Inhibition of STAT3 reverses Taxol-resistance in ovarian cancer by down-regulating G6PD expression in vitro.

Ovarian cancer is the eminent gynecological malignancy and chemoresistance remains a major reason for poor in ovarian cancer patients. Taxol has been proved as the most effective chemotherapeutic agent against ovarian cancer. However development of Taxol resistance remains a major problem. Here, we report that STAT3, directly activates pentose-phosphate pathway to exert pro-oncogenic effects on Taxol resistance of ovarian cancer. In addition, we found that STAT3, p-STAT3 and glucose-6-phosphate dehydrogenase (G6PD) protein levels are upregulated in Taxol resistant cell lines compared with Taxol sensitive cell lines. Furthermore, inhibition of STAT3 decreased G6PD mRNA expression level and enhanced the sensitivity of Taxol resistant cell to Taxol. Finally, we found that STAT3 directly binds to the G6PD promoter region and promotes the expression of G6PD at transcriptional level. Taken together, our data indicate that activation of STAT3 promotes ovarian cancer cell proliferation, colony formation, and Taxol resistance via augmenting G6PD expression and pentose-phosphate metabolism flux, which provides a potential therapeutic target that may improve prognosis by decreasing G6PD expression and enhancing Taxol-sensitivity.

Occurrence of parabens and their metabolites in the paired urine and blood samples from Chinese university students: Implications on human exposure.

Parabens, a group of p-hydroxybenzoic acid esters, are extensively used in cosmetics, personal care products, pharmaceuticals, and foodstuff. In the present study, the total forms (free plus conjugated) of four parent parabens, such as methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP), and four metabolites, namely methyl protocatechuate (OH-MeP), ethyl protocatechuate (OH-EtP), p-hydroxy benzoic acid (4-HB), and 3,4-dihydroxy benzoic acid (3,4-DHB), were detected in paired urine and blood samples collected from 196 Chinese university students. The median urinary and blood parabens and their metabolites concentrations ranged from 0.24 to 167 ng/mL and from <0.02 to 2.88 ng/mL, respectively. MeP was the predominant parent parabens, accounting for 68% and 52% of urine and blood samples, respectively. Furthermore, 4-HB predominantly contributed to the parabens and their metabolites in urine (54%) and blood (41%). Significant positive correlations were observed between the urinary levels and blood levels. Moreover, relatively high levels of parabens and their metabolites were detected in urine samples. Our results imply that urinary concentrations are good predictors of human exposure to parabens and metabolites. Gender-related difference in urinary concentrations of parabens and their metabolites were found. The median urinary levels of the tested compounds in females were significantly higher than those in males (Mann Whitney U test, p < 0.05 or 0.01). The estimated daily intakes (EDIs) of MeP, EtP, and PrP were also evaluated. The median values of EDIMeP, EDIEtP, and EDIPrP for all of the university students were estimated to be 25.9, 1.61, and 3.82 µg/kg bw/day, respectively. The median values (µg/kg bw/day) of EDIMeP, EDIEtP, and EDIPrP were higher in females (53.7, 8.65, and 5.22) than in males (8.41, 0.85, and 2.57). This study is the first study to report the occurrence of parabens and their metabolites in paired urine and blood samples in China.

circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis.

Background and aim: As non-coding RNAs, circular RNAs (circRNAs) contribute to the progression of malignancies by regulating various biological processes. In prostate cancer, however, there is still a lack of understanding regarding the potential molecular pathways and roles of circRNAs. Methods: Loss-off function experiments were performed to investigate the potential biological function of circRNA in the progression of prostate cancer. Western blot, qRT-PCR, and IHC assay were used to examine the expression level of different genes or circRNAs. Further molecular biology experiments were conducted to uncover the molecular mechanism underlying circRNA in prostate cancer using dual luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: A novel circRNA (hsa_circ_0124696, named circROBO1) was identified as a significantly upregulated circRNA in both prostate cancer cells and tissues. Suppression of circROBO1 significantly attenuated the proliferation of prostate cancer cells. In addition, we found that the knockdown of circROBO1 remarkably increased the sensitivity of prostate cancer to enzalutamide treatment. A deceleration in glycolysis rate was observed after inhibition of circROBO1, which could suppress prostate cancer growth and overcome resistance to enzalutamide. Our results revealed that circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis. Conclusion: Our study identified the biological role of the circROBO1-miR-556-5p-PGK1 axis in the growth and enzalutamide resistance of prostate cancer, which is the potential therapeutic target of prostate cancer.

[Geochemical Background and Baseline Value of Soil Chemical Elements in Hebei Province].

Geochemical background and baseline values are important parameters for understanding the geochemical characteristics of soil elements, but the research degree of these two parameters is lacking in Hebei Province. Therefore, data from the multi-purpose regional geochemical survey and land quality geochemical assessment in Hebei Province from 2004 to 2018 were collected, covering approximately 71% of the land area of the whole province. Based on the data of surface soil and deep soil, scientific and robust methods including median value and median absolute deviation were used to calculate the geochemical background values, geochemical baseline values, as well as variation ranges of 54 indexes (Ag, Al2O3, As, Au, B, Ba, Be, Bi, Br, CaO, Cd, Ce, Cl, Co, Cr, Cu, F, Fe2O3, Ga, Ge, Hg, I, K2O, La, Li, MgO, Mn, Mo, N, Na2O, Nb, Ni, P, Pb, pH, Rb, S, Sb, Sc, Se, SiO2, Sn, Sr, Th, Ti, Tl, U, V, W, Y, Zn, Zr, total carbon (TC), and organic carbon (Corg)) in Hebei Province and 11 prefecture-level cities. The change rate in geochemical background for each index was also calculated. The results showed that the geochemical background and baseline values of most soil chemical elements in Hebei Province were lower than those nationwide, but the values of Ba, Br, Cl, MgO, Na2O, P, pH, S, Sr, and TC were higher, with CaO being the highest. Compared with those in north China, there was no significant difference in the geochemical background and baseline values for the 54 indexes, with the ratios of 0.83-1.17 and 0.79-1.19, respectively. Significant changes in the geochemical background for Corg, Hg, N, P, S, and Se were observed in Hebei Province, indicating that these indexes were greatly influenced by human factors. Preliminary analysis suggests that coal burning emissions and agricultural chemical use were two very important inducing factors.

Genetic screening for chromosomal abnormalities and Y chromosome microdeletions in Chinese infertile men.

PURPOSES: To investigate the frequency and type of both chromosomal abnormalities and Y chromosome microdeletions and analyze their association with defective spermatogenesis in Chinese infertile men. METHODS: This is a single center study. Karyotyping using G-banding and screening for Y chromosome microdeletion by multiplex polymerase chain reaction(PCR)were performed in 200 controls and 1,333 infertile men, including 945 patients with non-obstructive azoospermia and 388 patients with severe oligozoospermia. RESULTS: Out of 1,333 infertile patients, 154(11.55%) presented chromosomal abnormalities. Of these, 139 of 945 (14.71%) were from the azoospermic and 15 of 388 (3.87%) from the severe oligozoospermic patient groups. The incidence of sex chromosomal abnormalities in men with azoospermia was 11.53% compared with 1.03% in men with severe oligozoospermia (P < 0.01). Also 144 of 1,333(10.80%) patients presented Y chromosome microdeletions. The incidence of azoospermia factor(AZF) microdeletion was 11.75% and 8.51% in patients with azoospermia and severe oligozoospermia respectively. Deletion of AZFc was the most common and deletions in AZFa or AZFab or AZFabc were found in azoospermic men. In addition, 34 patients had chromosomal abnormalities among the 144 patients with Y chromosome microdeletions. No chromosomal abnormality and microdeletion in AZF region were detected in controls. CONCLUSIONS: There was a high incidence (19.80%) of chromosomal abnormalities and Y chromosomal microdeletions in Chinese infertile males with azoospermia or severe oligozoospermia. These findings strongly suggest that genetic screening should be advised to infertile men before starting assisted reproductive treatments.

[Rapid detection of SOX2 gene by primed in situ labeling].

OBJECTIVE: To rapidly detect SOX2 gene using primed in situ labeling (PRINS). METHODS: Human peripheral blood samples were cultured using an optimized method. Sequence of the SOX2 gene was amplified in situ with biotin-labeled specific primers and processed with a tyramide signal amplification (TSA) biotin system. Subsequently, fluorescence-stained signal was detected by streptavidin-Texas red. For the control group, MCF-10F cells were transfected with Lentivirus hSox2. RESULTS: By VideoTesT-FISH software analysis, the long arm of chromosome 3 in the experimental group showed a specific red fluorescence signal, whilst the control samples showed no specific signals for SOX2. Transfected MCF-10F cells showed various efficiency of SOX2 gene integration. CONCLUSION: PRINS utilizes a highly sensitive in situ PCR technique combined with fluorescence labeled oligodeoxynucleotides can synthesize probes in situ, thus greatly reducing the cost of probe and time for detection. It can facilitate identification and classification of induced pluripotent stem cells, and has many potential applications in this prospect.

[Screening and clinical phenotype analysis of microdeletions of azoospermia factor region on Y chromosome in 1011 infertile men].

OBJECTIVE: To investigate the prevalence and subtypes of microdeletions in azoospermia factor (AZF) region in infertile men from Sichuan in order to correlate genotypes with phenotypes. METHODS: Multiplex-PCR was used to detect sequence tagged sites (STS) of AZF microdeletions in 1011 infertile men including 713 cases of non-obstructive azoospermia and 298 cases of severe oligospermia. RESULTS: The overall prevalence of microdeletions was 10.48% (106/1011), and the deletion rates were 11.08% (79/713) in non-obstructive azoospermia and 9.06% (27/298) in severe oligospermia. Complete AZFa or AZFb deletions were associated with azoospermia, whereas AZFc deletion (60.38%) was the most frequent deletion. The deletions were associated with variable spermatogenic phenotypes, and 37.50% of the patients with a deletion had sperms in the ejaculate. A mild decline in sperm concentration was found in two cases with partial AZFb deletion and one case with partial AZFb-c deletion. CONCLUSION: Deletions of the AZFc region were most commonly found in our patients. All cases with complete AZFa or AZFb deletions and a proportion of cases with AZFc deletion were associated with azoospermia. Our study has provided more insight into the genotype-phenotype correlation, and confirmed that Yq microdeletion screening has a significant value for the diagnosis for male infertility.

MRI-based radiomics models can improve prognosis prediction for nasopharyngeal carcinoma with neoadjuvant chemotherapy.

BACKGROUND: The purpose of this study was to explore the prognostic value of imaging features and related models in nasopharyngeal carcinoma (NPC) patients that received neoadjuvant chemotherapy. MATERIALS AND METHODS: We systematically reviewed the data of 110 NPC patients who received radiotherapy and neoadjuvant chemotherapy. The patients were randomly divided into the training cohort (n = 88) and the verification cohort (n = 22). The imaging data collected in this study were screened via Pyramidics and used to construct prediction models based on histology and clinical nomographs. The models' accuracy was evaluated via calibration curves and the consistency index (C-index). In addition, we also explored the correlation between radiomics expression patterns, quantitative histological characteristics, and clinical data and then constructed a model to predict the prognosis of NPC. RESULTS: The models that integrated radiomics contours with all the clinical data were superior to those based on the clinical data alone (C-index 0.746 vs. C-index 0.814, respectively) and the calibration curves showed good consistency. The heat map showed that the radiomics expression pattern and selected histological characteristics were correlated with the clinical stage, T stage, and N stage (p < 0.05), and no radiomics feature was associated with lactate dehydrogenase expression, lymphocyte count, or mononuclear cell count. CONCLUSION: MRI-based radiomics can significantly improve the efficacy of traditional TNM staging and clinical data in predicting the progression-free survival (PFS) of patients with advanced NPC, which may provide an opportunity for precision medicine.

Three-dimensional pulsed continuous arterial spin labeling and intravoxel incoherent motion imaging of nasopharyngeal carcinoma: correlations with Ki-67 proliferation status.

BACKGROUND: Recurrence and distant metastasis are still the main problems affecting the long-term prognosis of nasopharyngeal carcinoma (NPC) patients, and may be related to the Ki-67 proliferation status. We therefore explored the potential correlation between Ki-67 proliferation status in NPC with the parameters derived from two imaging techniques: three-dimensional pulsed continuous arterial spin labeling (3D pCASL) and intravoxel incoherent motion (IVIM). METHODS: Thirty-six patients with pathologically confirmed NPC were included, and the Ki-67 labeling index (LI) was measured by immunohistochemistry. All patients underwent plain and contrast-enhanced magnetic resonance imaging (MRI), IVIM, and 3D pCASL examination. The mean, maximum, and minimum of blood flow (BF), minimum of apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) parameters were all measured, and Spearman's correlation analysis was performed to evaluate the relationships between these parameters and the Ki-67 LI. According to the Ki-67 values, the patients were divided into two groups: high (>50%) and low (≤50%). The rank-sum test (Mann-Whitney U test) was then used to compare the differences in quantitative parameters between the high and low Ki-67 groups. RESULTS: Ki-67 LI was positively correlated with BFmean and BFmax (r=0.415 and 0.425). D*mean and D*min did have positive correlation with Ki-67, but this was not significant (P=0.082 and 0.072). BFmax was significantly different between the high and low Ki-67 groups (P=0.028). CONCLUSIONS: 3D pCASL and IVIM are noninvasive functional MR perfusion imaging techniques that can evaluate perfusion information and perfusion parameters. Our study suggests that 3D pCASL is more effective than IVIM for assessing the proliferation status of NPC, which is beneficial for evaluating the prognosis of patients. Furthermore, BFmax is the best biomarker for distinguishing high from low Ki-67 levels.

Occurrence of bisphenol A and its alternatives in paired urine and indoor dust from Chinese university students: Implications for human exposure.

Bisphenol analogs (BPs), as the industrial chemicals, are widely used in consumer products. Limited information exists regarding human exposure to BPs in university students in China. In this study, we detected concentrations of seven BPs, namely bisphenol A (BPA), bisphenol AF (BPAF), bisphenol P (BPP), bisphenol AP (BPAP), bisphenol Z (BPZ), bisphenol S (BPS), and bisphenol F (BPF), in paired urine (n = 160) and indoor dust samples (n = 40) from university students in South China. High detection rates and levels (median) was found in BPA in paired urine (99%, 3.57 ng/mL) and indoor dust (80%, 2.98 µg/g) samples, followed by BPS (88%, 0.24 ng/mL; 78%, 0.22 µg/g). These findings suggest that BPA remains the major BPs used in consumer products. A positive relationship between urinary ∑BPs (sum of six BPs) concentration and indoor dust was observed (r = 0.444, p < 0.01), indicated that exposure to non-dietary BPs may also be significant to human exposure. The median EDIurine values (ng/kg bw/day) of ∑BPs in males (119.6) were relatively higher than (p < 0.05) those in females (84.6). By contrast, the median EDIdust of BPs (except for BPAF) in dust form female dormitories were slightly higher than that in dust from male dormitories. Notably, BPF was the most ingested from indoor dust (dormitory dust). This study is the first time to document the occurrence of BPs in paired urine and indoor dust in university students from China.

Corilagin Counteracts IL-13Rα1 Signaling Pathway in Macrophages to Mitigate Schistosome Egg-Induced Hepatic Fibrosis.

The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-ß was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-ß compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.

Mechanism of Corilagin interference with IL-13/STAT6 signaling pathways in hepatic alternative activation macrophages in schistosomiasis-induced liver fibrosis in mouse model.

This study tried to find the mechanism of Corilagin interference with interleukin (IL)-13/signal transducer and activator of transcription (STAT) 6 signaling pathways in IL-13-activated liver alternative activation macrophages in schistosomiasis-induced liver fibrosis in Balb/c mice. As a result, IL-13 in serum and the mRNA expression of IL-13 Receptor α1, IL-4 Receptor α and downstream mediators supressor of cytokine signaling (SOCS) 1, Kruppel-like factor (KLF) 4, peroxisome proliferator-activated receptor (PPAR) δ in the liver tissue were significantly inhibited by Corilagin (P<0.05 or 0.01). The protein expression of IL-13 Receptor α1, IL-4 Receptor α, SOCS1, KLF4, PPARγ, PPARδ and Phospho-STAT6 (P-STAT6) in Corilagin group were also markedly suppressed when compared with the model group (P<0.05 or 0.01). Furthermore, the inhibitory effect was enhanced when the concentration of Corilagin increased (P<0.05). By hematoxylin and eosin (HE) staining, when compared with the model group, the Corilagin group showed smaller granulomas (P<0.05 or 0.01). The area of positive cells and integrated optical density (IOD) of CD68, CD206 and KLF4 was significantly decreased by Corilagin stained by IHC (P<0.05 or 0.01). In conclusion, Corilagin had potential to relieve hepatic fibrosis caused by egg granuloma in Schistosoma japonicum infection by decreasing the expression of molecules associated with IL-13/STAT6 signaling pathway in liver alternative activation macrophages.

Effect of Corilagin on the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model.

This study sought to investigate the anti-fibrotic effect of Corilagin via interference with the miR-21/smad7/ERK signaling pathway in a schistosomiasis-induced hepatic fibrosis mouse model. Mice were infected with Schistosoma japonicum cercaria to establish the mouse model of schistosomiasis-induced hepatic fibrosis. At four weeks after infection, the groups were given different medications. The living conditions were observed. Real-time PCR was employed to detect the mRNA levels of miR-21, smad7 and connective tissue growth factor (CTGF), and western blotting was used to examine the protein levels of smad7, CTGF, smad1, p-smad1, smad2, p-smad2, ERK1/2, p-ERK1/2 and TGF-ß receptor I. Immunohistochemistry was used to examine the expression of CTGF. Compared with the model group, increasing concentrations of Corilagin improved the quality of life, inhibited the mRNA expression of miR-21, promoted smad7 protein expression, and inhibited CTGF protein expression (p<0.05 or 0.01). Moreover, Corilagin significantly reduced the protein levels of p-smad1, p-smad2, p-ERK1/2, and TGF-ß receptor I (p<0.05 or 0.01). CTGF staining in the cytoplasm was markedly decreased by Corilagin (p<0.05 or 0.01). In conclusion, Corilagin inhibited schistosomiasis-induced hepatic fibrosis via the miR21/smad7/ERK pathway in this animal model.

Effect of bone marrow mesenchymal stem cells on the Smad expression of hepatic fibrosis rats.

OBJECTIVE: To investigate the impact of bone marrow mesenchymal stem cells on Smad expression of hepatic fibrosis rats. METHODS: A total of 48 adult female SD rats were randomly divided into three groups, normal control group (n=10), observation group (n=19) with liver fibrosis model rats injected with BMSCs cells; model group (n=19), with liver fibrosis model rats injected with physiological saline. Serum index, TGF-ß1 and Smad expression were detected. RESULTS: Type III procollagen, IV collagen, hyaluronic acid, laminin levels of observation group were significantly lower than those of model group (P<0.05). The content and expression of TGF-ß1 in serum and liver tissue of observation group were significantly lower than those of model group(P<0.05). Compared with normal control group, the Smad3, Smad4 mRNA and protein expression of model group were significantly increased, the Smad7 mRNA and protein expression were significantly reduced (P<0.05). Compared with model group, Smad3, Smad4 mRNA and protein expression of observation group were significantly reduced, and Smad7 mRNA expression were significantly increased (P<0.05). CONCLUSIONS: BMSCs can regulate Smad expression to some extent, and reduce the degree of liver fibrosis.

Effect of Rougan Huaqian granules combined with human mesenchymal stem cell transplantation on liver fibrosis in cirrhosis rats.

OBJECTIVE: To observe the effect of Rougan Huaqian granules combined with human mesenchymal stem cell (hMSC) transplantation on the liver fibrosis in carbon tetrachloride-induced cirrhosis rats. METHODS: Sixty SD rats were randomly divided into five groups. The rats in control group received intraperitoneal injection of saline, while those in model control group, treatment group A, group B and group C received intraperitoneal injection of carbon tetrachloride oily solution to induce liver cirrhosis within 8 weeks. Then, the rats in the model control group, treatment group A, treatment group B, treatment group C received vein tail injection of saline, Rougan Huaqian granules, hMSC suspension and Rougan Huaqian granules combined with hMSC suspension. RESULTS: The treatment groups had significantly different liver function (AST levels), liver fibrosis index (laminin and HA), hepatic sinusoidal wallsα-smooth muscle actin, IV collagen and laminin protein expression and I, III collagen from the model group (P<0.05). The transplanted cells showed human hepatocyte-like cells differentiation trend in the liver. CONCLUSIONS: The Rougan Huaqian granules combined with hMSC transplantation can alleviate liver fibrosis in cirrhosis rats.

Askin tumor: four case reports and a review of the literature.

Askin tumor is an uncommon malignant neoplasm in the thoracopulmonary region mainly occurring in children and adolescents. Four young patients with histologically proven Askin tumors were treated in our hospital. In all patients, chest computed tomography imaging demonstrated a chest wall mass with or without destruction of ribs. All patients underwent radical mass resection and postoperative chemotherapy. By the time this article was completed, two of the patients had died with local chest wall recurrences. Here we focus on the imaging features, differential diagnosis, pathology and prognosis of this rare disease.