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1.
J Inorg Biochem ; 205: 111014, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32044395

RESUMO

Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](PF6) (Ir-2, DCPIP = 2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(TCPIP)](PF6) (Ir-3, TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The complexes Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes to form Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo. Morphology, size distribution, and zeta potential of liposomes were examined by transmission electron microscopy (TEM) and Zetasizer. The cytotoxic activity in vitro of Ir-1, Ir-2 and Ir-3 against cancer A549, HTC-116, HepG2, BEL-7402, Eca-109, B16, HeLa SGC-7901 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir-2 and Ir-3 show no cytotoxic activity against the selected cancer cells, and Ir-1 displays moderate cytotoxic effect on the cell growth in A549 cells. However, Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes, the cytotoxic activity was greatly enhanced. In particular, Ir-1-Lipo and Ir-2-Lipo can effectively inhibit the cell growth in A549 cells with a low IC50 value of 3.1 ± 0.3 and 1.2 ± 0.4 µM. The apoptosis was assayed by flow cytometry. Ir-1, Ir-2 and Ir-3 reveal weak apoptotic effect, whereas Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo induce an apoptotic percentage of 55.6%, 69.3% and 16.7% in A549 cells, respectively. Specially, in the assay of antitumor activity in vivo, the inhibiting percentage of tumor growth induced by Ir-2 is 27.65%, while inhibiting percentage of tumor growth caused by Ir-2-Lipo is 57.45%. Obviously, the liposomes can enhance anticancer activity in vitro and in vivo compared with the complexes. The results show that the iridium(III) complexes encapsulated liposomes induce apoptosis in A549 cells through ROS-mediated lysosome-mitochondria dysfunction pathway and target the microtubules.

2.
Mol Med Rep ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32016476

RESUMO

The present study aimed to identify sensitive, specific and independent prognostic biomarkers in head and neck cancer (HNC) based on microRNA expression profiles and other high­throughput sequencing data in The Cancer Genome Atlas (TCGA) database. Identification of such prognostic biomarkers could provide insight into HNC diagnosis and treatment. The differential expression profiles of microRNAs between HNC tissues and adjacent cancer tissues in the TCGA database were analyzed (log fold­change >2; P<0.01). Univariate and multivariate Cox regression analyses of the differentially expressed microRNAs were performed to determine those significantly related to the survival of patients with HNC. The identified microRNAs were verified by survival and receiver operating characteristic curve analyses. To better predict prognosis, a combined prognostic model (risk equation) was established based on the risk coefficient of each microRNA, calculated by a multivariate Cox regression analysis, and the risk score was calculated. To explore the signaling pathways related to prognosis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed on the differentially expressed genes between the high­risk and low­risk groups, grouped according to the median risk score. A total of 89 differentially expressed microRNAs between HNC and adjacent cancer tissues were screened, 11 of which were identified as risk factors related to HNC survival by the univariate Cox regression analysis (P<0.05). The multivariate Cox regression analysis showed that three of the 11 microRNAs, hsa­miR­99a, hsa­miR­499a and hsa­miR­1911 (all P<0.01), were identified as independent risk factors significantly related to patient survival. The risk equation used was as follows: Risk score=(­0.1597 x hsa­miR­99a) + (0.1871 x hsa­miR­499a) + (0.1033 x hsa­miR­1911). KEGG and GO analyses showed that the JAK­STAT signaling pathway and some metabolic pathways were associated with HNC prognosis. The present study suggested that hsa­miR­99a, hsa­miR­499a and hsa­miR­1911 may serve as potential prognostic biomarkers in HNC.

3.
Clin Interv Aging ; 15: 47-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021132

RESUMO

Aim: The aim of this study was to examine the association between air temperature and incidence of acute coronary heart disease in Northeast China. Methods: We obtained coronary heart disease (CHD) daily hospitalization data from January 2017 to June 2019, and collected meteorological data including average daily air temperature, air pressure, relative humidity, wind velocity, sunshine duration and water vapor pressure, for the same period. Totally, This study included data from 6775 patients with CHD. Results: After adjusting for confounding factors, low air temperature was inversely associated with CHD. Additionally, in the warm season (April-September), the number of daily hospital admissions for CHD was higher (≥24.2°C) if the average daily air temperature was low (≤15.4°C). Conclusion: Low air temperature might be a risk factor for CHD among the elderly, especially in the warm season.

4.
Medicine (Baltimore) ; 99(5): e18666, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000373

RESUMO

Ovarian cancer has the highest mortality among gynecological cancers. Although ovarian cancer usually responds well to chemotherapy, most patients still have a poor prognosis. EIF2B5 is a crucial molecule in posttranscriptional modifications involved in tumor progression, and here we investigated the prognostic role of EIF2B5 in ovarian cancer. We examined the differential expression of EIF2B5 mRNA in ovarian cancer by exploring The Cancer Genome Atlas (TCGA) database. The chi square test was used to identify a clinical correlation. Survival analysis and Cox regression model were performed to determine the association between EIF2B5 expression and overall survival (OS) in ovarian cancer patients. As a result, Low EIF2B5 expression was found in ovarian cancer tissues and correlated with survival status. Survival analysis showed that ovarian cancer patients with low EIF2B5 expression had a short OS. Moreover, Cox regression analysis indicated that low EIF2B5 expression was an independent risk factor for a poor prognosis in ovarian cancer. Additionally, according to gene set enrichment analysis, mesenchymal transition, angiogenesis, coagulation, and bile acid metabolism were differentially enriched in ovarian cancer with high EIF2B5 expression. In conclusion, Low EIF2B5 expression is an independent risk factor for a poor prognosis in ovarian cancer patients.

5.
J Cell Mol Med ; 24(3): 2215-2228, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943775

RESUMO

Increasing evidence has verified that small nucleolar RNAs (snoRNAs) play significant roles in tumorigenesis and exhibit prognostic value in clinical practice. In the study, we analysed the expression profile and clinical relevance of snoRNAs from TCGA database including 530 ccRCC (clear cell renal cell carcinoma) and 72 control cases. By using univariate and multivariate Cox analysis, we established a six-snoRNA signature and divided patients into high-risk or low-risk groups. We found patients in high-risk group had significantly shorter overall survival and recurrence-free survival than those in low-risk group in test series, validation series and entire series by Kaplan-Meier analysis. We also confirmed this signature had a great accuracy and specificity in 64 clinical tissue cases and 50 serum samples. Then, depending on receiver operating characteristic curve analysis we found the six-snoRNA signature was an superior indicator better than conventional clinical factors (AUC = 0.732). Furthermore, combining the signature with TNM stage or Fuhrman grade were the optimal indicators (AUC = 0.792; AUC = 0.800) and processed the clinical applied value for ccRCC. Finally, we found the SNORA70B and its hose gene USP34 might directly regulate Wnt signalling pathway to promote tumorigenesis in ccRCC. In general, our study established a six-snoRNA signature as an independent and superior diagnosis and prognosis indicator for ccRCC.

6.
Sci Total Environ ; 713: 136662, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31958734

RESUMO

To determine the bioavailability and translocation of metal oxide nanoparticles (MONPs) in the soil-rice plant system, we examined the accumulation and micro-distribution of ZnO nanoparticles (NPs), CuO NPs and CeO2 NPs (50, 100 and 500 mg/kg) in the paddy soil and rice plants under flooded condition for 30 days using single-step chemical extraction and diffusive gradients in thin films (DGT) technique combined with micro X-ray fluorescence spectroscopy (µ-XRF). The results show that various MONPs changed the soil properties, especially the redox potential was enhanced to -165.33 to -75.33 mV compared to the control. The extraction efficiency of Zn, Cu and Ce in the paddy soil from high to low was EDTA, DTPA, CaCl2 and DGT. Moreover, exposure to 500 mg/kg CuO NPs and CeO2 NPs induced the primary accumulation of Cu and Ce elements in rice roots as high as 235.48 mg Cu/kg and 164.84 mg Ce/kg, respectively, while the Zn concentration in shoots was up to 313.18 mg/kg under highest ZnO NPs with a 1.5 of translocation factor. The effect of MONPs on the plant growth was mainly related to the chemical species and solubility of MONPs. Micro-XRF analysis shows that Zn was mostly located in the root cortex while Cu was primarily accumulated in the root exodermis and few Ce distributed in the root. Pearson correlation coefficients indicate that only DTPA-extracted metals in soil were significantly and well correlated to the Zn, Cu and Ce accumulation in rice seedlings exposed to MONPs. This work is of great significance for evaluating the environmental risks of MONPs in soil and ensuring the safety of agricultural products.

7.
Transfusion ; 60(2): 326-333, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912898

RESUMO

BACKGROUND: In China, there is a rising concern on the increasing trends of HIV infections in high-risk groups, who make blood donations that might potentially challenge the blood safety. Analyses on current risk factors for HIV infection among Chinese blood donors are urgently needed for developing effective strategies to defer high-risk donors and to warrant the safety of the blood supply. STUDY DESIGN AND METHODS: We recruited 313 HIV-positive and 762 HIV-negative donors from seven study sites in China and evaluated donor demographic characteristics, current medical and behavioral risk factors associated with HIV infection in a case-control survey. Univariable analyses examined the relationship between HIV infection and donor and donation characteristics, medical and behavioral risks, living conditions, and lifestyles. Multivariable logistic regression analyses evaluated the association between selected individual risks and HIV infection. Regression tree analysis was used to select covariates correlated with both HIV infection and individual risks and thus need to be controlled for in logistic regression models. RESULTS: Being a man who has sex with men was associated with the highest odds of HIV infection. Not using a condom, having sex with HIV-infected individuals, having sex partners with sexually transmitted diseases (STDs), having more than two concurrent sex partners, or having an STD were all associated with more than five times higher odds of having HIV. Having remunerated sex was associated with a 2.4 increased odds of having HIV infection. CONCLUSION: High-risk sexual behaviors were among the major risks for HIV infection among Chinese blood donors.

8.
Inorg Chem ; 59(2): 1522-1531, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31913028

RESUMO

The hexagonal copper-tin alloy (Cu-Sn) nanoplates were synthesized using a high temperature solvent method, the length of six equilateral edges of hexagonal Cu-Sn nanoplates was 23 nm, and the thickness was 13 nm. The obtained hexagonal Cu-Sn nanoplates were highly monodisperse and allowed the formation of nanoarrays arranged with long-range order. The hexagonal Cu-Sn nanoplates exhibited high catalytic activity on catalytic hydrogenation of 4-nitrophenol to 4-aminophenol. Due to the promotion effect of Sn, the apparent rate constant (ka) of hexagonal Cu-Sn nanoplates was three times that of Cu nanoparticles. The density functional theory (DFT) calculations and experimental results demonstrated that Sn could promote the coordination process of -NO2 of 4-nitrophenol with Cu-Sn nanoplates and contribute to activation of 4-nitrophenol. In addition, the hexagonal Cu-Sn nanoplates showed high stability and reusability for the reduction reaction, good adaptability in different pH and the ionic strength, and wide applicability for the degradation of methylene blue, methyl orange, and rhodamine B, even in the industrial wastewater, suggesting that the Cu-Sn nanoplates are promising catalysts in organic industry wastewater treatment.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31909548

RESUMO

OBJECTIVES: To evaluate the feasibility of classifying sonographic images of fetal brain images taken in standard axial planes as normal or abnormal, using deep learning algorithms. METHODS: A total of 92748 prenatal examinations were used in the study. After inclusion and exclusion, 10251 normal and 2529 abnormal pregnancies were included. Abnormal cases were confirmed by neonatal ultrasound, follow-up examination or autopsy. After a series of data pretraining processes, 15372 normal and 14047 abnormal fetal brain images were included. They were divided into training and test datasets (on a case level rather than on an image level), at a ratio of approximately 8:2. Training data were used to train the algorithms to classify images as normal or abnormal, and the accuracy was then tested on the test datasets. The algorithms were trained for three purposes: image segmentation along fetal skull, classifying the image and localizing the lesion. Performance of segmentation was assessed using precision, recall, and Dice's coefficient (DICE), calculated to measure the extent of overlap between human-labeled and machine-segmented regions. Sensitivity and specificity were calculated for classification accuracy assessment. Additionally, for abnormal images, how well a lesion was localized was determined. RESULTS: Segmentation precision, recall and DICE were 97.9%, 90.9% and 94.1%, respectively. For classification the overall accuracy was 96.3%. The sensitivity and specificity for abnormal images were 96.9% and 95.9%, respectively. The area under the receiver operating characteristic curve was 0.989 (95% CI: 0.986-0.991). For 2491 abnormal fetal brain images, the lesions were precisely, closely and irrelevantly located in 61.6% (1535/2491), 24.7% (614/2491) and 13.7% (342/2491), respectively. CONCLUSIONS: Deep learning algorithms could be trained for segmentation and classification of normal and abnormal images and provide heat maps for lesion localization. This study laid a foundation for further research on the differential diagnosis of fetal intracranial abnormalities. This article is protected by copyright. All rights reserved.

10.
Rev Esp Enferm Dig ; 112(1): 27-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31823639

RESUMO

BACKGROUND: liver cancer is a malignant tumor with a high morbidity and mortality that endangers human health. High mobility group A2 (HMGA2) is a chromosome associated protein that participates in embryogenesis, tissue development, tumorigenesis and development. OBJECTIVE: to explore the relationship between HMGA2 expression and the clinicopathological parameters and survival of liver cancer patients using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (HCC) data. METHODS: RNA-sequencing data and the corresponding clinical characteristics of the patients were downloaded from the Atlas database. The Chi-squared test was used to assess the relationship between HMGA2 expression and clinical variables. Cox regression analysis was used to compare survival rates between the high- and low-expressing groups; the p-values and Kaplan-Meier survival curves were compared using the log-rank test. RESULTS: RNA-seq data from 373 cases of liver cancer cases were analyzed. HMGA2 was overexpressed in liver cancer and significantly associated with gender (p = 0.0357), T classification (p = 0.0063), clinical classification (p = 0.0026) and overall survival (p = 0.0386). According to the multivariate analysis, HMGA2 could independently predict overall survival in liver cancer. CONCLUSIONS: HMGA2 independently predicts poor prognosis in liver cancer and serves as a molecular marker to determine disease prognosis.

11.
J Cell Biochem ; 121(2): 1842-1854, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31633246

RESUMO

Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori (H. pylori) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (-) GC that can sensitively and efficiently predict the prognostic. The RNA-seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (-) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven-mRNA signature (TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2, and CHAF1A) closely related to the prognosis of patients with H. pylori (-) GC. The seven-mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high-risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low-risk scores (P < .0001). In this study, we developed a seven-mRNA signature related to G2/M checkpoint from H. pylori (-) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.

12.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117534, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31685424

RESUMO

Two novel ruthenium(II) polypyridyl complexes, namely, [Ru(dmp)2(CAPIP)](ClO4)2 (Ru(II)-1) and [Ru(dmp)2(CFPIP)](ClO4)2 (Ru(II)-2), which respectively contain (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phen-anthroline (CAPIP) and (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline. (CFPIP), were first designed and characterized (dmp = 2,9-dimethyl-1,10-phenanthroline). DNA binding experiments indicated that Ru(II) complexes interact with CT DNA through intercalative mode. In addition, the complexes Ru(II)-1 and Ru(II)-2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 4.1 ±â€¯1.4 µM and 6.1 ±â€¯1.4 µM on the A549 cancer cells. These values indicated higher activity than CAPIP, CFPIP, cisplatin (8.2 ±â€¯1.4 µM) and other corresponding Ru(II) polypyridyl complexes. Furthermore, the Ru(II) complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. Significantly, complexes Ru(II)-1 and Ru(II)-2 induced A549 cells apoptosis was mediated by increase of ROS levels and dysfunction of mitochondria, and resulted in cell cycle arrest and increased anti-migration activity on A549 cells. Overall, these results indicated that complexes Ru(II)-1 and Ru(II)-2 could be suitable candidates for further investigation as a chemotherapeutic agent in the treatment of tumors.

13.
Biotechnol Lett ; 42(1): 135-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734772

RESUMO

OBJECTIVES: To characterize a glycosyltransferase (UGT74AN3) from Catharanthus roseus and investigate its specificity toward cardiotonic steroids and phenolic compounds. RESULTS: UGT74AN3, a novel permissive GT from C. roseus, displayed average high conversion rate (> 90%) toward eight structurally different cardiotonic steroids. Among them, resibufogenin, digitoxigenin, and uzarigenin gave 100% yield. Based on LC-MS, 1H-NMR and 13C-NMR analysis, structure elucidation of eight glycosides was consistent with 3-O-ß-D-glucosides. We further confirmed UGT74AN3 was permissive enough to glycosylate curcumin, resveratrol, and phloretin. The cDNA sequence of UGT74AN3 contained an ORF of 1,425 nucleotides encoding 474 amino acids. UGT74AN3 performed the maximum catalytic activity at 40 °C, pH 8.0, and was divalent cation-independent. Km values of UGT74AN3 toward resibufogenin, digitoxigenin, and uzarigenin were 7.0 µM, 12.3 µM, and 17.4 µM, respectively. CONCLUSIONS: UGT74AN3, a glycosyltransferase from a noncardenolide-producing plant, displayed catalytic efficiency toward cardiotonic steroids and phenolic compounds, which would make it feasible for glycosylation of bioactive molecules.

14.
J Hazard Mater ; 384: 120948, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610345

RESUMO

Facile and ultrasensitive detection of Hg2+ in water environment remains challenging. Exonuclease III (Exo-III)-assisted target recycling is one of the most popular amplification strategies. Although the magnesium (II) ions are widely acting as cofactors of Exo-III, we recognized that Mg2+ cofactors would strongly disturb the charge distribution on citrate-stablized gold nanoparticles (in the general sense, unmodified AuNPs) surface, thus generate false positive colorimetric signals. To address this issue, we first put forward the view that the cobalt (II) ions can function as the Exo-III cofactor and successfully construct a novel label-free colorimetric aptasensor for facile and ultrasensitive detection of Hg2+ using Hg2+-triggered Exo-III-assisted signal amplification and unmodified AuNPs as indicators. A hairpin-looped DNA probe was rationally designed with thymine-rich recognition termini and specifically recognized trace Hg2+ by a stable T-Hg2+-T structure. A blue-to-red color change of AuNPs with the addition of Hg2+ provided the quantitative detection of Hg2+ with a limit of detection of 0.2 nM and a linear working range from 0.5 nM to 5.0 nM. The whole testing time for one assay was approximately 40 min. Real water samples, even containing Hg2+ at 1 nM, could be determined by the aptasensor with recovery rates from 97% to 103%.

15.
Cytokine ; 127: 154936, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31786500

RESUMO

BACKGROUND: Immuno-inflammation plays an important role in the pathophysiological process of sepsis-associated acute hepatic injury (AHI). Interleukin 27 (IL-27) is an important inflammatory regulator; however, its role in this condition is not clear. METHODS: The clinical data and IL-27 serum levels in sepsis patients with or without AHI were analysed. Classical caecal ligation puncture (CLP) models were established in wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R-/-) mice. In addition, exogenous IL-27 was injected into these mice, and the levels of IL-27, IL-6, and tumour necrosis factor alpha (TNF-α) in the serum and liver were then measured by enzyme-linked immunoassay (ELISA), quantitative PCR, and Western blotting. The severity of liver damage was evaluated by haematoxylin and eosin staining of liver tissue, TUNEL assay and evaluation of alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Furthermore, the effects of IL-27 on the levels of phosphorylated c-Jun N-terminal kinase (JNK) in macrophages were assessed by Western blotting, and the effects of IL-27 on the expression of IL-6 and TNF-α in macrophages were assessed by ELISA. RESULTS: IL-27 was elevated in sepsis patients with acute hepatic injury, which correlated with the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHEII) scores, Sequential Organ Failure Assessment (SOFA) scores, and procalcitonin, C-reactive protein, IL-6, and TNF-α expression. In the CLP-WT group, IL-27 was highly expressed in the serum and liver, which correlated with the elevated content of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver. In CLP-IL-27R-/- group, however, the levels of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver were decreased. Treatment with exogenous IL-27 led to a further increase in these cytokines in WT mice after CLP. IL-27 treatment and lipopolysaccharide stimulation in vitro increased the expression of p-JNK, IL-6, and TNF-α in macrophages, and these changes were decreased by a JNK signalling pathway inhibitor. CONCLUSION: IL-27 is elevated in sepsis patients, especially those with acute hepatic injury. In addition, IL-27 can promote inflammatory reactions in the CLP-induced hepatic injury mice model.

16.
Oncogene ; 39(3): 530-545, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31501521

RESUMO

Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.

17.
Cytokine ; 125: 154837, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514105

RESUMO

Nonalcoholic fatty liver disease (NAFLD) commonly occurs in patients with type 2 diabetes mellitus (T2DM). Osteopontin (OPN) is a multifunctional protein with pleiotropic physiological functions. This study aimed to investigate the interrelation between circulating OPN and NAFLD in T2DM patients. Overall, 249 subjects were classified into 4 groups: 53 patients with NAFLD and T2DM; 57 with newly diagnosed T2DM; 59 with NAFLD; and 80 healthy age- and sex-matched controls. Serum OPN was measured by ELISA. The OPN distribution in the pooled data was divided into quartiles; significant trends across increasing quartiles were estimated by the Cochran-Armitage trend test. Compared with the controls, circulating OPN concentrations were significantly elevated in NAFLD patients and T2DM patients with or without NAFLD. Serum OPN levels were higher in the overweight/obese group than that in the lean group. Circulating OPN levels were positively correlated with CRP, age, BMI, SBP, DBP, HbA1c, UA, TGs, WBCs, neutrophils, FBG, and HOMA-IR and negatively correlated with ADP, albumin and HDL. Age, albumin, HbA1c, HDL and hsCRP were independently related to circulating OPN. The relative risks for NAFLD, T2DM and T2DM with NAFLD increased significantly along with increasing OPN quartiles based on the Cochran-Armitage trend test. OPN is an optimal predictor in the diagnosis of T2DM with NAFLD and T2DM and may contribute to the aggravation of the metabolic state.

18.
J Clin Invest ; 130(2): 981-997, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31855575

RESUMO

The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

19.
RNA Biol ; 17(1): 87-97, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31532701

RESUMO

Formed by back splicing or back fusion of linear RNAs, circular RNAs (circRNAs) constitute a new class of non-coding RNAs of eukaryotes. Recent studies reveal a spliceosome-dependent biogenesis of circRNAs where circRNAs arise at the intron-exon junctions of mRNAs. In this study, using a novel de novo identification method, we show that circRNAs can originate from the interior regions of exons, introns, and intergenic transcripts in human, mouse and rice, which were referred to as interior circRNAs (i-circRNAs). Many i-circRNAs have some remarkable characteristics: multiple i-circRNAs may arise from the same genomic locus; their back fusion points may not be associated with the AG/GT splicing sites, but rather a new pair of motif AC/CT, their back fusion points are adjacent to complementary sequences; and they may circulate on short homologous sequences. We validated several i-circRNAs in HeLa cells by Polymerase Chain Reaction followed by Sanger sequencing. Our results combined showed that i-circRNAs are bona fide circRNAs, indicated novel biogenesis pathways independent of the splicing apparatus, and expanded our understanding of the origin, diversity, and complexity of circRNAs.

20.
Nanomedicine (Lond) ; 15(1): 77-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31868112

RESUMO

Aim: We aim to demonstrate that a local nanoparticle-mediated hyperthermia can effectively eliminate tumor-associated Tregs and thereby boost checkpoint blockade-based immunotherapy. Materials & methods: Photothermal therapy (PTT), mediated with systemically administered stealthy iron-oxide nanoparticles, was applied to treat BALB/c mice bearing 4T1 murine breast tumors. Flow cytometry was applied to evaluate both Treg and CD8+ T-cell population. Tumor growth following combination therapy of both PTT and anti-CTLA-4 was further evaluated. Results: Our data reveal that tumor-associated Tregs can be preferentially depleted via iron-oxide nanoparticles-mediated PTT. When combining PTT with anti-CTLA-4 immunotherapy, we demonstrate a significant inhibition of syngeneic 4T1 tumor growth. Conclusion: This study offers a novel strategy to overcome Treg-mediated immunosuppression and thereby to boost cancer immunotherapy.

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