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1.  Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia 
Disease Models & Mechanisms  2015;8(8):989-998.
Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase. Human patients with APOC2 deficiency display severe hypertriglyceridemia while consuming a normal diet, often manifesting xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease. Animal models to study hypertriglyceridemia are limited, with no Apoc2-knockout mouse reported. To develop a genetic model of hypertriglyceridemia, we generated an apoc2 mutant zebrafish characterized by the loss of Apoc2 function. apoc2 mutants show decreased plasma lipase activity and display chylomicronemia and severe hypertriglyceridemia, which closely resemble the phenotype observed in human patients with APOC2 deficiency. The hypertriglyceridemia in apoc2 mutants is rescued by injection of plasma from wild-type zebrafish or by injection of a human APOC2 mimetic peptide. Consistent with a previous report of a transient apoc2 knockdown, apoc2 mutant larvae have a minor delay in yolk consumption and angiogenesis. Furthermore, apoc2 mutants fed a normal diet accumulate lipid and lipid-laden macrophages in the vasculature, which resemble early events in the development of human atherosclerotic lesions. In addition, apoc2 mutant embryos show ectopic overgrowth of pancreas. Taken together, our data suggest that the apoc2 mutant zebrafish is a robust and versatile animal model to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases.
Highlighted Article: Apoc2 loss-of-function zebrafish display severe hypertriglyceridemia, which is characteristic of human patients with defective lipoprotein lipase activity.
PMCID: PMC4527288  PMID: 26044956
Zebrafish; Apolipoprotein C-II; APOC2; Lipoprotein lipase; Hyperlipidemia
2.  Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent 
The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase–ligand interaction space in the PDB.
PMCID: PMC4517520
EGFR; kinase; inhibitor; protein crystal complex; FBDD; erlotinib
3.  Giant anisotropic magnetoresistance in a quantum anomalous Hall insulator 
Nature Communications  2015;6:7434.
When a three-dimensional ferromagnetic topological insulator thin film is magnetized out-of-plane, conduction ideally occurs through dissipationless, one-dimensional (1D) chiral states that are characterized by a quantized, zero-field Hall conductance. The recent realization of this phenomenon, the quantum anomalous Hall effect, provides a conceptually new platform for studies of 1D transport, distinct from the traditionally studied quantum Hall effects that arise from Landau level formation. An important question arises in this context: how do these 1D edge states evolve as the magnetization is changed from out-of-plane to in-plane? We examine this question by studying the field-tilt-driven crossover from predominantly edge-state transport to diffusive transport in Crx(Bi,Sb)2−xTe3 thin films. This crossover manifests itself in a giant, electrically tunable anisotropic magnetoresistance that we explain by employing a Landauer–Büttiker formalism. Our methodology provides a powerful means of quantifying dissipative effects in temperature and chemical potential regimes far from perfect quantization.
When magnetized out-of-plane, three-dimensional ferromagnetic topological insulator thin films exhibit the quantum anomalous Hall effect. Here, the authors follow the evolution of this dissipationless chiral edge transport effect as the magnetization is brought in-plane under an applied magnetic field.
PMCID: PMC4507013  PMID: 26151318
4.  Diagnostic Value of Convex Probe Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Mediastinal Tuberculous Lymphadenitis: A Systematic Review and Meta-Analysis 
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used in the diagnosis of mediastinal lymphadenopathies. Here, we performed a systematic review and meta-analysis to explore the diagnostic value of EBUS-TBNA in mediastinal tuberculous lymphadenopathy (TBLA).
PubMed, EMBASE, and Sinoced were systematically searched for articles published in English or Chinese that reported the diagnostic yield of EBUS-TBNA in mediastinal TBLA. The quality of studies was assessed using the QualSyst tool. Using 95% confidence intervals (CI), the diagnostic yields of EBUS-TBNA were calculated for the individual studies, and the results were then pooled using a random-effects model. Heterogeneity and publication bias were also assessed.
A total of 14 studies, consisting of 684 patients with mediastinal TBLA, were finally included. The pooled diagnostic yield of EBUS-TBNA for mediastinal TBLA was 80% (95% CI: 74–86%). Significant heterogeneity (I2=77.9%) and significant publication bias were detected (Begg’s test p=0.05 and Egger’s test p=0.02). From subgroup analyses, significant differences in the diagnostic yield of EBUS-TBNA were associated with Asian vs. European (UK) studies, retrospective vs. prospective studies, those employing rapid on-site cytological evaluation vs. not, those employing different anesthetic types, and those employing smear vs. culture. However, microbiological examination and the number of lymph node passes did not have a significant effect on the diagnostic yield of EBUS-TBNA. Fifteen minor complications for EBUS-TBNA were reported.
EBUS-TBNA appears to be an efficacious and safe procedure and should be used as an initial diagnostic tool for mediastinal TBLA.
PMCID: PMC4510950  PMID: 26177653
Bronchial Provocation Tests; Meta-Analysis; Tuberculosis, Cutaneous
5.  Yeast model identifies ENTPD6 as a potential non-obstructive azoospermia pathogenic gene 
Scientific Reports  2015;5:11762.
Approximately ten percent of male infertility is caused by non-obstructive azoospermia (NOA), but the etiologies of many NOA remain elusive. Recently, a genome-wide association study (GWAS) of NOA in Han Chinese men was conducted, and only a few genetic variants associated with NOA were found, which might have resulted from genetic heterogeneity. However, those variants that lack genome-wide significance might still be essential for fertility. Functional analysis of genes surrounding these variants in Drosophila identified some spermatogenesis-essential genes. As a complementary method of Drosophila screening, SK1 background Saccharomvces cerevisiae was used as a model to screen meiosis-related genes from the NOA GWAS data in this study. After functional screening, GDA1 (orthologous to humanENTPD6) was found to be a novel meiosis-related gene. The deletion of GDA1 resulted in the failure of yeast sporulation. Further investigations showed that Gda1p was important for pre-meiotic S phase entry. Interestingly, the meiotic role of Gda1p was dependent on its guanosine diphosphatase activity, but not it’s cytoplasmic, transmembrane or stem domains. These yeast data suggest that ENTPD6 may be a novel meiosis-associated NOA-related gene, and the yeast model provides a good approach to analyze GWAS results of NOA.
PMCID: PMC4495445  PMID: 26152596
6.  Clopidogrel resistance response in patients with coronary artery disease and metabolic syndrome: the role of hyperglycemia and obesity 
Despite the proven benefits of clopidogrel combined aspirin therapy for coronary artery disease (CAD), CAD patients with metabolic syndrome (MS) still tend to have coronary thrombotic events. We aimed to investigate the influence of metabolic risk factors on the efficacy of clopidogrel treatment in patients with CAD undergoing percutaneous coronary intervention (PCI).
Cohorts of 168 MS and 168 non-MS subjects with CAD identified by coronary angiography (CAG) were enrolled in our study. MS was defined by modified Adult Treatment Panel III criteria. All subjects had taken 100 mg aspirin and 75 mg clopidogrel daily for more than 1 month, and administered loading doses of 600 mg clopidogrel and 300 mg aspirin before PCI. Blood samples were taken 24 h after the loading doses of clopidogrel and aspirin. Platelet aggregation was measured using light transmittance aggregometry (LTA) and thrombelastography (TEG). Clopidogrel resistance was defined as more than 50% adenosine diphosphate (ADP) induced platelet aggregation as measured by TEG.
Platelet aggregation inhibition rate by ADP was significantly lower in patients with MS as measured both by TEG (55% ± 31% vs. 68% ± 32%; P < 0.001) and LTA (29% ± 23% vs. 42% ± 29%; P < 0.001). In the multivariate analysis, elderly [OR (95% CI): 1.483 (1.047–6.248); P = 0.002], obesity [OR (95% CI): 3.608 (1.241–10.488); P = 0.018], high fasting plasma glucose level [OR (95% CI): 2.717 (1.176–6.277); P = 0.019] and hyperuricemia [OR (95% CI): 2.583 (1.095–6.094); P = 0.030] were all statistically risk factors for clopidogrel resistance. CAD patients with diabetes and obesity were more likely to have clopidogrel resistance than the CAD patients without diabetes and obesity [75% (61/81) vs. 43% (67/156); P < 0.001].
CAD patients with MS appeared to have poorer antiplatelet response to clopidogrel compared to those without MS. Obesity, diabetes and hyperuricemia were all significantly associated with clopidogrel resistance.
PMCID: PMC4554785  PMID: 26347447
Clopidogrel resistance; Coronary artery disease; Metabolic syndrome
7.  K-ras genetic mutation and influencing factor analysis for Han and Uygur nationality colorectal cancer patients 
To investigate the K-ras genetic mutation status in colorectal cancer patients, compare the difference of K-ras genetic mutation rate in Han and Uygur nationality and analyze the influencing factor. 91 cases (52 cases of Han nationality and 39 cases of Uygur nationality) of colorectal biopsy or surgical ablation pathology specimen from the first affiliated hospital of Xinjiang Medical University during January, 2010 to March, 2013 were collected to detect the 12th and 13th code mutation status of K-ras gene exon 2 with pyrosequencing method and compare the difference of K-ras gene mutation rate between Han and Uygur nationality patients. Single factor analysis and multiple factor logistic regression analysis were utilized to analyze the influencing factor for K-ras genetic mutation. 33 cases of patients with K-ras genetic mutation were found from the 91 cases colorectal cancer patients and the total mutation rate was 36.3%. Among them, 24 cases (72.7%) were found with mutation only in the 12th code, 9 cases (27.3%) were found with mutation only in the 13th code and no one case was found with mutation in both the two codes. Mutation rate of the 12th code in the Uygur nationality was significantly higher than that in the Han nationality (P<0.05), but there were no significant difference in the comparison of the total mutation rate and the 13th code mutation rate between the two groups (P>0.05). There were no associativity (P>0.05) between the K-ras genetic mutation and sex, age, smoking history, drinking history, tumor location, macropathology type, differentiation level, staging, invasive depth, lymph nodes transferring and metastasis in colorectal cancer patients (P>0.05). K-ras genetic mutation rate is high in colorectal cancer patients. The mutation rate of 12th code in Uygur nationality is higher than that in Han nationality. There is no significant associativity between K-ras genetic mutation rate and patients’ clinical pathology characteristic.
PMCID: PMC4538044  PMID: 26309716
Colorectal cancer; Han nationality; Uygur nationality; gene; mutation
8.  Long-term tolerance to factor VIII is achieved by administration of IL-2/IL-2mAb complexes and low dosages of factor VIII 
Regulatory T cells (Tregs) play a pivotal role in regulating anti-factor VIII (FVIII) immune responses. Interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb; JES6-1) can induce selective expansion of Tregs in vivo.
In the prevention experiments, we treated hemophilia A mice with IL-2/IL-2mAb complexes (3x/week), and concurrently with FVIII protein (80U/kg/week) for 4 weeks. Generation of anti-FVIII immune responses was examined afterwards. Next, in order to induce long-term tolerance to FVIII, a series of treatment dosages and schedules for administering IL-2/IL-2mAb complexes and FVIII protein in hemophilia A mice was evaluated.
Compared to control FVIII only treated mice which produced high-titer anti-FVIII antibodies, mice treated with IL-2/IL-2mAb complexes + FVIII produced no antibodies. A marked 7 fold increase in CD4+CD25+Foxp3+Helios+ natural Tregs was maintained for 4 weeks in blood, spleen and lymph nodes, and dropped to normal levels within the next 10 days. The suppressive functions of expanded Tregs were demonstrated by suppressive, proliferative and cytokine assays. Administration of anti-CD25 mAb (PC-61) blocked this protective effect, confirming the involvement of Tregs in suppressing anti-FVIII immune responses. Importantly, administration of IL-2/IL-2mAb complexes (3x/week for 8 weeks) combined with contiguous weekly injections of low dosage FVIII protein (20U/kg/week for 18 weeks) not only abrogated the formation of anti-FVIII antibodies, but also induced long-term tolerance to FVIII.
Treatment of IL-2/IL-2mAb complexes is highly promising for induction and maintenance of FVIII-specific tolerance following FVIII protein replacement therapy.
PMCID: PMC4055525  PMID: 24684505
IL-2; anti-IL2 antibody; factor VIII; hemophilia; immune tolerance; immunomodulation; regulatory T cell; protein replacement therapy
9.  rhEPO affects apoptosis in hippocampus of aging rats by upregulating SIRT1 
The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of erythropoietin (EPO) and to clarify whether recombinant human EPO (rhEPO) affects apoptosis in the aging rat hippocampus by upregulating Sirtuin 1 (SIRT1). In this study, a rat model of aging was established using D-galactose. Behavioral changes were monitored by the Morris water maze test. Using immunohistochemistry, we studied the expression of SIRT1, B-cell lymphoma/leukemia-2 gene (Bcl-2), and Bcl-2 associated X protein (Bax) expression, and apoptotic cells in the hippocampus of a rat model of aging in which rhEPO was intraperitoneally injected. The escape latency in rats from the EPO group shortened significantly; however, the number of platform passes increased significantly from that in the D-gal group (P < 0.05). Compared to the D-gal group, in the EPO group, the number of SIRT1 and Bcl-2-positive cells increased (P < 0.05), but the number of Bax-positive cells and apoptotic cells decreased in the hippocampus of aging rats (P < 0.05). These results suggest that rhEPO regulates apoptosis-related genes and affects apoptosis in the hippocampus of aging rats by upregulating SIRT. This may be one of the important pathways underlying the anti-aging property of EPO.
PMCID: PMC4525908  PMID: 26261574
Erythropoietin; aging; Sirtuin 1; B-cell lymphoma/leukemia-2 gene; Bcl-2 association X protein
10.  Cellular and Molecular Mechanisms Underlying Oxygen-Dependent Radiosensitivity 
Radiation research  2015;183(5):487-496.
Molecular oxygen has long been recognized as a powerful radiosensitizer that enhances the cell-killing efficiency of ionizing radiation. Radiosensitization by oxygen occurs at very low concentrations with the half-maximum radiosensitization at approximately 3 mmHg. However, robust hypoxia-induced signal transduction can be induced at <15 mmHg and can elicit a wide range of cellular responses that will affect therapy response as well as malignant progression. Great strides have been made, especially since the 1990s, toward identification and characterization of the oxygen-regulated molecular pathways that affect tumor response to ionizing radiation. In this review, we will discuss the current advances in our understanding of oxygen-dependent molecular modification and cellular signal transduction and their impact on tumor response to therapy. We will specifically address mechanistic distinctions between radiobiological hypoxia (0–3 mmHg) and pathological hypoxia (3–15 mmHg). We also propose a paradigm that hypoxia increases radioresistance by maintaining the cancer stem cell phenotype.
PMCID: PMC4441855  PMID: 25938770
11.  Clinicopathological analysis of 12 patients with autoimmune pancreatitis 
Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis that is often misdiagnosed as pancreatic cancer (PaC). This study was undertaken to investigate the clinicopathological characteristics of AIP, in order to improve the diagnosis and treatment of the disease. Among the 271 patients with PaC who underwent pancreatoduodenectomy between January 2003 and December 2012 at the Sun Yat-Sen Memorial Hospital, chronic pancreatitis was identified and tissue samples obtained from 16 patients. The clinicopathological and imaging characteristics of 16 of the patients with chronic pancreatitis were analyzed retrospectively. The expression of immunoglobulin G4 (IgG4) in the pancreas tissue was detected by immunohistochemistry. Immunohistochemistry showed that IgG4 was highly expressed in 12 out of the 16 patients, and those 12 patients were diagnosed with AIP. Among those 12 patients, 6 presented with emaciation and 7 with jaundice and abdominal pain, respectively. Among the 16 included patients, 12 had an elevated level of serum γ-glutamyltransferase and 9 had an elevated level of serum carbohydrate antigen 19-9. The imaging features were as follows: Pancreatic enlargement in 11 patients (particularly pancreatic head enlargement), pancreatic miniature in 1, ‘sausage-like’ pancreatic changes in 4 and ‘halo’ sign pancreatic changes in 5. Massive plasma cell infiltration (11/12) and parenchymal fibrosis (8/12) were observed in the pancreatic tissues through pathology. These results suggest that combining imaging with IgG4 expression for the purpose of diagnosis can enhance the preoperative diagnostic value and reduce the rate of AIP misdiagnosis.
PMCID: PMC4487082  PMID: 26170922
autoimmune pancreatitis; immunoglobulin G4; diagnosis; differentiation
12.  A cultural look at moral purity: wiping the face clean 
Morality is associated with bodily purity in the custom of many societies. Does that imply moral purity is a universal psychological phenomenon? Empirically, it has never been examined, as all prior experimental data came from Western samples. Theoretically, we suggest the answer is not so straightforward—it depends on the kind of universality under consideration. Combining perspectives from cultural psychology and embodiment, we predict a culture-specific form of moral purification. Specifically, given East Asians' emphasis on the face as a representation of public self-image, we hypothesize that facial purification should have particularly potent moral effects in a face culture. Data show that face-cleaning (but not hands-cleaning) reduces guilt and regret most effectively against a salient East Asian cultural background. It frees East Asians from guilt-driven prosocial behavior. In the wake of their immorality, they find a face-cleaning product especially appealing and spontaneously choose to wipe their face clean. These patterns highlight both culturally variable and universal aspects of moral purification. They further suggest an organizing principle that informs the vigorous debate between embodied and amodal perspectives.
PMCID: PMC4428058  PMID: 26029134
morality; purity; embodiment; metaphor; face; culture
13.  Fabrication and Robotization of Ultrasensitive Plasmonic Nanosensors for Molecule Detection with Raman Scattering 
Sensors (Basel, Switzerland)  2015;15(5):10422-10451.
In this work, we introduce the history and mechanisms of surface enhanced Raman scattering (SERS), discuss various techniques for fabrication of state-of-the-art SERS substrates, and review recent work on robotizing plasmonic nanoparticles, especially, the efforts we made on fabrication, characterization, and robotization of Raman nanosensors by design. Our nanosensors, consisting of tri-layer nanocapsule structures, are ultrasensitive, well reproducible, and can be robotized by either electric or magnetic tweezers. Three applications using such SERS nanosensors were demonstrated, including location predictable detection, single-cell bioanalysis, and tunable molecule release and monitoring. The integration of SERS and nanoelectromechanical system (NEMS) devices is innovative in both device concept and fabrication, and could potentially inspire a new device scheme for various bio-relevant applications.
PMCID: PMC4481927  PMID: 25946633
SERS; sensors; NEMS; nanomotors; drug delivery; manipulation
14.  Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice 
Objective. The effects of Flos Puerariae extract (FPE) on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ) for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA) and total cholesterol (TCH) in serum, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.
PMCID: PMC4427852  PMID: 26060502
15.  Mutation breeding of high 4-androstene-3,17-dione-producing Mycobacterium neoaurum ZADF-4 by atmospheric and room temperature plasma treatment*  
Steroid medication is used extensively in clinical applications and comprises a large and vital part of the pharmaceutical industry. However, the difficulty of separating 4-androstene-3,17-dione (AD) from 1,4-androstadiene-3,17-dione (ADD) restricts the application of the microbial transformation of phytosterols in the industry. A novel atmospheric and room temperature plasma (ARTP) treatment, which employs helium as the working gas, was used to generate Mycobacterium neoaurum mutants producing large amounts of AD. After treatment of cultures with ARTP, four mutants were selected using a novel screening method with a color assay. Among the mutants, M. neoaurum ZADF-4 was considered the best candidate for industrial application. When the fermentation medium contained 15 g/L phytosterols and was cultivated on a rotary shaker at 160 r/min at 30 °C for 7 d, (6.28±0.11) g/L of AD and (0.82±0.05) g/L of ADD were produced by the ZADF-4 mutant, compared with (4.83±0.13) g/L of AD and (2.34±0.06) g/L of ADD by the original strain, M. neoaurum ZAD. Compared with ZAD, the molar yield of AD increased from 48.3% to 60.3% in the ZADF-4 mutant. This result indicates that ZADF-4 may have potential for industrial production of AD.
PMCID: PMC4399429  PMID: 25845362
Mycobacterium neoaurum; Atmospheric and room temperature plasma (ARTP); Mutation breeding; 4-Androstene-3,17-dione (AD); 1,4-Androstadiene-3,17-dione (ADD)
16.  Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population 
To investigate the association between gastric cardia adenocarcinoma (GCA) and ten functional single nucleotide polymorphisms (SNPs), including TP53BP1 rs560191 G>C, CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A, and six C1orf10/CRNN variants. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs.
Two hundred and forty-three GCA cases and 476 controls were enrolled in this study. A custom-by-design 48-Plex SNPscanTM Kit was used to determine their genotypes.
When the TP53BP1 rs560191 GG homozygote genotype was used as the reference group, the GC genotype was associated with a significantly increased risk of GCA. The CC genotype was not associated with the risk of GCA compared with the GG genotype. None of the CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls.
The results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility. However, the statistical power of our study was limited. Large, well-designed studies and further functional investigations are needed to confirm our findings.
PMCID: PMC4409978  PMID: 25937777
TP53BP1; polymorphisms; gastric cardia adenocarcinoma (GCA); molecular epidemiology
17.  Subxiphoid single-incision thoracoscopic surgery for bilateral primary spontaneous pneumothorax 
It has been reported that single-incision thoracoscopic surgery can reduce postoperative pain without compromising the main surgical steps required for treating patients affected by primary spontaneous pneumothorax. However, all the reported thoracoscopic surgery cases with a single-incision procedure were via the intercostal route for unilateral pulmonary lesions. We present a novel single-incision thoracoscopic technique via a subxiphoid route to perform one-stage bilateral thoracoscopic surgery for bilateral spontaneous pneumothorax. Reduced postoperative pain, shorter operative time, and better cosmetic results are potential benefits of this technique in selected patients. The subxiphoid single-incision procedure may be indicated in patients with bilateral pulmonary lesions requiring surgical resections.
PMCID: PMC4414099  PMID: 25960803
pneumothorax; subxiphoid; single-incision
18.  Neuroprotective effects of SMADs in a rat model of cerebral ischemia/reperfusion 
Neural Regeneration Research  2015;10(3):438-444.
Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.
PMCID: PMC4396107  PMID: 25878593
nerve regeneration; brain injury; neuroprotection; inflammation; apoptosis; cerebral ischemia; SMAD3; transforming growth factor β1; NSFC grant; neural regeneration
19.  Local renin-angiotensin system regulates hypoxia-induced vascular endothelial growth factor synthesis in mesenchymal stem cells 
The use of mesenchymal stem cell (MSC) transplantation for ischemic heart disease has been reported for several years. The main mechanisms responsible for the efficacy of this technique include the differentiation of MSCs into cardiomyocytes and endothelial cells, as well as paracrine effects. However, the differentiation rates of MSCs are very low, and the differentiated cells are not mature. In addition, MSCs undergo massive cell death within a few days after transplantation to the ischemic myocardium. Paracrine effects may thus play a major role in MSCs transplantation. Angiotensin II (Ang II) is known to be produced locally in the ischemic myocardium, but the effects of hypoxia on the local renin-angiotensin system (RAS) in MSCs, and the role of the RAS in hypoxia-induced vascular endothelial growth factor (VEGF) secretion remain unknown. In this study, we demonstrated that hypoxia stimulated the local RAS in MSCs, while pretreatment with the Ang II type 1 (AT1) receptor antagonist losartan reduced hypoxia-induced hypoxia-inducible factor 1α (HIF-1α) and VEGF production. The ERK1/2 inhibitor U0126 and the Akt inhibitor LY294002 also inhibited hypoxia-induced HIF-1α and VEGF production. Overall, these results indicate that the local RAS in MSCs regulates hypoxia-induced VEGF production through ERK1/2, Akt and HIF-1α pathways via the AT1 receptor.
PMCID: PMC4440065  PMID: 26045756
Mesenchymal stem cell; hypoxia; renin-angiotensin system; vascular endothelial growth factor
20.  Upregulation of arginase activity contributes to intracellular ROS production induced by high glucose in H9c2 cells 
Arginase is upregulated in some tissues under diabetes states. Arginase can compete with nitroxide synthase (NOS) for the common substrate L-arginine and thus increases oxidative stress by NOS uncoupling. We want to analyze whether arginase is upregulated and contribute to oxidative stress in H9c2 cells during high glucose treatment. H9c2 cells were cultured in normal or high glucose DMEM. Arginase activity increased in parallel with increased cell death and oxidative stress. Arginase inhibitor N ω-hydroxy-nor-l-arginine (nor-NOHA) and NOS inhibitor N ω-nitro-l-arginine methyl ester (L-NAME) could reverse these effects. Despite of upregulated NOS activity, NO production was impaired which could be preserved by nor-NOHA, suggesting a decreased substrate availability of NOS due to increased arginase activity. L-arginine supplementation decreased superoxide production while it could not protect cells from death. Upregulated arginase activity in H9c2 treated with high glucose can cause NOS uncoupling and subsequently reactive oxygen species augmentation and cell death. These findings suggest that arginase will be a novel therapeutic target for treatment of diabetic cardiomyopathy.
PMCID: PMC4440087  PMID: 26045778
Arginase; cardiomyocyte; diabetes; oxidative stress; NOS uncoupling
21.  MiR-21/RASA1 axis affects malignancy of colon cancer cells via RAS pathways 
AIM: To determine how the oncogene miR-21 regulates the RAS signaling pathways and affects colon cancer cell behaviors.
METHODS: RAS p21 GTPase activating protein 1 (RASA1) protein expression in six colon cancer cell lines was assessed by Western blot. Colon cancer RKO cells were chosen for transfection because they are KRAS wild type colon cancer cells whose RASA1 expression is significantly decreased. RKO cells were transfected with vectors overexpressing or down-regulating either miR-21 or RASA1. Furthermore, a luciferase reporter assay was used to determine whether RASA1 is a gene target of miR-21. Then, changes in mRNA and protein levels of RASA1, RAS-GTP, and other components of the RAS signaling pathways were assessed in transfected RKO cells by real-time quantitative reverse transcription-polymerase chain reaction, Western blot and immunoprecipitation. Finally, cell proliferation, apoptosis, invasion, and tumor formation ability were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay, flow cytometry, transwell assay, and animal experiment, respectively.
RESULTS: RASA1 protein levels were significantly decreased in RKO cells compared with the other 5 colon cancer cell lines, and RASA1 was confirmed as a target gene of miR-21. Interestingly, RASA1 mRNA and protein levels in pre-miR-21-LV (up-regulation of miR-21) cells were lower than those in anti-miR-21-LV (down-regulation of miR-21) cells (P < 0.05). In addition, pre-miR-21-LV or siRASA1 (down-regulation of RASA1) cells showed higher cell proliferation, reduced apoptosis, increased expression of RAS-GTP, p-AKT, Raf-1, KRAS, and p-ERK1/2, and higher invasion and tumor formation ability, compared with control, anti-miR-21-LV or pcDNA3.1-RASA1 (up-regulation of RASA1) cells (P < 0.05).
CONCLUSION: RASA1 is a target gene of miR-21, which promotes malignant behaviors of RKO cells through regulation of RASA1 expression.
PMCID: PMC4316091  PMID: 25663768
Colon cancer; miR-21; RAS; RASA1; RAS signaling pathways
22.  Hospital type- and volume-outcome relationships in esophageal cancer patients receiving non-surgical treatments 
AIM: To study the “hospital type-outcome” and “volume-outcome” relationships in patients with esophageal cancer who receive non-surgical treatments.
METHODS: A total of 6106 patients with esophageal cancer diagnosed between 2008 and 2011 were identified from a national population-based cancer registry in Taiwan. The hospital types were defined as medical center and non-medical center. The threshold for high-volume hospitals was based on a median volume of 225 cases between 2008 and 2011 (annual volume, > 56 cases) or an upper quartile (> 75%) volume of 377 cases (annual volume > 94 cases). Cox regression analyses were used to determine the effects of hospital type and volume outcome on patient survival.
RESULTS: A total of 3955 non-surgically treated patients were included in the survival analysis. In the unadjusted analysis, the significant prognostic factors included cT, cN, cM stage, hospital type and hospital volume (annual volume, > 94 vs ≤ 94). The 1- and 3-year overall survival rates in the non-medical centers (36.2% and 13.2%, respectively) were significantly higher than those in the medical centers (33.5% and 11.3%, respectively; P = 0.027). The 1- and 3-year overall survival rates in hospitals with an annual volume of ≤ 94 (35.3% and 12.6%, respectively) were significantly higher than those with an annual volume of > 94 (31.1% and 9.4%, respectively; P = 0.001). However, in the multivariate analysis, the hospital type was not statistically significant. Only cT, cN, and cM stages and hospital volume (annual volume > 94 vs ≤ 94) were independent prognostic factors.
CONCLUSION: Whether the treatment occurs in medical centers is not a significant prognostic factor. High-volume hospitals were not associated with better survival rates compared with low-volume hospitals.
PMCID: PMC4306168  PMID: 25632197
Cancer registry; Esophageal cancer; Hospital volume; Hospital type; Survival
23.  Increased expression of miR-93 is associated with poor prognosis in head and neck squamous cell carcinoma 
Tumour Biology  2015;36(5):3949-3956.
MicroRNA-93-5p (miR-93) is a novel oncogenic microRNA (miRNA) and is elevated in diverse human malignancies. Aberrant expression and dysfunction of miR-93 are involved in many types of human tumours. However, the exact role of miR-93 remains unclear in head and neck squamous cell carcinoma (HNSCC). The objective of this study is to determine the expression pattern and clinical significance of miR-93 in HNSCC. MiR-93 expression levels in 103 primary HNSCC tissues and 16 corresponding non-cancerous epithelia were analysed by miRNA in situ hybridisation and correlated with the clinicopathological parameters and patient outcomes. Moreover, the expression of miR-93 was examined in four HNSCC cell lines and 17 pairs of HNSCC tissues and their corresponding adjacent tissues using quantitative real-time PCR (qRT-PCR). The miR-93 levels in HNSCC tissues and cell lines were significantly higher than those in the non-cancerous tissues. Notably, high miR-93 expression was significantly associated with T classification, lymph node metastasis and clinical stage. Kaplan–Meier survival analysis demonstrated that patients with high miR-93 expression had poorer overall survival than patients with low miR-93 expression. Multivariate Cox regression analysis revealed that miR-93 overexpression and lymph node metastasis were independent prognostic factors in patients with HNSCC. This study demonstrated that miR-93 expression was significantly increased in HNSCC tissue samples and cell lines and that miR-93 overexpression was associated with tumour progression, metastasis and poor prognosis in HNSCC patients. These results suggest that miR-93 may play a critical role in the initiation and progression of HNSCC, indicating that miR-93 may be a valuable marker for the prediction of metastasis and prognosis in HNSCC.
PMCID: PMC4445482  PMID: 25578493
Head and neck squamous cell carcinoma; MicroRNA-93-5p; In situ hybridisation; Metastasis; Prognosis
24.  The Expression Levels of Transcription Factors T-bet, GATA-3, RORγt and FOXP3 in Peripheral Blood Lymphocyte (PBL) of Patients with Liver Cancer and their Significance 
Objectives: To investigate the expression of transcriptional factors (TFs) T-bet, GATA-3, RORγt and FOXP in peripheral blood mononuclear cells (PBMC) of patients with hepatocellular carcinoma (HCC) and to evaluate the correlation between the imbalances of Th1/Th2, Th17/Treg at the expression levels and liver cancer
Methods: The peripheral venous blood was drawn from 20 HCC-patients (HCC-group) and 20 health participants (C-group). The expression levels of Th1, Th2 and Th17 and the major Treg-specific TFs T-bet, GATA-3, RORγt and FOXP3 in the PBMC were measured with quantitative real-time PCR(RT-qPCR).
Results: The mRNA level of Th1-specific TF T-bet in HCC-group was significantly lower than that of C-group (52.34±34.07 VS 104.01±56.00, P<0.01); the mRNA level of Th2-specifc TF, GATA-3, in HCC group was significantly higher than that in C-group (1.38±1.15 VS 0.58±0.65, P<0.05) and T-bet mRNA/GATA-3 mRNA ratio was significantly lower in HCC-group than in C-group (86.01±116.71 VS 461.88±708.81, P<0.05). The mRNA level of Th17-specific TF RORγt in HCC-group was significantly higher than that of C-group (72.32±32.82 VS 33.07±22.86, P<0.01). Treg-specific TF FOXP3 mRNA level was significant higher in HCC-group than in C-group (3.17±1.59 VS 1.39±1.13, P<0.01)
Conclusion: T-bet mRNA level was reduced whereas GATA-3 mRNA level was increased and T-bet/GATA-3 ratio was significantly reduced in PBMC, indicating that Th1/Th2 ratio was of imbalance at TF levels in PBMC of HCC, displaying Th2 thrift phenomena. The mRNA levels of RORγt and FOXP3 in PBMC of HCC were significantly increased, indicating the existence of a predominant phenomenon of Th17- and Treg-expressing PBMC in HCC.
PMCID: PMC4278870  PMID: 25552913
RORγt; Th1; Th2; Th17; Treg; Hepatocellular carcinoma (HCC).
25.  Association between ADIPOQ +45T>G Polymorphism and Type 2 Diabetes: A Systematic Review and Meta-Analysis 
Recently, a number of studies have reported the association between the single nucleotide polymorphisms (SNPs) +45T>G polymorphism in the adiponectin (ADIPOQ) gene and type 2 diabetes mellitus (T2DM) risk, though the results are inconsistent. In order to obtain a more precise estimation of the relationship, a meta-analysis was performed. In this current study, the Medline, Embase, Pubmed, ISI Web of Knowledge, Ovid, Science Citation Index Expanded Database, Wanfang Database, and China National Knowledge Infrastructure were searched for eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Forty-five publications were included in the final meta-analysis with 9986 T2DM patients and 16,222 controls for ADIPOQ +45T>G polymorphism according to our inclusion and exclusion criteria. The +45T>G polymorphism was associated with an overall significantly increased risk of T2DM (G vs. T: OR = 1.18, 95% CI = 1.06–1.32; The dominant model: OR = 1.18, 95% CI = 1.03–1.33; The recessive model: OR = 1.47, 95% CI = 1.20–1.78; The homozygous model: OR = 1.62, 95% CI = 1.25–2.09; Except the heterozygous model: OR = 1.11, 95% CI = 0.98–1.24). Subgroup analysis revealed a significant association between the +45T>G polymorphism and T2D in an Asian population. Thus, this meta-analysis indicates that the G allele of the ADIPOQ +45T>G polymorphisms associated with a significantly increased risk of T2DM in the Asian population.
PMCID: PMC4307270  PMID: 25561226
ADIPOQ; single nucleotide polymorphisms (SNPs); type 2 diabetes mellitus; meta-analysis

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