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With the acceleration of economic globalization in recent years, china has assessed the situation and joined the pace of integration into the world financial system. With the continuous progress of global economy and the continuous improvement of corporate business needs, internal control plays an increasingly important role in the survival and development of enterprises. Successful internal control is conducive to the company's expansion of production scale, improvement of the core competitiveness of the industry, more effective operation of the company, and even a successful listing of the company. Therefore, the study of internal control is very necessary. This paper first describes the background of internal control in china, and then summarizes the contents of the five elements of internal control. Through the contents of the five elements, it analyzes the hardships of the listing of guangdong marus biotechnology co., ltd. (hereinafter referred to as marus), the protagonist of this paper, and the major reasons for the failure of listing.in addition, it is necessary to find relevant remedial measures to help marumi get out of the predicament of ipo failure, and what kind of preventive measures to prevent ipo failure for enterprises that want to go public based on the five elements of internal control. Finally, the conclusion of the study gives us some enlightenment. The purpose of this paper is to make an in-depth analysis of various problems arising from the failure of marumi stock listing from the perspective of internal control and give constructive suggestions, so as to inspire various unlisted enterprises on how to improve their internal control and prevent ipo failure from the perspective of internal control.

BackgroundFolate was involved in oxidative stress, hepatic lipid metabolism and chronic hepatic inflammation. However, evidence about the association between serum folate level and non-alcoholic fatty liver disease (NAFLD) in general population is scarce. This study aimed to explore the relationship between serum folate level and NAFLD among adults.Methods7,146 adult participants aged 20 years and over who have complete data of serum folate level and liver function biomarkers in NHANES 2011–2018 were included. Serum folate level was measured by isotope-dilution high-performance liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). And suspected NAFLD was defined according to the United States fatty liver index (USFLI). Logistic regression and the restricted cubic spline models were performed.ResultsSerum folate level was inversely associated with the presence of NAFLD. When comparing the second, third and fourth quartiles of serum folate level to the lowest quartile, the adjusted ORs of the presence of NAFLD were 0.62 (0.49–0.78), 0.65 (0.51–0.84), and 0.43 (0.32–0.56) respectively (p for trendp for non-linearity ConclusionHigher serum folate level may be negatively associated with NAFLD.

Supplementary Tables 1-5. Supplementary Table S1. Clinicopathologic classification and CDK1 expression for the discovery GIST cohort (n=43). Supplementary Table S2: List of all 14280 genes expressed in GIST. Supplementary Table S3: List of 568 genes with a higher expression level in advanced GIST than in early-stage GIST. Supplementary Table S4: Ranked CRISPR scores for each gene from a genome-wide CRISPR screen in GIST430/654 cells. Supplementary Table S5: Clinicopathologic classification and CDK1 expression for the validation GIST cohort (n=92).

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials.Significance:These findings propose CDK1 as a novel cell-cycle–independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.

With the development of an ecological civilization gaining increasing attention in our country, an analysis of the environmental and economic impacts of all aspects of life has been developed gradually. However, because the study on the environmental and economic benefits of the tailwater diversion project is a weak link, the discussion on the environmental and economic benefits of the tailwater diversion project is novel. The variable fuzzy evaluation model is used to evaluate the comprehensive environmental and economic benefits of tailwater diversion engineering, in order to facilitate the exploration and application of tailwater diversion engineering. Simultaneously, by evaluating the method using the analytic hierarchy process and fuzzy optimum seeking method, linear comprehensive fuzzy optimization, average comprehensive fuzzy optimization, and variable fuzzy pattern recognition model of optimizing method, the results demonstrate that the method not only can be used to plan optimization but can also provide a good evaluation for each program, the result is reasonable and reliable, and applicable to the comprehensive benefits of water resource management.

Objective:Traditional chemical synthesis methods are cumbersome and inefficient. In this study, a novel antitumor molecule, 4-(4-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)phenyl sulfurofluoridate (P19G1), was identified by screening a library of Erlotinib derivatives synthesized by modular click chemistry, and the antitumor activity and underlying mechanism of P19G1 were further revealed. Methods: A series of Erlotinib derivatives (840 compounds) were synthesized using a modular click-chemistry method, and then the thiazolyl blue (MTT) method was used to screen and evaluate the inhibitory effect of these compounds on the growth and metastasis of A549 lung adenocarcinoma cells. Among them, the compound P19G1 showed the best inhibitory activity. Furthermore, the antitumor activity and mechanism of P19G1 were investigated with in vitro cell biology and in vivo assays in an animal model. Results: In vitro pharmacological studies showed that P19G1 had inhibitory effects on a variety of tumor cell lines with IC50 values in the range of 1 to 5 μM. Moreover, P19G1 significantly inhibited the proliferation and migration of the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line RKO and promoted cell apoptosis. In vivo tumor-bearing mouse model experiments revealed that 50 mg/kg P19G1 effectively inhibited the growth and metastasis of A549 tumors without obvious toxicity to the host. Conclusions: The rapid structural modification of lead compounds using novel modular click-chemistry reactions holds great potential for use in obtaining diverse derivatives for tumor drug screening and development. P19G1 was discovered because of the application of click chemistry in this study, and it is an antitumor candidate molecule worthy of development.

Encouraging farmers to adopt green prevention and control techniques (GCTs) is conducive to ensuring the quality and safety of agricultural products, the ecological environment and agricultural production in China. To explore the factors influencing vegetable farmers’ adoption of GCTs, this study utilized the “information-motivation-behavior” intervention (IMB) model and ordered logistic model to empirically study the adoption behavior of 653 vegetable farmers in Henan Province, China. Estimation results indicated that the IMB model significantly predicted farmers’ adoption of GCTs: 1) From the perspective of adoption decisions, 88.82% of the farmers have adopted GCTs, but the degree of adoption is low. 2) the farmers’ adoption of GCTs IMB model specifies that higher levels of GCTs information, motivation, and behavioral skills should result in a greater likelihood of engaging in GCTs adoption behavior. 3) Motivation and behavioral skills are activated through information. 4) Finally, motivation can indirectly affect farmers’ GCTs adoption behavior through behavioral skills. The results of this study support the need for the government to promote the use of GCTs for vegetable pest control, as well as advance integrated prevention and control in the agricultural industry.

Virtual reality (VR) has developed rapidly, drawing more businesses to such development. Based on the diffusion of innovations theory (DIT), the study combines the flow theory and the satisfaction perspective to explore purchase intention influencing customers’ adoption of the VR shopping platform system. This study found that satisfaction and flow experience enhance their purchase intention. In technological characteristics, relative advantage, service compatibility, spatial presence, and complexity are important in satisfaction. Among them, both relative advantage and spatial presence impact flow experience. Additionally, a cluster analysis based on gender was conducted, and the study found a significant difference between relative advantages, service compatibility, and complexity in women and men users. The flow experience is an important factor affecting women users’ shopping intention, while insignificant for male users. The implications of these findings are discussed.

The Montney Play Trend (MPT) is a 1090 km2 region in northeast British Columbia that produces approximately one-third of western Canada’s natural gas output. In response to a proposed expansion of the MPT in 2016, the Government of British Columbia launched a Regional Strategic Environmental Assessment (RSEA) to identify the necessary conditions to achieve sustainable environmental outcomes. In this paper, we describe the methods and scenario planning tools that were developed to estimate how the development of the MPT might affect the subsistence economies of First Nations in the region. To demonstrate the utility of our approach, two impact assessments—Prince Rupert gas transmission pipeline and the Coastal GasLink pipeline—are presented. While no scenario can provide a definitive portrayal of exactly what will happen in the future, the tools that were co-developed are serving as an effective starting point for exploring possibilities that are at least consistent with current knowledge and can serve as a platform for collaborative learning and conflict management.

It is believed in many studies that the servitization of manufactures is driven by internal economy, but the situation in China may be somewhat different. In this study, we consider the influence of external institutional environment on manufacturers’ servitization and the final performance, and discuss the moderating effect of organizational identity orientation on firms’ response to external institutional pressures. We conduct a survey where we collect responses from 312 manufacturers in China. Regression analyses are performed to test whether institutional pressures (normative pressure, mimetic pressure, and coercive pressure) coming from the external institutional environment have a positive effect on the level of manufacturing servitization or not. Moreover, we study if this positive effect is moderated by the individualistic identity orientation and the relational identity orientation. We also examine the impact of servitization strategy on manufacture’s market performance and financial performances. Furthermore, we separate out the influences comes from institutional pressures by using a new estimated method and try to explain the cause of “servitization paradox.” Our study is innovative in that it bridges the servitization and institutional theory, and provides practical guidance for the adoption of manufacturing servitization strategy.

Several studies have indicated an association between dietary copper and zinc intake and hypertension, but mainly limited to adult studies. Few studies have examined the associations between copper and zinc and high blood pressure (BP) in children. This study aims to evaluate the associations of zinc and copper with the risk of high BP in children and adolescents aged 8–17 years using the 2007–2016 National Health and Nutritional Examination Surveys (NHANES). A total of 7749 participants (3912 males and 3837 females) were included in the analyses. High BP was defined as (1) the participant (age ≥ 16 years) or the participant’s parent/guardian (age

The water–energy–food (WEF) nexus has emerged as a leading tool for assessing integrated resource management strategies and for monitoring progress towards the WEF-related Sustainable Development Goals. A notable outcome of WEF nexus research has been the calculation of the global WEF Nexus Index, which provides a quantitative ranking of country-level WEF security for 170 nations. As valuable as this ranking is, the aggregation of country-level WEF data obscures regional differences, particularly in remote regions that are sparsely populated and differ in geography, economy, and climate. This has proven to be the case for northern Canada, which despite representing 40% of Canada’s total land area, accounts for less than 1% of the Canadian population, most of whom are Indigenous. Whereas Canada ranks 5th globally in their WEF security, northern Canada, if treated independently, would rank 67th on the global WEF Nexus Index rankings. Evaluating each WEF sector independently, northern Canada would rank 22nd in water security, 90th in energy security, and 113th in food security. Our results further reveal that considerable inter-regional variability exists between northern territories and provinces, where Nunavik would rank 54th, Northwest Territories 67th, Yukon 69th, Labrador 80th, and Nunavut 107th on the global index. By highlighting these differences, we hope that this research can aid decision-makers in developing informed, regionally specific, and integrative resource policy responses that remedy rather than amplify existing WEF-related inequalities.

The booming Internet celebrity economy has led enterprises to increasingly value online star endorsements. Online stars are moving beyond promotions on social media to endorse products on multiple media platforms. However, few studies have addressed the effect of online star endorsement on consumers’ purchase intention. To address this gap in the field, this paper examines the effects of celebrity and online star endorsements on consumers’ purchase intention and aims to clarify the underlying mechanism and boundary conditions via comparison with the condition of no endorsement. The results of four studies revealed the following: (1) compared with no endorsement, both celebrity endorsement and online star endorsement led to increases in consumers’ purchase intention, with no significant difference between the two. (2) Self-concept is the mechanism that mediates these relationships; specifically, celebrity and online star endorsements activate the ideal and actual self, respectively, and enhance consumers’ willingness to purchase. (3) The effect of endorsements on consumers’ purchase intention is moderated by advertising appeals. That is, celebrity endorsement enhances purchase intention when consumers are exposed to symbolic appeals in advertisements, and online star endorsement enhances purchase intention when it is matched with functional appeals.

Background: Zicao is the dried root of Lithospermum erythrorhizon Sieb, et Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge and is commonly used to treat viral infection, inflammation, arthritis, and cancer in traditional Chinese medicine. Shikonin (SKN), a naturally occurring naphthoquinone, is a major active chemical component isolated from Zicao and exhibits anticancer activity according to previous research. However, the underlying mechanism has not been elucidated, so further research is necessary to verify its traditional application. The purpose of the present study was to investigate the antitumor mechanism of SKN in colorectal cancer (CRC) through network pharmacology and experiments.Methods: The SymMap database and GeneCards were adopted to predict the potential targets of SKN and CRC, while cotargets were obtained via a Venn diagram. The cotargets were imported from the String and DAVID websites, the protein-protein interaction (PPI) network was constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. With regard to the prediction of KEGG by DAVID, the compound-target-pathway network was generated by connecting potential pathways with the corresponding targets. According to the network pharmacological analysis, cytological experiments, real-time PCR (RT-PCR), and Western blot (WB) were used to verify the key signaling pathway.Results: According to the network pharmacological analysis, the most relevant target of SKN to the treatment of colorectal cancer was IL6. GO and KEGG enrichment analyses indicated that various kinases and the PI3K/AKT signaling pathway were the most enriched molecules and pathways. SKN inhibited CRC cell (HT29 and HCT116) proliferation, migration, and invasion and promoted cell apoptosis by targeting IL6 and inhibiting the IL6R/PI3K/AKT signaling pathway.Conclusions: SKN promotes apoptosis and suppresses CRC cell (HT29 and HCT116) activities through the PI3K-Akt signaling pathway. This research not only provides a theoretical and experimental basis for more in-depth studies but also offers an efficient method for the rational utilization of a series of traditional Chinese medicines as anti-CRC drugs.

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Chromosome 22q deletions are well-recognized frequent abnormalities in GISTs, occurring in ∼50% of GISTs. These deletions are thought to contribute to the pathogenesis of this disease via currently unidentified tumor suppressor mechanisms. Using whole exome sequencing, we report recurrent genomic inactivated DEPDC5 gene mutations in GISTs (16.4%, 9 of 55 patients). The demonstration of clonal DEPDC5 inactivation mutations in longitudinal specimens and in multiple metastases from individual patients suggests that these mutations have tumorigenic roles in GIST progression. DEPDC5 inactivation promotes GIST tumor growth in vitro and in nude mice. DEPDC5 reduces cell proliferation through the mTORC1-signaling pathway and subsequently induces cell-cycle arrest. Furthermore, DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and the combination therapy with mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inactivation. These findings of recurrent genomic alterations, together with functional data, validate the DEPDC5 as a bona fide tumor suppressor contributing to GIST progression and a biologically relevant target of the frequent chromosome 22q deletions.

Background: Peptide receptor radionuclide therapy (PRRT) is an emerging therapeutic option for the treatment of neuroendocrine tumors (NETs), and the number of publications in this field has been increasing in recent years. The aim of the present study was to present the research status and summarize the key topics through bibliometric analysis of published PRRT literature.Methods: A literature search for PRRT research from 2000 to 2019 was conducted using the Science Citation Index Expanded of Web of Science Core Collection (limited to SCIE) on August 4, 2020. The VOSviewer, R-bibliometrix, and CiteSpace software were used to conduct the bibliometric analysis.Results: From 2000 to 2019, a total of 681 publications (523 articles and 158 reviews) were retrieved. Annual publication outputs grew from three to 111 records. Germany had the largest number of publications, making the largest contribution to the field (n = 151, 22.17%). Active cooperation between countries/regions was observed. Kwekkeboom from the Erasmus Medical Center is perhaps a key researcher in the field of PRRT. The European Journal of Nuclear Medicine and Molecular Imaging and Journal of Nuclear Medicine ranked first for productive (n = 84, 12.33%) and co-cited (n = 3,438) journals, respectively. Important topics mainly included matters related to the efficacy of PRRT (e.g., 90Y-dotatoc and 177Lu-dotatate), the long-term adverse effects of PRRT (e.g., hematologic and renal toxicities), standardization of NETs and PRRT in practice, the development of medical imaging techniques, and the individual dose optimization of PRRT.Conclusion: Using bibliometric analysis, we gained deep insight into the global status and trends of studies investigating PRRT for the first time. The PRRT field is undergoing a period of rapid development, and our study provides a valuable reference for clinical researchers and practitioners.

Recurrent inactivated mutations in central precocious puberty-associated gene MKRN3 lead to lung cancer proliferation and progression through PABPC1 ubiquitination–mediated global protein synthesis. MKRN3 is a bona fide tumor suppressor, and MKRN3-PABPC1 deregulation represents a key pathway in NSCLC oncogenesis., Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non–small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell–specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry–based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor., Graphical Abstract

In the paper, we report the results for the NLPCC2021 shared-task of Few-shot Learning for Chinese NLP. This shared task is proposed in the context of pre-trained language models, where models only have access to limited human-labeled data. The goal of the task is to compare different learning schemes. The task includes nine sub-tasks and three task forms: single sentence classification, sentence pair classification, and machine reading comprehension. In order to accommodate the properties of few-shot learning, we sampled the examples using various sampling methods, some with 32 examples in total for one dataset, while others with 4 to 16 examples per class. Ninety teams registered for the shared task, employing a wide range of learning schemes, including data augmentation, utilizing multiple templates rather than a single template, using unlabeled data for pre-training or semi-supervised training. The best model achieved 65.3 in the mean accuracy, compared with the human score of 83.9. This result is 8 points higher than our baseline model (using the PET scheme). We believe our few-shot learning tasks and results demonstrate the potential of the recently introduced few-shot learning methods and provide guidance and important empirical evidence for future research.

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials. Significance: These findings propose CDK1 as a novel cell-cycle–independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.

OBJECTIVES To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the rates of misdiagnosis and missed diagnoses in China. METHODS The EMBASE, Cochrane Library, PubMed and SinoMed databases were searched for studies involving Chinese CF patients from January 1975 to August 2019. RESULTS In total, 113 Chinese patients, including 53 males and 60 females, were reported. Nineteen patients had a family history of CF. The median age at diagnosis was 8.7 years. Among Chinese CF patients, 70.8% had bronchiectasis, 9.7% had a hemoptysis history, 33.6% had clubbed fingers, 17.7% had allergic bronchopulmonary aspergillosis, and 29.2% had chronic diarrhea; the incidence of malnutrition was 52.2%. Five patients had jaundice, 26 patients had hepatomegaly, and 9 patients had meconium ileus in the neonatal period, and the incidence of liver cirrhosis was 5.3%. The predominant organism in airways was Pseudomonas aeruginosa, followed by Staphylococcus aureus. Seventy-nine patients underwent the sweat test, and all of them were positive, with an average chloride ion level of 122.2 mmol/L. Eighty-eight Chinese CF patients underwent genetic testing, and 74 CF transmembrane conductance regulator (CFTR) gene mutations were reported. The most common gene mutation was c.2909G→A. One Phe508del gene mutation was observed. CONCLUSION The common clinical manifestations and CFTR gene mutations in Chinese CF patients are different from those in Caucasian patients. The age at CF diagnosis in China is relatively old, suggesting that the CF incidence in China may be seriously underestimated.

The majority of GISTs express mutationally activated KIT. Imatinib and sunitinib are approved KIT-inhibiting therapies. Their efficacy is usually hampered by the acquired multiple secondary drug-resistance KIT mutations. The most problematic resistance subset is GISTs with acquisition of secondary mutations in the KIT activation loop. Here, we establish the spectrum of activity of dasatinib against a comprehensive collection of clinically relevant KIT mutants associated with drug-sensitive and drug-resistant GIST. The cellular and in vitro activities of tyrosine kinase inhibitors (TKIs) against mutant KIT were assessed using a panel of engineered and GIST-derived cell lines. The in vivo activities of dasatinib were determined using TKI-resistant xenograft models. In engineered and GIST-derived cell lines, dasatinib potently inhibited KIT with primary mutations in exon 11 or 9 and a range of secondary imatinib-resistant mutations in exons 13 and 14, encoding the ATP-binding pocket, and in exons 17 and 18, encoding the activation loop, with the exception of a substitution at codon T670. Our data show that dasatinib is more potent than imatinib or sunitinib at inhibiting the activity of drug-resistant KIT mutants. Dasatinib also induces regression in GIST-derived xenograft models containing these secondary mutations. A major determinant of the efficacy of dasatinib for the treatment of advanced GIST is the activity of this inhibitor against KIT mutants. Dasatinib shows efficacy in cancer models, inhibiting a wide range of oncogenic primary and drug-resistant KIT mutants. These results have implications for the further development of dasatinib precision therapy in GIST patients.

A sandwich-structured SnS2@reduced graphene oxide (SnS2@rGO) nanocomposite consisting of SnS2 sheets uniformly anchored on both sides of rGO sheets is presented. The SnS2@rGO nanocomposites, prepared through a dipping process combining with a hydrothermal method, show good electrochemical performance, including the high reversible capability of 959.2 mA h g−1 at 500 mA g−1 over 500 cycles, and superior rate performance. A full cell consisting of a commercial LiCoO2 cathode and the SnS2@rGO anode delivers the stable capacity of ∼821.3 mA h g−1 (anode basis) after 200 cycles at 100 mA g−1. The sandwich-structured SnS2@rGO nanocomposite accommodates volume changes during Li+ insertion and extraction and facilitates the rapid transport of ions and electrons. This high performance indicates that the presented SnS2@rGO nanocomposite is a promising anode candidate for practical application in Li-ion batteries.

Quick and efficient detection of low concentrations of hydrogen remains a challenge because of the stability of hydrogen. A sensor based on reduced oxide graphene functionalized with Pt nanoparticles is successfully fabricated using a freeze-drying method followed by heat treatment. The structure and morphology of the Pt@rGO nanocomposites are well analyzed by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. The as-prepared Pt@rGO nanocomposites show excellent hydrogen gas sensing properties at a low working temperature of 50 °C. The sensitivity toward 0.5% hydrogen is 8%. The response and recovery times of the sensor exposed to 0.5% hydrogen are 63 and 104 s, respectively. The gas-sensing mechanism of Pt@rGO sensor is also discussed.

A facile electrochemical sensor for dopamine detection was successfully fabricated by the modification of gold nanoparticles (AuNPs) and poly(hydroquinone) film on three-dimensional nickel foam. The results of scanning electron microscopy, electrochemical impedance spectroscopy, and cyclic voltammetry measurements demonstrated the successfully preparation of the sensor. The effect factors of electrodeposition time of AuNPs, polymerization pH, cycles of polymerization and rate of polymerization were optimized for the sensor preparation. Under the optimized conditions, the prepared sensor exhibited selective and sensitive detection capacities toward dopamine. The linear response to dopamine ranged from 1.0 × 10 − 7 mol/L to 1.0 × 10 − 5 mol/L with a detection limit of 4.19 × 10 − 8 mol/L. Moreover, the sensor could be applied in the detection of dopamine in real samples with satisfactory results.

CBLB502 derived from Salmonella flagellin is a novel agonist of Toll-like receptor 5 (TLR5). It has been shown that CBLB502 can exert high radioprotective efficacy on mice and primates from both GI and hematopoietic syndromes during whole-body irradiation with low toxicity and immunogenicity. However, no effective system has been used to investigate the protective effect of CBLB502 against irradiation and the related mechanism in vitro. In this study, we investigated the radioprotective properties of CBLB502 in HEK293-N-T cells constitutively expressing human TLR5 and NF-κB-dependent luciferase. HEK293-N-T cells were treated with different doses of CBLB502 prior to 60Co-γ ray irradiation. After irradiation, cell viability was real-time measured for 4 days by using the real-time cell analysis system. We found that CBLB502 was capable of efficiently maintaining the survival rate of irradiated HEK293-N-T cells. Then apoptotic cell death and cell cycle were detected by flow cytometry. The results showed that CBLB502 pre-treatment could reduce the apoptosis and promote the recovery of irradiated HEK293-N-T cells from G2-phase arrest in a dose-dependent manner. Our data indicated that CBLB502 has a direct radioprotective effect in vitro via anti-apoptosis and promotes cell cycle recovery. The method developed here could be an effective in vitro system to screen other TLR5-target radioprotectants like CBLB502.

A new strategy based on sign-on and sign-off was proposed for propyl gallate (PG) determination by an electrochemical sensor. The successively modified poly(thionine) (PTH) and molecular imprinted polymer (MIP) showed an obvious electrocatalysis and a good recognition toward PG, respectively. Furthermore, the rebound PG molecules in imprinted cavities not only were oxidized but also blocked the electron transmission channels for PTH redox. Thus, a sign-on from PG current and a sign-off from PTH current were combined as a dual-sign for PG detection. Meanwhile, the modified MIP endowed the sensor with recognition capacity. The electrochemical experimental results demonstrated that the prepared sensor possessed good selectivity and high sensitivity. A linear ranging from 5.0×10(-8) to 1.0×10(-4)mol/L for PG detection was obtained with a limit of detection of 2.4×10(-8)mol/L. And the sensor has been applied to analyze PG in real samples with satisfactory results. The simple, low cost, and effective strategy reported here can be further used to prepare electrochemical sensors for other compounds selective recognition and sensitive detection.

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Chromosome 22q deletions are well-recognized frequent abnormalities in GISTs, occurring in ∼50% of GISTs. These deletions are thought to contribute to the pathogenesis of this disease via currently unidentified tumor suppressor mechanisms. Using whole exome sequencing, we report recurrent genomic inactivated DEPDC5 gene mutations in GISTs (16.4%, 9 of 55 patients). The demonstration of clonal DEPDC5 inactivation mutations in longitudinal specimens and in multiple metastases from individual patients suggests that these mutations have tumorigenic roles in GIST progression. DEPDC5 inactivation promotes GIST tumor growth in vitro and in nude mice. DEPDC5 reduces cell proliferation through the mTORC1-signaling pathway and subsequently induces cell-cycle arrest. Furthermore, DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and the combination therapy with mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inactivation. These findings of recurrent genomic alterations, together with functional data, validate the DEPDC5 as a bona fide tumor suppressor contributing to GIST progression and a biologically relevant target of the frequent chromosome 22q deletions.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with few therapeutic options, representing one of the great challenges in oncology. Activating KRAS mutation, occurring in >90% PDACs, is present in pancreatic intraepithelial neoplasia lesions, the precursor ductal lesions of PDAC, indicating additional genetic alterations contribute to the pathogenesis of PDAC. PDAC sequencing projects identify recurrent genomic ERBB2 alterations, mutations and amplifications, in 8.5% of PDAC patients, ranking as the top hit among the 100 receptor tyrosine kinases-encoding genes. Introduction of the ERBB2 mutations encoding protein variants S310F, S423R, R678Q, Q679L, E717D, L755S, V777L and V842I into human pancreatic epithelial cells causes oncogenic transformation, increasing ERBB2 signaling, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. Interestingly, in many PDACs, mutations in ERBB2 and KRAS occur together. ERBB2 activating mutants facilitate KRAS-driven oncogenic properties. Introduction of ERBB2 mutations into KRAS-mutant PDAC cells activates ERBB2 signaling, promotes tumor growth and attenuates KRAS dependency. In contrast, a CRISPR-mediated knockout (KO) of ERBB2 in ERBB2-amplified PDAC cells inhibits ERBB2 signaling, colony formation, anchorage-independent growth and tumor xenograft formation. Finally, oncogenic ERBB2 aberrations can be abrogated by treatment with small-molecule inhibitors. ERBB2 and KRAS inhibition cooperate to suppress PDAC cell growth in vitro and to promote tumor regression in nude mice, providing a rationale for testing an anti-ERBB2 drug in combination with a KRAS inhibitor in ERBB2-mutant PDAC patients that are currently untreatable.

BACKGROUND: Stem cell therapy (SCT) is an emerging and promising treatment measure for many conditions (e.g., chronic liver disease, diabetes mellitus, and knee osteoarthritis). Although there are numerous meta-analyses (MAs) concerning SCT, the quality of these MAs and the efficacy and safety data for SCT reported in these MAs remain unknown. Therefore, it is of utmost importance to conduct an overview of existing MAs concerning SCT for evaluating these parameters. METHODS: We will systematically search PubMed and EMBASE databases from inception to October 2020 for identifying MAs of SCT published in English. Two independent reviewers will select appropriate MAs against the predefined eligibility criteria. The efficacy and safety data of SCT reported in MAs will be descriptively summarized. Following this, the reporting quality and methodological quality of included MAs will be appraised using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) and A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) tools by two reviewers, respectively. Further, the evidence mapping method will be used to present assessment results. The key information will also be extracted by two independent reviewers. The Spearman’s correlation coefficient will be used to explore the association between reporting quality and methodological quality. The factors influencing the quality will be assessed through linear regression analyses. The sensitivity analysis will also be conducted. Data analyses will be performed using Stata 16.0 and Excel 2016. P

The applications of Li S batteries are restricted by the issues of the imperfect conductivity and severe volumetric change of active materials together with shuttle effect of lithium polysulfides, which requires a kind of material with appropriately multifunctional structure as sulfur host. Herein, an N–doped hierarchical porous carbon composite is synthesized via a high temperature carbonization method. The N–doped hierarchical porous carbon with a large number of micropores, mesopores and macropores provides the abundant interconnected network matrixes and high specific surface area, thus guaranteeing a high sulfur loading, and adapting the volumetric expansion during the lithium intercalation process. The macropore channels and conductive interconnected networks can accelerate the diffusion of electrons/ions among the cathode. Moreover, the mesopores and micropores besides the high amount N–doping accommodate high–level sulfur loading and immobilize lithium polysulfides via physical absorption and chemical confinement. The as–prepared N–doped hierarchical porous carbon compounded with sulfur as a cathode delivers a satisfactory initial capacity of 1285 mAh g−1 at 0.2 A g−1 and a reversible capacity of 517 mAh g−1 at 0.5 A g−1 over 1000 cycles, illustrating the improved electrochemical performances of the cathode. The high temperature carbonization method provides a new way to construct the hierarchical porous structured carbon with chemical doping.

The authors report on a ratiometric electrochemical sensor for paracetamol (PR) which was fabricated by successively electropolymerizing a layer of Prussian blue (PB) and a layer of molecularly imprinted polypyrrole (MIP) on the surface of a glassy carbon electrode (GCE). The binding of PR molecules to the MIP has two effects: The first is an increase of the oxidation current for PR at 0.42 V (vs. SCE), and the second is a decrease in the current for PB (at 0.18 V) due to partial blocking of the channels which results in reduced electron transmissivity. Both currents, and in particular their ratio, can serve as analytical information. Under optimized conditions, the sensor displays enhanced sensitivity for PR in the 1.0 nM to 0.1 mM concentration range and a 0.53 nM lower limit of detection. The sensor was applied to the determination of PR in tablets and urines where it gave recoveries in the range between 94.6 and 104.9 %. This dual-signal (ratiometric) detection scheme (using electropolymerized Prussian Blue and analyte-specific MIP) in our perception has a wide scope in that it may be applied to numerous other electroactive species for which specific MIP can be made available.

Prior empirical studies provide indefinite conclusions to the political connection (PC) - internationalization link and the boundary conditions. In this paper, we conduct a meta-analytic review of ...

This study investigated whether low-level blood and urinary lead, cadmium and mercury exposures were associated with blood pressure (BP) in children and adolescents. Data from National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 for children and adolescents aged 8–17 years (n = 7076) were analyzed. Outcome variables were systolic BP, diastolic BP and high BP status. High BP was defined as: self-reported antihypertensive medication usage or a diagnosis of hypertension; classified as having elevated BP/hypertension according to 2017 AAP guidelines. Multivariable linear and logistic regressions models were performed and stratified by race/ethnicity and gender. Blood lead was negatively associated with diastolic BP among blacks, and positively associated with diastolic BP among whites. For a two-fold increase of blood lead concentration, the change in diastolic BP was −1.59 mm Hg (95% CI: −3.04 to −0.16 mm Hg) among blacks and 1.38 mm Hg (95% CI: 0.40 to 2.36 mm Hg) among whites. No significant associations between either systolic BP or diastolic BP with urinary lead were observed. The inverse associations between blood lead and high BP were found in females, Mexican Americans and other Hispanics. No associations between blood cadmium and BP were observed, except in other Hispanics. Urinary cadmium levels were inversely correlated with systolic BP, diastolic BP and high BP in all participants and in men. When compared to the lowest quartile of urinary cadmium levels, participants with a urinary cadmium level ≥ 0.12 μg/L had 0.48 (95% CI: 0.29–0.78) times and 0.53 (95% CI: 0.30–0.94) times reduced odds of having high BP in all participants and in men, respectively. No associations between either blood mercury or urinary mercury with systolic BP were observed. Significant inverse associations were found between blood total mercury and methyl mercury with diastolic BP in all participants and in men. Future prospective studies are warranted to confirm these findings.

A new strategy for a composite film based electrochemical sensor was developed in this work. A layer of conductive film of poly(p-aminobenzene sulfonic acid) (pABSA) was electropolymerized onto glassy carbon electrode surface and exhibited a high electrocatalytic active for paracetamol (PR) redox. The subsequent formation of a layer of molecular imprinted polymer (MIP) film on pABSA modified electrode endowed the sensor with plentiful imprinted cavities for PR specific adsorption. The advantages of the composite film made the prepared sensor display high sensitivity and good selectivity for PR detection and recognition. Under the optimal conditions, the sensor could recognize PR from its interferents. A linear ranging from 5.0×10−8 to 1.0×10−4 mol/L for PR detection was obtained with a detection limit of 4.3×10−8 mol/L. The sensor has been applied to analyze PR in tablets and human urine samples with satisfactory results. The simple, low cost, and efficient strategy reported here can be further used to prepare electrochemical sensors for other compounds recognition and detection.

Three gold complexes with pyridine-based SNS type ligands, 2,6-bis(1-methylimidazole-2-thione)pyridine (Bmtp), 2,6-bis(1-ethylimidazole-2-thione)pyridine (Betp) and 2,6-bis(1-isopropylimidazole-2-thione)pyridine (Bptp) have been synthesized and characterized. Reactions of HAuCl4·H2O with three pyridine-based SNS ligands result in the formation of the complexes [(L)AuCl2]Cl (L = Bmtp (1); L = Betp (2) and L = Bptp (3)). All compounds are investigated by elemental analysis, NMR, MS and UV-Vis as well as IR spectral analysis. The molecular structure of 3 has been confirmed by X-ray crystallography. Moreover, all gold complexes are efficient homogeneous catalysts and catalyze the reduction of 4-nitrophenol (4-NP) to 4-nitroaniline (4-AP) in the presence of NaBH4 reducing agent in water. And complex 3 exhibits an exceptionally high turn over frequency (TOF) of 1.20 min−1 for the reduction of 4-NP.

A sol–gel based electrochemical sensor was developed for melamine (Mel) direct and selective detection in real samples. Thin film of molecularly imprinted sol–gel polymers with specific binding sites for Mel was fabricated on glassy carbon electrode surface by electropolymerization method. Oxidation peak of Mel was chosen as a detected signal for the properties study of the sensor. The molecularly imprinted polymers film modified method, electropolymerization scan rate, scan cycles, potential range, amount of Mel and extraction conditions for sensor preparation were optimized. Under the optimized conditions, the sensor displayed an excellent recognition capacity towards Mel compared with other structural similar molecules. With acceptable regeneration and stability the sensor could detect Mel in the range of 6.3 10 7