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1.  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.
doi:10.2147/DDDT.S85357
PMCID: PMC4517520
EGFR; kinase; inhibitor; protein crystal complex; FBDD; erlotinib
2.  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.
doi:10.1038/ncomms8434
PMCID: PMC4507013  PMID: 26151318
3.  Diagnostic Value of Convex Probe Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Mediastinal Tuberculous Lymphadenitis: A Systematic Review and Meta-Analysis 
Background
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).
Material/Methods
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.
Results
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.
Conclusions
EBUS-TBNA appears to be an efficacious and safe procedure and should be used as an initial diagnostic tool for mediastinal TBLA.
doi:10.12659/MSM.894526
PMCID: PMC4510950  PMID: 26177653
Bronchial Provocation Tests; Meta-Analysis; Tuberculosis, Cutaneous
4.  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.
doi:10.1038/srep11762
PMCID: PMC4495445  PMID: 26152596
5.  Long-term tolerance to factor VIII is achieved by administration of IL-2/IL-2mAb complexes and low dosages of factor VIII 
Summary
Background
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.
Methods
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.
Results
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.
Conclusions
Treatment of IL-2/IL-2mAb complexes is highly promising for induction and maintenance of FVIII-specific tolerance following FVIII protein replacement therapy.
doi:10.1111/jth.12576
PMCID: PMC4055525  PMID: 24684505
IL-2; anti-IL2 antibody; factor VIII; hemophilia; immune tolerance; immunomodulation; regulatory T cell; protein replacement therapy
6.  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.
doi:10.1667/RR13959.1
PMCID: PMC4441855  PMID: 25938770
7.  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.
doi:10.3892/etm.2015.2492
PMCID: PMC4487082  PMID: 26170922
autoimmune pancreatitis; immunoglobulin G4; diagnosis; differentiation
8.  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.
doi:10.3389/fpsyg.2015.00577
PMCID: PMC4428058  PMID: 26029134
morality; purity; embodiment; metaphor; face; culture
9.  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.
doi:10.3390/s150510422
PMCID: PMC4481927  PMID: 25946633
SERS; sensors; NEMS; nanomotors; drug delivery; manipulation
10.  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.
doi:10.1155/2015/873243
PMCID: PMC4427852  PMID: 26060502
11.  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.
doi:10.1631/jzus.B1400274
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)
12.  Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3978/j.issn.1000-9604.2015.03.05
PMCID: PMC4409978  PMID: 25937777
TP53BP1; polymorphisms; gastric cardia adenocarcinoma (GCA); molecular epidemiology
13.  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.
doi:10.5114/wiitm.2015.48572
PMCID: PMC4414099  PMID: 25960803
pneumothorax; subxiphoid; single-incision
14.  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.
doi:10.4103/1673-5374.153693
PMCID: PMC4396107  PMID: 25878593
nerve regeneration; brain injury; neuroprotection; inflammation; apoptosis; cerebral ischemia; SMAD3; transforming growth factor β1; NSFC grant; neural regeneration
15.  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
16.  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
17.  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.
doi:10.3748/wjg.v21.i5.1488
PMCID: PMC4316091  PMID: 25663768
Colon cancer; miR-21; RAS; RASA1; RAS signaling pathways
18.  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.
doi:10.3748/wjg.v21.i4.1234
PMCID: PMC4306168  PMID: 25632197
Cancer registry; Esophageal cancer; Hospital volume; Hospital type; Survival
19.  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.
doi:10.1007/s13277-015-3038-6
PMCID: PMC4445482  PMID: 25578493
Head and neck squamous cell carcinoma; MicroRNA-93-5p; In situ hybridisation; Metastasis; Prognosis
20.  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.
doi:10.7150/ijms.8352
PMCID: PMC4278870  PMID: 25552913
RORγt; Th1; Th2; Th17; Treg; Hepatocellular carcinoma (HCC).
21.  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.
doi:10.3390/ijms16010704
PMCID: PMC4307270  PMID: 25561226
ADIPOQ; single nucleotide polymorphisms (SNPs); type 2 diabetes mellitus; meta-analysis
22.  Ontogenesis of NADPH-diaphorase positive neurons in guinea pig neocortex 
In mammalian cerebrum there exist two distinct types of interneurons expressing nitric oxide synthase (NOS). Type I neurons are large in size and exhibit heavy nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemical reaction, while type II cells are small with light NADPH-d reactivity. The time of origin of these cortical neurons relative to corticogenesis remains largely unclear among mammals. Here we explored this issue in guinea pigs using cell birth-dating and double-labeling methods. Bromodeoxyuridine (BrdU) pulse-chasing (2 doses at 50 mg/kg, 12 h apart) was given to time-pregnant mothers, followed by quantification of NADPH-d/BrdU colocalization in the parietal and temporal neocortex in offspring at postnatal day 0 (P0), P30 and P60. Type I neurons were partially colabeled with BrdU at P0, P30 and P60 following pulse-chasing at embryonic day 21 (E21), E28 and E35, varied from 2–11.3% of total population of these neurons for the three time groups. Type II neurons were partially colabeled for BrdU following pulse-chasing at E21, E28, E35 and E42 at P0 (8.6%–16.5% of total population for individual time groups). At P60, type II neurons were found to co-express BrdU (4.8–11.3% of total population for individual time groups) following pulse-chasing at E21, E28, E35, E42, E49, E56 and E60/61. These results indicate that in guinea pigs type I neurons are generated during early corticogenesis, whereas type II cells are produced over a wide prenatal time window persisting until birth. The data also suggest that type II nitrinergic neurons may undergo a period of development/differentiation, for over 1 month, before being NADPH-d reactive.
doi:10.3389/fnana.2015.00011
PMCID: PMC4329812  PMID: 25762900
corticogenesis; GABAergic; interneuron; neuronal development; nitric oxide
23.  Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans 
Scientific Reports  2014;4:7465.
EPAS1 involves in the hypoxic response and is suggested to be responsible for the genetic adaptation of high-altitude hypoxia in Tibetans. However, the detailed molecular mechanism remains unknown. In this study, a single nucleotide polymorphism rs56721780:G>C and an insertion/deletion (indel) polymorphism −742 indel in the promoter region showed divergence between Tibetans and non-Tibetan lowlanders. rs56721780:G>C regulated the transcription of EPAS1 by IKAROS family zinc finger 1 (IKZF1), which was identified as a new transcriptional repressor for EPAS1 gene. It demonstrated that the C allele of rs56721780:G>C decreased the binding of IKZF1, leading to the attenuated transcriptional repression of EPAS1 gene. The insertion at −742 indel provided a new binding site for Sp1 and was related to the activation of EPAS1 promoter. Further functional analysis revealed that lysyl oxidase (LOX) gene, which was reported to be responsible for extracellular matrix protein cross-linking of amnion previously, was a direct target of EPAS1. The CC genotype at rs56721780:G>C and the insertion genotype at −742 indel were found associated with higher EPAS1 and LOX expression levels in amnion, as well as higher birth weight of Tibetan newborns, suggesting that EPAS1 gene might play important roles in the development of amnion, fetus growth and high-altitude adaptation of Tibetans.
doi:10.1038/srep07465
PMCID: PMC4264014  PMID: 25501874
24.  Selenium Supplementation for Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis 
Many studies have reported that selenium (Se) has a close relationship with autoimmune thyroiditis (AIT). The therapeutic effect of Se supplementation in AIT treatment remains unclear. The objective of the present study was to determine the efficacy of Se supplementation for the treatment of AIT. A structured literature search was undertaken to identify all randomized controlled trials conducted in patients with AIT receiving Se supplementation or placebo. Nine studies enrolling a total of 787 patients were included. The results showed that Se supplementation with duration 6 months significantly dropped the TPOAb titers but did not decrease the TgAb titers. Patients assigned to Se supplementation for 12-month duration showed significantly lower TPOAb titers and TgAb titers. Patients after Se supplementation had a higher chance to improve the mood or well-being compared with controls. Se supplementation is associated with a significant decrease in TPOAb titers at 6 and 12 months; meanwhile, the TgAb titers can be dropped at 12 months. After Se supplementation treatment, patients had a higher chance to improve the mood without significant adverse events.
doi:10.1155/2014/904573
PMCID: PMC4276677  PMID: 25574167
25.  Inactivation of Fam20C in Cells Expressing Type I Collagen Causes Periodontal Disease in Mice 
PLoS ONE  2014;9(12):e114396.
Background
FAM20C is a kinase that phosphorylates secretory proteins. Previous studies have shown that FAM20C plays an essential role in the formation and mineralization of bone, dentin and enamel. The present study analyzed the loss-of-function effects of FAM20C on the health of mouse periodontal tissues.
Methods
By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20Cfl/fl mice, we created 2.3 kb Col 1a1-Cre;Fam20Cfl/fl (cKO) mice, in which Fam20C was inactivated in the cells that express Type I collagen. We analyzed the periodontal tissues in the cKO mice using X-ray radiography, histology, scanning electron microscopy and immunohistochemistry approaches.
Results
The cKO mice underwent a remarkable loss of alveolar bone and cementum, along with inflammation of the periodontal ligament and formation of periodontal pockets. The osteocytes and lacuno-canalicular networks in the alveolar bone of the cKO mice showed dramatic abnormalities. The levels of bone sialoprotein, osteopontin, dentin matrix protein 1 and dentin sialoprotein were reduced in the Fam20C-deficient alveolar bone and/or cementum, while periostin and fibrillin-1 were decreased in the periodontal ligament of the cKO mice.
Conclusion
Loss of Fam20C function leads to periodontal disease in mice. The reduced levels of bone sialoprotein, osteopontin, dentin matrix protein 1, dentin sialoprotein, periostin and fibrillin-1 may contribute to the periodontal defects in the Fam20C-deficient mice.
doi:10.1371/journal.pone.0114396
PMCID: PMC4257665  PMID: 25479552

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