E2F1-driven histone demethylase KDM6B enhances thyroid malignancy via manipulating TFEB-dependent autophagy axis.

Aberrant epigenetic modifications or events regulate autophagy to influence tumor progression, which has gained increasing attention. KDM6B is an essential histone demethylase that participates in multiple processes of tumors, but its role in thyroid carcinoma (THCA) remains to be unknown. Here, in this study, we used the MTT assay to screen and validate that KDM6B is an essential demethylase for THCA. KDM6B promotes THCA proliferation, migration, invasion in vitro and in vivo. Transcriptional factor E2F1 directly binds to the promoter region of KDM6B and regulates its mRNA levels in THCA. E2F1 partially depended on KDM6B to exert its oncogenic functions. Mechanistically, KDM6B binds to TFEB promoter region and mediates the demethylation of H3K27me3. KDM6B depended on TFEB to activate a series of lysosomal-related genes. KDM6B enhances autophagy process, as evidenced by elevated p62 and Beclin-1 proteins. KDM6B depended on TFEB-driven autophagy activity to accelerate THCA progression. Lastly, targeting autophagy with 3-MA could notably abrogate growth of KDM6Bhigh THCA, but has mild influence on KDM6Blow THCA. Together, this study identified KDM6B as an essential epigenetic regulator for THCA, functioning as an autophagy regulator. The fundamental mechanisms underlying E2F1/KDM6B/TFEB axis provided novel vulnerabilities for THCA treatment.

Effects of specialized nursing intervention based on quantitative assessment strategy on psychological state and quality of life of patients with senile dementia.

OBJECTIVES: To explore the effects of specialized nursing intervention based on quantitative evaluation strategy on the psychological state and quality of life of senile dementia patients. METHODS: 92 senile dementia patients were divided into the control and intervention groups (n = 46 each). Control group was given routine nursing intervention, while intervention group was given specialized nursing intervention based on the quantitative evaluation strategy. Patients' self-care ability, cognitive function, nursing compliance, psychological state, quality of life, and patient satisfaction indexes were measured. RESULTS: After nursing interventions, the self-care ability (71.73 ± 4.31 vs 63.82 ± 3.97 points) and cognitive functions such as orientation (7.96 ± 1.02 vs 6.53 ± 1.15), memory (2.16 ± 0.39 vs 1.69 ± 0.31), visual-spatial copying (3.78 ± 0.53 vs 3.02 ± 0.65), language skills (7.49 ± 1.26 vs 6.05 ± 1.28), and recall ability (2.13 ± 0.26 vs 1.75 ± 0.28) were significantly improved in the intervention group compared to the control group (P ˂ 0.05). The patient's compliance in the intervention group (95.65%) was prominently higher than the control group (80.43%) (P < 0.05). Notably, patient's psychological state (anxiety and depression) in the intervention group (47.42 ± 3.12 vs 51.39 ± 3.16, 48.52 ± 2.51 vs 52.83 ± 2.49) was better than the control group (P < 0.05). Furthermore, the quality of life was significantly improved in the intervention group (88.11 ± 1.11 vs 71.52 ± 1.24) compared to the control group (P < 0.05). Also, patients' satisfaction with nursing services in the intervention group (97.83%) was higher than the control group (78.26%) (P < 0.05). CONCLUSIONS: Specialized nursing intervention based on quantitative evaluation strategy can effectively improve patients' self-care ability, and cognitive function, reduce anxiety and depression and enhance the quality of life, which is worthy of clinical promotion and application.

Apatinib suppresses lung cancer stem-like cells by complex interplay between ß-catenin signaling and mitochondrial ROS accumulation.

The abnormal activation of Wnt/ß-catenin signaling plays a critical role in the development of lung cancer, which is also important in the generation and maintenance of lung cancer stem cell (CSC). CSCs have unique capabilities to resist anticancer therapy, seed recurrent tumors, and disseminate to and colonize distant tissues. Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, shows highly efficient antitumor activity in heavily treated, chemoresistant, and metastatic lung cancer. We speculated that inhibition of Wnt/ß-catenin signaling and targeting lung CSCs could be one of the anti-tumor mechanisms of apatinib. In the present study we demonstrated that apatinib repressed lung CSC-like traits by hindering sphere formation ability, lung CSC-related marker expression and decreasing chemoresistance derived stemness. Mechanistically, apatinib exerted its anti-CSC effects by inhibiting ß-catenin and its downstream targets. Moreover, apatinib induced the production of reactive oxyen species (ROS), which participated in the inhibitory effects of apatinib on lung CSCs. It was found that ß-catenin regulated apatinib-induced production of ROS. Inhibition or promotion of ROS production with N-acetyl-L-cysteine or H2O2 not only upregulated or downregulated ß-catenin expression, but also prevented or promoted DNA damage, rescued or impeded sphere formation, respectively. Collectively, our findings reveal that apatinib directly inhibits ß-catenin signaling and promotes ROS generation to suppress lung CSC-like characteristics. A clearer understanding of the anti-cancer mechanisms of apatinib is required for its better application in combating advanced and refractory/recurrent lung cancer when combined with conventional chemotherapy.

Potential role of iodine excess in papillary thyroid cancer and benign thyroid tumor: A case-control study.

BACKGROUND AND OBJECTIVES: The relationship between nutritional status of iodine and thyroid tumor is unclear. We investigated the association between urinary iodine concentration and thyroid function in patients with papillary thyroid cancer, benign thyroid tumor and healthy individuals. METHODS AND STUDY DESIGN: We compared the biomarkers of thyroid function and urinary iodine concentration within and between each group. A regression analysis was used to identify risk factors for papillary thyroid cancer. Correlation analysis was performed to determine whether any significant correlation exists between urinary iodine concentration and thyroid function biomarkers. RESULTS: The iodine nutrition statuses of these three groups were adequate (median urinary iodine concentration= 100-199 µg/L). However, the median urinary iodine concentration of papillary thyroid cancer (174.7 µg/L) and benign thyroid tumor (165.04 µg/L) groups was significantly higher than that of the healthy control group (135.8 µg/L) (p<0.05). The regression analysis showed that thyroglobulin antibody was an independent risk factor for papillary thyroid cancer. After adjusting for age and gender, the association between thyroglobulin antibody and urinary iodine concentration was significant (ß: 0.002; p<0.05). In subgroup analyses, significant correlations was noted only in the papillary thyroid cancer group (adjusted ß: 0.002; 95% confidence interval: 0.000- 0.003). CONCLUSIONS: Excessive iodine in patients with thyroid tumors may affect thyroglobulin antibody, which may be an independent risk factor for papillary thyroid cancer.

Effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection for papillary thyroid carcinoma.

BACKGROUND: The purpose of present study is to assess the effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection (CND) for papillary thyroid carcinoma (PTC). METHODS: A classification of IPGs according to their location and vascular features was developed, and, based on this classification, a CND procedure was designed, and IPGs and their vascular were actively localized and strategically preserved. A total of 197 patients with PTC who underwent a total thyroidectomy and concomitant CND were enrolled. Eighty-nine patients with traditional meticulous fascia dissection were allocated to group A, and 108 patients with active location and vascular preservation of IPGs were allocated to group B. Those with inferior parathyroid glands auto-transplantation in each group were assigned as group At (18) and group Bt (12). Variables including serum intact parathyroid hormone (PTH), total calcium, the incidence of transient, and permanent hypoparathyroidism were studied. RESULTS: Compared with group A, serum intact PTH (P < 0.001) and total calcium levels (P < 0.05) in group B significantly improved on the first postoperative day, and the incidence of transient hypoparathyroidism significantly dropped in group B (P < 0.001). A total of 170 patients in the two groups had complete follow-up data. The incidence of permanent hypoparathyroidism significantly decreased in group B, from 8.8% to 1.0% (P = 0.017). However, there were no significant differences in all variables between group Bt and group At. CONCLUSION: Active location and vascular preservation of inferior parathyroid glands effectively protected the function of IPGs in CND for PTC.

Mechanism investigation on Bisphenol S-induced oxidative stress and inflammation in murine RAW264.7 cells: The role of NLRP3 inflammasome, TLR4, Nrf2 and MAPK.

Bisphenol S is considered as a safer alternative to bisphenol A. In the present study, we used murine macrophages to investigate the effects of BPS exposure on oxidative stress and inflammatory response as well as the underlying mechanism. Cells were exposed to BPS at various concentrations for short period of times. Results showed that 10-8 M BPS triggered oxidative stress by increasing ROS/RNS production, increased the levels of oxidant enzyme NOX1/2, and decreased the levels of antioxidant enzymes SOD1/2, CAT and GSH-Px. 10-8 M BPS exposure significantly induced the production of proinflammatory mediators. Activation of the NLRP3 inflammasome, TLR4, and MAPK pathways was involved in this process. Furthermore, we illustrated that NAC pretreatment diminished these effects triggered by BPS exposure. Collectively, our data suggested that BPS at a dose relevant to human serum concentration induced oxidative stress and inflammatory response in macrophages. These novel findings shed light on the concerns regarding the potential adverse effects of BPS exposure that requires further careful attention.

Modulation of autophagy in the protective effect of resveratrol on PM2.5-induced pulmonary oxidative injury in mice.

Ambient fine particulate matter (PM2.5) is capable of inducing pulmonary oxidative injury. Autophagy maintains basal cellular homeostasis and plays a critical role in the pathogenesis of lung diseases. Resveratrol, a natural polyphenol, is an effective antioxidant agent against particulate matter (PM)-induced injuries. The current study was designed to investigate whether resveratrol can regulate autophagy in the process of PM2.5-mediated pulmonary oxidative injury. In the mice model of PM2.5 exposure, we found that PM2.5 increased the contents of malondialdehyde (MDA) and nitric oxide (NO) while decreased the expression of nuclear factor erythroid-2-related factor 2 in the lungs. The levels of 8-hydroxydeoxyguanosine and inflammatory cytokines were increased following PM2.5 exposure. Histological analysis of the lungs revealed inflammatory change in PM2.5 group. Meanwhile, PM2.5 triggered autophagy, as evidenced by the elevated expression of microtubule-associated proteins light chain 3II, Beclin1 and p62. Transmission electron microscopy images showed that autophagosomes accumulated in the lungs after PM2.5 exposure. Furthermore, resveratrol intervention suppressed autophagy and attenuated the oxidative injury resulting from PM2.5 exposure. Our findings provided a valuable insight into the underlying mechanism for the protective effects of resveratrol against PM2.5-induced lung injury, which involves suppression of the autophagic process.

Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis.

BACKGROUND: The strategy of using fecal microbiota transplantation (FMT) for refractory ulcerative colitis (UC) remains unclear if single FMT failed to induce remission. This study aimed to evaluate the efficacy and safety of a designed step-up FMT strategy for the steroid-dependent UC. METHODS: Fifteen patients with steroid-dependent UC were enrolled, and treated with step-up FMT strategy. Follow-up clinical data was collected for a minimum of 3 months. Fecal microbiota composition before and post FMT of patients and related donors were analyzed by 16S rRNA sequencing. RESULTS: Eight of fourteen (57.1 %) patients achieved clinical improvement and were able to discontinue steroids following step-up FMT. One patient was lost to follow-up. Among the 8 patients who responded, five (35.7 %) received one FMT therapy, one (7.1 %) received two FMTs, and two (14.2 %) received two FMTs plus a scheduled course of steroids. Four (28.6 %) of the 8 patients who responded maintained long-term remission during follow-up (3-18 months). Six patients (42.9 %) failed to meet the criteria of clinical improvement and maintained steroid dependence, though three experienced transient or partial improvement. Microbiota analysis showed that FMT altered the composition greatly, and a microbiota composition highly similar to that of the donor emerged in the patients with successful treatment. No severe adverse events occurred during treatment and follow-up. CONCLUSIONS: Step-up FMT strategy shows promise as a therapeutic strategy for patients with steroid-dependent UC, likely due to the successful restructuring of gut microbial composition. TRIAL REGISTRATION: ClinicalTrials.gov, Number NCT01790061.

Comparative investigations on the biological effects of As (III) and As (V) in clam Ruditapes philippinarum using multiple biomarkers.

Inorganic arsenic is a known pollutant with two chemical forms, arsenite (As (III)) and arsenate (As (V)), in marine environment. Clam Ruditapes philippinarum is an important fishery species along the Bohai coast. In this study, the biological effects induced by the two arsenic chemical forms (arsenite and arsenate) were compared using multiple biochemical indices in the digestive glands of clam R. philippinarum. The production of reactive oxygen species, antioxidant enzyme activities and metabolic responses exhibited that both As (III) and As (V) induced immune, oxidative and osmotic stresses in clam digestive glands. The differential metabolic biomarkers, histidine and taurine, indicated the differential responsive mechanisms in osmotic regulation in clam digestive glands. In addition, both arsenic treatments enhanced the anaerobiosis metabolism in clam digestive glands. Overall, this work illustrated that arsenite and arsenate induced similar biological effects in clams, which might be accounted for the biological transformation of arsenate to arsenite in clams.

The anti-tumor performance of docetaxel liposomes surface-modified with glycyrrhetinic acid.

PURPOSE: Anti-tumor performance of docetaxel liposomes surface-modified with glycyrrhetinic acid (GA-DX-Lip) as a new hepatocytes-targeted delivery vehicle was investigated, unmodified docetaxel liposome (DX-Lip) was chosen as a comparison. METHODS: GA-DX-Lip was prepared by film dispersion method. The physicochemical properties were characterized. The cellular uptake mechanism of GA-modified liposomes was studied in hepatocytes and nonparenchymal cells. Pharmacokinetics and the anti-tumor activity in vitro and in vivo of GA-DX-Lip were investigated. RESULTS: The size of GA-DX-Lip was about 90 nm with negative charge and the entrapment efficiency was more than 95%. GA-modified liposomes had the specific receptor-mediated cellular endocytosis to hepatocytes, and the uptake ratio of hepatocytes to nonparenchymal cells was 2.28 times. The tumor inhibitory ratio of GA-DX-Lip in vitro was 2.03 times of DX-Lip, the T/C of GA-DX-Lip was 20.14%, better than the 33.27% of DX-Lip. There was no obvious difference in pharmacokinetics parameters. DISCUSSION AND CONCLUSION: The preliminary cellular uptake test showed the receptor-mediated endocytosis and enhanced hepatocytes-target for GA-modified liposomes. Compared with the unmodified liposome, GA-DX-Lip possessed better anti-tumor activity and unchanged pharmacokinetic behavior. The present results suggest that the GA-modified liposomes may be a promising delivery system for hepatocytes-target.