
CONCLUSION: The real-time magnetic imaging system is of benefit in training and educating inexperienced endoscopists and improves the cecal intubation rate for experienced and inexperienced endoscopists.
doi:10.3748/wjg.v19.i41.7197
PMCID: PMC3819558  PMID: 24222966
Colonoscope; Magnetic endoscope imaging; Magnetic; Standard colonoscope; Meta-analysis
21.  Protective Role of AMP-Activated Protein Kinase-Evoked Autophagy on an In Vitro Model of Ischemia/Reperfusion-Induced Renal Tubular Cell Injury 
PLoS ONE  2013;8(11):e79814.
Ischemia/reperfusion (I/R) injury is a common cause of injury to target organs such as brain, heart, and kidneys. Renal injury from I/R, which may occur in renal transplantation, surgery, trauma, or sepsis, is known to be an important cause of acute kidney injury. The detailed molecular mechanism of renal I/R injury is still not fully clear. Here, we investigate the role of AMP-activated protein kinase (AMPK)-evoked autophagy in the renal proximal tubular cell death in an in vitro I/R injury model. To mimic in vivo renal I/R injury, LLC-PK1 cells, a renal tubular cell line derived from pig kidney, were treated with antimycin A and 2-deoxyglucose to mimic ischemia injury followed by reperfusion with growth medium. This I/R injury model markedly induced apoptosis and autophagy in LLC-PK1 cells in a time-dependent manner. Autophagy inhibitor 3-methyladenine (3MA) significantly enhanced I/R injury-induced apoptosis. I/R could also up-regulate the phosphorylation of AMPK and down-regulate the phosphorylation of mammalian target of rapamycin (mTOR). Cells transfected with small hairpin RNA (shRNA) for AMPK significantly increased the phosphorylation of mTOR as well as decreased the induction of autophagy followed by enhancing cell apoptosis during I/R. Moreover, the mTOR inhibitor RAD001 significantly enhanced autophagy and attenuated cell apoptosis during I/R. Taken together, these findings suggest that autophagy induction protects renal tubular cell injury via an AMPK-regulated mTOR pathway in an in vitro I/R injury model. AMPK-evoked autophagy may be as a potential target for therapeutic intervention in I/R renal injury.
doi:10.1371/journal.pone.0079814
PMCID: PMC3819246  PMID: 24223196
22.  Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial 
OncoTargets and therapy  2013;6:1589-1596.
Objective
To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer.
Methods
This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy.
Results
There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405).
Conclusion
Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.
doi:10.2147/OTT.S50945
PMCID: PMC3825695  PMID: 24235844
esophageal neoplasms; nimotuzumab; radiotherapy; targeted therapy; treatment outcomes
23.  Diversity of Both the Cultivable Protease-Producing Bacteria and Bacterial Extracellular Proteases in the Coastal Sediments of King George Island, Antarctica 
PLoS ONE  2013;8(11):e79668.
Protease-producing bacteria play a vital role in degrading sedimentary organic nitrogen. However, the diversity of these bacteria and their extracellular proteases in most regions remain unknown. In this paper, the diversity of the cultivable protease-producing bacteria and of bacterial extracellular proteases in the sediments of Maxwell Bay, King George Island, Antarctica was investigated. The cultivable protease-producing bacteria reached 105 cells/g in all 8 sediment samples. The cultivated protease-producing bacteria were mainly affiliated with the phyla Actinobacteria, Firmicutes, Bacteroidetes, and Proteobacteria, and the predominant genera were Bacillus (22.9%), Flavobacterium (21.0%) and Lacinutrix (16.2%). Among these strains, Pseudoalteromonas and Flavobacteria showed relatively high protease production. Inhibitor analysis showed that nearly all the extracellular proteases from the bacteria were serine proteases or metalloproteases. These results begin to address the diversity of protease-producing bacteria and bacterial extracellular proteases in the sediments of the Antarctic Sea.
doi:10.1371/journal.pone.0079668
PMCID: PMC3817139  PMID: 24223990
24.  The Dynamic Growth Exhibition and Accumulation of Cadmium of Pak Choi (Brassica campestris L. ssp. chinensis) Grown in Contaminated Soils 
The accumulation of heavy metals, especially cadmium (Cd), in leafy vegetables was compared with other vegetables. Pak choi (Brassica campestris L. ssp. chinensis) is a leafy vegetable consumed in Taiwan and its safety for consumption after growing in contaminated soils is a public concern. A pot experiment (50 days) was conducted to understand the dynamic accumulation of Cd by pak choi grown in artificially contaminated soils. The edible parts of pak choi were sampled and analyzed every 2–3 days. The dry weight (DW) of pak choi was an exponential function of leaf length, leaf width, and chlorophyll content. The accumulation of Cd increased when the soil Cd concentration was raised, but was kept at a constant level during different growth stages. Pak choi had a high bioconcentration factor (BCF = ratio of the concentration in the edible parts to that in the soils), at values of 3.5–4.0. The consumption of pak choi grown in soils contaminated at levels used in this study would result in the ingestion of impermissible amounts of Cd and could possibly have harmful effects on health.
doi:10.3390/ijerph10115284
PMCID: PMC3863846  PMID: 24284350
bioconcentration factor (BCF); cadmium (Cd); dynamic accumulation; pak choi
25.  Geometric Control of Cell Migration 
Scientific Reports  2013;3:2827.
Morphological polarization involving changes in cell shape and redistribution of cellular signaling machinery, initiate the migration of mammalian cells. Golgi complex typically localizes in front of the nucleus, and this frontwards polarization has been proposed to be involved in directional migration. However, the sequence of events remains unresolved. Does Golgi polarization precede directional migration or vice-versa? We address this question by constraining cells to specific areas and shapes then tracking their motile behavior and the spatio-temporal distribution of Golgi apparatus upon release. Results show that while the position of the Golgi complex depends on the cell geometry, the subcellular localization of the Golgi complex does not define the cell's leading edge. Cells constrained within elongated geometries exhibit polarized extension of lamellipodia and upon release, migrate preferentially along the long axis of the cell. Minimally constrained cells released from larger areas however, exhibit retarded migration regardless of lamellipodia protrusion activity.
doi:10.1038/srep02827
PMCID: PMC3789147  PMID: 24089214

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