Effects of selenium-enriched yeast dietary supplementation on egg quality, gut morphology and caecal microflora of laying hens.

Selenium (Se) is an essential micronutrient for humans and animals and is a powerful antioxidant that can promote reproductive and immune functions. The purpose of this study was to evaluate the effects of supplemental dietary selenium-enriched yeast (SeY) on egg quality, gut morphology and microflora in laying hens. In total, 100 HY-Line Brown laying hens (45-week old) were randomly allocated to two groups with 10 replicates and fed either a basal diet (without Se supplementation) or a basal diet containing 0.2 mg/kg Se in the form of SeY for 8 weeks. The Se supplementation did not have a significant effect on egg quality and intestinal morphology of laying hens. Based on the 16S rRNA sequencing, SeY dietary supplementation effectively modulated the cecal microbiota structure. An alpha diversity analysis demonstrated that birds fed 100 mg/kg SeY had a higher cecal bacterial diversity. SeY dietary addition elevated Erysipelotrichia (class), Lachnospiraceae (family), Erysipelotrichaceae (family) and Ruminococcus_torques_group (genus; p < .05). Analysis of microbial community-level phenotypes revealed that SeY supplementation decreased the microorganism abundance of facultatively anaerobic and potentially pathogenic phenotypes. Overall, SeY supplementation cannot significantly improve intestinal morphology; however, it modulated the composition of cecal microbiota toward a healthier gut.

Fruquintinib in combination with sintilimab or TAS-102 as third-line or above treatment in patients with metastatic colorectal cancer: a real-world study.

Background: For metastatic colorectal cancer (mCRC), the efficacy of third-line or above treatments is not ideal. Combining targeted vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) biological agents with chemotherapy or anti-programmed death receptor 1 (PD-1) treatment can bring longer survival benefits to patients with mCRC compared with the application of a single drug. In this study, fruquintinib was used as the research drug, and the main purpose was to compare the efficacy and safety of fruquintinib in combination with sintilimab (FS) or trifluridine and tipiracil (TAS-102) (FT) in the third-line or above treatment in mCRC patients. Methods: Based on real-world clinical practice, mCRC patients who progressed after second-line or higher-line chemotherapy regimens and received FS or FT as third-line or above treatment from December 2020 to November 2022 were analyzed. Progression-free survival (PFS) was the primary endpoint. Safety, disease control rate (DCR) and objective response rate (ORR) were secondary end points. Results: In the FS group, 47 patients received FS, and in the FT group, 45 patients received FT. The DCR values in the FS and FT groups were 80.9% (38/47) and 55.6% (25/45), respectively (P<0.05). The median PFS (mPFS) in the FS group was 6.0 months, and the mPFS in the FT group was 3.5 months (P<0.05). Most adverse events (AEs) were grade 1-2 in severity. Conclusions: As a third-line or above regimen in mCRC patients, compared to FT, treatment with FS provides a higher DCR and longer mPFS and is better tolerated. The combination of fruquintinib and sintilimab may become a new treatment option for mCRC patients.

S-1 maintenance therapy in advanced gastric cancer without disease progression after first-line chemotherapy: A retrospective analysis.

For patients with advanced gastric cancer after chemotherapy, the optimal mode of maintenance therapy is not yet clear. This research aimed to compare the efficacy and adverse effects of S-1 maintenance therapy and follow-up observation in patients with advanced gastric cancer without disease progression after first-line combined chemotherapy. This study retrospectively analyzed 106 patients from January 2018 to December 2021. The primary endpoints were overall survival and progression-free survival, the secondary endpoint was chemotherapy-related toxicity, and the curative effects and baseline characteristics of the patients were analyzed. Longer progression-free survival and overall survival were observed in the S-1 maintenance treatment group than in the follow-up observation group (p < 0.001). No obvious differences existed in the subgroup results regarding progression-free survival or overall survival (p > 0.05). In the maintenance treatment group, the occurrence of thrombocytopenia and hand-foot syndrome was significantly increased (p < 0.001). No toxicity-related deaths occurred. The included patients without disease progression after first-line combined chemotherapy can achieve significant survival benefits by receiving S-1 maintenance therapy. The patient's tolerance to S-1 maintenance therapy was good.

Nestin Expression and the Survival of Patients With Digestive Tract Cancers: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Several cancers have been associated with poor prognoses based on nestin, a confirmed marker of cancer stem cells. However, there is conflicting evidence regarding the prognostic value of tumor nestin expression in patients with digestive tract cancers. An investigation of the association between nestin and survival in patients with digestive tract cancers was performed in this meta-analysis. MATERIALS AND METHODS: Meta-analyses were conducted using PubMed, Embase, and Web of Science databases to search for cohort studies. We analyzed the data using a random-effects model that incorporates differences between studies. RESULTS: The pooled analysis showed a negative association between nestin expression and overall survival (hazard ratio: 1.38, 95% CI: 1.11 to 1.72, P = .004, I2 = 68%) and disease-free survival (hazard ratio: 1.48, 95% CI: 1.12 to 1.96, P = .005, I2 = 56%). Subgroup analysis showed that nestin expression was associated with poorer overall survival in gastric cancer (hazard ratio: 1.46, P < .001) and liver cancer (hazard ratio: 2.05, P < .001) patients, but not in colorectal cancer (hazard ratio: 1.03, P = .89) or pancreatic cancer (hazard ratio: 0.96, P = .80) patients. Further subgroup analysis showed a consistent association between nestin expression and poor overall survival in Asian and non-Asian studies, and in studies with univariate and multivariate regression models. CONCLUSION: To sum up, the presence of high nestin expression in digestive tract cancer patients is associated with poorer survival, particularly in patients with gastric and liver cancers.

Prognostic significance of platelet lymphocyte ratio in patients with melanoma: A meta-analysis.

BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of platelet lymphocyte ratio (PLR) in patients with melanoma through performing a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched for potential studies. The basic characteristics and relevant data were extracted. Hazard ratios with 95% confidence intervals (CIs) were pooled to evaluate the prognostic role of PLR in patients with melanoma. RESULTS: Ten studies enrolling 2422 patients were included. The pooled hazard ratios of higher PLR for overall survival and progression-free survival in melanoma were 1.70 (95% CI, 1.22-2.37) and 1.65 (95% CI, 1.10-2.47), respectively. Sensitivity analysis and subgroup analyses were also performed. No significant publication bias was observed. CONCLUSION: Our results showed that higher PLR was associated with poorer overall survival and progression-free survival in patients with melanoma. These findings may help to determine the prognosis and explore future novel therapies based on modulating inflammation and immune responses in melanoma.

Establishing a three-miRNA signature as a prognostic model for colorectal cancer through bioinformatics analysis.

BACKGROUND: Identification of more promising microRNAs (miRNAs) are being extensively studied with respect to colorectal cancer (CRC), since CRC is the leading cause of cancer deaths and most common malignant tumors worldwide. A series of colon cancer (CCa) samples from The Cancer Genome Atlas (TCGA) were analyzed to provide a new perspective into this field. METHODS: The expression of miRNAs, mRNAs and the clinical data of 437 CRC patients were downloaded from the TCGA database. The survival-related differentially expressed miRNAs (sDMIRs) and mRNAs were detected by COX regression analysis. The high-risk group and low-risk group were separated by the median risk score of the risk score model. The potential clinical characteristics of these sDMIRs were analyzed by R software. The potential molecular mechanisms of these sDMIRs were explored by computational biology. The expression levels of three sDMIRs were explored by qPCR in CRC samples. RESULTS: Three DMIRs (hsa-miR-21-3p, hsa-miR-194-3p and hsa-miR-891a-5p) correlated with the most remarkable prognostic values of CRC patients were selected to establish the risk score model (RSM) by univariate and multivariate COX regression analysis and the survival probability of the low-risk group was longer than that in the high-risk group. We detected the target genes of three sDMIRs and the potential molecular mechanisms of these sDMIRs. We further verified the high expression levels of hsa-miR-21-3p and hsa-miR-194-3p were associated with the early T-stages, while hsa-miR-891a-5p illustrated the reversed result. CONCLUSION: Our study demonstrated three sDMIRs with significantly clinical values illustrated the potential predicting values in the prognosis of CRC patients. Our results may provide a new perspective for the diagnostic methods and treatment strategies in CRC patients.

Efficacy and Safety of Apatinib in the Treatment of Postoperative Recurrence of Fibrosarcoma.

OBJECTIVE: To evaluate the efficacy and safety of apatinib in patients with relapse after surgery for fibrosarcoma. METHODS: We reviewed the clinical data of 56 patients who experienced recurrence after fibrosarcoma resection and who received chemotherapy from September 2015 to September 2017 (no significant difference in general data of patients) (p>0.05). Differences in drug use and adverse effects were observed between patients who received monotherapy and those who received regular chemotherapy (MAID/AI). RESULTS: Compared with the regular chemotherapy group, patients in the apatinib monotherapy group exhibited an improved overall response rate (ORR) and disease control rate (DCR). In patients treated with apatinib, the incidence of adverse reactions was improved, and the symptoms were mild (P<0.05). CONCLUSION: Apatinib is a single-drug regimen that can be used in cases of recurrence of fibrosarcoma with high expression of vascular endothelial growth factor receptor-2 (VEGFR-2); its short-term efficacy is excellent, and its side effects are minimal. This drug may be used as part of a regular chemotherapy program.

Maintenance Versus Intermittent Strategies in the Treatment of Metastatic Colorectal Cancer: A Meta-Analysis from Another Angle.

INTRODUCTION: Considering the differences in overall survival (OS) and progression-free survival (PFS), treatment options for metastatic colorectal cancer (mCRC) are still inconclusive. We carried out a meta-analysis of maintenance and intermittent strategies for the treatment of mCRC aiming at providing an accurate estimation of different treatments in increasing the chance and duration of survival. METHODS: PubMed, Embase and CNKI were systematically searched. The pooled hazard ratio (HR) and 95% confidence interval (CI) were counted. We used STATA 12.0 and RevMan 5.2 for statistical analyses. RESULTS: A total of six publications with a population of 1975 mCRC patients were included in our meta-analysis. Analysis of OS revealed a statistically significant benefit associated with maintenance therapy (HR: 0.86, 95% CI 0.75-0.98, P = 0.02). Comparing maintenance therapy with an intermittent strategy, the first progression-free survival (PFS1) showed no significant difference (HR, 0.77; 95% CI 0.48-1.24, P = 0.29), but maintenance therapy improved the second progression-free survival (PFS2) significantly (HR, 0.66; 95% CI 0.54-0.81, P < 0.001). Sensitivity analysis was carried out to assess the stability of results. No publication bias was detected during analysis. CONCLUSION: Compared with the maintenance strategy, first-line chemotherapy that was completely stopped until disease progression did not benefit mCRC patients in terms of OS and PFS2. Therefore, a maintenance strategy is a good option for individualized mCRC patients.

Pleural effusion as a substitute for tumor tissue in detecting EGFR/ALK mutations in non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Pleural effusion (PE) has been reported useful in many studies for testing epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) with variable results. This systematic review and meta-analysis was performed to elucidate whether PE could be used as a surrogate for tumor tissue to detect EGFR mutations. METHODS: We extracted 2 × 2 diagnostic table from each included study and calculated data on specificity, sensitivity, negative likelihood ratio (NLR), positive likelihood ratio (PLR) ,and diagnostic odds ratio (DOR). We used the area under curve (AUC) and summary receiver operating characteristic curve (SROC) to summarize the overall diagnostic performance and assessed publication bias by Deeks' funnel plot. RESULTS: Our meta-analysis included 15 eligible publications. The following summary estimates for diagnostic parameters of the EGFR mutations detection in PE were made: sensitivity, 0.86 (95%CI 0.83-0.89); specificity, 0.93 (95%CI 0.91-0.95); PLR, 8.53 (95%CI 5,94-12.25); NLR, 0.18 (95%CI 0.13-0.25); DOR, 63.40 (95%CI 38.83-103.51); and AUC, 0.94. Funnel plot indicated publication bias insignificant. CONCLUSIONS: The meta-analysis suggests that EGFR mutation detecting in PE, especially supernatants, is a promising surrogate for tumor tissue in EGFR mutations testing of patients with NSCLC.

[Comparative study on contents of four alkaloids in homologous herbal medicines--Arecae Pericarpium and Arecae Semen].

To establish a high performance liquid chromatography (HPLC) method for simultaneous determination of four alkaloids(arecoline， guvacoline， arecaidine， and guvacine) in Arecae Pericarpium (AP) and Arecae Semen (AS), and compare the contents of these four alkaloids between different medicinal parts. The chromatographic conditions were as follows:Welch SCX（4.6 mm×250 mm， 5 µm）column, with acetonitrile-0.2% phosphoric acid solution (adjusted to pH 3.85-3.90 with ammonium hydroxide) at 50:50 as the mobile phase, at a flow rate of 0.5 mL·min⁻¹. The column temperature was set at 35 °C, and the detection wavelength was 215 nm. The results of content determination in 7 batches of AS and 10 batches of AP showed that, the contents of 4 alkaloids in AS (arecaidine 0.020%-0.045%, guvacine 0.031%-0.086%, arecoline 0.194%-0.346%, and guvacoline 0.065%-0.094%) were generally higher than those in AP (arecaidine 0.10%-0.032%, guvacine 0.006%-0.029% arecoline 0.00%-0.070%, and guvacoline 0.00%-0.020%), and most of the APs had no arecoline and arecaidine at all in fruit peel. The above results indicated that different alkaloids can be used to distinguish the different medicinal parts of Arera catechu. Arecoline， guvacoline， arecaidine， and guvacine can be used as the quality control markers of AS, while for AP, only arecaidine and guvacine were needed.

[HPLC fingerprint of Zishen Yutai pills and simultaneous determination of 5 index components].

To establish the HPLC fingerprint and determine five index components (loganic acid， chlorogenic acid， loganin， sweroside and asperosaponin Ⅵ) of Zishen Yutai pills by high performance liquid chromatography, and provide a scientific basis for its quality control. The fingerprint chromatogram was analysed by the chromatographic fingerprint similarity evaluation system for tradition Chinese medicine (2012), fifteen common peaks were obtained at the wavelength of 254 nm. Different batches of Zishen Yutai pills showed a similarity of above 0.90 in HPLC fingerprint profiles. For the quantitive analysis method, The separation of five components showed good regression (r>0.999 2) with linear ranges, and the mean recoveries were in the range of 97.62%-101.9%, with the RSD (n=9) less than 3%. The established fingerprint and quantitative analysis methods are highly specific, simple and accurate, which can reflect the quality of Zishen Yutai pills more comprehensively, and can be used for its quality control.

Role of Kruppel-like factor 4 in regulating inhibitor of apoptosis-stimulating protein of p53 in the progression of gastric cancer.

Gastric cancer (GC) remains one of the leading causes of cancer-associated mortality. The overexpression of inhibitor of apoptosis-stimulating protein of p53 (iASPP) has been detected in GC tissues but the function of iASPP in the viability of GC cells and its underlying molecular mechanism remains unknown. Kruppel-like factor 4 (KLF4) is a tumor suppressor gene in GC and it may interact with p53. iASPP is an evolutionarily conserved inhibitor of p53, whereas KLF4 may be negatively associated with iASPP in GC. However, whether KLF4 has regulatory effects on iASPP remains to be investigated. The objective of the present study was to examine the function of iASPP and KLF4 in the proliferation of GC cells and to determine whether KLF4 has regulatory effects on iASPP. It was demonstrated that iASPP was upregulated and KLF4 was downregulated in GC cell lines. Downregulation of iASPP inhibited the proliferation and colony formation ability, and promoted the apoptosis of GC cells. Additionally, upregulation of KLF4 inhibited the proliferation and colony formation ability, and promoted apoptosis of GC cells. Furthermore, upregulation of KLF4 inhibited the expression of iASPP. Upregulation of iASPP following overexpression of KLF4 reversed the KLF4-mediated effects in GC cells. In vivo upregulation of KLF4 or downregulation of iASPP inhibited the growth of tumors, whereas upregulation of iASPP promoted the growth of tumors. In conclusion, iASPP may act as an oncogene that promotes the proliferation of GC cells. The results demonstrated that KLF4 was a negative regulatory factor of iASPP and that overexpression of iASPP inhibited the effects of KLF4. Thus, downregulation of KLF4 in GC may lead to overexpression of iASPP and promote the development of cancer.

The effect of icotinib combined with chemotherapy in untreated non-small-cell lung cancer that harbored EGFR-sensitive mutations in a real-life setting: a retrospective analysis.

PURPOSE: This study was conducted to compare the efficacy of a combination of icotinib and chemotherapy with icotinib or chemotherapy alone in untreated non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-sensitive mutations and to analyze the curative effect of different treatments on different genetic mutations (EGFR 19 exon deletion and L858R mutation) in a real-life setting. PATIENTS AND METHODS: One hundred ninety-one patients were studied in this retrospective analysis from January 2013 to December 2015. The baseline characteristics, curative effects and adverse events of patients were analyzed. The primary endpoint was progression free survival (PFS). RESULTS: Longer PFS and overall survival (OS), and better objective response rate (ORR) were observed in the combination group compared to icotinib or chemotherapy along. For patients with an EGFR 19 exon deletion, the PFS, OS, and ORR in the combination group were superior to those in the icotinib or chemotherapy group. For the patients with the EGFR L858R mutation, better PFS and ORR were observed in the combination group, but OS was not obviously prolonged. Grade 3 or 4 adverse events were most commonly reported with combination therapy or chemotherapy alone. No possible drug-related interstitial lung disease or of drug related deaths occurred. CONCLUSION: The combination of icotinib and chemotherapy in patients with untreated NSCLC harboring sensitive EGFR mutations resulted in improved PFS and OS, especially in those who harbored the EGFR exon 19 deletion.

Inhibition of miR-182-5p protects cardiomyocytes from hypoxia-induced apoptosis by targeting CIAPIN1.

Myocardial infarction (MI), a type of ischemic heart disease, is generally accompanied by apoptosis of cardiomyocytes. MicroRNAs play the vital roles in the development and physiology of MI. Here, we established a downregulation model of miR-182-5p in H9c2 cells under hypoxic conditions to investigate the potential molecular mechanisms for miR-182-5p in hypoxia-induced cardiomyocyte apoptosis (HICA). RT-qPCR indicated that miR-182-5p levels exhibit a time-dependent increase in the rate of apoptosis induced by hypoxia. The results from the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and LDH (lactate dehydrogenase) assays indicated that cardiomyocyte injury noticeably increased after exposure to hypoxia. Meanwhile, hypoxia dramatically increased the apoptosis rate [which was reflected in the results from the annexin V - propidium iodide (PI) assay], enhanced caspase-3 activity, and reduced the expression of Bcl-2. Downregulation of miR-182-5p can significantly reverse hypoxia-induced cardiomyocyte injury or apoptosis. Importantly, bioinformatic analysis and dual-luciferase reporter assay revealed that CIAPIN1 (cytokine-induced apoptosis inhibitor 1) was a direct functional target of miR-182-5p, and that inhibition of miR-182-5p can lead to an increase in CIAPIN1 expression at both the mRNA and protein levels. Furthermore, the knockdown of CIAPIN1 with small interfering RNAs (siRNAs) efficiently abolished the protective effects of miR-182-5p inhibitor on HICA, demonstrating that miR-182-5p plays a pro-apoptotic role in cardiomyocytes under hypoxic conditions by downregulating CIAPIN1. Collectively, our results demonstrate that miR-182-5p may serve an underlying target to prevent cardiomyocytes from hypoxia-induced injury or apoptosis.

The hepatic ectonucleotide pyrophosphatase/phosphodiesterase 1 gene mRNA abundance is reduced by insulin and induced by dexamethasone.

Hormones regulate hepatic gene expressions to maintain metabolic homeostasis. Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been thought to interfere with insulin signaling. To determine its potential role in the regulation of metabolism, we analyzed its gene (Enpp1) expression in the liver of rats experiencing fasting and refeeding cycles, and in primary rat hepatocytes and human hepatoma HepG2 cells treated with insulin and dexamethasone using northern blot and real-time PCR techniques. Hepatic Enpp1 expression was induced by fasting and reduced by refeeding in the rat liver. In primary rat hepatocytes and HepG2 hepatoma cells, insulin reduced Enpp1 mRNA abundance, whereas dexamethasone induced it. Dexamethasone disrupted the insulin-reduced Enpp1 expression in primary hepatocytes. This is in contrast to the responses of the expression of the cytosolic form of phosphoenolpyruvate carboxykinase gene to the same hormones, where insulin reduced it significantly in the process. In addition, the dexamethasone-induced Enpp1 gene expression was attenuated in the presence of 8-Br-cAMP. In conclusion, we demonstrated for the first time that hepatic Enpp1 is regulated in the cycle of fasting and refeeding, a process that might be attributed to insulin-reduced Enpp1 expression. This insulin-reduced Enpp1 expression might play a role in the development of complications in diabetic patients.

The hepatic ectonucleotide pyrophosphatase/phosphodiesterase 1 gene mRNA abundance is reduced by insulin and induced by dexamethasone

Hormones regulate hepatic gene expressions to maintain metabolic homeostasis. Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been thought to interfere with insulin signaling. To determine its potential role in the regulation of metabolism, we analyzed its gene (Enpp1) expression in the liver of rats experiencing fasting and refeeding cycles, and in primary rat hepatocytes and human hepatoma HepG2 cells treated with insulin and dexamethasone using northern blot and real-time PCR techniques. Hepatic Enpp1 expression was induced by fasting and reduced by refeeding in the rat liver. In primary rat hepatocytes and HepG2 hepatoma cells, insulin reduced Enpp1 mRNA abundance, whereas dexamethasone induced it. Dexamethasone disrupted the insulin-reduced Enpp1 expression in primary hepatocytes. This is in contrast to the responses of the expression of the cytosolic form of phosphoenolpyruvate carboxykinase gene to the same hormones, where insulin reduced it significantly in the process. In addition, the dexamethasone-induced Enpp1 gene expression was attenuated in the presence of 8-Br-cAMP. In conclusion, we demonstrated for the first time that hepatic Enpp1 is regulated in the cycle of fasting and refeeding, a process that might be attributed to insulin-reduced Enpp1 expression. This insulin-reduced Enpp1 expression might play a role in the development of complications in diabetic patients.

Effect of shRNA interfering BAMBI on malignant biological behaviors of human colon cancer SW480 cell / 中国肿瘤生物治疗杂志

@# Objective: To explore the effect of shRNA interfering BAMBI (bone morphogenetic protein and activin membrane bound inhibitor) on the proliferation, apoptosis, invasion and migration of human colon cancer SW480 cells and the possible mechanisms. Methods: After successful transfection with sh-BAMBI in SW480 cells, the mRNA and protein epxressions of BAMBI were detected by qRT-PCR and Western blotting, respectively. Cell proliferation was measured by MTT; apoptosis was tested by Hoechst33258 staining; cell invasion was detected by transwell assay; and cell migration was measured by wound healing assay. The expressions of TGF-β/ Smad/2 signaling pathway related proteins were detected by Western blotting. Results: The mRNA and protein levels of BAMBI in shBAMBI group were lower than those of control group (P<0.05). Compared with control group, cell proliferation in sh-BAMBI group was obviously decreased (P<0.05), while apoptosis was obviously increased (P<0.01); in the meanwhile, cell invasion and migration in sh-BAMBI group were significantly reduced (P<0.05). In addition, the protein level of TGF-β and the ratio of p-Smad/2/ Smad/2 in shBAMBI group were significantly higher than those in control group (P<0.05). Conclusion: Interference of BAMBI by shRNA inhibits proliferation, invasion and migration but induces apoptosis of human colon cancer SW480 cells and activates TGF-β/Smad/2 pathway.

Inhibition of Hes1 enhances lapatinib sensitivity in gastric cancer sphere-forming cells.

It has been considered that the neurogenic locus notch homolog protein (Notch) signaling pathway serves an essential role in cellular differentiation, proliferation and apoptosis. However, the function of the Notch signaling pathway in gastric cancer stem cells (GCSCs) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity remains unclear. The present study aimed to delineate the role of the Notch1 signaling pathway in GCSCs and lapatinib sensitivity. Sphere-forming cells were separated from human gastric cancer MKN45 parental cells. The sphere-forming cells exhibited characteristics of CSCs and higher Notch1 expression compared with that of parental cells. To investigate the role of the Notch1 signaling pathway in GCSCs, the expression of transcription factor Hes1 (Hes1) was knocked down using small interfering RNA against Hes1. It was observed that Hes1 expression was significantly downregulated in knocked down cells. The inhibition of Hes1 suppressed the properties of CSCs, as indicated by significant decreases in the expression of the transcription factor sex determining region Y-box 2, epithelial cell adhesion molecule and the homeobox protein Nanog and reduced spheroid colony formation. In addition, epithelial-mesenchymal transition was significantly impaired in sphere-forming cells following Hes1 knockdown. Furthermore, the inhibition of Hes1 effectively enhanced lapatinib sensitivity in sphere-forming cells. These results suggest that sphere-forming gastric cancer cells possess the characteristics of CSCs, and that the Notch1 signaling pathway serves an essential role in the maintenance of CSCs and lapatinib sensitivity.

Pregabalin can decrease acute pain and postoperative nausea and vomiting in hysterectomy: A meta-analysis.

BACKGROUND: Whether the preoperative administration of pregabalin plays a beneficial role in controlling acute pain after hysterectomy is unknown. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the efficacy and safety of the preoperative use of pregabalin to treat acute postoperative pain following hysterectomy. METHODS: In April 2017, a systematic computer-based search was conducted in the PubMed, EMBASE, Web of Science, Cochrane Library, and Google databases. RCTs comparing pregabalin with placebo in patients undergoing hysterectomy were retrieved. The primary endpoint was the visual analog scale (VAS) score with rest or mobilization at 2 h, 4 and 24 hours and cumulative morphine consumption at 2, 4, 24, and 48 hours. The secondary outcomes were complications of nausea, vomiting, sedation, and dizziness. After tests for publication bias and heterogeneity among studies were performed, the data were aggregated for random-effects models when necessary. RESULTS: Ten clinical studies with 1207 patients (pregabalin = 760, control = 447) were finally included in this meta-analysis. Preoperative administration of pregabalin was associated with a significant reduction of VAS with rest or mobilization at 2, 4, and 24 hours after hysterectomy. Further, the preoperative administration of pregabalin was associated with a reduction in total morphine consumption at 2, 4, 24, and 48 hours after hysterectomy. The occurrence of morphine-related complications (nausea and vomiting) was also reduced in the pregabalin group. However, the preoperative administration of pregabalin was associated with an increase in the occurrence of dizziness. There was no significant difference in the occurrence of sedation. CONCLUSIONS: The preoperative use of pregabalin reduced postoperative pain, total morphine consumption, and morphine-related complications following hysterectomy. The doses of pregabalin were different, and large heterogeneity was the limitation of the current meta-analysis. Further studies should determine the optimal dose for controlling acute pain after hysterectomy.

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non-small-cell lung cancer.

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer.