Setting 6-Minute Minimal Examination Time Improves the Detection of Focal Upper Gastrointestinal Tract Lesions During Endoscopy: A Multicenter Prospective Study.

INTRODUCTION: Positive correlation between examination time and neoplasm detection using esophagogastroduodenoscopy (EGD) has been described by observational studies, but the effect of setting minimal examination time still requires investigation. METHODS: This prospective, 2-stage, interventional study was conducted in 7 tertiary hospitals in China, enrolling consecutive patients undergoing intravenously sedated diagnostic EGDs. In stage I, the baseline examination time was collected without informing the endoscopists. In stage II, the minimal examination time was set for the same endoscopist according to the median examination time of normal EGDs in stage I. The primary outcome was the focal lesion detection rate (FDR), defined as the proportion of subjects with at least one focal lesion among all subjects. RESULTS: A total of 847 and 1,079 EGDs performed by 21 endoscopists were included in stages I and II, respectively. In stage II, the minimal examination time was set as 6 minutes, and the median time for normal EGD increased from 5.8 to 6.3 minutes ( P < 0.001). Between the 2 stages, the FDR was significantly improved (33.6% vs 39.3%, P = 0.011), and the effect of the intervention was significant (odds ratio, 1.25; 95% confidence interval, 1.03-1.52; P = 0.022) even after adjusting for subjects' age, smoking status, endoscopists' baseline examination time, and working experience. The detection rate of high-risk lesions (neoplastic lesions and advanced atrophic gastritis) was also significantly higher in stage II (3.3% vs 5.4%, P = 0.029). In the endoscopist-level analysis, all practitioners reached a median examination time of 6 minutes, and the coefficients of variation of FDR (36.9%-26.2%) and examination time (19.6%-6.9%) decreased in stage II. DISCUSSION: Setting a 6-minute minimal examination time significantly improved the detection of focal lesions during EGDs and has the potential to be implemented for quality improvement.

Machine learning-based automated sponge cytology for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction: a nationwide, multicohort, prospective study.

BACKGROUND: Oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction have a dismal prognosis, and early detection is key to reduce mortality. However, early detection depends on upper gastrointestinal endoscopy, which is not feasible to implement at a population level. We aimed to develop and validate a fully automated machine learning-based prediction tool integrating a minimally invasive sponge cytology test and epidemiological risk factors for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction before endoscopy. METHODS: For this multicohort prospective study, we enrolled participants aged 40-75 years undergoing upper gastrointestinal endoscopy screening at 39 tertiary or secondary hospitals in China for model training and testing, and included community-based screening participants for further validation. All participants underwent questionnaire surveys, sponge cytology testing, and endoscopy in a sequential manner. We trained machine learning models to predict a composite outcome of high-grade lesions, defined as histology-confirmed high-grade intraepithelial neoplasia and carcinoma of the oesophagus and oesophagogastric junction. The predictive features included 105 cytological and 15 epidemiological features. Model performance was primarily measured with the area under the receiver operating characteristic curve (AUROC) and average precision. The performance measures for cytologists with AI assistance was also assessed. FINDINGS: Between Jan 1, 2021, and June 30, 2022, 17 498 eligible participants were involved in model training and validation. In the testing set, the AUROC of the final model was 0·960 (95% CI 0·937 to 0·977) and the average precision was 0·482 (0·470 to 0·494). The model achieved similar performance to consensus of cytologists with AI assistance (AUROC 0·955 [95% CI 0·933 to 0·975]; p=0·749; difference 0·005, 95% CI, -0·011 to 0·020). If the model-defined moderate-risk and high-risk groups were referred for endoscopy, the sensitivity was 94·5% (95% CI 88·8 to 97·5), specificity was 91·9% (91·2 to 92·5), and the predictive positive value was 18·4% (15·6 to 21·6), and 90·3% of endoscopies could be avoided. Further validation in community-based screening showed that the AUROC of the model was 0·964 (95% CI 0·920 to 0·990), and 92·8% of endoscopies could be avoided after risk stratification. INTERPRETATION: We developed a prediction tool with favourable performance for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction. This approach could prevent the need for endoscopy screening in many low-risk individuals and ensure resource optimisation by prioritising high-risk individuals. FUNDING: Science and Technology Commission of Shanghai Municipality.

[Effects of different long-term fertilization patterns on net carbon sink effect and economic benefits in double cropping rice paddy ecosystem in southern China]. / 长期不同施肥模式对南方双季稻田生态系统净碳汇效应和经济收益的影响.

There is close relationship between fertilizer managements and net carbon (C) sink effect, economic benefits in rice paddy ecosystem. Based on a long-term (35-year) field experiment, we analyzed the effects of different fertilization patterns on soil C sequestration rate, C density of topsoil, annual C balance, and economic benefits in the double cropping rice paddy in southern China. There were four fertilization treatments, chemical fertilizer alone (MF), rice straw and chemical fertilizer (RF), 30% organic manure and 70% chemical fertilizer (OM), and without any fertilizer input as a control (CK). The results showed that soil C pool in the double cropping rice paddy field under different fertilization treatments changed from 216.02 to 866.74 kg·hm-2·a-1, and soil C pool under OM treatment were significantly higher than that of MF, RF and CK. The soil C sequestration rates in the double cropping rice paddy field under different fertilization treatments ranged from 51.5 to 650.7 kg·hm-2·a-1, and that of C density of topsoil was from 55.64 to 78.42 t·hm-2. The order of soil C sequestration rates and C density of topsoil was OM>RF>MF>CK. The change range of C adsorption in the double cropping rice paddy field ecosystem was from 4.42 to 9.32 t C·hm-2·a-1, with an order of OM>RF>MF>CK. Compared with the MF treatment, soil net C sink under OM and RF treatments increased by 27.6% and 13.6%, respectively. The change range of C cost material input ranged from 1.49 to 2.17 t C·hm-2·a-1, and that of annual economic benefits was from 1.30×103 to 7.83×103 yuan·hm-2·a-1 with an order of RF>OM>MF>CK. The net income of economic benefits of OM, RF and MF treatments were significantly higher than that of CK. Generally, soil C sequestration rate, C sink effect and annual economic benefits were increased by the long-term application of organic manure and rice straw returning together with chemical fertilizer, which could increase soil organic carbon storage in the double cropping rice paddy field of southern China.

[Impacts of long-term different fertilization managements on soil acid hydrolysable organic nitrogen fractions in double-cropping rice field]. / é•¿æœŸä¸åŒæ–½è‚¥æ¨¡å¼å¯¹åŒå­£ç¨»ç”°åœŸå£¤é ¸è§£æœ‰æœºæ°®ç»„åˆ†çš„å½±å“.

To clarify the impacts of long-term different fertilization modes on the soil acid hydrolysable organic nitrogen and its components in the double-cropping rice field of southern China, a long-term (36-year) location field experiment was used as a platform to systematically analyze the variations of soil acid hydrolysable organic nitrogen and its components (amino acid nitrogen, amino sugar nitrogen, ammonium nitrogen, unidentified hydrolysable nitrogen) at 0-10 cm and 10-20 cm soil layers under four fertilization treatments, including chemical fertilizer alone (CF), rice straw and chemical fertilizer (RF), 30% organic manure and 70% chemical fertilizer (OM), and control (CK). The relationships of soil acid hydrolysable organic nitrogen content and soil total nitrogen, soil organic carbon content were also analyzed. The results showed that compared with CK, OM and RF treatments significantly increased the contents of total nitrogen, available nitrogen, and organic carbon at both soil layers. The contents of soil acid hydrolysable organic nitrogen at 0-10 cm and 10-20 cm layers of OM, RF and CF treatments were 10.7%-42.6% and 12.2% -51.5% higher than that of CK, respectively. Compared with CF and CK treatments, OM and RF treatments significantly increased the contents of amino acid nitrogen, ammonium nitrogen, unidentified hydrolysable nitrogen and amino sugar nitrogen contents atboth soil layers. The soil acid hydrolysable organic nitrogen and non-hydrolysable nitrogen contents at 0-10 cm and 10-20 cm paddy soils under different fertilization treatments decreased in an order of OM>RF>CF>CK. The contents of soil amino acid nitrogen, ammonium nitrogen, amino sugar nitrogen and non-hydrolysable nitrogen at 0-10 cm soil layer of each fertilization treatment were higher than those at 10-20 cm soil layer. In addition, the contents of soil acid hydrolyzed organic nitrogen were positively correated with the contents of soil total nitrogen and soil organic carbon. In conclusion, RF and OM treatments were beneficial to increase organic nitrogen content at 0-10 and 10-20 cm soil layers of double cropping paddy fields, with postive consequences on nitrogen supply capacity and soil fertility.

[Corrigendum] Synergic effect between 5­fluorouracil and celecoxib on hypoxic gastric cancer cells.

Following the publication of the above article, the authors have realized that Fig. 2 was published with an incorrect data panel: Essentially, Fig. 2D was erroneously selected from the representative images of the Fig. 1C data group during figure compilation. The authors were able to locate their original data, and the corrected version of Fig. 2, featuring the corrected data panel for Fig. 2D, is shown below. All the authors agree with this Corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them to publish it. The authors also regret that this inadvertent error was included in the paper, even though it did not substantially alter any of the major conclusions reported in the study, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 11: 1160­1166, 2014; DOI: 10.3892/mmr.2014.2783].

Effects of long-term fertilizer management on soil labile organic carbon fractions and hydrolytic enzyme activity under a double-cropping rice system of southern China.

Fertilization is an effective way to improve soil quality, increase soil fertility and soil microbial diversity in paddy soil. To explore the changes of soil labile organic carbon (C) fractions and hydrolytic enzyme activity after 34 years fertilization treatments in a field experiment in double-cropping rice system of southern China. There were four treatments, including chemical fertilizer alone (MF), rice residue and chemical fertilizer (RF), 30% organic matter and 70% chemical fertilizer (OM), and the control without fertilizer input (CK). We measured soil organic carbon (SOC) content, soil labile organic C fractions, SOC related hydrolytic enzyme activity, correlation coefficients of soil enzyme activity with SOC content and its labile organic C fractions. The results showed that MF, RF and OM increased SOC content by 4.5%, 22.4% and 53.5%, respectively. Compared with MF and CK, RF and OM increased soil labile organic C fractions [cumulative C mineralization (Cmin), permanganate oxidizable C (KMnO4-C), particulate organic C (POC), dissolved organic C (DOC), light fraction organic C (LFOC), microbial biomass C (MBC)] and the proportion of each labile organic C fractions to total organic C. The contents of Cmin, KMnO4-C, POC, DOC, LFOC and MBC under OM treatment were 3.5, 3.1, 3.7, 1.9, 1.2 and 1.9 times higher than CK treatment, respectively. The proportion of labile organic C fractions to total organic C of RF and OM treatments was significantly higher than that in CK. The order of soil hydrolytic enzyme activity [α-glucosidase (αG), ß-glucosidase (ßG), ß-xylosidase (ßX), cellobiohydrolase (GBH), and N-acetyl-ß-glucosaminidase (NAG)] was OM>RF>MF>CK. The soil hydrolytic enzyme activity under OM treatment increased by 111.8%, 14.1%, 127.3%, 285.6% and 91.4% compared with CK, respectively. Furthermore, RF and OM treatments were beneficial to soil peroxidase (POD) activity. MF treatment was beneficial to soil polyphenol oxidase (PPO) activity. There was a significant positive correlation between soil hydrolytic enzyme activity and SOC content and its labile organic C fractions. In conclusion, the combined application of organic manure, rice straw returning and chemical fertilizer is an effective method to improve soil labile organic C fractions and hydrolytic enzyme activity in a double-cropping rice paddy field of southern China.

Overexpression of Stat3 increases circulating cfDNA in breast cancer.

PURPOSE: Current studies on circulating cell-free DNA (cfDNA) have been focusing on its potential as biomarkers in liquid biopsy by detecting its content or genetic and epigenetic changes for the evaluation of tumor burden and therapeutic efficacy. However, the regulatory mechanism of cfDNA release remains unclear. Stat3 has been documented as an oncogene for the development and metastasis of breast cancer cells. In this study, we investigated whether Stat3 affects the release of cfDNA into blood and its association with the number of circulating tumor cells (CTCs). METHODS: The cfDNA level in plasma of patients with breast cancer and healthy volunteers were determined by quantitative real-time PCR. Three mouse breast cancer models with different Stat3 expression were generated and used to established three breast cancer orthotopic animal models to examine the effect of Stat3 on cfDNA release in vivo. Stat3 mediated Epithelial-mesenchymal phenotype transition of CTCs was determined by immunofluorescence assay and Western blot assay. RESULTS: The data showed that Stat3 increased circulating cfDNA, which is correlated with the increased volume of primary tumors and number of CTCs, accompanied with the dynamic EMT changes regulated by Snail induction. Furthermore, the high level of total circulating cfDNA and Stat3-cfDNA in patients with breast cancer were detected by quantitative real-time PCR using GAPDH and Stat3 primers. CONCLUSION: Our results suggested that Stat3 increases the circulating cfDNA and CTCs in breast cancer.

Effectiveness and Safety of Acupuncture for Migraine: An Overview of Systematic Reviews.

Background: Migraine is a common neurological disease, which burdens individuals and society all over the world. Acupuncture, an important method in Traditional Chinese Medicine, is widely used in clinical practice as a treatment for migraine. Several systematic reviews (SRs) have investigated the effectiveness and safety of acupuncture for migraine. Objective: To summarize and critically assess the quality of relevant SRs and present an objective and comprehensive evidence on the effectiveness and safety of acupuncture for migraine. Data Sources. MEDLINE, Embase, Cochrane Library, PROSPERO database, Chinese National Knowledge Infrastructure (CNKI), Chinese Biological Medicine (CBM), China Science and Technology Journal (SCTJ), and WanFang database (WF) were searched from inception to December 2019 and grey literatures were manually searched. Selection Criteria. SRs which meet the criteria were independently selected by 2 reviewers according to a predetermined protocol. Data Extraction. Characteristics of included SRs were independently extracted by 2 reviewers following a predefined data extraction form. Review Appraisal. The methodological quality, risk of bias, and reporting quality of included SRs were assessed, respectively, by a Measurement Tool to Assess Systematic Reviews (AMSTAR) 2, the Risk of Bias in Systematic reviews (ROBIS) tool, and the Preferred Reporting Item for Systematic Review and Meta-analysis-Acupuncture (PRISMA-A) statement. The quality of outcomes was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: A total of 15 SRs were included. All the SRs were published between 2011-2019. Based on AMSTAR 2, 14 out of 15 SRs were rated critically low quality and 1 was rated low quality. According to ROBIS tool, 9 SRs (60%) were low risk of bias. With the PRISMA-A checklist, we found 11 out of 15 SRs were found adequately reported over 70%. With the GRADE tool, we found high quality of evidence indicated that the effective rate of acupuncture was superior to western medicine in treatment of migraine. Besides, acupuncture reduced more headache days and the times of using painkiller and was more effective in reducing the frequency and degree of headache than western medicine and sham acupuncture. Limitations. There might be some missing information. The accuracy of the conclusions may be decreased reduced since we were unable to synthesis all the evidence. Conclusions: Based on high quality of evidence, we concluded that acupuncture may be an effective and safe therapy for migraine. However, the quality of SRs in acupuncture for migraine still needs more improvement.

Acupuncture for poststroke spasticity: A protocol of a systematic review and meta-analysis.

INTRODUCTION: Spasticity is the most common complication after stroke, which is the main obstacle in the recovery of motor function. Spasticity seriously affects the quality of life and brings a heavy burden to families and society. Acupuncture is an effective method for stroke. However, whether acupuncture is effective for poststroke spasticity is still unknown. The purpose of this systematic review (SR) is to evaluate the effectiveness and safety of acupuncture for poststroke spasticity. METHODS AND ANALYSIS: We will search the following databases from inception to July 2019: China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP), PubMed, Embase, The Cochrane Library, and Web of Science. All relevant randomized controlled trials (RCTs) utilizing acupuncture for poststroke spasticity will be included. The primary outcome is the modified Ashworth scale. Secondary outcomes include composite spasticity scale, clinic spasticity index, electromyographic activity, Hoffmann reflex activity, or other spasticity-related outcomes. Study selection, data extraction, and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias and data synthesis will be conducted using Review Manager V5.3 software. ETHICS AND DISSEMINATION: The ethical approval is not required since SR is based on published studies. The results of this SR will be published in a peer-reviewed scientific journal according to the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA) guidelines. PROSPERO REGISTRATION NUMBER: CRD42019129779.

Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066.

Doxorubicin (Dox) is widely used in the treatment of triple-negative breast cancer cells (TNBCs), however resistance limits its effectiveness. Cancer stem cells (CSCs) are associated with Dox resistance in MCF-7 estrogen receptor positive breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) may functionally shift non-CSCs towards CSCs. However, whether Stat3 drives the formation of CSCs during the development of resistance in TNBC, and whether a Stat3 inhibitor reverses CSC-mediated Dox resistance, remains to be elucidated. In the present study, human MDA-MB-468 and murine 4T1 mammary carcinoma cell lines with the typical characteristics of TNBCs, were compared with estrogen receptor-positive MCF-7 cells as a model system. The MTT assay was used to detect cytotoxicity of Dox. In addition, the expression levels of CSC-specific markers and transcriptional factors were measured by western blotting, immunofluorescence staining and flow cytometry. The mammosphere formation assay was used to detect stem cell activity. Under long-term continuous treatment with Dox at a low concentration, TNBC cultures not only exhibited a drug-resistant phenotype, but also showed CSC properties. These Dox-resistant TNBC cells showed activation of Stat3 and high expression levels of pluripotency transcription factors octamer-binding transcription factor-4 (Oct-4) and c-Myc, which was different from the high expression of superoxide dismutase 2 (Sox2) in Dox-resistant MCF-7 cells. WP1066 inhibited the phosphorylation of Stat3, and decreased the expression of Oct-4 and c-Myc, leading to a reduction in the CD44-positive cell population, and restoring the sensitivity of the cells to Dox. Taken together, a novel signal circuit of Stat3/Oct-4/c-Myc was identified for regulating stemness-mediated Dox resistance in TNBC. The Stat3 inhibitor WP1066 was able to overcome the resistance to Dox through decreasing the enrichment of CSCs, highlighting the therapeutic potential of WP1066 as a novel sensitizer of Dox-resistant TNBC.

[Knockout of LSD1 Gene by CRISPR/Cas9 System Significantly Inhibited Proliferation and Expression of CD235a in K562 Cells].

OBJECTIVE: To study the effect of LSD1 knock-out on human chronic myeloid leukemia cells(K562 cells). METHODS: The LSD1 gene in K562 cells was knocked-out specifically by using CRISPR/Cas9 system, the single cells were gained by flow cytometric sorting technique, the LSD1+/- and LSD1-/- cell lines were gained after amplificantion and culture, identification of Western blot and sequencing. The MTS assay was used to detect the effect of LSD1 knockout on the proliferation of K562 cells, the flow cytometry was used to examine the expression of K562 cell surface marker after LSD1 knockout. RESULTS: The LSD1 stable knockout cell line of K562 (LSD1+/- and LSD1-/-)were successfully costructed. It was found that knockout of LSD1 significantly inhibited the proliferation of K562 and the expression of CD235a. CONCLUSION: LSD1 plays a key role in the regulation of K562 cell proliferation and CD235a expression.

The pharmacogenomics of valproic acid.

Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.

Influence of PRKCH gene polymorphism on antihypertensive response to amlodipine and telmisartan.

This study aimed to evaluate the effect of PRKCH rs2230500 genetic polymorphism on efficacy of amlodipine and telmisartan for patients with hypertension. A total of 136 essential hypertension (EH) patients were treated with amlodipine (70 patients) or telmisartan (66 patients), respectively. Genetic polymorphism was genotyped by Sanger sequencing. Both baseline and post-treatment blood pressure (BP) and heart rate were measured to evaluate the influence of genetic polymorphism on the antihypertensive response. No significant difference in the absolute decrease in diastolic blood pressure (DBP),systolic blood pressure (SBP), and mean arterial pressure (MAP) was observed among PRKCH rs2230500 genotypes after 4-week amlodipine or telmisartan therapy (p > 0.05). However, when compared with carriers or GG genotype, the antihypertensive effect of PRKCH rs2230500 GA/AA carriers was superior in telmisartan treatment group. PRKCH rs2230500 gene polymorphism is significantly related to the efficiency in telmisartan therapy (p = 0.02). The PRKCH rs2230500 may influence the antihypertensive efficacy of telmisartan in Chinese EH patients, and further studies are needed to confirm these findings.

Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition.

Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5-fluorouracil (5-FU) in vivo and in vitro. The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (ΔΨM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis.

Pharmacokinetics and pharmacodynamics of a polyethylene glycol (PEG)-conjugated GLP-receptor agonist once weekly in Chinese patients with type 2 diabetes.

This multi-center, randomized, double-blind, multiple dose-escalation study was conducted to assess the pharmacokinetics and pharmacodynamics of a newly developed polyethylene glycol (PEG)-conjugated glucagon-like peptide-1 (GLP-1) receptor agonist, PEX168 once weekly in Chinese patients with type 2 diabetes (T2DM). Fifty patients aged 20-65 years, either treatment-naive or having been treated with single oral antidiabetic agents were eligible. Antidiabetic agents were stopped for 14 days before the study was initiated. Patients were allocated randomly into groups with subcutaneous PEX168 or placebo once-weekly for 8 weeks followed by 6 weeks observation. From baseline to 8 weeks, HbA1c were decreased by up to 0.0, 0.2, 0.6, 0.9, and -0.4% in the 50, 100, 200, 300 µg PEX168 groups, and placebo group respectively. The mean elimination half-life of PEX168 was 131.8-139.8 hours. The mean tmax was 67.3 hours. Steady-state plasma PEX168 concentrations were attained after 4 weeks. PEX168 once-weekly were tolerable by the patients: adverse effects reported ranged from 'mild' to 'moderate'. The most frequent drug-related adverse effects were nausea, vomiting, and diarrhea of mild to moderate severity. Administration of the PEG-conjugated GLP-1 receptor agonist PEX168 resulted in dose-proportional pharmacokinetic and antidiabetic pharmacodynamic activity.

Synergic effect between 5­fluorouracil and celecoxib on hypoxic gastric cancer cells.

5­fluorouracil (5­FU) is commonly used in the treatment of gastric cancer; however, resistance to this drug occurs under hypoxic conditions. Celecoxib may be used to reverse this resistance. The aim of the present study was to elucidate the inhibitory effects and mechanisms of 5­FU and celecoxib on the gastric cancer cell line SGC7901 under hypoxic conditions. SGC7901 cells were divided into four groups: Hypoxic control group, 5­FU group, celecoxib group and 5­FU/celecoxib combination group. Following treatment, the inhibition rates of cells were determined using an MTT assay. Protein and messenger RNA (mRNA) expression of hypoxia­inducible factor 2α (HIF­2α), adenosine triphosphate­binding cassette sub­family G member 2 (ABCG2) and octamer binding protein 4 (Oct­4) were determined using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT­qPCR) and western blot analysis. The results demonstrated that the 5­FU/celecoxib combination group had a significantly higher inhibition rate than the individually treated 5­FU and celecoxib groups (P<0.05); inhibition rates were 66.09, 52.61 and 46.1%, respectively. mRNA and protein expression levels of HIF­2α, ABCG2 and Oct­4 were significantly lower in the celecoxib and 5­FU/celecoxib combination groups (P<0.01) compared with those of the hypoxia control and 5­FU groups. The 5­FU group demonstrated the highest levels of the respective mRNA and proteins. In conclusion, the results of the present study indicated that celecoxib had anti­tumor effects, as it was shown to inhibit tumor cell growth via the inhibition of HIF­2α, ABCG2 and Oct­4. The 5­FU/celecoxib combination had a synergic effect on tumor growth inhibition. This therefore suggested that inhibition of HIF­2α, ABCG2 and Oct­4 may be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment.

Preparation and antitumor activity of a tamibarotene-furoxan derivative.

Multi-target drug design, in which drugs are designed as single molecules to simultaneously modulate multiple physiological targets, is an important strategy in the field of drug discovery. QT-011, a tamibarotene-furoxan derivative, was here prepared and proposed to exert synergistic effects on antileukemia by releasing nitric oxide and tamibarotene. Compared with tamibarotene itself, QT-011 displayed stronger antiproliferative effects on U937 and HL-60 cells and was more effective evaluated in a nude mice U937 xenograft model in vivo. In addition, QT-011 could release nitric oxide which might contribute to the antiproliferative activity. Autodocking assays showed that QT-011 fits well with the hydrophobic pocket of retinoic acid receptors. Taken together, these results suggest that QT-011 might be a highly effective derivative of tamibarotene and a potential candidate compound as antileukemia agent.

A new cell counting method to evaluate anti-tumor compound activity.

Determining cell quantity is a common problem in cytology research and anti-tumor drug development. A simple and low-cost method was developed to determine monolayer and adherent-growth cell quantities. The cell nucleus is located in the cytoplasm, and is independent. Thus, the nucleus cannot make contact even if the cell density is heavy. This phenomenon is the foundation of accurate cell-nucleus recognition. The cell nucleus is easily recognizable in images after fluorescent staining because it is independent. A one-to-one relationship exists between the nucleus and the cell; therefore, this method can be used to determine the quantity of proliferating cells. Results indicated that the activity of the histone deacetylase inhibitor Z1 was effective after this method was used. The nude-mouse xenograft model also revealed the potent anti-tumor activity of Z1. This research presents a new anti-tumor-drug evaluation method.

[Effects of phosphorous fertilizers on phytoavailability of cadmium in its contaminated soil and related mechanisms].

To explore an effective measure to ensure the safety of rice quality in cadmium (Cd)-contaminated farmland, a pot culture experiment was conducted to study the effects of of low Cd content (Cd < 0.2 mg x kg(-1)) phosphorous fertilizers with an application rate of 0.10 or 0.20 g P2O5 x kg(-1) on the phytoavailability of Cd in its contaminated p add y soil, with the related mechanisms discussed. Compared with no phosphorous fertilization, applying 0.10 P2O5 x kg(-1) of calcium magnesium phosphate (CMP) and monopotassium phosphate (MKP) increased soil pH and decreased soil available Cd content significantly, and CMP and calcium superphosphate (CSP) decreased the Cd accumulation in rice significantly. When the application rate was up to 0.20 g P2O5 x kg(-1), calcium hydrogen phosphate (CHP) increased the soil pH and decreased the soil available Cd content significantly, and CMP, MKP, and CHP decreased the DTPA-extractable soil Cd content by 11.8%, 9.8%, and 11.8%, and the NH4 OAc-extractable soil Cd content by 9.5%, 7.1%, and 7.1%, respectively. All test phosphorous fertilizers could significantly decrease the stem and leaf Cd contents, with a decrement of 24.9%-50.8%, and except CHP, the others could significantly decrease the Cd content of brown rice. With the application CMP and CSP, the Cd content of brown rice was close to the National Hygienic Standard for Grains (GB 2715-2005). Among the test phosphorous fertilizers, those can increase soil pH (CMP, MKP, and CHP) could significantly decrease the availability of soil Cd significantly, and those containing calcium (CMP and CSP) were more effective in decreasing the Cd accumulation in rice. The efficiency of the phosphorous fertilizers was mainly determined by their chemical properties. Alkaline calcium-containing phosphorous fertilizers were more effective in decreasing the Cd absorption and accumulation in rice plant in Cd-contaminated farmland.

[Effects and mechanism of alkaline wastes application and zinc fertilizer addition on Cd bioavailability in contaminated soil].

The effects of paper mill sludge, red mud and zinc fertilizer addition on remediation of acid cadmium contaminated paddy soil were studied in a pot experiment, and their beneficial effects were verified in a field experiment, by using lime as comparison. The pot experiment results showed that a single application (2 g x kg(-1)) of lime, paper mill sludge or red mud increased soil pH significantly. Compared with no applying alkaline substances, the soil exchangeable Ca content was increased by 33.1%-76.0% at 7 days after applying alkaline substances and 31.0%-78.3% at 30 days after rice transplanting, respectively. The soil available Cd content was significantly decreased by 38.4%-45.0% at 7 days after the three alkaline substances applications, and was decreased by 37.4%-52.9% and 33.2%-38.7% at 30 days and 60 days after rice transplanting, respectively. The Cd content in rice root and brown rice was decreased by 24.0%-48.5% and 26.3%-44.7%, respectively. With equal applications of lime, paper mill sludge and red mud, the effects on increase of soil pH and decrease in Cd accumulation by rice was lime > red mud > paper mill sludge. Compared with a single application (2 g x kg(-1)) of paper mill sludge or red mud, Cd accumulation decreased significantly following the application of zinc fertilizer (0.2 g x kg(-1)) field experimental results were similar to the pot experiment that Cd accumulation apparently declined in the first and second crops (late rice and autumn rape) following the application of paper mill sludge, red mud and addition of zinc fertilizer. The Cd content in brown rice and rape seeds was decreased by 27.1-65.1% and 16.4%-41.6%, respectively, compared with no alkaline substances application. The Cd content in brown rice reached the National Hygienic Standard for Grains (GB 2715-2005). Therefore, combined application of paper mill sludge or red mud with zinc fertilizer was a feasible method to remediate acid cadmium contaminated paddy soil. Rice quality was guaranteed by determination of rational amount of alkaline wastes and a proportion of zinc fertilizer which was in accord with soil Cd contamination level and chemical properties, etc.