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This article explores the impact mechanism of different types of environmental regulations on corporate green technology innovation (GTI). The research focuses on analyzing three types of environmental regulations: command based environmental regulation (ER1), market-oriented environmental regulation (ER2), and voluntary environmental regulation (ER3), and how they affect corporate GTI. This study selected enterprise GTI as the dependent variable and measured it by the number of applications for green invention patents and green utility model patents. The independent variables are the three types of environmental regulations mentioned above. According to data from Chinese A-share listed companies. Using benchmark regression models to analyze the impact of different environmental regulations on GTI, and constructing a moderating effect model to study the role of corporate R&D investment and government support in the process of environmental regulations affecting GTI. The results indicate that (1) ER1, ER2, and ER3 can all promote enterprise GTI, and the three environmental regulatory methods have a better synergistic effect. (2) R&D investment has a positive correlation with the relationship between ER2 and GTI, and a negative correlation with ER 3 and ER 1. (3) There are differences in the GTI performance of enterprises in different regions, ownership nature, factor density, and industry types under the influence of environmental regulations. (4) The impact of environmental regulatory policies on corporate GTI is mainly short-term. This study provides a new perspective on how environmental regulations affect corporate GTI, especially in the context of developing countries like China. The research findings emphasize the role of different types of environmental regulations in incentivizing corporate GTI, while also pointing out factors that governments need to consider when formulating environmental policies, such as regional differences and corporate characteristics, which are of great significance for promoting green development of enterprises and achieving broader sustainable development goals.

Objectives Fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine. We conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in such patients. Methods The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts were systematically searched. Randomized controlled trials (RCTs) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer were included. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. Statistical analyses were performed by using Review Manager 5.3. Egger’s test was performed to assess the statistical evidence of publication bias by using stata 12.0. Results A total of 1183 patients from six randomized controlled trials were included for this analysis. Fluoropyrimidine combination therapy increased ORR [RR 2.82 (1.83–4.33), pConclusions Compared with fluoropyrimidine monotherapy, fluoropyrimidine combination therapy had a higher response rate and longer PFS in patients with gemcitabine-refractory advanced pancreatic cancer. Fluoropyrimidine combination therapy could be recommended in the second line setting. However, due to concerns about toxicities, the dose intensities of chemotherapy drugs should be carefully considered in patients with weakness.

Forsythia suspensa is a traditional Chinese herb. Its numerous metabolites have important roles, as they possessed a wide range of biological activities. This study explored the accumulations of F. suspensa metabolites by performing widely targeted metabolomic analysis. The metabolites were studied at four stages of fruit development. Metabolites in the fruits and leaves of F. suspensa during fruit development included phenolic acids, flavonoids, lipids, lignans and coumarins, amino acids and their derivatives, terpenes, organic acids, nucleotides and their derivatives, alkaloids, quinones, steroids, and tannins. Fourteen Forsythia related metabolites were detected. Their contents varied among the developmental stages. Statistically significant correlations were found between the levels of forsythoside B and 11-methyl-forsythide, and forsythialan B and phillygenin, in both leaves and fruits. According to the correlation analysis between metabolites, Forsythia related metabolites were divided into two classes and five subclasses. In total, 33 compounds presented significant correlations in both fruits and leaves, which indicated the potential relationship in the synthesis of Forsythia related metabolites. Forsythialan B and phillygenin were both negatively correlated with L-valine, while Z-6,7-epoxyligustilid was positively correlated with both compounds. The quality control compounds forsythiaside A and phillyrin were positively and negatively correlated with uracil, respectively. These metabolomics results may facilitate the biosynthesis of Forsythia related metabolites.

Topiramate (TPM) was an antiepileptic agent commonly used in clinical. Studies showed that an oral preparation of TPM with extended-release manner could bring some benefits for epileptics. In this paper, controlled release push-pull osmotic pump (PPOP) tablets of sparingly water-soluble TPM were successfully prepared. This bi-layer tablet core mainly consisted of sodium chloride as osmotic promoting agent and polyethylene oxide as suspending and pushing agents. The influences of osmotic agents, pushing agents and the compositions of coating membrane on TPM release profiles were evaluated. An optimal formulation of TPM-PPOP was obtained through single-factor experiments. In vitro release tests showed that the optimum formulation could release TPM at an approximate zero-order rate up to 8 h. Pharmacokinetic behaviors of TPM-PPOP tablets were evaluated and compared with the immediate release capsules after an oral single dose in beagle dogs. Pharmacokinetics results demonstrated that the TPM-PPOP tablet was able to provide a prolonged release of TPM with longer tmax and mean residence time. Lower fluctuations of drug plasma levels could also be achieved with TPM-PPOP tablets. These results suggested that sparely water-soluble drugs as TPM can be designed to PPOP for efficacy and safety use.

This article adds to the existing literature on global rating agencies (GRAs, i.e., the S&P, Moody's, and Fitch) and domestic rating agencies (DRAs). In our research, we introduce the reputation, rating cost and rating accuracy of rating agencies to improve the Hotelling model. According to the theoretical analysis and empirical tests, the results show that the open policy of the Chinese rating industry contributes to higher rating quality in the domestic bond market. This open policy leads to rating convergence between DRAs and GRAs from in the long term.

Many different treatments may affect the serum lipid profiles of breast cancer patients. This study analyzed serum lipid levels at different periods during treatment to observe the changes in lipid profiles during and after chemotherapy and to compare the different effects of different chemotherapy regimens on serum lipid profiles. A total of 805 patients were included in this study. We measured the lipid profiles of patients who received surgery without chemotherapy prior to the operation and at 3, 6 and 12 months after operation. In addition, in patients who underwent chemotherapy, the lipid profiles were measured prior to chemotherapy, prior to the last cycle of chemotherapy and 6 months after chemotherapy. Lipid profile measurements included total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), homocysteine (HCY), and uric acid (UA). (Neo)Adjuvant chemotherapy exerted an adverse temporary effect on lipid levels (manifested as increased TG and LDL-C levels, and decreased HDL-C levels, particularly in the adjuvant chemotherapy group) during the chemotherapy periods. However, this influence was not sustained, as the lipid profiles levels were generally restored to baseline levels 6 months after chemotherapy completion. Different age groups showed different changes in lipid levels that were influenced by chemotherapy. The younger group (20-40 years old) showed a greater increase in TC and LDL-C levels during chemotherapy than the 41-65-year-old group. Chemotherapy exerts an adverse temporary effect, and the effects of different regimens on lipid levels are similar. Furthermore, lipid profiles in younger women may be more sensitive to chemotherapy.

WRKY transcription factors (TFs) play crucial roles in plant resistance responses to pathogens. Wheat stripe rust, caused by the fungal pathogen Puccinia striiformis f. sp. tritici (Pst), is a destructive disease of wheat (Triticum aestivum) worldwide. In this study, the two WRKY genes TaWRKY49 and TaWRKY62 were originally identified in association with high-temperature seedling-plant resistance to Pst (HTSP) resistance in wheat cultivar Xiaoyan 6 by RNA-seq. Interestingly, the expression levels of TaWRKY49 and TaWRKY62 were down- and up-regulated, respectively, during HTSP resistance in response to Pst. Silencing of TaWRKY49 enhanced whereas silencing TaWRKY62 reduced HTSP resistance. The enhanced resistance observed on leaves following the silencing of TaWRKY49 was coupled with increased expression of salicylic acid (SA)- and jasmonic acid (JA)-responsive genes TaPR1.1 and TaAOS, as well as reactive oxygen species (ROS)-associated genes TaCAT and TaPOD; whereas the ethylene (ET)-responsive gene TaPIE1 was suppressed. The decreased resistance observed on leaves following TaWRKY62 silencing was associated with increased expression of TaPR1.1 and TaPOD, and suppression of TaAOS and TaPIE1. Furthermore, SA, ET, MeJA (methyl jasmonate), hydrogen peroxide (H2O2) and abscisic acid (ABA) treatments increased TaWRKY62 expression. On the other hand, MeJA did not affect the expression of TaWRKY49, and H2O2 reduced TaWRKY49 expression. In conclusion, TaWRKY49 negatively regulates while TaWRKY62 positively regulates wheat HTSP resistance to Pst by differential regulation of SA-, JA-, ET and ROS-mediated signaling.

Breast cancer is a worldwide threat to female health with patient outcomes varying widely. The exact correlation between global outcomes of breast cancer and the national socioeconomic status is still undetermined. Mortality-to-incidence ratio (MIR) of breast cancer was calculated with the contemporary age standardized incidence and mortality rates for countries with data available at GLOBOCAN 2012 database. The MIR matched national human development indexes (HDIs) and health system attainments were respectively obtained from Human Development Report and World Health Report. Correlation analysis, regression analysis, and Tukey-Kramer post hoc test were used to explore the effects of HDI and health system attainment on breast cancer MIR. Our results demonstrated that breast cancer MIR was inversely correlated with national HDI (r = -.950; P < .001) and health system attainment (r = -.898; P < .001). Countries with very high HDI had significantly lower MIRs than those with high, medium and low HDI (P < .001). Liner regression model by ordinary least squares also indicated negative effects of both HDI (adjusted R2 = .903, standardize β = -.699, P < .001) and health system attainment (adjusted R2 =. 805, standardized β = -.009; P < .001), with greater effects in developing countries identified by quantile regression analysis. It is noteworthy that significant health care disparities exist among countries in accordance with the discrepancy of HDI. Policies should be made in less developed countries, which are more likely to obtain worse outcomes in female breast cancer, that in order to improve their comprehensive economic strength and optimize their health system performance.

Age is an important risk factor for breast cancer, but data regarding whether patient age at diagnosis is related to breast cancer survival are conflicting. This population-based study evaluated the effect of age on breast cancer prognosis and identified outcome-related factors.We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled female primary non-metastatic cases. Patients were subdivided into seven groups, and analyses of the associations between age and overall survival (OS) and breast cancer-specific survival (BCSS) were carried out using the Kaplan-Meier method and Cox regression model, respectively. We also assessed differences in survival among three specific age groups, using the ages of 30 and 50 years as cut-offs. Stratified analyses regarding race, histology, grade, stage and hormone receptor status were also carried out.A total of 133,057 female patients diagnosed with breast cancer from 2004 to 2008 were included in the current study (6.4%

BACKGROUND:Universal Zero-Markup Drug Policy (UZMDP) mandates no price mark-ups on any drug dispensed by a healthcare institution, and covers the medicines not included in the China's National Essential Medicine System. Five tertiary hospitals in Beijing, China implemented UZMDP in 2012. Its impacts on these hospitals are unknown. We described the effects of UZMDP on a participating hospital, Jishuitan Hospital, Beijing, China (JST). METHODS:This retrospective longitudinal study examined the hospital-level data of JST and city-level data of tertiary hospitals of Beijing, China (BJT) 2009-2015. Rank-sum tests and join-point regression analyses were used to assess absolute changes and differences in trends, respectively. RESULTS:In absolute terms, after the UZDMP implementation, there were increased annual patient-visits and decreased ratios of medicine-to-healthcare-charges (RMOH) in JST outpatient and inpatient services; however, in outpatient service, physician work-days decreased and physician-workload and inflation-adjusted per-visit healthcare charges increased, while the inpatient physician work-days increased and inpatient mortality-rate reduced. Interestingly, the decreasing trend in inpatient mortality-rate was neutralized after UZDMP implementation. Compared with BJT and under influence of UZDMP, JST outpatient and inpatient services both had increasing trends in annual patient-visits (annual percentage changes[APC] = 8.1% and 6.5%, respectively) and decreasing trends in RMOH (APC = -4.3% and -5.4%, respectively), while JST outpatient services had increasing trend in inflation-adjusted per-visit healthcare charges (APC = 3.4%) and JST inpatient service had decreasing trend in inflation-adjusted per-visit medicine-charges (APC = -5.2%). CONCLUSION:Implementation of UZMDP seems to increase annual patient-visits, reduce RMOH and have different impacts on outpatient and inpatient services in a Chinese urban tertiary hospital.

OBJECTIVE: To introduce a robot-assisted surgical system for spinal posterior fixation that can automatically recognize the drilling state and stop potential cortical penetration with force and image information and to further evaluate the accuracy and safety of the robot for sheep vertebra pedicle screw placement. METHODS: The Robotic Spinal Surgery System (RSSS) was composed of an optical tracking system, a navigation and planning system, and a surgical robot equipped with a 6-DOF force/torque sensor. The robot used the image message and force signals to sense the different operation states and to prevent potential cortical penetration in the pedicle screw insertion operation. To evaluate the accuracy and safety of the RSSS, 32 screw insertions were conducted. Furthermore, six trajectories were deliberately planned incorrectly to explore whether the robot could recognize the different drilling states and immediately prevent cortical penetration. RESULTS: All 32 pedicle screws were placed in the pedicle without any broken pedicle walls. Compared with the preoperative planning, the average deviations of the entry points in the axial and sagittal views were 0.50 ± 0.33 and 0.65 ± 0.40 mm, and the average deviations of the angles in the axial and sagittal views were 1.9 ± 0.82° and 1.48 ± 1.2°. The robot successfully recognized the different drilling states and prevented potential cortical penetration. In the deliberately incorrectly planned trajectory experiments, the robot successfully prevented the cortical penetration. CONCLUSION: These results verified the RSSS's accuracy and safety, which supported its potential use for the spinal surgery.

To evaluate the efficacy and safety profile of combining vandetanib with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts, ESMO Abstracts, Wanfang Database, CNKI were searched. Eligible studies were the randomized clinical trials (RCTs) that compared the efficacy and safety profile of adding vandetanib to chemotherapy with single chemotherapy in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. All meta-analysis were performed using Review Manager 5.1. The fixed-effect model weighted by the Mantel-Haenszel method was used. When considerable heterogeneity was found (p50%), further analysis (subgroup analysis, sensitivity analysis or random-effect model) was performed to identify potential cause.Results reported from 5 RCTs involving 2284 patients were included in the analysis. Compared to chemotherapy alone, the addition of vandetanib resulted in a significant longer PFS (HR 0.79 [0.72-0.87], p

Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival and growth. The transcriptional activity and subcellular localization of FOXO are tightly regulated by post-translational modifications. Here we report that IKBKE regulates FOXO3a through phosphorylation of FOXO3a-Ser644. The phosphorylation of FOXO3a resulted in its degradation and nuclear-cytoplasmic translocation. Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32, Ser253 and Ser315. However, the activity of Akt-nonphosphorytable FOXO3a-A3 (i.e., converting 3 serine residues to alanine) was inhibited by IKBKE. Furthermore, overexpression of IKBKE correlates with elevated levels of pFOXO3a-S644 in primary lung and breast tumors. IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but, to a much less extent, of FOXO3a-S644A. These findings suggest that IKBKE regulates FOXO3a primarily through phosphorylation of SerS644 and that IKBKE exerts its cellular function, at least to some extent, through regulation of FOXO3a.

The nature of the cellular and molecular mechanisms for the transition of avascular cartilage replacement with bone during endochondral ossification remains poorly understood. One of the driving forces is hypoxia. As a master regulator of hypoxia, hypoxia-inducible factor-1α (HIF-1α) has been reported to couple angiogenesis to osteogenesis. Our recent study has demonstrated that osteoblast growth is inhibited under hypoxia and that HIF-1α cooperates with Osterix (Osx) to inhibit Wnt pathway. However, molecular mechanisms for inhibitory effects of HIF-1α on Wnt pathway are not well understood. In this study, our quantitative RT-PCR results revealed that the expression of a Wnt antagonist Sclerostin (Sost) was upregulated in osteoblasts during hypoxia while HIF-1α was upregulated. Treatment of desferrioxamine (DFO), a HIF-1α activator, led to further increase of Sost expression, suggesting that HIF-1α may activate Sost expression. The regulation of Sost gene expression by HIF-1α was then investigated. We performed loss-of-function experiments to examine Sost expression by using siRNA approach against HIF-1α, and found that the inhibition of HIF-1α by siRNA in osteoblasts led to the decrease of Sost expression. To address transcriptional regulation of Sost gene by HIF-1α, transient transfection assay was performed and showed that HIF-1α activated Sost-1 kb promoter reporter activity in a dose-dependent manner. To narrow down the minimal region of Sost promoter activated by HIF-1α, we generated a series of deletion mutants of Sost constructs. It was demonstrated that Sost-260 was the minimal region of Sost promoter for HIF-1α activation and that Sost-106 construct, which lack hypoxia response element, abolished HIF-1α-mediated Sost reporter activation. Gel shift assay showed that HIF-1 bound to the promoter sequence of Sost directly. These findings support our hypothesis that HIF-1α activates Sost expression. This study provides a novel molecular mechanism through which HIF-1α inhibits Wnt signaling in osteoblasts.

Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation. Inhibition of Wnt pathway by Osx highlights the potential for feedback control mechanisms involved in bone formation. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of hypoxia. HIF-1α has been reported to couple angiogenesis to osteogenesis. Our recent study has demonstrated that Osx and HIF-1α cooperatively regulate VEGF expression in osteoblasts. Effects of hypoxia/HIF-1α on osteoblast proliferation and related mechanisms are not well understood. In this study, osteoblast growth under hypoxia was examined. We observed that osteoblast growth was inhibited under hypoxia. To explore possible mechanisms for hypoxia/HIF-1α to inhibit osteoblast proliferation, we tested the effect of hypoxia/HIF-1α on Wnt pathway. Quantitative RT-PCR results revealed that Wnt target genes such as cyclin D1 and c-Myc were downregulated under hypoxia while HIF-1α was upregulated. Treatment of desferrioxamine, a HIF-1α activator, led to further downregulation of expressions of cyclin D1 and c-Myc in osteoblasts. On the contrary, the inhibition of HIF-1α by siRNA in osteoblasts led to the expression increase of cyclin D1 and c-Myc. These data suggest that HIF-1α inhibits Wnt pathway in osteoblasts. To examine the effect of HIF-1α on Wnt pathway, HIF-1α was cotransfected with β-catenin along with Topflash reporter in transient transfection assay. Our results showed that HIF-1α inhibited β-catenin-induced Topflash reporter activity. Interestingly, a synergistic interplay was observed between Osx and HIF-1α in the inhibition of β-catenin-induced Topflash expression. Our findings indicate that Osx and HIF-1α cooperatively inhibit Wnt pathway. This study revealed additional new information of the cooperation between HIF-1α and Osx in osteoblasts.

Many mitosis inhibitors are powerful anticancer drugs. Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs. We have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker. LJK-11 inhibited growth and induced apoptosis of many different types of tumor cells. It prevented mitotic spindle formation and arrested cells at early phase of mitosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole. Therefore, LJK-11 represents a novel anti-microtubule structure. Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

The SLC30A8 gene codes for a pancreatic beta-cell-expressed zinc transporter, ZnT8. A polymorphism in the SLC30A8 gene is associated with susceptibility to type 2 diabetes, although the molecular mechanism through which this phenotype is manifest is incompletely understood. Such polymorphisms may exert their effect via impacting expression level of the gene product. We used an shRNA-mediated approach to reproducibly downregulate ZnT8 mRNA expression by >90% in the INS-1 pancreatic beta cell line. The ZnT8-downregulated cells exhibited diminished uptake of exogenous zinc, as determined using the zinc-sensitive reporter dye, zinquin. ZnT8-downregulated cells showed reduced insulin content and decreased insulin secretion (expressed as percent of total insulin content) in response to hyperglycemic stimulus, as determined by insulin immunoassay. ZnT8-depleted cells also showed fewer dense-core vesicles via electron microscopy. These data indicate that reduced ZnT8 expression in cultured pancreatic beta cells gives rise to a reduced insulin response to hyperglycemia. In addition, although we provide no direct evidence, these data suggest that an SLC30A8 expression-level polymorphism could affect insulin secretion and the glycemic response in vivo.

Background: Emodin has been showed to induce apoptosis of pancreatic cancer cells and inhibit tumor growth in our previous studies. This study was designed to investigate whether emodin could inhibit the angiogenesis of pancreatic cancer tissues and its mechanism. Methodology/Principal Finding: In accordance with our previous study, emodin inhibited pancreatic cancer cell growth, induced apoptosis, and enhanced the anti-tumor effect of gemcitabine on pancreatic caner cells in vitro and in vivo by inhibiting the activity of NF- κB. Here, for the first time, we demonstrated that emodin inhibited tumor angiogenesis in vitro and in implanted pancreatic cancer tissues, decreased the expression of angiogenesis-associated factors (NF-κB and its regulated factors VEGF, MMP-2, MMP-9, and eNOS), and reduced eNOS phosphorylation, as evidenced by both immunohistochemistry and western blot analysis of implanted tumors. In addition, we found that emodin had no effect on VEGFR expression in vivo. Conclusions/Significance: Our results suggested that emodin has potential anti-tumor effect on pancreatic cancer via its dual role in the promotion of apoptosis and suppression of angiogenesis, probably through regulating the expression of NF-κB and NF-κB-regulated angiogenesis-associated factors. [ABSTRACT FROM AUTHOR]