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Nan Guo,1 Peng Qu,2 Hao Li,2 Liuli Liu,2 Hao Jin,3 Renqi Liu,3 Zhen Zhang,3 Xuan Zhang,2 Yingchun Li,4 Xiaobo Lu,2 Yuejiao Zhao1 1Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of China; 2Department of Toxicology, School of Public Health, China Medical University, Shenyang, People’s Republic of China; 3Jin Zhou Center for Disease Control and Prevention, Jinzhou, People’s Republic of China; 4Department of Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, People’s Republic of ChinaCorrespondence: Yuejiao ZhaoDepartment of Head and Neck Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning Province, People’s Republic of ChinaTel +86 24 31916833Email yuejiaozhao@126.comXiaobo LuDepartment of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People’s Republic of ChinaTel +86 24 31939077Email xblu@cmu.edu.cnObjective: To investigate the associations of polymorphisms in the following DNA double-strand break repair (DSBR) genes with papillary thyroid carcinoma (PTC) risk (including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440).Materials and Methods: A matched case–control study was implemented to examine associations between PTC risk and the above polymorphisms. Subsequently, we evaluated the effects of the potential PTC susceptibility-related variant rs15869 on BRCA2 mRNA secondary structure and BRCA2 expression through bioinformatics analysis and experiment validation. Additionally, luciferase assay was used to identify whether rs15869 polymorphism can substantially affect the binding of hsa-miR-1178-3p to BRCA2 mRNA. Finally, Pearson correlation analysis was performed to determine the correlation between the expression of hsa-miR-1178-3p and BRCA2 mRNA and protein in thyroid tissues harboring rs15869 different genotypes.Results: BRCA2 rs15869 CC genotype was associated with a higher risk of PTC than its AA genotype. Subsequently, stratified analyses came to the same conclusion in the female or age< 50 population. Furthermore, we confirmed that the A-to-C substitution of rs15869 changed BRCA2 mRNA secondary structure and contributed to a decreased BRCA2 expression. Mechanistically, a significantly decreased luciferase activity verified a greater binding between hsa-miR-1178-3p and rs15869 C allele, but not the A allele, which was evidenced by the significant negative correlation between hsa-miR-1178-3p with BRCA2 mRNA and protein levels in thyroid tissues with AC and CC genotype but not AA genotype at rs15869.Conclusion: BRCA2 rs15869 is characterized as a potential biomarker associated with PTC risk, highlighting the contribution of the hsa-miR-1178-3p via functional exploration.Keywords: papillary thyroid carcinoma, DNA double-strand break repair, BRCA2, rs15869 polymorphism, hsa-miR-1178-3p

Background and aims Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child-Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child-Pugh B cirrhosis and AVB. Approach and results We analyzed the pooled individual data from two previous studies of 608 patients with Child-Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF-C ADs for 6-week and 1-year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P 56), with a 5.6%, 16.8%, and 25.4% risk of 6-week death, respectively. Nevertheless, the performance of CLIF-C ADs for predicting a composite endpoint of 6-week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF-C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725). Conclusions In patients with Child-Pugh B cirrhosis and AVB, risk stratification using CLIF-C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6-week death or further bleeding, the data-driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.

Activation of transient receptor potential vanilloid 4 (TRPV4) can increase hippocampal neuronal excitability. TRPV4 has been reported to be involved in the pathogenesis of epilepsy. Voltage-gated potassium channels (VGPCs) play an important role in regulating neuronal excitability and abnormal VGPCs expression or function is related to epilepsy. Here, we examined the effect of TRPV4 activation on the delayed rectifier potassium current (IK ) in hippocampal pyramidal neurons and on the Kv subunits expression in male mice. We also explored the role of TRPV4 in changes in Kv subunits expression in male mice following pilocarpine-induced status epilepticus (PISE). Application of TRPV4 agonists, GSK1016790A and 5,6-EET, markedly reduced IK in hippocampal pyramidal neurons and shifted the voltage-dependent inactivation curve to the hyperpolarizing direction. GSK1016790A- and 5,6-EET-induced inhibition of IK was blocked by TRPV4 specific antagonists, HC-067047 and RN1734. GSK1016790A-induced inhibition of IK was markedly attenuated by calcium/calmodulin-dependent kinase II (CaMKII) antagonist. Application of GSK1016790A for up to 1 hr did not change the hippocampal protein levels of Kv1.1, Kv1.2, or Kv2.1. Intracerebroventricular injection of GSK1016790A for 3 d reduced the hippocampal protein levels of Kv1.2 and Kv2.1, leaving that of Kv1.1 unchanged. Kv1.2 and Kv2.1 protein levels as well as IK reduced markedly in hippocampi on day 3 post PISE, which was significantly reversed by HC-067047. We conclude that activation of TRPV4 inhibits IK in hippocampal pyramidal neurons, possibly by activating CaMKII. TRPV4-induced decrease in Kv1.2 and Kv2.1 expression and IK may be involved in the pathological changes following PISE.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

Background Prenatal stress (PRS) is considered a risk factor for depressive disorder. Adult hippocampal neurogenesis is believed to play a role in the regulation of affective behaviors. GABAergic interneuron is a key modulator in adult hippocampal neurogenesis. Growing evidence indicates that PRS has adverse effects on adult hippocampal neurogenesis and DNA epigenetic modifications of the GABAergic system. The aim of this study was to investigate whether epigenetic GABAergic dysfunction participates in the negative impact of PRS on adult hippocampal neurogenesis and related emotional behaviors. Methods Behavioral tests were used to explore PRS-induced depression-like behaviors of adult female mice. Immunohistochemistry staining, real-time reverse transcription-polymerase chain reaction, western blot, and chromatin immunoprecipitation were employed to detect adult neurogenesis and epigenetic changes of the GABAergic system in the hippocampus of PRS mice. Results PRS mice developed a depression phenotype accompanied by the inhibited maturation of hippocampal newborn neurons. Compared with control mice, PRS mice showed decreased expression of glutamic acid decarboxylase 67 at the mRNA and protein levels. GABAA receptor agonist phenobarbital could rectify the decrease of 5-bromo-2-deoxyuridine/neuronal nuclei double-positive (BrdU+/NeuN+) cells in PRS mice. PRS mice also showed increased expression of DNA methyltransferase 1 and increased binding of DNA methyltransferase 1 to glutamic acid decarboxylase 67 promoter region. The treatment with DNA methyltransferase 1 inhibitor 5-aza-deoxycytidine restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in PRS mice via improving GABAergic system. Conclusions The present results indicate that epigenetic changes of the GABAergic system are responsible for adult hippocampus neurogenesis and depression-like behaviors in PRS mice.

IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.

Over the past decade, a variety of carbon monoxide releasing molecules (CORMs) have been developed and tested. Some CORMs spontaneously release CO once in solution, while others require a trigger mechanism to release the bound CO from its molecular complex. The modulation of biological systems by CORMs depends largely on the spatiotemporal release of CO, which likely differs among the different types of CORMs. In spontaneously releasing CORMs, CO is released extracellularly and crosses the cell membrane to interact with intracellular targets. Other CORMs can directly release CO intracellularly, which may be a more efficient method to modulate biological systems. In the present study, we compared the efficacy of extracellular and intracellular CO-releasing CORMs that either release CO spontaneously or require an enzymatic trigger. The efficacy of such CORMs to modulate HO-1 and VCAM-1 expression in TNF-α-stimulated human umbilical vein endothelial cells (HUVEC) was evaluated.

Ovarian cancer is a leading cause of death among gynecological malignancies, and novel therapies are urgently needed. Here we report preliminary findings on the potential safety and efficacy of 6B11-OCIK, an adoptive cell therapy of autologous T cells induced by the humanized anti-idiotypic antibody 6B11 minibody plus dendritic cells and cytokines, against platinum-resistant recurrent or refractory ovarian cancer in three patients. We found that 6B11-OCIK treatment was safe and well tolerated after five cycles of intravenous infusion with an initial dose of 1–2×109 cells and a dose-climbing strategy. Hemoglobin, platelets, white cell count, creatinine or liver enzyme values, coagulation function, kidney and heart function were not significantly affected over the duration of therapy. Two of the three enrolled patients showed potentially drug-related grade 1 and 2 weakness, and no other adverse events were observed. Of the three enrolled patients, one had stable disease and two showed disease progression. The patient with favorable clinical efficacy had better immune response as measured by 6B11-OCIK proliferation capacity, activation ability of CD3+CD8+ tumor-specific cytotoxic T lymphocytes and CD3+CD56+ cytokine-induced killer cells, and tumor cell killing efficiency. Changes in circulating tumor cells after treatment were consistent with serum level CA125 in the patient with stable disease (both decreased), while differences were observed in the two patients with disease progression (increased CA125 in both and decreased CTC in the patient with better immune response), suggesting that variation of circulating tumor cells was more consistent with immune response and reflected efficacy directly. This preliminary study suggested that autologous 6B11-OCIK treatment was safe and had potential clinical efficacy against ovarian cancer. Patients with better immune response had more favorable efficacy. In addition to imaging, CA125 and immunophenotypes, CTC monitoring may represent a potential indicator of immunotherapy response.

Colorectal cancer (CC), as a malignancy threatening life and health, has a rising incidence in recent years. It has been reported that gambogic acid (GA) has antitumor activity in various tumors, but its effect on CC remains to be elucidated. In this investigation, the influence of GA nanoparticles on microRNA-199a-3p (miR-199a-3p) in CC was analyzed to provide a reliable reference for future clinical practice. Through PCR detection, we first determined that miR-199a-3p presented low expression in CC and had a significant effect in predicting the onset and prognosis of CC. Through in vitro experiments, the enhanced CC cell viability after inhibition was determined; however, decreased cell viability and increased miR-199a-3p level were also observed after GA nanoparticles addition. Hence, GA nanoparticles may influence CC cell biological behaviors by modulating miR-199a-3p, providing a novel treatment scheme for CC in the future.

Purpose Increasing evidence suggests that lysyl oxidase-like 2 (LOXL2) contributes to tumor progression. However, the role of LOXL2 in cervical cancer still remains unclear. Patients and methods We used the TCGA database to analyze the expression of LOXL2 in cervical cancer and its role on survival. The effects of LOXL2 on cervical cancer metastasis and EMT were verified by transwell and wound healing assay. Western blot assay was used to detect the effect of LOXL2 on EMT-related gene expression. In addition, we used animal experiments to observe the role of LOXL2 on tumor genesis and metastasis in cervical cancer. Results Here we found that LOXL2 participates in epithelial-mesenchymal transition-related cervical cancer progression. LOXL2 ablation in cervical cancer cells inhibited cell metastatic ability, whereas LOXL2 overexpression promoted cell metastasis. In addition, more clinical data from TCGA revealed that LOXL2 is closely related to the prognosis and is highly expressed in highly malignant and metastatic cervical tumors. Conclusion Taken together, our findings established a pathophysiologic role and new function for LOXL2 in cervical cancer metastasis.

Background Many studies have explored the prognostic value of T-cell lymphoma invasion and metastasis inducing factor 1 (Tiam1) and its association with lymphatic metastasis in malignant solid tumors, but the conclusions remain controversial. Therefore, we performed a meta-analysis to systematically assess the prognostic value of Tiam1 expression and its association with lymphatic metastasis in malignant solid tumors. Methods We searched eligible studies in PubMed, Web of Science and EMBASE databases (from inception up to October 2018). The combined HR with 95% CI was used to estimate the prognostic value of Tiam1 expression. The correlation between Tiam1 expression and lymphatic metastasis was assessed using the combined odds ratio (OR) with 95% CI. Results A total of 17 studies with 2,228 patients with solid tumors were included in this meta-analysis. The overall estimated results showed that high Tiam1 expression was significantly associated with shorter overall survival (HR= 2.08, 95% CI: 1.62–2.68, P

BACKGROUND This study aimed to investigate the role of the long noncoding RNA (lncRNA), LINC01555, on the migration and invasion of colorectal cancer (CRC) cells, its expression in CRC tissue, and its interaction with the neuropeptide, neuromedin U (NmU). MATERIAL AND METHODS LINC01555 expression in SW620 and HCT116 CRC cells, and NCM460 normal colorectal cells, and 48 resection specimens containing CRC and adjacent normal tissue, was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cox regression analysis was used to assess the relationship between LINC01555 expression and patient survival. The effects of LINC01555 expression on CRC cell proliferation, migration, and invasion were assessed using the cell counting kit-8 (CCK-8) assay, the colony formation assay, and the transwell assay. Functional studies determined the interaction between LINC01555 and NmU in the development of CRC. RESULTS The Cancer Genome Atlas (TCGA) dataset showed that LINC01555 was highly expressed in CRC tissue when compared with adjacent normal colorectal tissue. LINC01555 expression was positively correlated with tumor stage, but negatively correlated with disease-free survival (DFS) and overall survival (OS) and was an independent risk factor for CRC. The receiver operating characteristic (ROC) curve analysis showed the diagnostic specificity of LINC01555 in CRC. Knockdown of LINC01555 inhibited cell proliferation, migration, and invasion of CRC cells. Functional studies showed that knockdown of NmU reduced cell migration and invasion of CRC cells that overexpressed LINC01555. CONCLUSIONS Increased expression of LINC01555 was found in CRC tissues and promoted the invasion of CRC cells by upregulating the expression of NmU.

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1+) and GFAP-positive (GFAP+) cells in hippocampi, which indicated TRPV4-induced microglial cell and astrocyte activation. The protein levels of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome components NLRP3, apoptosis-related spotted protein (ASC) and cysteinyl aspartate-specific protease-1 (caspase-1) were increased in GSK1016790A-injected mice, which indicated NLRP3 inflammasome activation. GSK1016790A also increased proinflammatory cytokine IL-1β, TNF-α and IL-6 protein levels, which were blocked by caspase-1 inhibitor Ac-YVAD-cmk. GSK1016790A-induced neuronal death was attenuated by Ac-YVAD-cmk. Icv. injection of TRPV4-specific antagonist HC-067047 markedly increased the number of surviving cells 3 d post status epilepticus in pilocarpine model of temporal lobe epilepsy in mice (pilocarpine-induced status epilepticus, PISE). HC-067047 also markedly blocked the increase in Iba-1 and GFAP protein levels, as well as Iba-1+ and GFAP+ cells 3 d post-PISE. Finally, the increased protein levels of NLRP3, ASC and caspase-1 as well as IL-1β, TNF-α and IL-6 were markedly blocked by HC-067047. We conclude that TRPV4-induced neuronal death is mediated at least partially by enhancing the neuroinflammatory response, and this action is involved in neuronal injury following status epilepticus.

Background Kashin-Beck disease (KBD) is one of the major endemic diseases in China, which severely impacts the physical health and life quality of people. A better understanding of the spatial distribution of the health loss from KBD and its influencing factors will help to identify areas and populations at high risk so as to plan for targeted interventions. Methods The data of patients with KBD at village-level were collected to estimate and analyze the spatial pattern of health loss from KBD in Bin County, Shaanxi Province. The years lived with disability (YLDs) index was applied as a measure of health loss from KBD. Spatial autocorrelation methodologies, including Global Moran’s I and Local Moran’s I, were used to describe and map spatial clusters of the health loss. In addition, basic individual information and environmental samples were collected to explore natural and social determinants of the health loss from KBD. Results The estimation of YLDs showed that patients with KBD of grade II and patients over 50 years old contributed most to the health loss of KBD in Bin County. No significant difference was observed between two genders. The spatial patterns of YLDs and YLD rate of KBD were clustered significantly at both global and local scales. Villages in the southwestern and eastern regions revealed higher health loss, while those in the northern regions exhibited lower health loss. This clustering was found to be significantly related to organically bound Se in soil and poverty rate of KBD patients. Conclusions Our results suggest that future treatment and prevention of KBD should focus on endemic areas with high organically bound Se in soil and poor economic conditions. The findings can also provide important information for further exploration of the etiology of KBD.

Purpose18F labelled PSMA-1007 presents promising results in detecting prostate cancer (PC), while some pitfalls exists meanwhile. An intra-individual comparison of 18F-FDG and 18F-PSMA-1007 in patients with prostate cancer were aimed to be performed in the present study. Then, the pitfalls of 18F-PSMA-1007 PET/CT in imaging of patients with prostate cancer were analyzed.Methods and Material21 prostate cancer patients underwent 18F-PSMA-1007 PET/CT as well as 18F-FDG PET/CT before treatment. All positive lesions were noticed in both 18F-PSMA-1007 PET/CT and 18F-FDG PET/CT, then differentiated PC metastasis from benign lesions. the SUVmax, SUVmean and TBR of lesions, up to 10 metastases and 10 benign lesions per patients were recorded (5 for bone, 5 for soft tissue metastasis ). The distribution of positive lesions were analyzed for two imaging. Detection rates, SUVmax, SUVmean and TBR in 18F-PSMA-1007 PET/CT and 18F-FDG PET/CT were compared, respectively. The optimal cut-off values of SUVmax, SUVmean for metastases vs. benign lesions was found through areas under ROC in 18F-PSMA-1007.ResultsThe detection rates of primary lesions in 18F-PSMA-1007 PET/CT was higher than that of 18F-FDG PET/CT(100% (21/21) vs. 67%(14/21)). For extra- prostatic lesions, 18F-PSMA-1007 PET/CT revealed 124 positive lesions, 49(49/124, 40%) attributed to a benign origin; 18F-FDG PET/CT revealed 68 positive lesions, 14(14/68, 21%) attributed to a benign origin. The SUVmax, SUVmean, TBR of primary tumor in 18F-PSMA-1007 PET/CT was higher than that in 18F-FDG PET/CT (15.20 vs. 4.20 for SUVmax; 8.70 vs. 2.80 for SUVmean; 24.92 vs. 4.82 for TBR, respectively); The SUVmax, SUVmean, TBR of metastases in 18F-PSMA-1007 PET/CT was higher than that in 18F-FDG PET/CT (10.72 vs. 4.42 for SUVmax; 6.67 vs. 2.59 for SUVmean; The TBR of metastases was 13.3 vs. 7.91). For 18F-FDG PET/CT, the SUVmax, SUVmean in metastases was higher than that in benign lesions (4.42 vs. 3.04 for SUVmax, 2.59 vs. 1.75 for SUVmean, respectively). Similarly, for 18F-PSMA-1007 PET/CT, the SUVmax, SUVmean in metastases was significantly higher than that in benign lesions(10.72 vs. 3.14 for SUVmax, 6.67 vs. 1.91 for SUVmean, respectively), ROC suggested that SUVmax=7.71, SUVmean=5.35 might be the optimal cut-off values for metastases vs. benign lesions.ConclusionThe pilot study suggested that 18F-PSMA-1007 showed superiority over 18F-FDG because its high detecting rate of PC lesions and excellent tumor uptake. While non-tumor uptake in 18F-PSMA-1007 may lead to misdiagnosis, recognizing these pitfalls and careful analysis can improve the accuracy of diagnosis.

Preemptive TIPS Individual Data Metanalysis, International Variceal Bleeding Study and Baveno Cooperation Study groups., [Background & Aims] Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS., [Method] We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients., [Results] Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323–0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307–0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253–0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy., [Conclusions] In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy., Juan Carlos García-Pagán received support in part through grants from the Spanish Ministry of Education and Science (SAF-2016–75767-R and PIE 15/00027) and from the “Commissioner for Universities and Research of the Generalitat de Catalunya” (AGAUR SGR 2017). CIBERehd is funded by the Instituto de Salud Carlos III. Edilmar Alvarado-Tapias and Anna Baiges are recipients of a "Río Hortega" fellowship grant from the Instituto de Salud Carlos III. The study was partially supported by a GORE grant for statistical support.

China is recognized as a selenium-deficient country, and nutritional selenium intake has always been a concern. To clarify the current inhabitants&rsquo, selenium nutrition status and the characteristics of dietary consumption in low-selenium areas, samples of human hair and grains were collected, and food frequency questionnaires were administered in Binxian County, Shaanxi Province, a typical low-selenium area in the Loess Plateau. The subject number of the study is 85, and the age range is from 11 to 81 years, with an average of 60. The results showed that the average hair selenium content of the residents was 231.7 &mu, g/kg, and 62.4% of the participants had levels higher than the selenium deficiency threshold (200 &mu, g/kg). There was a significant positive correlation between the hair selenium content and the food consumption score after adjusting for rice outsourcing. Three different dietary patterns were noted according to hierarchical cluster analysis. This study provides a tool for assessing the selenium nutrition of inhabitants in low-selenium areas and has considerable significance for improving the dietary pattern of residents.

The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, butin vitrodifferentiation remains difficult. We earlier reported thein vivogeneration of lung organsviablastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids ofFgf10Ex1mut/Ex3mutmice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) inFgf10Ex1mut/Ex3mutmiceviablastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells ofFgf10Ex1mut/Ex3mutchimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generationin vivo viablastocyst complementation will aid functional thyroid regeneration.

Background This study was aimed at investigating the effects of long noncoding RNA (lncRNA) LINC02323 in ovarian cancer and its possible mechanism. Methods Microarray analysis and QPCR were utilized to identify lncRNA LINC02323 expression in patients with ovarian cancer. MTT assay was used for analysis of ovarian cancer cell proliferation. Western blot was utilized to investigate its possible mechanism. Results In patients with ovarian cancer, lncRNA LINC02323 expression was up‐regulated and miR‐1343‐3p expression was down‐regulated. Over‐expression of lncRNA LINC02323 promoted cell growth and reduced LDH activity levels in vitro model by suppression of miR‐1343‐3p expression. Down‐regulation of lncRNA LINC02323 reduced cell growth and increased LDH activity levels in vitro model by induction of miR‐1343‐3p expression. Over‐expression of miR‐1343‐3p reduced cell growth and reduced LDH activity levels in vitro model by suppression of TGF‐β receptor. Down‐regulation of miR‐1343‐3p promoted cell growth and reduced LDH activity levels in vitro model by induced of TGF‐β receptor. Conclusion Our findings show that Novel long noncoding RNA LINC02323 promotes cell growth of ovarian cancer via TGF‐β receptor 1 by miR‐1343‐3p., Serum levels of lncRNA LINC02323 in patients with ovarian cancer (A) and the risk of developing cancer (B), OS, and DFS (C and D).

IntroductionThis study was undertaken to examine the anticancer effects of the natural product rhein on human leukaemia cells.Material and methodsCell viability was determined by MTT assay. Immunofluorescence staining, DAPI, AO/EB, and annexin V/PI staining were used for the detection of apoptosis. qRT-PCR analysis was used to examine protein expression. Western blot analysis was used to determine protein expression.ResultsThe results revealed that rhein caused a significant (p < 0.05) and dose-dependent decrease in the viability of AML-193 leukaemia cells. It was also revealed that rhein caused morphological changes such as cell rounding in rhein-treated AML-193 cells. The DAPI and AO/EB staining showed that rhein caused remarkable changes in the nuclear morphology of the AML-193 cells, characteristic of apoptosis. The percentage of apoptosis was found to be 3.12%, 14.80%, 30.31%, and 60.85% at the concentrations of 0, 3.5, 7, and 14 µM of rhein, respectively. The expression of Bax, cleaved caspase-3, 9, and cleaved PARP increased concentration dependently, while the expression of Bcl-2 decreased. The effects of rhein were also examined on 11 different miRs, and it was found that rhein specifically and significantly (p < 0.05) inhibited the expression of miR-27. Additionally, inhibition of miR-27 resulted in the decrease of AML-193 viability and upregulation of Cullin 5 (CUL5).ConclusionsTaken together, rhein triggers apoptosis in leukaemia cells and modulates the miR-27/CUL5 axis. As such, rhein may prove to be beneficial in the treatment of leukaemia.

Prenatal stress (PRS) had a long-term adverse effect on motor behaviors. Corticostriatal synaptic plasticity, a cellular basis for motor controlling, has been proven to participate in the pathogenesis of many behavior disorders. Based on the reports about the involvement of epigenetic DNA alterations in PRS-induced long-term effects, this research investigated the influence of PRS on the development and maturation of corticostriatal synaptic plasticity and related behaviors and explored the underlying epigenetic mechanism. Subjects were male offspring of dams that were exposed to stress three times per day from the 10th day of pregnancy until delivery. The development and maturation of plasticity at corticostriatal synapses, dopamine signaling, behavioral habituation, and DNA methylation were examined and analyzed. Control mice expressed long-term potentiation (LTP) at corticostriatal synapses during postnatal days (PD) 12-14 and produced long-term depression (LTD) during PD 20-60. However, PRS mice exhibited sustained LTP during PD 12-60. The treatment with dopamine 2 receptor (D2R) agonist quinpirole recovered striatal LTD and improved the impaired behavioral habituation in PD 45 adult PRS mice. Additionally, adult PRS mice showed reduced D2R, excess DNA methyltransferase 1 (DNMT1), increased binding of DNMT1 to D2R promoter, and hypermethylation at D2R promoter in the striatum. The DNMT1 inhibitor 5-aza-deoxycytidine restored striatal synaptic plasticity and improved behavioral habituation in adult PRS mice via D2R-mediated dopamine signaling. DNMT1-associated D2R hypermethylation is responsible for altering the maturation of plasticity at corticostriatal synapses and impairing the behavioral habituation in PRS mice.

Objective. To study the biological function of circular RNA RNF13 (circRNF13) in acute myeloid leukemia (AML) and its relationship with prognosis. Methods. We constructed stable AML cell lines with downregulated expression of circRNF13, and then, we explored the effect of downregulation of circRNF13 expression on the proliferation, migration, and invasion through qRT-PCR, MTT curve, colony formation, transwell migration and invasion experiment, cell cycle, apoptosis, Caspase 3/7 assay, and other experiments. We also studied the expression of C-myc and Tenascin-C by qRT-PCR to explore the role of circRNF13. Results. When the expression of circRNF13 was downregulated, the proliferation rate of AML cells decreased significantly, the cell cycle was blocked to G1 phase, and apoptosis rate increased significantly. C-myc related to cell proliferation decreased significantly at RNA level. Furthermore, when the expression of circRNF13 was downregulated, the migration and invasion ability of AML cells was significantly reduced, and the expression of Tenascin-C related to migration and invasion also decreased significantly. The luciferase reporter assay system confirmed that miRNA-1224-5p was the direct target of circRNF13. Conclusion. CircRNF13 inhibited the proliferation, migration, and invasion of AML cells by regulating the expression of miRNA-1224-5p. This study provides some clues for the diagnosis and treatment of AML.

Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.

Background Prenatal stress is considered a risk factor for anxiety disorder. Downregulation in the expression of GABAergic gene, that is, glutamic acid decarboxylase 67, associated with DNA methyltransferase overexpression in GABAergic neurons has been regarded as a characteristic component of anxiety disorder. Prenatal stress has an adverse effect on the development of the basolateral amygdala, which is a key region in anxiety regulation. The aim of this study is to analyze the possibility of epigenetic alterations of GABAergic neurons in the basolateral amygdala participating in prenatal stress-induced anxiety. Methods Behavioral tests were used to explore the prenatal stress-induced anxiety behaviors of female adult mice. Real-time RT-PCR, western blot, chromatin immunoprecipitation, and electrophysiological analysis were employed to detect epigenetic changes of GABAergic system in the basolateral amygdala. Results Prenatal stress mice developed an anxiety-like phenotype accompanied by a significant increase of DNA methyltransferase 1 and a reduced expression of glutamic acid decarboxylase 67 in the basolateral amygdala. Prenatal stress mice also showed the increased binding of DNA methyltransferase 1 and methyl CpG binding protein 2 to glutamic acid decarboxylase 67 promoter region. The decrease of glutamic acid decarboxylase 67 transcript was paralleled by an enrichment of 5-methylcytosine in glutamic acid decarboxylase 67 promoter regions. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-basolateral amygdala synaptic transmission of prenatal stress mice. 5-Aza-deoxycytidine treatment restored the increased synaptic transmission and anxiety-like behaviors in prenatal stress mice via improving GABAergic system. Conclusion The above results suggest that DNA epigenetic modifications of GABAergic interneurons in the basolateral amygdala participate in the etiology of anxiety-like phenotype in prenatal stress mice.

We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for the activation of transient-receptor-potential channels of the vanilloid-receptor subtype 1 (TRPV1) and inhibition of inflammation. The potency of NOD in activating TRPV1 was significantly higher compared with those of variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted ( N-octanoyl tyramine), or the ester functionality consisted of a bulky fatty acid ( N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its potency, which was further increased when the carbonyl and amide groups (ΔNODR) were interchanged. With the exception of ΔNOD, the presence of an intact catechol structure was obligatory for the inhibition of VCAM-1 and the induction of HO-1 expression. Because TRPV1 activation and the inhibition of inflammation by N-acyl dopamines require different structural entities, our findings provide a framework for the rational design of TRPV1 agonists with improved anti-inflammatory properties.

Toxicity assessment is necessary in many fields, but the common animal experiments and traditional cell-based bioassays are endpoint tests and limited in the aspects of cost, complex operation, individual difference, etc. Herein, a cell-involved platform for facilely assessing risk of chemicals was established based on electrochemical biosensing and microfluidic technology. Through in situ monitoring responses of live cells cultivated in sensor chamber towards exterior chemical stimuli, a preliminary categorization of chemicals on reversibility of cell injury has been achieved. The device consists of two core units: a bioreactor and a cell metabolism monitoring chip (CMMC). The bioreactor is for culturing live cells and meanwhile delivering real-time electrochemical impedance of cells via a built-in interdigital electrode. The CMMC is connected to the bioreactor and the installed enzymatic screen-printed electrodes (SPEs) fulfill on-line detection of glucose (Glu) and lactic acid (LA) flowing out of the bioreactor. Impedance values have to do with cell growth and reproduction, while the amounts of Glu and LA reflect respiration state of cells. To test validity of the platform, HepG2 cells were cultured in the bioreactor and treated with five chemicals. The influence induced by these chemicals was studied by monitoring and analyzing the variations of three signals (cell adhesion, Glu uptake and LA generation). The whole system allows for preliminary understanding of toxicity and possible mechanism of chemicals acting on cells, which is also expected to be applied in varied fields including ecological safety, biomedicine, etc.

// Xue Ying 1 , Yahua Wang 1 , Haolun Xu 1 , Xia Li 1 , Helu Yan 1 , Hui Tang 1 , Chen Wen 1 and Yingchun Li 1, 2 1 School of Pharmaceutical Sciences, Shihezi University, Shihezi 832002, People’s Republic of China 2 School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, People’s Republic of China Correspondence to: Xue Ying, email: yingxue@shzu.edu.cn Yingchun Li, email: liyingchun@hit.edu.cn Keywords: glioblastoma, multifunctional targeting ursolic acids liposomes, glioma stem cell, apoptosis, brain glioma-bearing mice Received: February 06, 2017 Accepted: June 20, 2017 Published: August 02, 2017 ABSTRACT Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells.

This paper presents the results of numerical studies that illustrate the performance of a new joint constitutive model developed for the stability analysis of large-scale jointed rock masses. The joint model features the reduction of stiffness and strength due to joint initial opening and scale effect, which has been demonstrated by performing a series of direct shear tests. The study thus focuses on the model’s applicability to field-scale rock joints. The movement of a real rock slope is first investigated numerically where the mechanical behaviour of joints is represented by the Mohr–Coulomb model and the proposed joint model. The slope is appraised to be much less stable by the simulation using the developed joint model, which agrees more with the qualitative observation on the site. The response of jointed rock masses to excavation is also examined by simulating two underground rock structures where the mechanical behaviour of joints obeys the developed model in the numerical modelling. Predi...

Converging evidence from laboratory models pointed that the widely used antidiabetic drug metformin has direct effects on cancer cells. Thus far, relatively little attention has been addressed to the drug exposures used experimentally relative to those achievable clinically. Here, we demonstrated that metformin loaded on carbon nanotubes under near-infrared (NIR) irradiation led to the remarkably enhancement in response towards cancer cells. The dose of metformin has reduced to only 1/280 of typical doses in monotherapy (35: 10 000–30 000 µM) where the realization of metformin in conventional antidiabetic doses for cancer therapies becomes possible. The heat generated from carbon nanotubes upon NIR irradiation has mediated a strong and highly localized hyperthermia-like condition that facilitated the enhancement. Our work highlight the promise of using highly localized heating from carbon nanotubes to intensify the efficacy of metformin for potential cancer therapies.

The purpose of this study is to determine the efficacy of adjuvant immunotherapy with autologous cytokine-induced killer (CIK) for postoperative patients with gastric cancer and to investigate the impacts of the predictors on the efficacy of CIK immunotherapy. Ninety-two gastric cancer patients who have accepted radical resection were enrolled. The CIK and control groups were established by 1:1 matching on their baseline. As prognosis indicators, preoperative blood cell counts, the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were analyzed, respectively. Statistical analyses were done using IBM SPSS Statistics ver.19.0. CIK treatment significantly prolonged disease-free survival (DFS) (p

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1

Growing evidence indicates that early-life inflammation has adverse effects on adult hippocampal neurogenesis and GABA system. Based the report that hippocampal GABA system is a key modulator in adult hippocampal neurogenesis, the aim of this study was to investigate whether and how early inflammation affects GABAergic system resulting in the alterations of adult hippocampal neurogenesis and related behaviors. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days (PND) 3–5. Behavioral tests were used to explore LPS-induced depression-like behaviors of adult mice. Immunohistochemistry staining and western blot were employed to detect adult neurogenesis, GABAergic system, glia activation and BDNF-TrkB pathway in the hippocampus. LPS-treated mice developed a depression phenotype with the inhibited maturation of hippocampal newborn neurons in adulthood. Compared with controls, LPS mice showed a decreased expression of GABAA receptor (GABAAR) protein. GABAAR agonist phenobarbital could rectify the decrease of BrdU+/NeuN+ cells in LPS mice. Additionally, postnatal LPS treatment resulted in the activation of astrocytes and the increase expression of toll-like receptor 4 (TLR4) in the second postnatal week and the downregulation of BDNF-TrkB pathway in adulthood. The treatment with TLR4 inhibitor TAK-242 restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in LPS mice via improving GABAAR. The results indicate that postnatal LPS exposure impairs adult hippocampal neurogenesis and causes depression-like behaviors through early astrocytes activation triggering the later GABAAR downregulation.

Notoginsenoside R1 (NGR1) is a neoteric phytoestrogen extracted from Panax notoginseng, and possesses comprehensive pharmacological functions in multitudinous ailments. But, whether NGR1 is utilized in neonatal pneumonia is not clear. This research study aspired to disclose the protective activity of NGR1 in neonatal pneumonia. WI-38 cells were co-stimulated with NGR1 and lipopolysaccharide (LPS, 10 ng/mL), CCK-8 and flow cytometry assays were implemented for cell viability and apoptosis assessment. Real-time quantitative plymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were executed for inflammatory cytokine determination. MicroRNA-181a (miR-181a) expression was evaluated through RT-qPCR, simultaneously, the impact of miR-181a was estimated in NGR1 and LPS co-managed cells. Dual luciferase report assay was performed to disclose the relation between miR-181a and Toll-like receptor 4 (TLR4). The nuclear factor-κB (NF-κB) and TAK1/JNK pathways were ultimately appraised. We found that NGR1 decreased cell viability, evoked apoptosis and impeded interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) expression and secretions in LPS-managed WI-38 cells. MiR-181a expression was enhanced by NGR1, and miR-181a inhibition inverted the impacts of NGR1 in LPS-managed WI-38 cells. Besides, TLR4 was predicted to be a firsthand direct target of miR-181a. Furthermore, NGR1 hindered NF-κB and TAK1/JNK pathways through modulating TLR4. These discoveries disclosed the fact that NGR1 protected WI-38 cells against LPS-triggered injury via adjusting the miR-181a/TLR4 and NF-κB and TAK1/JNK pathways.

In order to investigate the effects of MOFs by altering ligands with various functional groups on separation selection in pervaporation dehydration, three hydrophilic UiO-66-X nanoparticles were respectively synthesized and blended into poly (vinyl alcohol) matrix to fabricate water-selective membrane for ethanol dehydration via PV technology. Both the experimental and molecular simulation results confirmed the UiO-66-X counterbalancing factors of enhanced polarity and suitable pore size gave rise to the optimal performance in ethanol dehydration. The PV performances could be tuned by the type and quantity of functional groups carried by UiO-66-X nanoparticles. As a result, the pore aperture of UiO-66-(COOH)2 nanoparticles provided continuous channel for water diffusion, and water molecules could also be activated attributed to the strong interaction between the UiO-66-(COOH)2 nanoparticles and water molecules which enhanced the penetration and diffusion of water molecular in hybrid membrane to increase the water flux. The optimized hybrid membranes with UiO-66-(COOH)2 loading of 8 wt% exhibited the total flux of 979 ± 7 g/(m2·h) and a separation factor of 2084 ± 21.

Background Recent studies show that Liver X receptors (LXR) activation is involved in the regulation of tumor cell death in solid cancer via E2 factor (E2F) transcription factor or suppressor of cytokine signaling-3 (SOCS3) pathway. However, the effect of LXR activation on leukemic cell fate has not been tested. Methods Two human acute lymphoblastic leukemia (ALL) cell lines, Jurkat and SupT1, were cultured. Cells were transfected with small-interfering RNA (si-RNA) against SOCS3 and E2F family members (including E2F1, E2F2 and E2F3a) followed by treatment with LXR activator GW3965. The cellular biological behaviors, including proliferation, colony-forming ability and apoptosis were tested afterward. Results Activation of LXR by GW3965 significantly decreased the cell proliferation rates and colony-forming abilities in the Jurkat and SupT1 cells, but increased their apoptosis rates. Western blot assay show that GW3965 treatment dramatically up-regulated the SOCS3 protein in both cell lines, without affecting E2F1, E2F2 and F2F3a expression levels. SOCS3 inhibition by si-RNA transfection, instead of E2F1, E2F2 and F2F3a pathway inhibition, abolished the aforementioned effects of LXR activation on Jurkat and SupT1 cells. Conclusion Our finding suggests that LXR activation regulates leukemic cell fate and biological behavior via SOCS3 pathway, rather than E2F family members.

Previous studies have shown that bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. The present study focused on exploring the impact of exposure to low dose of BPA on male reproductive development during the early embryo stage and the underlying mechanisms. BPA (20 μg/kg/day) was orally administered to female mice on days 1-5 of gestation. The male offspring were euthanized at PND10, 20, 24, 35 or PND50. We found that the mice exposed to BPA before implantation (BPA-mice) displayed retardation of testicular development with reduction of testosterone level. The diameter and epithelium height of seminiferous tubules were reduced in BPA-mice at PND35. The numbers of spermatogenic cells at different stages were significantly reduced in BPA-mice at PND50. BPA-mice showed a persistent reduction in serum and testicular testosterone levels starting from PND24, whereas GnRH mRNA was significantly increased at PND35 and PND50. The expressions of testicular StAR and P450scc in BPA-mice also decreased relative to those of the controls at PND35 and PND50. Further analysis found that the levels of histone H3 and H3K14 acetylation (Ac-H3 and H3K14ac) in the promoter of StAR were decreased relative to those of control mice, whereas the level of Ac-H3 in the promoter of P450scc was not significantly different between the groups. These results provide evidence that exposure to BPA in preimplantation embryo retards the development of testes by reducing histone acetylation of the StAR promoter to disrupt the testicular testosterone synthesis.

A novel carbon foam (CF) was prepared via physically activating banana peel and applied for adsorbing various heavy metal ions including Cu2+, Pb2+, Cd2+ and Cr6+ in aqueous solution. The material was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and Brunauer–Emmett–Teller analysis. The influences of several variables such as pH, contact time, temperature and initial concentration of ions were investigated through batch experiments. The sorption capacities of our proposed CF are remarkably higher than those of similar products (banana peel-based) from other reports. Kinetic and equilibrium studies illustrate that the sorption behavior can be better described by pseudo-second-order kinetic and Langmuir isotherm models. The maximum sorption capacities of Cu2+, Pb2+, Cd2+ and Cr6+ are estimated to be 49.5, 45.6, 30.7 and 25.2 mg g−1 at an equilibrium time of 5 min. Evaluation of the thermodynamic parameters (ΔG° 0 and ΔS° > 0) show that the ion sorption onto the CF is an endothermic and spontaneous process. It is noteworthy that the efficiency of the produced material for removing metals can be up to 98% for the contact time of 1 h. The removal efficiency values for 10 kinds of metal ions are 1.3 to 98.6 times higher than those using commercial activated carbon as adsorbent. Among them, the removal efficiency for Cu2+, Pb2+, Cd2+ and Cr6+ is 7.5, 8.9, 8.7 and 16.6 times higher than that of commercial activated carbon, respectively. The obtained material displays a good application prospect in practical wastewater treatment due to its desirable performance, facile preparation and abundant raw material source with a low price.

Gallic acid (GA) holds great potential in anti-cancer, anti-mutagenesis and as antioxidant. Thus its quantification is essential for quality control of GA-based drugs and health-care products, as well as for ensuring appropriate usage in human body. We developed a facile colorimetric method of GA determination, in which perovskite LaFeO3 worked as nanozyme to catalyze oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) and GA as inhibitor to prevent occurrence of the reaction. LaFeO3 was synthesized by simple hydrothermal tactic and subsequent calcination, and appears as microspheres with mesopores on the surface. The steady-state kinetic study demonstrated that the mesoporous LaFeO3 microspheres owned higher affinity and larger maximum initial velocity (Vmax) for both TMB and H2O2 compared with natural horseradish peroxidase. Colorimetric analysis of GA was established based on its reducing property to measure GA in a dynamic range of 0.6∼36 μM, as well as a low detection limit of 0.4 μM (S/N = 3). In addition, the sensing system withstood interference of various interfering species and behaved well in monitoring actual samples including green tea, diet tea and pharyngitis tablets. With all these merits, the colorimetric sensor is expected to serve as a facile device for analysis of other substances.