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1.  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
2.  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
3.  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).
4.  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
5.  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.
PMCID: PMC4264014  PMID: 25501874
6.  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.
PMCID: PMC4276677  PMID: 25574167
7.  Inactivation of Fam20C in Cells Expressing Type I Collagen Causes Periodontal Disease in Mice 
PLoS ONE  2014;9(12):e114396.
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.
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.
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.
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.
PMCID: PMC4257665  PMID: 25479552
8.  Role of liver stem cells in hepatocarcinogenesis 
World Journal of Stem Cells  2014;6(5):579-590.
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the “cancer stem cell hypothesis”, which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.
PMCID: PMC4178257  PMID: 25426254
Liver cancer; Liver stem cells; Hepatocarcinogenesis; Tumorigenic transformation; Transdifferentiation
9.  Posterior pedicle screw fixation for complex atlantoaxial fractures with atlanto-dental interval of ≥5 mm or C2-C3 angulation of ≥11° 
Previous studies have demonstrated that the posterior pedicle screw fixation is an effective and safe method to treat atlantoaxial fractures. However, no report focuses on only the complex atlantoaxial fractures with atlanto-dental interval (ADI) of ≥5 mm or C2-C3 angulation of ≥11°.
This study was to retrospectively evaluate the outcome of 15 patients (six females and nine males; age, 27–55 years) who underwent posterior pedicle screw fixation for the above complex atlantoaxial fractures between July 2006 and March 2011. Fracture combinations included three Jefferson-type II odontoid, four anterior ring-type II odontoid, two posterior ring-type II odontoid, one lateral mass-type II odontoid, one Jefferson-hangman’s fracture, three anterior ring-hangman’s fracture, and one lateral mass-hangman’s fracture. Fracture healing and bone fusion were determined on X-ray scan. Upper limbs, lower limbs, and sphincter functions were assessed using the Japanese Orthopaedic Association (JOA) score. The Frankel grading system was used to determine the neurological situation.
The mean operative time, blood loss, and hospital stays were 108.9 ± 25.8 min, 508.0 ± 209.6 ml, and 13.3 ± 2.0 days. Fracture healing and graft fusion were obtained in all patients within 9 months. The ADI or C2-C3 angulation was reduced to ≤5 mm or ≤11°. The JOA score was significantly improved from 7.27 ± 1.10 preoperatively to 15.7 ± 2.1 postoperatively (P <0.001), with 88.1 ± 18.3% recovery rate and 93.3% excellent and good rate. The neurological situation was improved in all patients by at least 1 grade in the Frankel scale. After a mean of 36.5 months of follow-up (range, 18 to 58 months), no operative complications (spinal cord injury, vertebral artery injury, or cerebrospinal fluid leakage) were observed.
Posterior pedicle screw fixation is a reliable, effective, and minimally invasive procedure for patients suffering from complex atlantoaxial fractures.
PMCID: PMC4245791  PMID: 25407360
Complex atlantoaxial fractures; Surgical treatment; Screw fixation
10.  Diagnosis of 65 cases of ampullary renal pelvis after postnatal follow-up of 1,167 newborn infants with prenatally suspected hydronephrosis 
The aim of the present study was to assess the morbidity of ampullary renal pelvis (ARP) and document its natural history in post-natal life. A total of 1,167 newborn infants with prenatally suspected hydronephrosis were retrospectively analyzed. Of these, 65 patients were diagnosed with ARP by computed tomography urography (CTU) and/or magnetic resonance urography (MRU). All cases were followed up with ultrasonogrophy at 1, 3, 6 and 12 months after birth, and one case was followed up for 5 years. Changes in the separation of the renal pelvis collection system were recorded. Children with ARP accounted for 5.57% of the total cases (65/1,167) followed-up. No lack of connection between the renal calyces and the renal pelvis was detected. The long-term follow-up revealed that the separation of the renal pelvis collection system did not tend to increase over time. In addition to imaging examinations, long-term follow-up observation is recommended for the accurate diagnosis of pediatric ARP, particularly for differentiation from hydronephrosis.
PMCID: PMC4247286  PMID: 25452792
hydronephrosis; ampullary renal pelvis; follow-up studies
11.  Inverse correlation between Alzheimer’s disease and cancer: implication for a strong impact of regenerative propensity on neurodegeneration? 
BMC Neurology  2014;14(1):211.
Recent studies have revealed an inverse epidemiological correlation between Alzheimer’s disease (AD) and cancer − patients with AD show a reduced risk of cancer, while cancer survivors are less likely to develop AD. These late discoveries in human subjects call for explorative studies to unlock the underlying biological mechanism, but also may shed new light on conceptual interrogation of the principal pathogenic players in AD etiology.
Here we hypothesize that this negative correlation reflects a rebalance of biosynthetic propensity between body systems under the two disease statuses. In normal condition the body cellular systems are maintained homeostatically under a balanced cell degenerative vs. surviving/regenerative propensities, determined by biosynthetic resources for anabolic processing. AD pathogenesis involves neurodegeneration but also aberrant regenerative, or reactive anabolic, burden, while cancer development is driving by uncontrolled proliferation inherent with excessive anabolic activity. The aberrant neural regenerative propensity in AD pathogenesis and the uncontrolled cellular proliferative propensity in cancer pathogeneses can manifest as competitive processes, which could result in the inverse epidemiological correlation seen among the elderly.
The reduced prevalence of AD in cancer survivors may implicate a strong impact of aberrant neural regenerative burden in neurodegeneration. Further explorative studies into the inverse correlation between AD and cancer should include examinations of the proliferative propensity of tumor cells in AD models, and the development of AD-like neuropathology in cancer models as well as following anti-proliferative drug treatment.
PMCID: PMC4232711  PMID: 25394409
Aberrant neuroplasticity; Cell cycle activation; Neurodegeneration; Tumorogenesis
12.  The Male Advantage in Child Facial Resemblance Detection: Behavioral and ERP evidence 
Social neuroscience  2013;8(6):10.1080/17470919.2013.835279.
Males have been suggested to have advantages over females in reactions to child facial resemblance, which reflects the evolutionary pressure on males to solve the adaptive paternal uncertainty problem and to identify biological offspring. However, previous studies showed inconsistent results and the male advantage in child facial resemblance perception, as a kin detection mechanism, is still unclear. Here we investigated the behavioral and brain mechanisms underlying the self-resembling faces processing and how it interacts with sex and age using ERP technique. The results showed a stable male advantage in self-resembling child faces processing, such that males have higher detectability to self-resembling child faces than females. For ERP results, males showed smaller N2 and larger LPC amplitudes for self-resembling child faces, which may reflect face-matching and self-referential processing in kin detection, respectively. Further source analysis showed that the N2 and LPC components were originated from the anterior cingulate cortex and medial frontal gyrus, respectively. Our results support the male advantage in self-resembling child detection and further indicate that such distinctions can be found in both early and late processing stages in the brain at different regions.
PMCID: PMC3815694  PMID: 24053135
Kin recognition; Facial resemblance; Parental uncertainty; Paternity cue
13.  Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: role of protein-tyrosine phosphatase 1B 
BMB Reports  2014;47(10):552-557.
The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and β-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and β-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase Cα (PKCα). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation. [BMB Reports 2014; 47(10): 552-557]
PMCID: PMC4261512  PMID: 24393526
β-catenin; M3R; PTP1B; VE-cadherin
14.  Activation of the AT1R/HIF-1α/ACE Axis Mediates Angiotensin II-Induced VEGF Synthesis in Mesenchymal Stem Cells 
BioMed Research International  2014;2014:627380.
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.
PMCID: PMC4221905  PMID: 25401104
15.  Hypoxic preconditioning protects cardiomyocytes against hypoxia/reoxygenation injury through AMPK/eNOS/PGC-1α signaling pathway 
Objective: AMP-activated protein kinase (AMPK) is an important regulator of multiple cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in hypoxic preconditioning (HPC), protecting cardiomyocytes against hypoxia reoxygenation (H/R) injury remains uncertain. Methods: H9c2 cells were preconditioned by exposing to 10 min of hypoxia and 30 min of reoxygenation. Then, the preconditioned and non-preconditioned cardiomyocytes were exposed to 90 min of hypoxia followed by 120 min of reoxygenation. Results: HPC protected H9c2 cells against H/R injury, the AMPK inhibitor or eNOS inhibitor abolished the effect of HPC. Compared with H/R group, HPC significantly increased the expression of p-AMPK (Thr172). HPC also markedly increased p-eNOS (Ser1177) expression, which was abolished by AMPK inhibition. HPC significantly increased PGC-1α expression, which were nullified by AMPK inhibition or eNOS inhibition. HPC attenuated the oxidative stress by increasing the SOD activity and decreasing the MDA and ROS level, which were abolished by AMPK inhibition or eNOS inhibition. Interestingly, the AMPK activator metformin mimicked the effects of HPC in part. Conclusions: These results indicated that HPC protects H9c2 cells against H/R injury by reducing oxidative stress partly via AMPK/eNOS/PGC-1α signaling pathway.
PMCID: PMC4270574  PMID: 25550773
Hypoxia reoxygenation injury; hypoxic preconditioning; oxidative stress; AMPK
16.  CXCL17 Expression Predicts Poor Prognosis and Correlates with Adverse Immune Infiltration in Hepatocellular Carcinoma 
PLoS ONE  2014;9(10):e110064.
CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296–3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218–2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies.
PMCID: PMC4193880  PMID: 25303284
17.  Cross-Talk between cAMP and MAPK Pathways in HSD11B2 Induction by hCG in Placental Trophoblasts 
PLoS ONE  2014;9(9):e107938.
Overexposure of the fetus to glucocorticoids in gestation is detrimental to fetal development. The passage of maternal glucocorticoids into the fetal circulation is governed by 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) in the placental syncytiotrophoblasts. Human chorionic gonadotropin (hCG) plays an important role in maintaining placental HSD11B2 expression via activation of the cAMP pathway. In this study, we investigated the relationship between the activation of the cAMP pathway by hCG and subsequent phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) or p38 mitogen-activated protein kinase (MAPK) pathways in the regulation of placental HSD11B2 expression in human placental syncytiotrophoblasts. We found that treatment of the placental syncytiotrophoblasts with either hCG or dibutyl cAMP (dbcAMP) could promote the phosphorylation of p38 and ERK1/2. Inhibition of p38 MAPK with SB203580 not only reduced the basal HSD11B2 mRNA and protein levels but also attenuated HSD11B2 levels induced by either hCG or dbcAMP. By contrast, inhibition of ERK1/2 with PD98059 increased the basal mRNA and protein levels of HSD11B2 and had no effect on HSD11B2 mRNA and protein levels induced by either hCG or dbcAMP. These data suggest that p38 MAPK is involved in both basal and hCG/cAMP-induced expression of HSD11B2, and ERK1/2 may play a role opposite to p38 MAPK at least in the basal expression of HSD11B2 in human placental syncytiotrophoblasts and that there is complicated cross-talk between hCG/cAMP and MAPK cascades in the regulation of placental HSD11B2 expression.
PMCID: PMC4168233  PMID: 25229504
18.  MicroRNA expression profile in exosome discriminates extremely severe infections from mild infections for hand, foot and mouth disease 
BMC Infectious Diseases  2014;14(1):506.
Changes of miRNAs in exosome have been reported in different disease diagnosis and provided as potential biomarkers. In this study, we compared microRNA profile in exosomes in 5 MHFMD and 5 ESHFMD as well as in 5 healthy children.
Different expression of miRNAs in exosomes across all the three groups were screened using miRNA microarray method. Further validated test was conducted through quantitative real-time PCR assays with 54 exosome samples (18 ESHFMD, 18 MHFMD, and 18 healthy control). The judgment accuracy was then estimated by the receiver operating characteristic (ROC) curve analysis; and the specificity and sensitivity were evaluated by the multiple logistic regression analysis.
There were 11 different miRNAs in exosomes of MHFMD and ESHFMD compared to healthy children, of which 4 were up-regulated and 7 were down-regulated. Further validation indicated that the 4 significant differentially expressed candidate miRNAs (miR-671-5p, miR-16-5p, miR-150-3p, and miR-4281) in exosome showed the same changes as in the microarray analysis, and the expression level of three miRNAs (miR-671-5p, miR-16-5p, and miR-150-3p) were significantly different between MHFMD or ESHFMD and the healthy controls. The accuracy of the test results were high with the under curve (AUC) value range from 0.79 to 1.00. They also provided a specificity of 72%-100% and a sensitivity of 78%-100%, which possessed ability to discriminate ESHFMD from MHFMD with the AUC value of 0.76-0.82.
This study indicated that the exosomal miRNA from patients with different condition of HFMD express unique miRNA profiles. Exosomal miRNA expression profiles may provide supplemental biomarkers for diagnosing and subtyping HFMD infections.
PMCID: PMC4262082  PMID: 25231540
Exosomal microRNA Profile; HFMD; Diagnosis; Biomarker
19.  Dexamethasone attenuates bleomycin-induced lung fibrosis in mice through TGF-β, Smad3 and JAK-STAT pathway 
In order to find the possible mechanism of Dexamethasone (Dex) during curing fibrosis, the bleomycin (BLM)-induced mice model was used. After fibrosis were induced by BLM, histopathological evaluation and RT-PCR were employed to detect the expression of TGF-β1, Smad3 and STAT1. It was found that BLM promoted the development of inflammation, leading to severe pulmonary fibrosis with the increasing of TGF-β1, Smad3 and STAT1. After Dex treatment, the expression of TGF-β1, Smad3 and STAT1 showed a little higher with alleviation of the fibrosis. Thus it is concluded that there is a possible pathway of mouse pulmonary fibrosis model through TGF-β, Smad3 and JAK-STAT pathway.
PMCID: PMC4211771  PMID: 25356121
Bleomycin; dexamethasone; idiopathic pulmonary fibrosis; Smad3; JAK-STAT
20.  Relationship between lipids levels and right ventricular volume overload in congestive heart failure 
The relationship between lipids and coronary artery disease has been well established. However, this is not the case between lipids and heart failure. Ironically, high lipid levels are associated with better outcomes in heart failure, but the mechanisms underlying the phenomenon are not fully understood. This study was performed to test the hypothesis that reduced intestinal lipid absorption due to venous congestion may lead to low lipid levels.
We collected data of clinical characteristics, echocardiograph, and lipid profile in 442 unselected patients with congestive heart failure. Correlations between lipid levels [including total cholesterol (TCL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)] and right ventricle end diastolic diameter (RVEDD), left ventricle end diastolic diameter (LVEDD), right atrium diameter (RA), left atrium diameter (LA), or left ventricle ejection fraction (LVEF) were analyzed using Pearson correlation and partial correlation. RVEDD, LVEDD, RA, and LA were indexed to the body surface area.
There was a significantly inverse correlation between TCL levels and RVEDD (r = −0.34, P < 0.001) and RA (r = −0.36, P < 0.001). Other lipids such as LDL-C, HDL-C, and TG had a similar inverse correlation with RVEDD and RA. All these correlations remained unchanged after adjusting for age, gender, smoking status, physical activity levels, comorbidities, and medication use.
Lipid levels were inversely correlated to RVEDD in patients with congestive heart failure; however, because this was an observational study, further investigation is needed to verify our results as well as identify a causal relationship, if any.
PMCID: PMC4178509  PMID: 25278966
Lipid levels; Heart failure; Right ventricle; Volume overload; Correlation analysis
21.  MicroRNA-107 promotes proliferation of gastric cancer cells by targeting cyclin dependent kinase 8 
Diagnostic Pathology  2014;9(1):164.
The biological processes and molecular mechanisms underlying miR-107 remain unclear in gastric cancer(GC). In this study, we aimed to investigate the expression, biological functions and mechanisms of miR-107 in GC.
Quantitative real-time RT-PCR was used to test miR-107 expression. MTT and colony formation assays were conducted to explore the potential function of miR-107 in human GC cell line SGC7901. The target gene was determined by bioinformatic algorithms, dual luciferase reporter assay, RT-PCR and Western blot.
Expression of miR-107 was significantly elevated in GC cell line than that in gastric epithelial cell line(p = 0.012). We found that miR-107 inhibitor transfection significantly decreased the proliferation of GC cell line, and clone formation rate of miR-107 inhibitor transfected group was significantly lower than that of control group. Luciferase assays using a reporter carrying a putative miR-107 target site in the 3′untranslated region (3′-UTR) of cyclin dependent kinase 8 (CDK8) revealed that miR-107 directly targets CDK8. The expression level of CDK8 mRNA and protein in miR-107 inhibitor transfected GC cell line was significantly decreased compared with control group.
Our findings indicate that miR-107 is upregulated in GC and affects the proliferation of GC cells, partially through the regulation of CDK8.
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PMCID: PMC4169227  PMID: 25163571
MiRNA-107; Proliferation; CDK8; Gastric cancer
22.  Outcomes of surgery for unstable odontoid fractures combined with instability of adjacent segments 
At present, traumatic atlantoaxial dislocation or C2-3 instability complicating odontoid fractures remains rarely reported. The aim of this study was to further investigate the surgical treatment strategies and curative effects for odontoid fractures combined with instability of adjacent segments.
This is a retrospective study of 12 patients (5 females and 7 males; age, 21–65 years) who underwent internal fixation for odontoid fractures (type II and shallow type III) and atlantoaxial instability in 6 cases, C2-3 instability in 4 cases, simultaneous C1-2 and C2-3 instability in 2 cases between January 2005 and June 2012. Accordingly, individualized surgeries were performed. Fracture healing and bone fusion were determined on X-ray scan. Upper limbs, lower limbs and sphincter functions were assessed using the Japanese Orthopaedic Association (JOA) score. Frankel grading system was used for the evaluation of neurological situation.
Mean follow-up time of all 12 cases was 16.4 months (range, 12 to 48 months). Odontoid fracture healing was obtained in all patients within 9 months, and graft fusion was achieved within 6 months. JOA score was significantly improved from 6.3 ± 3.1 preoperatively to 11.1 ± 4.6 at 12 months after operation (P = 0.007), with 50.5 ± 25.7% recovery rate and 66.7% excellent and good rate. Except one patient still had Frankel grade B neurological injury at 12 months after surgery, the other patients improved their neurological situation (at 1 grade in Frankel scale). One patient developed wound fat liquefaction which resolved by changing the dressing. Cerebrospinal fluid leakage occurred in three patients, which resolved after the continuous drainage for 2 days.
According to the characteristics of odontoid fractures, the individualized operative procedure should be performed, resulting in high fracture healing rate, function recovery rate, and less, transient complications.
PMCID: PMC4237887  PMID: 25164238
Odontoid fractures; Adjacent section; Instability; Operative strategies; Surgical treatment
23.  Management of combination fractures of the atlas and axis: a report of four cases and literature review 
Four cases of combination fractures of the atlas and axis are presented. Three types of management were performed: plaster immobilization, odontoid screw fixation combined with atlantoaxial pedicle screw fixation, occipito-cervical fusion with anterior operation by staged. Based on a literature review and our experience, treatment strategies is discussed according to the stability of the upper cervical spine and neurological involvement, with a reminder that combined injuries in the upper cervical spine should be sought in any patient with a cervical injury and early surgical solution may bring benefits once injury attack.
PMCID: PMC4161549  PMID: 25232389
Cervical spine fracture; atlas; axis; plaster immobilization; cervical spine surgery
24.  Association of Notch1 with vasculogenic mimicry in human hepatocellular carcinoma cell lines 
Background and aims: According to recent findings, some tumor cells function as endothelial progenitor cells to initiate tumor vasculogenesis, known as “vasculogenic mimicry” (VM). Notch1, the key regulator of vasculogenesis and embryonic differentiation, has shown a correlation with a poor prognosis in hepatocellular carcinoma (HCC). We attempted to elucidate the relationship between Notch1 and the vascularization of HCC. Materials and methods: HCC cell lines were assayed for tube formation and low-density lipoprotein (LDL) absorption. The translation level of targets of interest was verified using western blot. Notch1 was silenced in HepG2, BEL-7402 and HCCLM6 using lentivirus shRNA. A hypoxic culture was conducted in an anaerobic culture chamber to induce VM in HepG2. Samples from 53 patients with HCC, i.e., 5 with metastasis and 48 without were tested for Notch1+ cells and CD34 negative plus Periodic Acid-Schiff (PAS) positive structures, respectively. Results: BEL-7402 and HCCLM6 were capable of tube formation and LDL absorption in vitro, while HepG2 was negative for both. Notch1 down-regulation suppressed endothelial marker expression and greatly impaired tube formation. After hypoxic culture, the tube formation capacity of HepG2 was significantly enhanced, along with an increase in Notch1 expression. Notch1 was strongly and profusely expressed in all 5 cases of distant metastasis, while 19 of the 48 cases without metastasis were sparsely positive (P < 0.05). Notch1 positivity was mainly seen in the cytoplasm and nuclei. VM structures were only found in 2 cases from the metastasis group (P < 0.05). Conclusions: HCC is capable of VM. Notch1 might serve as a potential target for VM development in HCC.
PMCID: PMC4203190  PMID: 25337219
Notch1; hepatocellular carcinoma; vasculogenesis
25.  BMPRIA Mediated Signaling Is Essential for Temporomandibular Joint Development in Mice 
PLoS ONE  2014;9(8):e101000.
The central importance of BMP signaling in the development and homeostasis of synovial joint of appendicular skeleton has been well documented, but its role in the development of temporomandibular joint (TMJ), also classified as a synovial joint, remains completely unknown. In this study, we investigated the function of BMPRIA mediated signaling in TMJ development in mice by transgenic loss-of- and gain-of-function approaches. We found that BMPRIA is expressed in the cranial neural crest (CNC)-derived developing condyle and glenoid fossa, major components of TMJ, as well as the interzone mesenchymal cells. Wnt1-Cre mediated tissue specific inactivation of BmprIa in CNC lineage led to defective TMJ development, including failure of articular disc separation from a hypoplastic condyle, persistence of interzone cells, and failed formation of a functional fibrocartilage layer on the articular surface of the glenoid fossa and condyle, which could be at least partially attributed to the down-regulation of Ihh in the developing condyle and inhibition of apoptosis in the interzone. On the other hand, augmented BMPRIA signaling by Wnt1-Cre driven expression of a constitutively active form of BmprIa (caBmprIa) inhibited osteogenesis of the glenoid fossa and converted the condylar primordium from secondary cartilage to primary cartilage associated with ectopic activation of Smad-dependent pathway but inhibition of JNK pathway, leading to TMJ agenesis. Our results present unambiguous evidence for an essential role of finely tuned BMPRIA mediated signaling in TMJ development.
PMCID: PMC4122352  PMID: 25093411

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