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1.  Draft Genome Sequence of Rhodobacteraceae Strain PD-2, an Algicidal Bacterium with a Quorum-Sensing System, Isolated from the Marine Microalga Prorocentrum donghaiense 
Genome Announcements  2015;3(1):e01549-14.
Rhodobacteraceae strain PD-2 was isolated from the marine microalga Prorocentrum donghaiense. It has algicidal activity toward its host and could produce N-acylhomoserine lactone signals. Here, we present the draft genome of strain PD-2, which contains 5,227,214 bp with an average GC content of 66.19%. There were 4,864 encoding gene sequences and two clusters of luxI and luxR homologues identified.
PMCID: PMC4335330
2.  Effects of Calcium Phosphate Nanocrystals on Osseointegration of Titanium Implant in Irradiated Bone 
BioMed Research International  2015;2015:783894.
Radiotherapy may compromise the integration of implant and cause implant loss. Implant surface modifications have the possibility of promoting cell attachment, cell growth, and bone formation which ultimately enhance the osseointegration process. The present study aimed to investigate the effects of calcium phosphate nanocrystals on implant osseointegration in irradiated bone. Sixteen rabbits were randomly assigned into control and nano-CaP groups, receiving implants with dual acid-etched surface or dual acid-etched surface discretely deposited of nanoscale calcium-phosphate crystals, respectively. The left leg of all the rabbits received 15 Gy radiation, followed by implants placement one week after. Four animals in each group were sacrificed after 4 and 12 weeks, respectively. Implant stability quotient (ISQ), ratio of bone volume to total volume (BV/TV), bone growth rate, and bone-to-implant contact (BIC) were evaluated. The nano-CaP group showed significantly higher ISQ (week 12, P = 0.031) and bone growth rate (week 6, P = 0.021; week 9, P = 0.001) than that in control group. No significant differences in BV/TV and BIC were found between two groups. Titanium implant surface modified with CaP nanocrystals provides a potential alternative to improve bone healing around implant in irradiated bone.
PMCID: PMC4317600
3.  Genome Sequence of the Petroleum Hydrocarbon-Degrading Bacterium Alcanivorax sp. Strain 97CO-5 
Genome Announcements  2014;2(6):e01277-14.
Alcanivorax sp. strain 97CO-5 was isolated from a crude-oil-degrading consortium, enriched from Yellow Sea sediment of China. Here, we present the draft genome of strain 97CO-5, which comprises 3,251,558 bp with a G+C content of 54.54% and contains 2,962 protein-coding genes and 42 tRNAs.
PMCID: PMC4263835  PMID: 25502673
4.  Anterior Insula GABA Levels Correlate with Emotional Aspects of Empathy: A Proton Magnetic Resonance Spectroscopy Study 
PLoS ONE  2014;9(11):e113845.
Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated.
Materials and Methods:
Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI).
Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p<0.05) and the personal distress score (r = 0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores.
Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities.
PMCID: PMC4242717  PMID: 25419976
5.  Effects of cigarette smoke on aerobic capacity and serum MDA content and SOD activity of animal 
Objective: Study the effects of cigarette smoke on aerobic capacity, serum MDA content and SOD activity of animal. Methods: 60 male mice are randomly divided into mild smoking group, heavy smoking group, and control group, and the exhausted swimming time, serum SOD activity and MDA content of the three groups of mice are respectively measured before and after the experiment. Results: After the experiment, the exhausted swimming time for the control group, mild smoking and heavy smoking groups is respectively 276.57 min, 215.57 min and 176.54 min, and the serum SOD activities for the three objects are 216.46 U/mL, 169.16 U/mL and 154.91 U/mL, and the MDA contents are respectively 16.41 mol/mL, 22.31 mol/mL and 23.55 mol/mL. According to the comparison, it is found that compared with the control group and pre-intervention, the exhausted swimming time and serum SOD activity of the smoking group decreases obviously, and its MDA content rises sharply, and the difference has significance (P < 0.05), moreover, the heavy smoking group has more obvious changes than the mild group. Conclusion: Cigarette smoke can significantly weaken the aerobic capacity and fatigue resistance of mice, and the more the smoking time is longer, the more the harmful effect is more serious, this is related to the SOD activity drops and MDA content rises due to smoking.
PMCID: PMC4276227  PMID: 25550969
Cigarette; aerobic exercise; superoxide dismutase (SOD); malonaldehyde (MDA); mouse
6.  Acoustic rainbow trapping by coiling up space 
Scientific Reports  2014;4:7038.
We numerically realize the acoustic rainbow trapping effect by tapping an air waveguide with space-coiling metamaterials. Due to the high refractive-index of the space-coiling metamaterials, our device is more compact compared to the reported trapped-rainbow devices. A numerical model utilizing effective parameters is also calculated, whose results are consistent well with the direct numerical simulation of space-coiling structure. Moreover, such device with the capability of dropping different frequency components of a broadband incident temporal acoustic signal into different channels can function as an acoustic wavelength division de-multiplexer. These results may have potential applications in acoustic device design such as an acoustic filter and an artificial cochlea.
PMCID: PMC4229664  PMID: 25392033
7.  Effect of epigallocatechin-3-gallate on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro 
In autologous chondrocyte implantation (ACI) to restore defective cartilage, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but their high cost and potential for tumorigenesis are major obstacles. To ensure successful ACI therapy, it is important to find an effective substitute pro-chondrogenic agent. Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, has been widely investigated in studies of interleukin-1β-induced chondrocytes. In the present study, the effects of EGCG on rabbit articular chondrocytes were investigated through the examination of cell proliferation, morphology, glycosaminoglycan synthesis and cartilage-specific gene expression. The results showed that EGCG could effectively promote chondrocyte growth and enhance the secretion and synthesis of the cartilage extracellular matrix by upregulating expression levels of aggrecan, collagen II and Sox9 genes. Expression of the collagen I gene was downregulated, which showed that EGCG effectively inhibited the dedifferentiation of chondrocytes. Hypertrophy, which may lead to chondrocyte ossification, was also undetectable in the EGCG groups. In conclusion, the recommended dose of EGCG was found to be in the range of 5 to 20 μM, with the most marked response observed with 10 μM. The present study may provide a basis for the development of a novel agent as a substitute for growth factors in the treatment of articular cartilage defects.
PMCID: PMC4247298  PMID: 25452805
epigallocatechin-3-gallate; pro-chondrogenic agent; chondrocyte; rabbit articular cartilage; dedifferentiation
8.  Polymorphisms in the Interleukin 18 Receptor 1 Gene and Tuberculosis Susceptibility among Chinese 
PLoS ONE  2014;9(10):e110734.
Tuberculosis (TB), an infectious disease caused by infection of Mycobacterium tuberculosis, is a major public health challenge globally. Genetic epidemiological evidence suggests a genetic basis for TB, but the molecular mechanism for a genetic predisposition to TB remains largely unknown. Thirty-five tag single-nucleotide polymorphisms (SNPs) across 11 candidate cytokines and related genes, including IL-12/IFN-γ axis genes (IL12B, IL12RB1, IL18R1, IL27, IFNGR1, IFNGR2 and STAT1), the TNF gene locus (TNF and LTA), IL10, and CCL2, were genotyped using Sequenom's iPLEX assays in 1,032 patients with TB and 1,008 controls of Chinese Han origin. We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex. However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10−4). Further analysis indicated that a SNP in absolute linkage disequilibrium with rs1974675, rs3755276, is located within a CpG dinucleotide and showed hypomethylation in controls than in patients (19.6% vs. 31.4%; P = 1.0×10−4) and genotype-specific DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels. In addition, DNA methylation levels were significantly inversely correlated with mRNA levels. Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk.
PMCID: PMC4216003  PMID: 25360588
9.  Xanthogranulomatous cystitis imitating bladder neoplasm: a case report and review of literature 
Xanthogranulomatous cystitis is a rare, benign chronic inflammatory disorder with unclear etiology. Since its similar features to bladder neoplasm, it is extremely easy to be mistaken for malignant tumor. We herein reported a case of xanthogranulomatous cystitis in a 54-year-old male who presented with low abdominal pain and painless, total macrohematuria. Microscopy showed proliferation of large foam histiocytes which expressed CD68 and vimentin. Ki-67 showed a lower proliferation index (< 10%). Histopathology and immunohistochemical findings confirmed the diagnosis. This case highlighted the significance of recognizing this unusual lesion and differentiating it from its histological mimics by immunohistochemical staining.
PMCID: PMC4270612  PMID: 25550882
Xanthogranulomatous cystitis; neoplasm; CD68; vimentin; Ki-67
10.  Systematic Analysis of Time-Series Gene Expression Data on Tumor Cell-Selective Apoptotic Responses to HDAC Inhibitors 
SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.
PMCID: PMC4211306  PMID: 25371703
11.  Dermatosis as the initial presentation of gastric cancer: two cases 
Paraneoplastic dermatoses are known to be certain dermatosis related with tumor. The common paraneoplastic dermatoses are acanthosis nigricans, acquired ichthyosis, dermatomyositis, erythroderma, and so on. Here we report two cases of paraneoplastic dermatoses associated with gastric cancer. One case was a 57-year-old man with dermatomyositis and proved to be associated with gastric cancer through stomachoscopy. The other was a 66-year-old man with erythroderma and proved to be associated with gastric cancer through stomachoscopy. Both cases were treated with radical total gastrectomy with lymphadenectomy (D2) and esophagojejunostomy of Roux-en-Y. The skin symptom of both cases had improved a lot but still existed after operation. Paraneoplastic dermatoses can be seen as the early manifestation of visceral carcinomas. As a result, gastric cancers should be excluded in the patients with paraneoplastic dermatoses.
PMCID: PMC4220258  PMID: 25400431
Paraneoplastic dermatoses; erythroderma; dermatomyositis; malignancy; gastric cancer
12.  Effect of Ovariectomy on Stimulating Intracortical Remodeling in Rats 
BioMed Research International  2014;2014:421431.
Objective. Technically primates and dogs represent ideal models to investigate diseases characterized by abnormal intracortical remodeling. High expenses and ethical issues, however, restrict the use of those animals in research. Rodent models have been used as alternatives instead, but their value is limited, if none, because these animals lack intracortical bone remodeling. This study aimed at investigating the effect of ovariectomy onto the stimulation of intracortical remodeling in rat mandibles. Materials and Methods. Sixteen 12-week-old Spraque-Dawly (SD) female rats were randomly assigned into two groups, receiving either ovariectomy or sham operation. All the rats were sacrificed 18 weeks postoperatively. The entire mandibles were harvested for microcomputed tomography (micro-CT) and histomorphometric assessments. Results. Micro-CT examination showed significantly decreased bone mineral density (0.95 ± 0.01 versus 1.01 ± 0.02 g/cm3, P < 0.001) and bone volume (65.78 ± 5.45 versus 87.41 ± 4.12%, P < 0.001) in ovariectomy group. Histomorphometric assessment detected a sixfold increased intracortical bone remodeling as well as an increased bone modeling in mandibles of ovariectomized rats. Conclusion. For the first time, to the authors' knowledge, it was detected that ovariectomy stimulates intracortical remodeling in rat mandibles. This animal model might be of use to study various bone diseases associated with an abnormal intracortical remodeling process.
PMCID: PMC4189761  PMID: 25309912
13.  Dendritic fibromyxolipoma on the nasal tip in an old patient 
Dendritic myxofibrolipoma is a newly described benign soft tissue tumor that could be easily mistaken for sarcoma. It develops primarily in the subcutis or muscular fascia of the head and neck, shoulders, etc. Histologically, the tumor is characterized by an admixture of mature adipose tissue, spindle and stellate cells, and abundant myxoid stroma with prominent collagenization. These neoplasms typically show positive immunoreactivity for CD-34, vimentin and Bcl-2. Herein, we described a rare case presenting with a papule on the nasal tip in a 69-year old patient. Histopathology and immunohistochemical staining confirmed the diagnosis. In short, it brings the attention of clinicians to the importance of proper identification and characterization of this tumor.
PMCID: PMC4230120  PMID: 25400797
Dendritic fibromyxolipoma; fibrous papule; spindle cell lipoma; solitary fibrous tumor; myxoid liposarcoma
14.  Oral epithelial stem cells – implications in normal development and cancer metastasis 
Experimental cell research  2014;325(2):111-129.
Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination.
PMCID: PMC4157336  PMID: 24803391
Oral squamous cell carcinoma; epithelial stem cells; invasion; metastasis; cancer stem cells; oral mucosa
15.  In vitro evaluation of Sialyl Lewis X relationship with head and neck cancer stem cells 
To evaluate in vitro the potential links between sialyl Lewis X (sLeX) and cancer stem cells (CSC) in head and neck squamous cell carcinoma (HNSCC). HNSCC is an aggressive malignancy with high mortality mainly due to metastasis. CSC have emerged as important players in HNSCC metastasis. sLeX is a tetrasaccharide carbohydrate known to play a key-role in metastatic dissemination by promoting binding of the tumor cells to the endothelium.
Study Design
Experimental, in vitro.
Laboratory of Head and Neck Cancer Metastasis, University of Michigan.
Subjects and Methods
A panel of stage- and anatomic-site specific primary and metastatic HNSCC cell lines was assessed by flow cytometry to quantify sLeX relative expression levels. Serum-free conditioned media from the same HNSCC lines was collected over a time-course of 72 hours and assessed by Western-blot for secreted sLeX expression. Representative HNSCC cell lines were cultured as floating orospheres (condition that enhance CSC growth) or under normal adherent conditions and characterized by flow cytometry for CSC markers (CD44, aldehyde dehydrogenase [ALDH]) comparatively with sLeX expression.
sLeX is predominantly expressed in carcinomas originating from the oral cavity. Secreted sLeX is also found to be high in oral carcinomas and increased over the analyzed time course. Floating orospheres were strongly positive for CD44 and ALDH confirming CSC enrichment of the orospheres. Tumor cells grown as orospheres are 95-100% positive for sLeX compared to 10-40% of adherent counterpart.
These studies provide the first evidence of sLeX relationship with CSC in HNSCC.
PMCID: PMC4157351  PMID: 23558285
head and neck squamous cell carcinomas; sLeX (sialyl Lewis X); CD44; stem cells; in vitro analysis
16.  Lung cancer survival among black and white patients in an equal access health system 
Racial disparities in lung cancer outcomes have been observed in the general population. However, it is unclear whether survival differences persist when patients have equal access to healthcare. Our objective was to determine if lung cancer survival differed among black and white patients in the U.S. Military Health System (MHS), an equal access healthcare system.
The study subjects were 10,181 black and white patients identified through the Department of Defense’s Automated Central Tumor Registry, who were ≥20 years old and diagnosed with lung cancer between 1990 and 2003. Racial differences in all-cause survival were examined using the Kaplan–Meier method and Cox proportional hazards regression models stratified by histology. For comparison, survival rates in the general population were calculated using Surveillance, Epidemiology and End Results (SEER)-9 data.
Analyses included 9,154 white and 1,027 black patients: 1,834 small cell lung cancers, 3,876 adenocarcinomas, 2,741 squamous cell carcinomas, and 1,730 large cell carcinomas. Although more favorable crude survival was observed among black patients than white patients with small cell lung cancer (p=0.04), survival was similar between the two groups after covariate adjustment. Racial differences in survival were non-significant for adenocarcinomas, squamous cell carcinomas and large cell carcinomas. Survival rates appeared to be better in the MHS than in the general population.
Conclusions and Impact
All-cause survival was similar among black and white lung cancer patients in the MHS. Providing equal access to healthcare may eliminate racial disparities in lung cancer survival while improving the outcome of all cases.
PMCID: PMC4151240  PMID: 22899731
equal access to healthcare; histologic subtypes; lung cancer; racial disparity; survival
17.  Impact of Body Mass Index on Plasma N-Terminal ProB-Type Natriuretic Peptides in Chinese Atrial Fibrillation Patients without Heart Failure 
PLoS ONE  2014;9(8):e105249.
An inverse relationship between body mass index (BMI) and circulating levels of N-terminal proB-type natriuretic peptide (NT-proBNP) has been demonstrated in subjects with and without heart failure. Obesity also has been linked with increased incidence of atrial fibrillation (AF), but its influence on NT-proBNP concentrations in AF patients remains unclear. This study aimed to investigate the effect of BMI on NT-proBNP levels in AF patients without heart failure.
A total of 239 consecutive patients with AF undergoing catheter ablation were evaluated. Levels of NT-proBNP and clinical characteristics were compared in overweight or obese (BMI≥25 kg/m2) and normal weight (BMI<25 kg/m2) patients.
Of 239 patients, 129 (54%) were overweight or obese. Overweight or obese patients were younger, more likely to have a history of nonparoxysmal AF, hypertension, and diabetes mellitus. Levels of NT-proBNP were significantly lower in overweight or obese than in normal weight subjects (P<0.05). The relationship of obesity and decreased NT-proBNP levels persisted in subgroup of hypertension, both gender and both age levels (≥65 yrs and <65 yrs).Multivariate linear regression identified BMI as an independent negative correlate of LogNT-proBNP level.
An inverse relationship between BMI and plasma NT-proBNP concentrations have been demonstrated in AF patients without heart failure. Overweight or obese patients with AF appear to have lower NT-proBNP levels than normal weight patients.
PMCID: PMC4140742  PMID: 25144363
18.  Downregulation of Ras Association Domain Family Member 6 (RASSF6) Underlies the Treatment Resistance of Highly Metastatic Nasopharyngeal Carcinoma Cells 
PLoS ONE  2014;9(7):e100843.
Radiation and cisplatin-based chemotherapy are major treatments for nasopharyngeal carcinoma (NPC). However, a major impediment for further improving the cure rate is the development of treatment resistance with an undetermined molecular mechanism in metastatic NPC cells. Our established, highly metastatic NPC cells have been reported to be more resistant to cisplatin chemotherapy. In the present study, we found that Ras association domain family member 6 (RASSF6) was downregulated in highly metastatic cells but upregulated in low metastatic cells in comparison to their parental cell line. Ectopic-expression of RASSF6 enhanced the sensitivity of highly metastatic NPC cells to cisplatin or radiation by enhancing apoptosis. RASSF6 depletion conversely reduced treatment sensitivity by decreasing the apoptosis rate. Over-expression of RASSF6 in highly metastatic NPC cells could enhance the phosphorylation of JNK when exposed to cisplatin or radiation treatment, while knocking down RASSF6 in low metastatic NPC cells could reduce the level of phospho-JNK when exposed to the same treatments. The activation of JNK signaling by RASSF6 and its subsequent sensitivity to apoptosis in NPC cells could be inhibited by applying the JNK inhibitor SP600125. In conclusion, the downregulation of RASSF6 in highly metastatic NPC cells contributed to their treatment resistance, and over-expression of RASSF6 conferred treatment sensitivity to highly metastatic NPC cells by activating JNK signaling. RASSF6 could be a valuable molecular marker for identifying sensitive metastatic NPC tumors during cisplatin treatment or radiotherapy.
PMCID: PMC4100732  PMID: 25028967
19.  Circadian Rhythms Regulate Amelogenesis 
Bone  2013;55(1):158-165.
Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24h) intervals both at RNA and protein levels. This study also reveals that two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stage of amelogenesis might be under circadian control. Changes in clock genes expression patterns might result in significant alterations of enamel apposition and mineralization.
PMCID: PMC3650122  PMID: 23486183
Clock genes; enamel; amelogenin; kallikrein-related peptidase 4; odontoblasts
20.  miR-365 Promotes Cutaneous Squamous Cell Carcinoma (CSCC) through Targeting Nuclear Factor I/B (NFIB) 
PLoS ONE  2014;9(6):e100620.
Aberrant expression of microRNAs plays vital roles in tumor development and progression. As transcription factors (TFs) are the critical components of signaling cascades, specific targeting effects of microRNAs to specific TFs may determine the role of microRNAs in different cancers. In this study, we identified Nuclear Factor I/B (NFIB) as one of the targets of miR-365 which was previously verified as an onco-miR in cutaneous squamous cell carcinoma (CSCC). Down-regulation of NFIB was a general feature in both CSCC cell lines and tumors from patients which show drastically up-regulated miR-365 expression levels. The siRNA-based knockdown of NFIB mimic the carcinogenic transformation of normal cells by ectopically expression of miR-365 which indicates depletion of NFIB is necessary for miR-365 to exert its pro-carcinogenic function. NFIB may represent a functional barrier targeted by miR-365 to the development of CSCC. Further studies also discovered a conserved feedback regulatory circuitry formed by NFIB and miR-365 in CSCC development which may be potentially utilized as therapeutic target to improve the clinical CSCC treatment.
PMCID: PMC4065106  PMID: 24949940
21.  Toll-Like Receptors Expressed by Synovial Fibroblasts Perpetuate Th1 and Th17 Cell Responses in Rheumatoid Arthritis 
PLoS ONE  2014;9(6):e100266.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone and cartilage erosion. Synovial fibroblast- and T cell-mediated inflammation plays crucial roles in the pathogenesis of RA. However how this inflammation is initiated, propagated, and maintained remains controversial. Here, we systemically examined the contribution of toll-like receptors (TLRs) to the inflammatory mediator production as well as Th1 and Th17 cell hyperactivity in RA. Our results show that rheumatoid arthritis synovial fibroblasts (RASF) express a series of TLRs, including TLR2, TLR3, TLR4, and TLR9, with the predominant expression of TLR3. Moreover, the expression levels of these TLRs were higher than those in osteoarthritis synovial fibroblasts (OASF). Ligation of TLR3, as well as TLR2 and TLR4, resulted in vigorous production of inflammatory cytokines, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) in RASF, with activation of the NF-κB, MAPK, and IRF3 pathways. More important, activation of these TLRs expressed by RASF exacerbated inflammatory Th1 and Th17 cell expansion both in cell-cell contact-dependent and inflammatory cytokine-dependent manners, which induced more IFN-γ and IL-17 accumulation. Targeting TLRs may modulate the inflammation in RA and provide new therapeutic strategies for overcoming this persistent disease.
PMCID: PMC4061069  PMID: 24936783
22.  Expression of CCL2 and CCR2 in the hippocampus and the interventional roles of propofol in rat cerebral ischemia/reperfusion 
The aim of the present study was to determine the roles of the chemotactic factor, chemokine ligand 2 (CCL2), and its receptor, chemokine receptor type 2 (CCR2), in the hippocampus of rats with cerebral ischemia/reperfusion injury. In total, 24 Sprague-Dawley rats, weighting 250–300 g, were randomly divided into three groups (n=8): Sham-operated (C group), cerebral ischemia/reperfusion injury (I/R group) and propofol-intervention (P group) groups. The rats were sacrificed at 6 h after the ischemia/reperfusion surgery, and the brains were obtained to isolate the hippocampus. The mRNA expression levels of CCL2 and CCR2 in the hippocampus were analyzed by quantitative polymerase chain reaction, while the protein expression levels of CCL2 and CCR2 were determined by western blot analysis. The expression levels of CCL2 and CCR2 in the procerebrum were markedly elevated in the I/R and P groups at 6 h after the ischemia/reperfusion surgery when compared with the C group (P<0.05). In addition, the mRNA expression levels of CCL2 and CCR2 decreased significantly in the P group as compared with that in the I/R group (P<0.05). Therefore, CCL2 and CCR2 may be involved in the mechanisms underlying cerebral ischemia/reperfusion injury, and propofol may protect the brain through regulating the expression of CCL2 and CCR2.
PMCID: PMC4079442  PMID: 25009636
chemokine ligand 2; chemokine receptor type 2; cerebral ischemia/reperfusion; hippocampus
23.  Stromal fibroblast activation and their potential association with uterine fibroids (Review) 
Oncology Letters  2014;8(2):479-486.
Uterine fibroids are the most common type of benign, gynecologic neoplasm and are the primary indication for performance of a hysterectomy, accounting for >200,000 hysterectomies annually in the USA. At present, females are younger and exhibit larger leiomyomas at the time of diagnosis. Cancer-associated fibroblasts in tumor microenvironments have emerged as an important target for cancer therapy. Repeated stimulation by infectious or non-infectious agents in the uterine tissues, including inflammation, mechanical forces or hypoxia, stimulate the resident fibroblasts to undergo specific activation and, thus, are significant in tumorigenesis. Furthermore, complex signaling pathways regulate the mechanisms of fibroblastic activation. The current review focuses on the molecular mechanisms of fibroblastic activation and the potential association with uterine leiomyoma pathogenesis, enabling an integrated pathogenic analysis for review of the therapeutic options.
PMCID: PMC4081411  PMID: 25013460
fibroblasts; fibroblast activation; uterine fibroids; α-smooth muscle actin; transforming growth factor-β
24.  Elevated serum CA19-9 level is a promising predictor for poor prognosis in patients with resectable pancreatic ductal adenocarcinoma: a pilot study 
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers. Several studies have reported that the carbohydrate antigen 19-9 (CA19-9) level is a useful marker for predicting the prognosis for PDAC after resection. However, the cutoff value of CA19-9 used to predict prognosis varied among these reports. The aims of this study were to evaluate whether the serum CA19-9 level is a significant predictor for survival and to determine the optimal cutoff value of CA19-9 for predicting prognosis.
A total of 120 consecutive patients who underwent surgery for potentially resectable primary PDAC were retrospectively analyzed. The variables included the following: age, sex, the location of the tumor, the maximal tumor size, the histological differentiation, the margin status, the tumor stage, serum CA19-9 levels, and serum total bilirubin (TBil) levels.
The overall 1-year survival rate was 62.5%. The receiver operating characteristic (ROC) curve indicated a significant result for the level of CA19-9 in predicting death within 1 year after surgery (Area under the curve (AUC), 0.612; 95% confidence interval (CI), 0.505-0.720; P = 0.040). The optimal cutoff point was 338.45 U/mL (sensitivity, 60.0%; specificity, 66.7%; accuracy, 64.2%). The strongest univariate predictor among the categorized CA19-9 values was CA19-9 greater than or equal to 338.45 U/mL. In the multivariate Cox proportional hazards mode analysis, the serum CA19-9 level, age and the histological differentiation were significant independent prognostic factors that were associated with the overall survival.
The preoperative elevated CA19-9 level is a promising independent factor for predicting a poor prognosis in PDAC, and the optimal cutoff value is 338.45 U/mL.
PMCID: PMC4064278  PMID: 24890327
Pancreatic ductal adenocarcinoma (PDAC); Carbohydrate antigen 19-9 (CA19-9); Prognosis; Overall survival (OS)
25.  Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells 
BMC Cancer  2014;14:373.
Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent.
PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots.
Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition.
This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent.
PMCID: PMC4047270  PMID: 24886166
Pancreatic cancer; SAHA; Vasculogenic mimicry; Proliferation and apoptosis

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