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1.
Nucleic Acids Res ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584083

RESUMO

We have found recently that nuclear uptake of the cell-impermeable DNA light-switching Ru(II)-polypyridyl cationic complexes such as [Ru(bpy)2(dppz)]Cl2 was remarkably enhanced by pentachlorophenol (PCP), by forming ion-pairing complexes via a passive diffusion mechanism. However, it is not clear whether the enhanced nuclear uptake of [Ru(bpy)2(dppz)]2+ is only limited to PCP, or it is a general phenomenon for other highly chlorinated phenols (HCPs); and if so, what are the major physicochemical factors in determining nuclear uptake? Here, we found that the nuclear uptake of [Ru(bpy)2(dppz)]2+ can also be facilitated by other two groups of HCPs including three tetrachlorophenol (TeCP) and six trichlorophenol (TCP) isomers. Interestingly and unexpectedly, 2,3,4,5-TeCP was found to be the most effective one for nuclear delivery of [Ru(bpy)2(dppz)]2+, which is even better than the most-highly chlorinated PCP, and much better than its two other TeCP isomers. Further studies showed that the nuclear uptake of [Ru(bpy)2(dppz)]2+ was positively correlated with the binding stability, but to our surprise, inversely correlated with the lipophilicity of the ion-pairing complexes formed between [Ru(bpy)2(dppz)]Cl2 and HCPs. These findings should provide new perspectives for future investigations on using ion-pairing as an effective method for delivering other bio-active metal complexes into their intended cellular targets.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31584262

RESUMO

The development of hydrogels with the excellent mechanical properties are highly desirable in both fundamental studies and practical applications. But it is difficult to construct the hydrogels both tough and stiff at the same time, as those properties often contradict each other. Here, we reported a facile and efficient method for ultrastiff and tough PNIPAM/clay plastic-like hydrogels (PHs) by immersing PNIPAM/clay hydrogel into NaCl aqueous solution. The optimized PH-2-6 presented superior strength, modulus, and toughness (4.1 ± 0.2MPa, 41.6 ± 8 MPa, and 15.85 ± 0.8 MJ m-3, respectively). The unique mechanical properties are attributed to the synergistic effect the osmotic pressure and strong affinity between Na+ ion and PNIPAM chain, which lead to high degree of PNIPAM chains entanglement and fixing. Note that the PHs were molded into any required shapes under an applied force, and retained permanently their shapes even if the load was removed, thus dispalying a typical plasticity. However, the deformed PHs could return to its original size and softness of hydrogel when immersing them into pure water, which is a kind of shape memory effect. The reversible conversion of elasticity and plasticity and shape memory come from a kind of dynamic physical across-linking of Na+ and PNIPAM molecular chains, which could exist in the salt aqueous and disintegrate in water reversibly. Moreover, the mechnical properties of hydrogel can be tuned by adjusting salt concentration and immersion time. The facile strategy may enrich the avenue in develping hydrogels with such versatile dynamic behaviors to expend their applications.

3.
Hepatology ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509261

RESUMO

We found that lncRNA PDIA3P1 (protein disulfide isomerase family A member 3 pseudogene 1) was up-regulated in multiple cancer types and upon treatment with DNA-damaging chemotherapeutic agents, like doxorubicin (Dox). Higher PDIA3P1 level was associated with poorer recurrence-free survival of human hepatocellular carcinoma (HCC). Both gain- and loss-of-function studies revealed that PDIA3P1 protected cancer cells from Dox-induced apoptosis and allowed tumor xenografts to grow faster and to be more resistant to Dox treatment. Mechanistically, miR-125a/b and miR-124 suppressed the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), but PDIA3P1 bound to miR-125a/b/miR-124 and relieved their repression on TRAF6, leading to activation of the nuclear factor-K B (NF-K B) pathway. Consistently, the effect of PDIA3P1 inhibition in promoting Dox-triggered apoptosis was antagonized by silencing the inhibitor of K Bα (IK Bαor overexpressing TRAF6. Administration of BAY 11-7085, an NF-K B inhibitor, attenuated PDIA3P1-induced resistance to Dox treatment in mouse xenografts. Moreover, up-regulation of PDIA3P1 was significantly correlated with elevation of TRAF6, phosphorylated p65, or NF-K B downstream anti-apoptosis genes in human HCC tissues. These data indicate that enhanced PDIA3P1 expression may confer chemoresistance by acting as a microRNA (miRNA) sponge to increase TRAF6 expression and augment NF-K B signaling. Subsequent investigations into the mechanisms of PDIA3P1 up-regulation revealed that human homologue of mRNA transport mutant 4 (hMTR4), which promotes RNA degradation, could bind to PDIA3P1, and this interaction was disrupted by Dox treatment. Overexpression of hMTR4 attenuated Dox-induced elevation of PDIA3P1, whereas silencing hMTR4 increased PDIA3P1 level, suggesting that Dox may up-regulate PDIA3P1 by abrogating the hMTR4-mediated PDIA3P1 degradation CONCLUSION: There exists a novel hMTR4-PDIA3P1-miR-125/124-TRAF6 regulatory axis that promotes NF-K B signaling and chemoresistance, which may be exploited for anticancer therapy.

4.
Biomater Sci ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31552923

RESUMO

One-dimensional hydroxyapatite (HA) particularly mimics the structure of mineralized collagen fibrils and displays superior mechanical properties such as toughness. Herein, we report Se-doped HA/chitosan (Se-HA/CS) biopapers constructed with self-assembled Se-doped HA nanowires and chitosan. The Se-HA/CS biopapers with high flexibility and manufacturability can not only be further processed into arbitrary shapes by folding or using scissors but also display high performances in in vitro/vivo anti-bone tumor studies. The Se-HA/CS biopapers are more inclined to inhibit the growth of tumor cells (HCS 2/8 and SJSA cells) than that of normal human bone marrow stromal cells (hBMSCs). The potential mechanisms of this meaningful anti-tumor effect were investigated, such as reactive oxygen species accumulation and the activation of apoptosis and the underlying signal pathway involved (including caspase family, Bcl-2 family and JNK/STAT3). The results demonstrate that Se-HA/CS biopapers may inhibit the growth of HCS 2/8 and SJSA cells by synchronously inducing JNK activation and STAT3 inhibition and consequently promote the apoptosis of these cells. Furthermore, the in vivo anti-tumor studies confirm that the Se-HA/CS biopapers obviously suppress the growth of patient-derived xenograft tumor models.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31532051

RESUMO

NIR light-responsive nanoplatforms hold great promise for on-demand drug release in precision cancer medicine. However, currently available systems utilize "always-on" photothermal transducers that lack target specificity, thus inaccurately differentiating tumors from normal tissues. Here, we develop a theranostic nanoplatform endowing H2S-mediated in situ production of NIR photothermal agents for imaging-guided and photocontrolled drug release with targeting ability for H2S-rich cancers. This nanoplatform shows H2S-activatable NIR-II emission and NIR light-controllable release of a drug Camptothecin-11. By administrating HCT116 tumor-bearing mice, we find that the tumor is greatly suppressed with minimal side effects, which arises from the cancer-specific and NIR light-activated synergistic therapy. This theranostic nanoplatform thus sheds light on precision medicine with NIR-II imaging guidance.

6.
Gut Liver ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31547641

RESUMO

The recurrence of colorectal polyps is caused by various factors and leads to the carcinogenesis of colorectal cancer, which ranks third in incidence and fourth in mortality among cancers worldwide. The potential risk factors for colorectal polyp recurrence have been demonstrated in multiple trials. However, an article that pools and summarizes the various results is needed. This review enumerates and analyzes some risk factors in terms of patient characteristics, procedural operations, polyp characteristics, and dietary aspects to propose some effective prophylactic measures. This review aimed to provide a reference for clinical application and guide patients to prevent colorectal polyp recurrence in a more effective manner.

7.
Ying Yong Sheng Tai Xue Bao ; 30(9): 3224-3232, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31529898

RESUMO

To solve the problem of soil acidification in the cultivation of Codonopsis tangshen, laboratory experiments were carried out to investigate C. tangshen seed germination, seedling growth and soil exchangeable acid, microbial community structure after applying quicklime (QL) and calcium magnesium phosphate fertilizer (CMP). The results showed that QL and CMP treatments significantly improved the survival rate of C. tangshen seedlings from 147.7% to 326.7% and from 270.1% to 311.2%, respectively. The maximum increase rates of the height of C. tangshen seedlings were 516.7% and 546.3%, and that of root length were 798.0% and 679.2% in the treatments of QL and CMP, respectively. 1‰-4‰ QL or CMP treatments increased the relative chlorophyll content, antioxidant enzyme activity and the content of soluble protein of C. tangshen seedlings, decreased the content of malondialdehyde and superoxide anion radical of seedlings, increased soil pH by 0.88-2.02 units and 0.23-1.19 units, and decreased the exchangeable aluminum content in soil by 53.0%-95.3% and 17.6%-81.3%, respectively. Soil bacterial and actinomycetic abundances were significantly higher in 2‰-4‰ QL or CMP treatments than that in the control. Soil fungal abundance was significantly lower in the QL treatment of 2‰ and CMP treatment of 4‰. 1‰-4‰ QL or CMP treatments significantly increased fresh weight of C. tangshen tubers by 40.5%-78.5% and 28.4%-78.8%, respectively. In conclusion, the suitable quantity of QL and CMP for acidified soil (pH=4.12, ρb=1.15 g·cm-3, tillage layer=15 cm) amendment were 1.73-3.45 t·hm-2 and 3.45-6.90 t·hm-2, and QL and CMP amendment could fit the optimum soil pH (5.5-6.5) for the growth of C. tangshen seedlings.


Assuntos
Codonopsis/crescimento & desenvolvimento , Fertilizantes , Fosfatos , Compostos de Cálcio , Medicamentos de Ervas Chinesas , Óxidos , Solo
8.
Sensors (Basel) ; 19(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505879

RESUMO

This paper proposed an optimal spectral resolution for diagnosing cadmium-lead (Cd-Pb) cross contamination with different pollution levels based on the hyperspectral reflectance of rice canopy. Feature bands were sequentially selected by two-way analysis of variance (ANOVA2) and random forests from the high-dimensional hyperspectral data after preprocessing. Then Support Vector Machine (SVM) was applied to diagnose the pollution levels using different feature bands combination with different spectral resolutions and cross validation was conducted to evaluate the distinguishing accuracies. Finally, the optimal spectral resolution could be determined by comparing the diagnosing accuracies of the optimal feature bands combination in each spectral resolution. In the experiments, the hyperspectral reflectance data of rice canopy with ten different spectral resolutions was captured, covering 16 pretreatments of Cd and Pb pollution. The experimental results showed the optimal spectral resolution was 9 nm with the highest average accuracy of 0.71 and relatively standard deviation of 0.07 for diagnosing the categories and levels of Cd-Pb cross contamination. The useful exploration provided an evidence for optimal spectral resolution selection to reduce the cost of heavy metal pollution diagnose.

9.
Anal Chem ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31509397

RESUMO

Effective extension of mass spectrometry-based proteomics to single cells remains challenging. Herein we combined microfluidic nanodroplet technology with tandem mass tag (TMT) isobaric labeling to significantly improve analysis throughput and proteome coverage for single mammalian cells. Isobaric labeling facilitated multiplex analysis of single cell-sized protein quantities to a depth of ∼1 600 proteins with a median CV of 10.9% and correlation coefficient of 0.98. To demonstrate in-depth high throughput single cell analysis, the platform was applied to measure protein expression in 72 single cells from three murine cell populations (epithelial, immune, and endothelial cells) in <2 days instrument time with over 2 300 proteins identified. Principal component analysis grouped the single cells into three distinct populations based on protein expression with each population characterized by well-known cell-type specific markers. Our platform enables high throughput and unbiased characterization of single cell heterogeneity at the proteome level.

10.
Int J Cancer ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509622

RESUMO

The N6 -Methyladenosine (m6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here we first systematically investigate the association of variants related to m6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (OR = 0.88, 95% CI= 0.84-0.92, P = 4.85×10-8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m6 A modification was catalysed by the "writer" complex (METTL3, METTL14 or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m6 A level, highlighting a clinical potential of variants-associated m6 A modification as a risk marker for CRC prevention. This article is protected by copyright. All rights reserved.

11.
J Oleo Sci ; 68(9): 863-871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484902

RESUMO

The variations in average particle size, zeta potential, free fatty acids (FFA) release rate, and the bioavailability of menthol under in vitro simulated digestion conditions of peppermint oil nanoemulsion were investigated. 3D confocal laser scanning microscopy and Cryo-scanning electron microscopy were used to observe the microstructure characteristics of peppermint oil nanoemulsion, which indicated that soybean protein was completely adsorbed at the oil-water interface of the nanoemulsion and presented a core shell structure. And the results indicated that FFA release rate and menthol bioavailability of peppermint oil nanoemulsion prepared by using high-pressure homogenization were much higher. In the simulated gastric digestion phase, the average particle size and the zeta potential of the nanoemulsion increased, and droplet polymerization appeared. After the simulated intestinal, the interfacial protein of nanoemulsion was hydrolyzed, and the oil droplets were digested, which resulted in the decreased particle size and increased absolute value of zeta potential.

12.
Int J Mol Med ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31485603

RESUMO

Although a number of experimental models have been developed for liver research, each has its own advantages and disadvantages. The present study attempted to develop a simple and effective 3­dimensional mouse liver microsphere tissue culture (LMTC) model in vitro for the analysis of hepatic functions. Hepatic characteristics and potential applications of this model were compared with that of mouse model in vivo and mouse primary hepatocytes in vitro. Using freshly­perfused mouse liver tissue passed through 80­mesh sift strainer (sift80), it was demonstrated that under the optimal culture conditions, the sift80 microsphere tissue cultured in 2% bovine calf serum medium remained viable with marked proliferating cell nuclear antigen and anti­Myc proto­oncogene protein expression, exhibited normal hepatic functions including indocyanine green (ICG) uptake/release and periodic acid­Schiff staining, and expressed hepatocyte­specific genes for up to 2 weeks. The microsphere tissue was responsive to bone morphogenic protein 9 (BMP9) stimulation leading to upregulation of downstream targets of BMP9 signaling. Furthermore, 3 commonly­used liver­damaging drugs were indicated to effectively inhibit hepatic ICG uptake, and induce the expression of hepatotoxicity­associated genes. Therefore, this simplified LMTC model may be a useful in vitro tissue culture model to investigate drug­induced liver injury and metabolism, and hepatocyte­based cell singling.

14.
Viruses ; 11(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443406

RESUMO

Members of the interleukin 12 (IL-12) family have been known to be inflammatory factors since their discovery. The IL-12 family consists of IL-12, IL-23, IL-27, IL-35, and a new member, IL-39, which has recently been identified and has not yet been studied extensively. Current literature has described the mechanisms of immunity of these cytokines and potential uses for therapy and medical cures. IL-12 was found first and is effective in combatting a wide range of naturally occurring viral infections through the upregulation of various cytokines to clear the infected cells. IL-23 has an essential function in immune networks, can induce IL-17 production, and can antagonize inhibition from IL-12 in the presence of T helper (Th) 17 cells, resulting in type II IFN (IFN-γ) regulation. IL-27 has a competitive relationship to IL-35 because they both include the same subunit, the Epstein-Barr virus-induced gene3 (EBi3). This review provides a simple introduction to the IL-12 family and focuses on their functions relevant to their actions to counteract viral infections.

15.
Acta Pharmacol Sin ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444477

RESUMO

Cathepsin L (CTSL), a cysteine protease, is responsible for the degradation of a variety of proteins. It is known to participate in neuronal apoptosis associated with abnormal cell cycle. However, the mechanisms underlying CTSL-induced cell apoptosis remain largely unclear. We reported here that rotenone caused an activation of CTSL expression in PC-12 cells, while knockdown of CTSL by small interfering RNAs or its inhibitor reduced the rotenone-induced cell cycle arrest and apoptosis. Moreover, elevation of CTSL and increased-apoptosis were accompanied by induction of B-Myb, a crucial cell cycle regulator. We found that B-Myb was increased in rotenone-treated PC-12 cells and knockdown of B-Myb ameliorated rotenone-stimulated cell apoptosis. Further analysis demonstrated that CTSL influenced the expression of B-Myb as suppression of CTSL activity led to a decreased B-Myb expression, whereas overexpression of CTSL resulted in B-Myb induction. Reduction of B-Myb in CTSL-overexpressing cells revealed that regulation of cell cycle-related proteins, including cyclin A and cyclin B1, through CTSL was mediated by the transcription factor B-Myb. In addition, we demonstrated that the B-Myb target, Bim, and its regulator, Egr-1, which was also associated with CTSL closely, were both involved in rotenone-induced apoptosis in PC-12 cells. Our data not only revealed the role of CTSL in rotenone-induced neuronal apoptosis, but also indicated the involvement of B-Myb in CTSL-related cell cycle regulation.

16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1131-1137, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418368

RESUMO

OBJECTIVE: To explore the clinical and pathologic features as well as prognosis of systemic EBV-positive T-cell lymphoma in children. METHODS: The clinical data including clinical manifestation, pathologic changes and treatment in 16 patients with children's systemic EBV-positive T-cell lymphoma were analyzed retrospectively, and follow-up of patients were carried out. RESULTS: The 16 cases included 12 males and 4  females with median age of 3.3 years old. It was demonstrated that the clinical and pathological features of the children's systemic EBV-positive T-cell lymphoma were as followed fever, hepatosplenomegaly, cytopenia, lymphadenopathy, and hemophagocytosis in bone marrow or organ. Histologically, the structures of lymph node was normal, partially or completely destoryed. The paracortical zone was expanded with prominent infiltration of small to medium-sized atypical lymphocytes. The major immunophenotypic characteristics were as follows: (1) Almost all biopsies exhibited prominent T cell proliferation. (2) CD3 was expressed in 16 patients (100%, 16/16), CD4 in 5 patients (31.3%, 5/16),CD5 in 13 patients (81.3%, 13/16),CD7 was expressed in 11 patients (68.8%, 11/16),CD8 in 15 patients (93.8%, 15/16),CD4 and CD8 were expressed in 5 patients (31.3%, 5/16),CD4 and CD8 double-negative in patients (6.3%, 1/16),16 patients were CD56 negative (100%, 16/16). (3) TCR gene cloning rearrangement in 16 patients (93.8%, 15/16). (4) EBV-EBER was expressed in 16 patients (100%, 16/16). 11 out of 16 cases died, 1 cese failed to be followed up, 1 case relapsed,and 3 cases survived, reseptively. The media survival time was 4 months. CONCLUSION: Systemic EBV-positive T-cell lymphoma predominantly occurred in childhood and early teen-age, and lacks specific clinic features, usually combined with hemophagocytic syndrome. The confirmed diagnosis requires comprehensive analysis of clinical manifestation, pathomorphology, immunohistochemical detection, EBV-EBER insite hybridization, and TCR gene test. The overall prognosis of the disease is poor and the fatality rate is high.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma de Células T , Adolescente , Pré-Escolar , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Humanos , Linfoma de Células T/etiologia , Masculino , Estudos Retrospectivos , Linfócitos T
17.
BMJ Open ; 9(7): e024409, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31371283

RESUMO

OBJECTIVE: Tuberculosis (TB) remains a major deadly threat in mainland China. Early warning and advanced response systems play a central role in addressing such a wide-ranging threat. The purpose of this study is to establish a new hybrid model combining a seasonal autoregressive integrated moving average (SARIMA) model and a non-linear autoregressive neural network with exogenous input (NARNNX) model to understand the future epidemiological patterns of TB morbidity. METHODS: We develop a SARIMA-NARNNX hybrid model for forecasting future levels of TB incidence based on data containing 255 observations from January 1997 to March 2018 in mainland China, and the ultimate simulating and forecasting performances were compared with the basic SARIMA, non-linear autoregressive neural network (NARNN) and error-trend-seasonal (ETS) approaches, as well as the SARIMA-generalised regression neural network (GRNN) and SARIMA-NARNN hybrid techniques. RESULTS: In terms of the root mean square error, mean absolute error, mean error rate and mean absolute percentage error, the identified best-fitting SARIMA-NARNNX combined model with 17 hidden neurons and 4 feedback delays had smaller values in both in-sample simulating scheme and the out-of-sample forecasting scheme than the preferred single SARIMA(2,1,3)(0,1,1)12 model, a NARNN with 19 hidden neurons and 6 feedback delays and ETS(M,A,A), and the best-performing SARIMA-GRNN and SARIMA-NARNN models with 32 hidden neurons and 6 feedback delays. Every year, there was an obvious high-risk season for the notified TB cases in March and April. Importantly, the epidemic levels of TB from 2006 to 2017 trended slightly downward. According to the projection results from 2018 to 2025, TB incidence will continue to drop by 3.002% annually but will remain high. CONCLUSIONS: The new SARIMA-NARNNX combined model visibly outperforms the other methods. This hybrid model should be used for forecasting the long-term epidemic patterns of TB, and it may serve as a beneficial and effective tool for controlling this disease.

18.
Future Oncol ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424272

RESUMO

Aim: The purpose of this study was to investigate the predictive power of the systemic immune inflammation index (SII) based on neutrophil (N), platelet (P) and lymphocyte (L) on the clinical outcomes of patients with SCLC. Patients & methods: Blood samples of 228 patients were obtained 1 week before treatment to measure the SII (SII = P × N/L). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier curves and Cox regression models. Results: Higher SII was associated with poorer OS (p < 0.001) and poorer PFS (p < 0.001). Multivariable analyses further revealed SII as an independent prognostic factor for OS (p < 0.001) and PFS (p < 0.001). Conclusion: Pretreatment SII was a valuable prognostic factor for PFS and OS in SCLC patients.

19.
Thyroid ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31452441

RESUMO

BACKGROUND: Co-occurrence of TERT promoter (TERTp) mutations with BRAF/RAS mutations is associated with significantly more aggressive thyroid cancer. TERTp mutations are hypothesized to generate de novo binding sites for ETS transcription factors, which are themselves activated by BRAF/RAS-stimulated MEK-ERK activity. To date, a detailed study of this mechanism has been limited to only a few cancer types, and we hypothesized that ETS factors involved in TERTp activation could vary between different cancers. METHODOLOGY: Here we sought to identify ETS factor(s) required for TERTp activation in thyroid cancer, using a combination of in silico analyses of TCGA data, and experimentation using in vitro thyroid cell models analysed by qRT-PCR, immunoprecipitation (IP), chromatin IP (ChIP) and gene reporter assays. RESULTS: We found that ETV5 was abundantly expressed in papillary thyroid cancers (PTCs) from the TCGA dataset, and in thyroid cancer cell-lines TPC1, SW1736 and C643. Furthermore, ETV5 demonstrated specific binding affinity for the -124bp(T) TERTp allele, and stimulated TERT transcription in thyroid cancer cells. In contrast GABPA, which is critical for TERTp activation in several other malignancies, was functionally redundant in our thyroid cancer models. We also found that ETV5 functionally cooperates with the transcription factor FOXE1 to further enhance TERTp activity, a mechanism that may at least partially explain why FOXE1 represents a significant genetic determinant of thyroid cancer risk. CONCLUSIONS: ETS factors that activate mutant TERTp vary between cancer types, and here we show for the first time that ETV5 demonstrates mutant allele-specific affinity for TERTp in thyroid cancer, a property that has previously only been attributable to GABPA.

20.
Ann Hepatol ; 18(5): 770-776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31422029

RESUMO

INTRODUCTION AND OBJECTIVES: Acute liver failure (ALF) is a severe disease which is associated with a high mortality rate. As mild hypothermia has been shown to have protective effects on the brain, this study aimed to determine whether it also provides protection to the liver in rats with ALF and to explore its underlying mechanism. MATERIALS AND METHODS: In total, 72 rats were divided into 3 groups: control group (CG, treated with normal saline), normothermia group (NG, treated with d-galactosamine and lipopolysaccharide; d-GalN/LPS), and mild hypothermia group (MHG, treated with d-GalN/LPS and kept in a state of mild hypothermia, defined as an anal temperature of 32-35°C). The rats were examined at 4, 8, and 12h after treatment. RESULTS: Mild hypothermia treatment significantly reduced serum alanine transaminase and aspartate transaminase levels and improved the liver condition of rats with d-GalN/LPS-induced ALF at 12h. Serum tumor necrosis factor-alpha levels were significantly lower in the MHG than in the NG at 4h, but no significant differences were observed in the interleukin-10 levels between the NG and MHG at any time. The serum and hepatic levels of high mobility group box 1 were significantly lower in the MHG than in the NG at 8 and 12h. The protein expression levels of cytochrome C and cleaved-caspase 3 in hepatic tissues were significantly lower in the MHG than in the NG at 8h. CONCLUSION: Mild hypothermia improved the liver conditions of rats with ALF via its anti-inflammatory and anti-apoptotic effects.

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