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1.  Domestication of rice has reduced the occurrence of transposable elements within gene coding regions 
BMC Genomics  2017;18:55.
Transposable elements (TEs) are prominent features in many plant genomes, and patterns of TEs in closely related rice species are thus proposed as an ideal model to study TEs roles in the context of plant genome evolution. As TEs may contribute to improved rice growth and grain quality, it is of pivotal significance for worldwide food security and biomass production.
We analyzed three cultivated rice species and their closest five wild relatives for distribution and content of TEs in their genomes. Despite that the three cultivar rice species contained similar copies and more total TEs, their genomes contained much longer TEs as compared to their wild relatives. Notably, TEs were largely depleted from genomic regions that corresponded to genes in the cultivated species, while this was not the case for their wild relatives. Gene ontology and gene homology analyses revealed that while certain genes contained TEs in all the wild species, the closest homologs in the cultivated species were devoid of them. This distribution of TEs is surprising as the cultivated species are more distantly related to each other as compared to their closest wild relative. Hence, cultivated rice species have more similar TE distributions among their genes as compared to their closest wild relatives. We, furthermore, exemplify how genes that are conferring important rice traits can be regulated by TE associations.
This study demonstrate that the cultivation of rice has led to distinct genomic distribution of TEs, and that certain rice traits are closely associated with TE distribution patterns. Hence, the results provide means to better understand TE-dependent rice traits and the potential to genetically engineer rice for better performance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3454-z) contains supplementary material, which is available to authorized users.
PMCID: PMC5223533  PMID: 28068923
Oryza; Transposable elements; Cultivated rice; Wild rice; Evolution
2.  Pre- and Postcycloplegic Refractions in Children and Adolescents 
PLoS ONE  2016;11(12):e0167628.
To determine the difference between cycloplegic and non-cycloplegic refractive error and its associated factors in Chinese children and adolescents with a high prevalence of myopia.
A school-based study including 1565 students aged 6 to 21 years was conducted in 2013 in Ejina, Inner Mongolia, China. Comprehensive eye examinations were performed. Pre-and postcycloplegic refractive error were measured using an auto-refractor. For cycloplegic refraction, one drop of topical 1.0% cyclopentolate was administered to each eye twice with a 5-minute interval and a third drop was administered 15 minutes after the second drop if the pupil size was less than 6 mm or if the pupillary light reflex was still present.
Two drops of cyclopentolate were found to be sufficient in 59% of the study participants while the other 41% need an additional drop. The prevalence of myopia was 89.5% in participants aged over 12 years and 68.6% in those aged 12 years or younger (P<0.001). When myopia was defined as spherical equivalent (SE) of less than -0.5 diopter (D), the prevalence estimates were 76.7% (95% confidence interval [CI] 74.6–78.8) and 54.1% (95%CI 51.6–56.6) before and after cycloplegic refraction, respectively. When hyperopia was defined as SE of more than 0.5D, the prevalence was only 2.8% (95%CI 1.9–3.6) before cycloplegic refraction while it was 15.5% (95%CI 13.7–17.3) after cycloplegic refraction. Increased difference between cycloplegic and non-cycloplegic refractive error was associated with decreased intraocular pressures (P = 0.01).
Lack of cycloplegia in refractive error measurement was associated with significant misclassifications in both myopia and hyperopia among Chinese children and adolescents. Decreased intraocular pressure was related to a greater difference between cycloplegic and non-cycloplegic refractive error.
PMCID: PMC5132192  PMID: 27907165
3.  Trichinella spiralis paramyosin activates mouse bone marrow-derived dendritic cells and induces regulatory T cells 
Parasites & Vectors  2016;9:569.
Dendritic cells (DCs) are antigen-presenting cells that regulate T cell responses for many infectious diseases. The tissue-dwelling nematode Trichinella spiralis expresses paramyosin (TsPmy) not only as a structural protein but also as an immunomodulator to alleviate complement attack by binding to some host complement components. Whether TsPmy is involved in other immunomodulatory pathway and how TsPmy interacts with host DCs is still unknown.
Mouse bone marrow-derived DCs were incubated with recombinant TsPmy (rTsPmy) for activation. Maturation of DC was determined by the expression of surface markers CD40, CD80, CD86 and MHCII. The rTsPmy-pulsed DCs were co-incubated with T. spiralis-sensitized or naïve mouse CD4+ T cells to observe their activation on T cells and polarizing regulatory T cells using flow cytometry. Cytokines were measured by enzyme-linked immunosorbent assays (ELISA).
TsPmy was able to activate mouse bone marrow-derived DCs to semi-mature status characterized by expressing surface CD40 and CD86, but not CD80 and MHCII. The semi-mature TsPmy-pulsed DCs were able to stimulate T. spiralis-sensitized CD4+ T cells to proliferate. Incubation of TsPmy-pulsed DCs with naïve CD4+ splenocytes polarized the latter to CD4+CD25+Foxp3+ regulatory T cells. However, mice immunized with rTsPmy only induce the CD4+CD25−Foxp3+ T cell population, associated with high level of IL-10, TGF-β and IL-17A.
During T. spiralis infection, TsPmy plays an important role in modulating the host immune system by stimulating DCs to differentiate the CD4+ T cells to regulatory T cells, in addition to binding to components of the host complement cascade, as survival strategies to live in host.
PMCID: PMC5095993  PMID: 27809931
Dendritic cells; Trichinella spiralis; Paramyosin; Regulatory T cells
4.  Iodine-125 irradiation inhibits invasion of gastric cancer cells by reactivating microRNA-181c expression 
Oncology Letters  2016;12(4):2789-2795.
Iodine-125 (125I) seed implantation has been widely used for the treatment of unresectable advanced tumors. However, the molecular mechanisms underlying the tumor-suppressive effects of 125I irradiation have not been fully elucidated. The present study demonstrated that 125I irradiation suppresses cell viability and inhibits cell invasiveness of gastric cancer KATO-III and MKN45 cells. Further mechanistic analysis suggested the involvement of microRNA (miR)-181c in the inhibitory effects induced by 125I irradiation. Methylated DNA immunoprecipitation coupled with quantitative-polymerase chain reaction demonstrated that treatment with 125I irradiation, at the dose of 4 Gy, induced promoter demethylation of the miR-181c gene in KATO-III and MKN45 cells. Following irradiation, the expression of miR-181c was significantly increased, which may be attributed to the demethylation caused by 125I irradiation. In addition, upregulation of miR-181c by administration of miR-181c mimics decreased cell invasion, suggesting the role of miR-181c as a tumor suppressor. More importantly, the tumor-suppressive effects of 125I irradiation were significantly compromised by the introduction of miR-181c inhibitors. Overall, these results reveal that 125I irradiation inhibits invasiveness of gastric cancer cells by reactivating miR-181c at the epigenetic level, thereby providing important molecular evidence for the anticancer effects of 125I irradiation.
PMCID: PMC5038846  PMID: 27698859
125I irradiation; gastric cancer; invasion; microRNA; miRNA; DNA methylation
5.  Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer 
Oncotarget  2016;7(22):33025-33034.
Monitoring disease progression through imaging is playing an increasingly important role in the treatment of prostate cancer. Here, we report that primary mouse prostate cancer cell lines stably expressing luciferase and tumor biomarkers can be monitored through bioluminescence imaging along with assays of serum biomarkers and immune function. Tumorigenesis in immunocompetent C57BL/6 mice can be monitored in by collecting samples from the dorsal flank, dorsolateral prostate, and tail vein to obtain real-time subcutaneous, orthotopic, and metastasis indicators, respectively. We used this technique to confirm the therapeutic effect of immune checkpoint blockade. Our findings suggest the presented indicators are ideally suited for real-time tracking of drug responses, tumor progression and immune function.
PMCID: PMC5078072  PMID: 27105511
prostate cancer; bioluminescence imaging; prostate specific antigen; immunotherapy; preclinical model
6.  Proteomic profiling of cellulase-aid-extracted membrane proteins for functional identification of cellulose synthase complexes and their potential associated- components in cotton fibers 
Scientific Reports  2016;6:26356.
Cotton fibers are an excellent model for understanding of cellulose biosynthesis in higher plants. In this study, we determined a high cellulose biosynthesis activity in vitro by optimizing biochemical reaction conditions in cotton fibers. By adding a commercial cellulase enzyme into fibers extraction process, we extracted markedly higher levels of GhCESA1 and GhCESA8 proteins and observed an increase in β-1,4-glucan and β-1,3-glucan products in vitro. LC-MS/MS analysis of anti-GhCESA8-immunoprecipitated proteins showed that 19 proteins could be found in three independent experiments including four CESAs (GhCESA1,2,7,8), five well-known non-CESA proteins, one callose synthase (CALS) and nine novel proteins. Notably, upon the cellulase treatment, four CESAs, one CALS and four novel proteins were measured at relatively higher levels by calculating total peptide counts and distinct peptide numbers, indicating that the cellulase-aid-extracted proteins most likely contribute to the increase in β-glucan products in vitro. These results suggest that the cellulase treatment may aid to release active cellulose synthases complexes from growing glucan chains and make them more amenable to extraction. To our knowledge, it is the first time report about the functional identification of the potential proteins that were associated with plant cellulose and callose synthases complexes by using the cellulase-aided protein extraction.
PMCID: PMC4872218  PMID: 27192945
7.  Fibre elongation requires normal redox homeostasis modulated by cytosolic ascorbate peroxidase in cotton (Gossypium hirsutum) 
Journal of Experimental Botany  2016;67(11):3289-3301.
Optimal H2O2 levels and redox state regulated by cytosolic ascorbate peroxidase are key mechanisms regulating fibre elongation in cotton.
High-quality cotton fibre equates to a more comfortable textile. Fibre length is an important index of fibre quality. Hydrogen peroxide (H2O2) acts as a signalling molecule in the regulation of fibre elongation. Results from in vitro ovule culture suggest that the alteration of fibre cell H2O2 levels affects fibre development. Ascorbate peroxidase (APX) is an important reactive oxygen species (ROS) scavenging enzyme, and we found that GhAPX1AT/DT encoded one member of the previously unrealized group of cytosolic APXs (cAPXs) that were preferentially expressed during the fibre elongation stage. Transgenic cottons with up- and down-regulation of GhAPX1AT/DT were generated to control fibre endogenous levels of H2O2. Suppression of all cAPX (IAO) resulted in a 3.5-fold increase in H2O2 level in fibres and oxidative stress, which significantly suppressed fibre elongation. The fibre length of transgenic lines with over-expression or specific down-regulation of GhAPX1AT/DT did not show any obvious change. However, the fibres in the over-expression lines exhibited higher tolerance to oxidative stress. Differentially expressed genes (DEGs) in fibres at 10 days post-anthesis (DPA) of IAO lines identified by RNA-seq were related to redox homeostasis, signalling pathways, stress responses and cell wall synthesis, and the DEGs that were up-regulated in IAO lines were also up-regulated in the 10 DPA and 20 DPA fibres of wild cotton compared with domesticated cotton. These results suggest that optimal H2O2 levels and redox state regulated by cytosolic APX are key mechanisms regulating fibre elongation, and dysregulation of the increase in H2O2 induces oxidative stress and results in shorter fibres by initiating secondary cell wall-related gene expression.
PMCID: PMC4892722  PMID: 27091877
Cytosolic ascorbate peroxidase; fibre elongation; Gossypium hirsutum; hydrogen peroxide; oxidative stress; redox homeostasis.
8.  ROS Homeostasis Regulates Somatic Embryogenesis via the Regulation of Auxin Signaling in Cotton*  
Somatic embryogenesis (S.E.) is a versatile model for understanding the mechanisms of plant embryogenesis and a useful tool for plant propagation. To decipher the intricate molecular program and potentially to control the parameters affecting the frequency of S.E., a proteomics approach based on two-dimensional gel electrophoresis (2-DE) combined with MALDI-TOF/TOF was used. A total of 149 unique differentially expressed proteins (DEPs) were identified at different stages of cotton S.E. compared with the initial control (0 h explants). The expression profile and functional annotation of these DEPs revealed that S.E. activated stress-related proteins, including several reactive oxygen species (ROS)-scavenging enzymes. Proteins implicated in metabolic, developmental, and reproductive processes were also identified. Further experiments were performed to confirm the role of ROS-scavenging enzymes, suggesting the involvement of ROS homeostasis during S.E. in cotton. Suppressing the expression of specifically identified GhAPX proteins resulted in the inhibition of dedifferentiation. Accelerated redifferentiation was observed in the suppression lines of GhAPXs or GhGSTL3 in parallel with the alteration of endogenous ascorbate metabolism and accumulation of endogenous H2O2 content. Moreover, disrupting endogenous redox homeostasis through the application of high concentrations of DPI, H2O2, BSO, or GSH inhibited the dedifferentiation of cotton explants. Mild oxidation induced through BSO treatment facilitated the transition from embryogenic calluses (ECs) to somatic embryos. Meanwhile, auxin homeostasis was altered through the perturbation of ROS homeostasis by chemical treatments or suppression of ROS-scavenging proteins, along with the activating/suppressing the transcription of genes related to auxin transportation and signaling. These results show that stress responses are activated during S.E. and may regulate the ROS homeostasis by interacting with auxin signaling.
PMCID: PMC5083107  PMID: 27073181
9.  ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma 
Oncotarget  2016;7(13):16910-16922.
Interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, is known for its anti-viral capacity. However, its role in tumorigenesis remains controversial. Here, using RNA-seq profiling analysis, we identified ISG15 as a differentially expressed gene in nasopharyngeal carcinoma (NPC) and validated its overexpression in NPC samples and cells. High ISG15 levels in NPC tissues were correlated with more frequent local recurrence and shorter overall survival and disease-free survival. ISG15 overexpression promoted a cancer stem cell phenotype in NPC cells, including increased colony and tumorsphere formation abilities, pluripotency-associated genes expression, and in vivo tumorigenicity. By contrast, knockdown of ISG15 attenuated stemness characteristics in NPC cells. Furthermore, overexpression of ISG15 increased NPC cell resistance to radiation and cisplatin (DDP) treatment. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for NPC.
PMCID: PMC4941359  PMID: 26919245
interferon-stimulated gene 15; nasopharyngeal carcinoma; prognosis; cancer stem cell
10.  Giant seminoma in an undescended testicle metastasizing to the neck and liver 
Molecular and Clinical Oncology  2016;4(6):983-985.
Germ cell tumors account for 98% of all testicular malignancies. Delays in seeking treatment are unfortunately common and may lead to metastatic spread. The present study reported a case of a 24-year-old man with a giant 12×10 cm left inguinal mass and a left neck mass that had grown rapidly during recent months. Computed tomography confirmed that the mass measured 12.1×9.4 cm and was a left undescended testicle malignancy, and also revealed widespread metastasis to the liver and a large retroperitoneal mass (12.6×8.2 cm). Immunohistochemical staining confirmed seminoma. The patient was treated with chemotherapy with the VIP protocol (cisplatin, etoposide and ifosfamide). Following courses of chemotherapy, the patient received complete clinical remission and was disease-free at the 6 month follow-up.
PMCID: PMC4887944  PMID: 27284433
cryptorchidism; chemotherapy; complete remission; late metastasis; seminoma
11.  Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation 
Cell Stress & Chaperones  2015;20(5):787-792.
Cellular senescence of endothelial cells is a damage and stress response which induces pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotypes. Donepezil is a drug used for the treatment of mild to moderate dementia of the Alzheimer’s disease (AD). The aim of the present study was to investigate the attenuation of endothelial cell senescence by donepezil and to explore the mechanisms underlying the anti-aging effects of donepezil. Our results indicated that high glucose (HG) markedly decreased cell viability of human umbilical vein endothelial cells (HUVECs), and this phenomenon was reversed by treatment with donepezil. Importantly, our results displayed that the frequency of senescent (SA-ß-gal-positive) cells and the expression level of senescence genes (PAI-1 and p21) were significantly higher in the HG group compared with the normal glucose (NG) group, and these changes were blocked by treatment with donepezil. Also, our results showed that donepezil inhibits the generation of reactive oxygen species (ROS), which promotes cellular senescence. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with donepezil. Indeed, our results indicated that donepezil increased the SIRT1 enzyme activity. Therefore, these results show that donepezil delays cellular senescence that is promoted under HG condition via activation of SIRT1.
PMCID: PMC4529865  PMID: 26194321
Alzheimer’s disease; Donepezil; Senescence; SIRT1
12.  miR-125b acts as a tumor suppressor in chondrosarcoma cells by the sensitization to doxorubicin through direct targeting the ErbB2-regulated glucose metabolism 
Chondrosarcoma is the second most common type of primary bone malignancy in the United States after osteosarcoma. Surgical resections of these tumors are the only effective treatment to chondrosarcoma patients due to their resistance to conventional chemo- and radiotherapy. In this study, miR-125b was found to perform its tumor-suppressor function to inhibit glucose metabolism via the direct targeting of oncogene, ErbB2. We report miR-125b was downregulated in both chondrosarcoma patient samples and cell lines. The total 20 Asian chondrosarcoma patients showed significantly downregulated miR-125b expression compared with normal tissues. Meanwhile, miR-125 was downregulated in chondrosarcoma cells and doxorubicin resistant cells. Overexpression of miR-125 enhanced the sensitivity of both parental and doxorubicin resistant cells to doxorubicin through direct targeting on the ErbB2-mediated upregulation of glycolysis in chondrosarcoma cells. Moreover, restoration of the expression of ErbB2 and glucose metabolic enzymes in miR-125 pretransfected cells recovered the susceptibility to doxorubicin. Our study will provide a novel aspect on the overcoming chemoresistance in human chondrosarcoma cells and may help in the development of therapeutic strategies for the treatments of patients.
PMCID: PMC4771406  PMID: 26966351
miR-125b; chondrosarcoma; doxorubicin; glucose metabolism; sensitization
13.  Embryonal rhabdomyosarcoma of the epididymis presenting as epididymitis: A case report 
Molecular and Clinical Oncology  2016;4(4):625-627.
Paratesticular rhabdomyosarcoma (RMS) is an extremely rare malignancy in adults, accounting for 7% of all RMS cases and 6% of all non-germinal intrascrotal tumors. The clinical signs are similar to those of a hydrocele or testicular tumor, typically presenting as a unilateral, painless mass in the inguinal canal or scrotum. No specific serum markers are currently available for this tumor. RMS of the epididymis is extremely rare. Particularly when it is associated with epididymitis, this malignancy is usually overlooked. We herein present a case of epididymal embryonal RMS, manifesting an painful scrotal edema, misdiagnosed as epididymitis. The patient received 3 cycles of adjuvant chemotherapy postoperatively and remained disease-free after 4 years of follow-up.
PMCID: PMC4812556  PMID: 27073679
embryonal rhabdomyosarcoma; epididymis; epididymitis
14.  A Novel FC116/BC10 Mutation Distinctively Causes Alteration in the Expression of the Genes for Cell Wall Polymer Synthesis in Rice 
We report isolation and characterization of a fragile culm mutant fc116 that displays reduced mechanical strength caused by decreased cellulose content and altered cell wall structure in rice. Map-based cloning revealed that fc116 was a base substitution mutant (G to A) in a putative beta-1,6-N-acetylglucosaminyltransferase (C2GnT) gene (LOC_Os05g07790, allelic to BC10). This mutation resulted in one amino acid missing within a newly-identified protein motif “R, RXG, RA.” The FC116/BC10 gene was lowly but ubiquitously expressed in the all tissues examined across the whole life cycle of rice, and slightly down-regulated during secondary growth. This mutant also exhibited a significant increase in the content of hemicelluloses and lignins, as well as the content of pentoses (xylose and arabinose). But the content of hexoses (glucose, mannose, and galactose) was decreased in both cellulosic and non-cellulosic (pectins and hemicelluloses) fractions of the mutant. Transcriptomic analysis indicated that the typical genes in the fc116 mutant were up-regulated corresponding to xylan biosynthesis, as well as lignin biosynthesis including p-hydroxyphenyl (H), syringyl (S), and guaiacyl (G). Our results indicate that FC116 has universal function in regulation of the cell wall polymers in rice.
PMCID: PMC5030303  PMID: 27708650
rice; cell wall; cellulose; fragile culm; mechanical strength
15.  Ascorbate Alleviates Fe Deficiency-Induced Stress in Cotton (Gossypium hirsutum) by Modulating ABA Levels 
Fe deficiency causes significant losses to crop productivity and quality. To understand better the mechanisms of plant responses to Fe deficiency, we used an in vitro cotton ovule culture system. We found that Fe deficiency suppressed the development of ovules and fibers, and led to tissue browning. RNA-seq analysis showed that the myo-inositol and galacturonic acid pathways were activated and cytosolic APX (ascorbate peroxidase) was suppressed in Fe-deficient treated fibers, which increased ASC (ascorbate) concentrations to prevent tissue browning. Suppression of cytosolic APX by RNAi in cotton increased ASC contents and delayed tissue browning by maintaining ferric reduction activity under Fe-deficient conditions. Meanwhile, APX RNAi line also exhibited the activation of expression of iron-regulated transporter (IRT1) and ferric reductase–oxidase2 (FRO2) to adapt to Fe deficiency. Abscisic acid (ABA) levels were significantly decreased in Fe-deficient treated ovules and fibers, while the upregulated expression of ABA biosynthesis genes and suppression of ABA degradation genes in Fe-deficient ovules slowed down the decreased of ABA in cytosolic APX suppressed lines to delay the tissue browning. Moreover, the application of ABA in Fe-deficient medium suppressed the development of tissue browning and completely restored the ferric reduction activity. In addition, ABA 8′-hydroxylase gene (GhABAH1) overexpressed cotton has a decreased level of ABA and shows more sensitivity to Fe deficiency. Based on the results, we speculate that ASC could improve the tolerance to Fe deficiency through activating Fe uptake and maintaining ABA levels in cotton ovules and fibers, which in turn reduces symptom formation.
PMCID: PMC5209387
abscisic acid; ascorbate; cotton fiber; cytosolic APX; Fe deficiency
16.  Detection of epidermal growth factor receptor mutation in plasma as a biomarker in Chinese patients with early-stage non-small cell lung cancer 
OncoTargets and therapy  2015;8:3289-3296.
This preplanned exploratory analysis was conducted to reveal the true status of correlation between tissue and plasma detection for early-stage non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutations, knowing that specific subgroups of NSCLC patients may be potential candidates for EGFR mutation analysis by using plasma samples.
Materials and methods
Tissue samples were surgically resected from 198 patients with stage I–IV NSCLC, where stage IA to IIIA accounted for 92.4%. EGFR mutations in all these tissues were positive. Paired plasma EGFR mutations were detected by real-time polymerase chain reaction; concentration of cell-free DNA (cfDNA) in plasma was measured by ultraviolet spectrophotometry.
EGFR-activating mutation was detected in 34 plasma samples, and their mutation types were matched with that in tissue. The sensitivity of EGFR mutation for the 198 paired tissue and plasma samples was 17.2%. The sensitivity positively correlated with disease stage and negatively correlated with tumor differentiation. The sensitivity of stage IA, IB, IIA, IIB, and IIIA was 1.6%, 7.9%, 11.1%, 20%, and 33.3%, respectively; the sensitivity of high differentiation was 0% versus 36.8% for poor differentiation. There was no correlation between plasma cfDNA concentration and patient characteristics.
We recommend using plasma cfDNA as a biomarker in stage IIIA or poorly differentiated tumors for gene diagnosis, especially in patients whose tissue samples cannot be obtained by surgery. Plasma samples can really reflect the patients’ EGFR mutation types and may contain comprehensive genotypic information that comes from different parts of the tumor than tissue specimens. The concentration of plasma cfDNA does not vary with patient characteristics.
PMCID: PMC4644181  PMID: 26609241
EGFR mutations; NSCLC; plasma; early stage; ARMS; targeted therapy
17.  A combination of YM-155, a small molecule survivin inhibitor, and IL-2 potently suppresses renal cell carcinoma in murine model 
Oncotarget  2015;6(25):21137-21147.
YM155, a small molecule inhibitor of the antiapoptotic protein survivin, has been developed as a potential anti-cancer drug. We investigated a combination therapy of YM155 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). YM155 caused cell cycle arrest and apoptosis in renal cancer (RENCA) cells. Next, luciferase-expressing RENCA cells were implanted in the left kidney and the lung of BALB/c mice to develop RCC metastatic model. In this orthotopic renal and metastatic lung tumors models, YM155 and IL-2 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Also, the combination significantly suppressed regulatory T cells and myeloid-derived suppressor cells compared with single agent treatment. We suggest that a combination of YM155 and IL-2 can be tested as a potential therapeutic modality in patients with RCC.
PMCID: PMC4673255  PMID: 26023798
renal cell carcinoma; YM155; interleukin-2; IVIS; Treg; MDSCs
18.  Reduced USP39 expression inhibits malignant proliferation of medullary thyroid carcinoma in vitro 
Medullary thyroid carcinoma (MTC) constitutes approximately 5 % of all thyroid cancers and carries a worse prognosis than other differentiated thyroid cancers. Targeted therapies are being investigated for systemic treatment of MTC. Ubiquitin-specific peptidase 39 (USP39) functions in pre-mRNA splicing as a component of the U4/U6-U5 tri-snRNP and also participates in spindle checkpoint and cytokinesis. In this study, we aimed to evaluate the potential role in MTC.
We used lentivirus-delivered short hairpin RNA (shRNA) to silence USP39 expression in one MTC cell line TT. USP39 expression was detected by qPCR and Western blot. For functional analysis, MTT assay was performed to evaluate the proliferation activity, and FACS was used to assess the cell distribution in the cell cycle. Moreover, the expressions of cell cycle-related proteins were examined by Western blot.
Both two shRNA sequences against USP39 could efficiently reduce its expression in TT cells. Knockdown of USP39 significantly decreased cell proliferation and caused cell cycle arrest at G2/M phase. Moreover, G2/M phase-associated proteins, Cyclin B1 and CDK1, were obviously down-regulated in TT cells after USP39 silencing.
Therefore, knockdown of USP39 is likely to provide a novel alternative to targeted therapy of MTC and deserves further investigation.
PMCID: PMC4549085  PMID: 26303214
Medullary thyroid carcinoma; Ubiquitin-specific peptidase 39; shRNA; Targeted therapy
19.  Gene expression profile of human esophageal squamous carcinoma cell line TE-1 
Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly causes of cancer worldwide. However, to date, the mechanisms underlying its pathogenesis remain unclear. The present study investigated the gene expression profile of human esophageal cancer cell line TE-1, a cell model for ESCC, to gain insight to the genetic regulation of this disease. Human esophageal cancer TE-1 cells and normal esophageal HET-1A cells were cultured for isolation of total RNA. Differential expression of RNA transcripts was assessed using the Agilent 4×44 K microarray, combined with real-time PCR (qRT-PCR) for validation. Classification and function of the differential genes were illustrated by bioinformatics processing including hierarchical clustering and gene ontology (GO) analysis. We identified 4,986 transcripts with differential expression (fold-change ≥1.5, P<0.05), including 2,368 up-regulated and 2,618 down-regulated transcripts. GO analysis showed that the dysregulated transcripts were associated with biological process, cellular component, and molecular function. After bioinformatic analysis of significantly regulated signaling pathways, we found these transcripts may target 35 gene pathways, including p53 signaling, glioma, ubiquitin-mediated proteolysis, insulin signaling, cell cycle, inositol phosphate metabolism, mTOR signaling, and MAPK signaling. The differentially expressed transcripts were screened between the esophageal cancer cell line TE-1 and normal esophageal cell line HET-1A, as well as their target gene pathways. Further data mining is related to prevention and treatment of esophageal cancer.
PMCID: PMC4613095  PMID: 26550410
Esophageal cancer; cDNA microarray; differential gene expression; cell line
20.  Free Migration of Intraocular Glass in Aphakia after Glaucoma Surgery 
Case Reports in Ophthalmology  2015;6(2):269-271.
To describe a case of free migration of intraocular glass in aphakia after glaucoma surgery.
We report the case of a 27-year-old man with a history of perforating injury to the right eye 10 years previously and glaucoma surgery 1 year previously presenting with 1 month of pain and frequent floaters in front of the right eye. On examination, the glass fragment was seen to lie free in the anterior chamber or migrate backwards through the pupil, remaining mobile on the inferior retinal surface when the patient was prone or supine, respectively.
The fragment was surgically removed.
Late migration of glass intraocular foreign bodies is a rare clinical entity, and the exact mechanism causing the migration of intraocular glass remains controversial. Early intervention must be weighed against the hazards of removal and the necessity of close follow-up.
PMCID: PMC4553914  PMID: 26327913
Glass intraocular foreign bodies; Glaucoma surgery; Corneal edema
21.  Positive selection drives adaptive diversification of the 4-coumarate: CoA ligase (4CL) gene in angiosperms 
Ecology and Evolution  2015;5(16):3413-3420.
Lignin and flavonoids play a vital role in the adaption of plants to a terrestrial environment. 4-Coumarate: coenzyme A ligase (4CL) is a key enzyme of general phenylpropanoid metabolism which provides the precursors for both lignin and flavonoids biosynthesis. However, very little is known about how such essential enzymatic functions evolve and diversify. Here, we analyze 4CL sequence variation patterns in a phylogenetic framework to further identify the evolutionary forces that lead to functional divergence. The results reveal that lignin-biosynthetic 4CLs are under positive selection. The majority of the positively selected sites are located in the substrate-binding pocket and the catalytic center, indicating that nonsynonymous substitutions might contribute to the functional evolution of 4CLs for lignin biosynthesis. The evolution of 4CLs involved in flavonoid biosynthesis is constrained by purifying selection and maintains the ancestral role of the protein in response to biotic and abiotic factors. Overall, our results demonstrate that protein sequence evolution via positive selection is an important evolutionary force driving adaptive diversification in 4CL proteins in angiosperms. This diversification is associated with adaption to a terrestrial environment.
PMCID: PMC4569036  PMID: 26380674
4-Coumarate: coenzyme A ligase; diversification; evolution; phylogeny; positive selection
22.  The application of porous tantalum cylinder to the repair of comminuted bone defects: a study of rabbit firearm injuries 
The aim of this study is to investigate the effect of porous tantalum material in repair tibial defects caused by firearm injuries in a rabbit model. A multifunctional biological impact machine was used to establish a rabbit tibial defect model of firearm injury. Porous tantalum rods were processed into a hollow cylinder. Kirschner wires were used for intramedullary fixation. We compared the differences of the bone ingrowth of the porous tantalum material by gross observations, X-rays and histological evaluations. The radiographic observations revealed that fibrous tissue covered the material surface after 4 weeks, and periosteal reactions and new bone callus extending materials appeared after 8 weeks. After 16 weeks, the calluses of the firearm injury group were completely wrapped around a porous tantalum material. The group with the highest Lane-Sandhu X-rays cores was the firearm injury and tantalum implant group, and the blank control group exhibited the lowest scores. The histological evaluations revealed that the presence of new bone around the biomaterial had grown into the porous tantalum. By the 16th week, the areas of bone tissue of the firearm injury group was significant higher than that of non-firearm injury group (P<0.05). The comminuted fractures treated with tantalum cylinders exhibited greater bone ingrowth in the firearm injury group. In conditions of firearm injuries, the porous tantalum biomaterial exhibited bone ingrowth that was beneficial to the treatment of bone defects.
PMCID: PMC4483870  PMID: 26131078
Firearm injury; tibial defect; porous tantalum
23.  Increased expression of metastasis-associated in colon cancer-1 in renal cell carcinoma is associated with poor prognosis 
Metastasis-associated in colon cancer-1 (MACC1) expression in tumor specimens is an independent prognostic indicator of metastasis, which has recently gained considerable attention in cancer research, due to its overexpression in several types of carcinoma. However, MACC1 expression patterns and its possible role in renal cell carcinoma remain unknown. This study aimed to investigate MACC1 expression in renal cell carcinoma via immunohistochemical analysis and determine the relationship between MACC1 expression and cancer prognosis. Positive MACC1 expression was found to significantly correlate with distant metastasis and TNM stage (P < 0.05). A Kaplan-Meier survival analysis revealed that patients with higher MACC1 expression had a significantly lower disease-free rate (P < 0.05). These results indicate that MACC1 expression is significantly associated with prognosis in patients with renal cell carcinoma. To the best of our knowledge, this is the first study on the significance of MACC1 as a prognostic marker in renal cell carcinoma. MACC1 expression may be a useful target for the development of new therapeutic approaches, including molecular targeted therapeutic agents, for renal cell carcinoma.
PMCID: PMC4466956  PMID: 26097569
MACC1; renal cell carcinoma; prognosis; biomarker
25.  Impact of phosphomimetic and non-phosphorylatable mutations of phospholemman on L-type calcium channels gating in HEK 293T cells 
Phospholemman (PLM) is an important phosphorylation substrate for protein kinases A and C in the heart. Until now, the association between PLM phosphorylation status and L-type calcium channels (LTCCs) gating has not been fully understood. We investigated the kinetics of LTCCs in HEK 293T cells expressing phosphomimetic or nonphosphorylatable PLM mutants.
The LTCCs gating was measured in HEK 293T cells transfected with LTCC and wild-type (WT) PLM, phosphomimetic or nonphosphorylatable PLM mutants: 6263AA, 6869AA, AAAA, 6263DD, 6869DD or DDDD.
WT PLM significantly slowed LTCCs activation and deactivation while enhanced voltage-dependent inactivation (VDI). PLM mutants 6869DD and DDDD significantly increased the peak of the currents. 6263DD accelerated channel activation, while 6263AA slowed it more than WT PLM. 6869DD significantly enhanced PLM-induced increase of VDI. AAAA slowed the channel activation more than 6263AA, and DDDD accelerated the channel VDI more than 6869DD.
Our results demonstrate that phosphomimetic PLM could stimulate LTCCs and alter their dynamics, while PLM nonphosphorylatable mutant produced the opposite effects.
PMCID: PMC4369820  PMID: 25656605
phospholemman; phosphorylation sites mutation; L-type calcium channels; activation; voltage-dependent inactivation; deactivation

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