IS6 family insertion sequences promote optrA dissemination between plasmids varying in transfer abilities.

Plasmids are the primary vectors for intercellular transfer of the oxazolidinone and phenicol cross-resistance gene optrA, while insertion sequences (ISs) are mobile genetic elements that can mobilize plasmid-borne optrA intracellularly. However, little is known about how the IS-mediated intracellular mobility facilitates the dissemination of the optrA gene between plasmid categories that vary in transfer abilities, including non-mobilizable, mobilizable, and conjugative plasmids. Here, we performed a holistic genomic study of 52 optrA-carrying plasmids obtained from searches guided by the Comprehensive Antibiotic Resistance Database. Among the 132 ISs identified within 10 kbp from the optrA gene in the plasmids, IS6 family genes were the most prevalent (86/132). Homologous gene arrays containing IS6 family genes were shared between different plasmids, especially between mobilizable and conjugative plasmids. All these indicated the central role of IS6 family genes in disseminating plasmid-borne optrA. Thirty-three of the 52 plasmids were harbored by Enterococcus faecalis found mainly in humans and animals. By Nanopore sequencing and inverse PCR, the potential of the enterococcal optrA to be transmitted from a mobilizable plasmid to a conjugative plasmid mediated by IS6 family genes was further confirmed in Enterococcus faecalis strains recovered from the effluents of anaerobic digestion systems for treating chicken manure. Our findings highlight the increased intercellular transfer abilities and dissemination risk of plasmid-borne optrA gene caused by IS-mediated intracellular mobility, and underscore the importance of routinely monitoring the dynamic genetic contexts of clinically important antibiotic resistance genes to effectively control this critical public health threat. KEY POINTS: • IS6 was prevalent in optrA-plasmids varying in intercellular transfer abilities. • Enterococcal optrA-plasmids were widespread among human, animal, and the environment. • IS6 elevated the dissemination risk of enterococcal optrA-plasmids.

Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma.

Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis-related gene prognostic signature for stomach adenocarcinoma (STAD) by systematic analysis of transcriptional profiles from The Cancer Genome Atlas (TCGA), GEO and a clinical cohort from our centre. We developed a predictive model based on three ferroptosis-related genes (CHAC1, NOX4 and HIF1A), gene expression data and corresponding clinical outcomes were obtained from the TCGA database, and the reliability of this model was verified with GSE15459 and 51 queues in our centre. ROC curve showed better predictive ability using the risk score. Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. The experimental results confirmed that NOX4 was upregulated and CHAC1 was downregulated in the STAD tissues compared with the normal stomach mucosal tissues (p < 0.05). In sum, the ferroptosis-related gene signature can accurately predict the outcomes of patients with STAD, providing valuable insights for personalized treatment. As the signature also has relevance to the immune characteristics, it may help improve the efficacy of personalized immunotherapy.

Identification and validation of the N6-methyladenosine RNA methylation regulator ZC3H13 as a novel prognostic marker and potential target for hepatocellular carcinoma.

N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify prognostic signature based on m6A methylation regulators for hepatocellular carcinoma (HCC) and provide candidate targets for HCC treatment. In this study, the expression levels, prognostic values, correlation with tumor grades and genetic variations of m6A-related genes in HCC were evaluated using bioinformatics analyses. Interestingly, the results show that methyltransferase zinc finger CCCH-type containing 13 (ZC3H13) was expressed at a significantly low level in HCC. Survival outcome analysis suggested that significant correlations existed between ZC3H13 downregulation and poor overall survival (OS) and poor recurrence-free survival (RFS) in HCC patients. Therefore, ZC3H13 was chosen for further experimental validation. The expression of ZC3H13 in HCC cell lines was investigated by western blotting. Knockdown of ZC3H13 significantly enhanced the migration and invasion of HCC cells, as demonstrated by wound healing and transwell assays. Moreover, upregulating ZC3H13 repressed the growth of xenograft tumors in vivo. Functional and pathway enrichment analyses indicated that ZC3H13 might be involved in transcriptional dysregulation or the JAK-STAT signaling pathway in cancer. Additionally, ZC3H13 expression was significantly correlated with lymphocytes and immunomodulators. Therefore, ZC3H13 is a promising candidate as a novel biomarker and therapeutic target for HCC.

5-Fluorouracil enhances the chemosensitivity of gastric cancer to TRAIL via inhibition of the MAPK pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to selectively trigger cancer cell apoptosis and can be used as a target for tumor therapy. However, gastric cancer cells are usually insensitive to TRAIL so reducing this drug resistance may improve the treatment of gastric cancer. In this study, we used Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) experiments to determine the effects of 5-fluorouracil (5-FU) and TRAIL on the proliferation of gastric cancer cells. An Annexin V/propidium iodide (PI) staining experiment was used to detect apoptosis, and Western blotting was used to analyze the expression levels of apoptosis-related proteins and mitogen-activated protein kinase (MAPK) pathway proteins. The antitumor effects of 5-FU and TRAIL were verified in vivo using a nude mouse tumorigenesis experiment, and a TUNEL assay was performed to evaluate apoptosis in tumor tissue from the nude mice. We found the combination of 5-FU and TRAIL had a greater inhibitory effect on the proliferation of gastric cancer cells than 5-FU or TRAIL alone both in vivo and in vitro. 5-FU enhanced TRAIL-induced gastric cancer cell apoptosis by inactivating the MAPK pathway. Overall, our analysis firstly provided new insights into the role of 5-FU in increasing sensitivity to TRAIL. 5-FU can be used as a sensitizer for TRAIL, and its administration is a potential strategy for the treatment of gastric cancer.

TRAIL promotes hepatocellular carcinoma apoptosis and inhibits proliferation and migration via interacting with IER3.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce substantial cytotoxicity in tumor cells but rarely exert cytotoxic activity on non-transformed cells. In the present study, we therefore evaluated interactions between TRAIL and IER3 via co-immunoprecipitation and immunofluorescence analyses, leading us to determine that these two proteins were able to drive the apoptotic death of hepatocellular carcinoma (HCC) cells and to disrupt their proliferative and migratory abilities both in vitro and in vivo. From a mechanistic perspective, we determined that TRAIL and IER3 were capable of inhibiting Wnt/ß-catenin signaling. Together, these results indicate that TRAIL can control the pathogenesis of HCC at least in part via interacting with IER3 to inhibit Wnt/ß-catenin signaling, thus indicating that this TRAIL/IER3/ß-catenin axis may be a viable therapeutic target in HCC patients.

Subunits of ARID1 serve as novel biomarkers for the sensitivity to immune checkpoint inhibitors and prognosis of advanced non-small cell lung cancer.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Biomarkers such as programmed death-ligand 1 (PD-L1), the tumor mutational burden (TMB) and the mismatch repair (MMR) status are used to predict the prognosis of ICIs therapy. Nevertheless, novel biomarkers need to be further investigated, and a systematic prognostic model is needed for the evaluation of the survival risks of ICIs treatment. METHODS: A cohort of 240 patients who received ICIs from the cBioPortal for Cancer Genomics was evaluated in this research. Clinical information and targeted sequencing data were acquired for analyses. The Kaplan-Meier plot method was used to perform survival analyses, and selected variables were then confirmed by a novel nomogram constructed by the "rms" package of R software. RESULTS: Seven percent of the NSCLC patients harbored ARID1A mutations, while 4% of the NSCLC patients harbored ARID1B mutations. Mutations in ARID1A and ARID1B were confirmed to be associated with sensitivity to ICIs. Patients harboring these mutations were found to have a better response to treatment (ARID1A: P = 0.045; ARID1B: P = 0.034) and prolonged progression-free survival (ARID1B: P = 0.032). Here, a novel nomogram was constructed to predict the prognosis of ICIs treatment. Elevation of the TMB, enhanced expression of PD-L1 and activation of the antigen presentation process and cellular immunity were found to be correlated with ARID1A and ARID1B mutations. CONCLUSION: ARID1A and ARID1B could serve as novel biomarkers for the prognosis and sensitivity to ICIs of advanced NSCLC.

Expression and function of transmembrane 4 superfamily proteins in digestive system cancers.

BACKGROUND: Although the medical level is constantly improving, cancer is still a major disease that threatens human health, and very effective treatments have not been found. In recent years, studies have found that four-transmembrane superfamily proteins are involved in multiple stages of tumorigenesis and development, but their expression and function in tumors have not been systematically studied. METHODS: We used the Oncomine database to analyze the mRNA expression levels of TSPAN family in various cancers. Then differentially expressed genes were screened out and verified by liver cancer, colorectal cancer, and gastric cancer cells by q-PCR and Western blot analysis. CCK8 and EDU analysis are used to detect cell proliferation, Cell wound scrape assay and Cell invasion assay are used to analyze cell invasion and metastasis. Nude tumor formation test used to verify the tumor suppressive effect of TSPAN7 in vivo. RESULTS: Differential analysis of 33 TSPAN proteins revealed that a total of 11 proteins showed differential expression in 10% of independent analyses, namely TSPAN1, TSPAN3, TSPAN5, TSPAN6, TSPAN7, TSPAN8, TSPAN13, TSPAN25, TSPAN26, TSPAN29, TSPAN30. TSPAN7 is the only four-transmembrane protein with reduced expression in three types of digestive tract tumors, so we chose TSPAN7 to be selected for cellular and molecular level verification. We found that compared with normal cells, the expression of TSPAN7 in liver cancer cells was significantly reduced, while the expression of gastric and colon cancer was not significantly different from that of normal cells. In addition, we also found that the high expression of Tspan7 not only inhibited the proliferation of HCC-LM3 cells, but also inhibited its invasion and metastasis. CONCLUSIONS: Our study evaluated the expression and function of the TSPANs family in digestive cancers and explored TSPAN7 in hepatoma cells in detail. We found some members of the TSPAN family show significant expression differences between cancer and normal tissues, of which TSPAN7 may be a potential biomarker for liver cancer.

TSPAN9 suppresses the chemosensitivity of gastric cancer to 5-fluorouracil by promoting autophagy.

BACKGROUND: The issue of drug resistance in gastric cancer has attracted global attention. TSPAN9, a 4-transmembrane protein that plays an important role in tumor progression and signal transduction, has been found to be closely related to tumor invasion, metastasis, and autophagy. METHODS: Immunoblotting was used to evaluate TSPAN9 expression in parental and drug-resistant gastric cancer cells. Functional assays, such as the CCK-8 assay, were used to detect the proliferation of gastric cancer cells and the response of TSPAN9 to 5-fluorouracil (5-FU). Western blotting was used to analyze the expression of constituents of the PI3K/AKT/mTOR-mediated autophagy pathway induced by TSPAN9. Coimmunoprecipitation was performed to assess the specific mechanism by which TSPAN9 affects the PI3K pathway. RESULTS: We demonstrated that TSPAN9 is overexpressed in 5-FU-resistant cells compared to parental cells. 5-FU-mediated inhibition of cell proliferation can be significantly restored by increasing TSPAN9 expression, and inhibiting this expression in drug-resistant cells can restore the sensitivity of the cells to 5-FU. In addition, TSPAN9 also significantly promoted autophagy in gastric cancer cells in vitro. Further studies indicated that TSPAN9 downregulates the expression of PI3K and proteins associated with PI3K-mediated autophagy. In addition, TSPAN9 interacts with PI3K and inhibits its catalytic activity. CONCLUSION: The current study reveals the important role of TSPAN9 in drug resistance to 5-FU in gastric cancer. It also provides a new target to clinically address drug-resistant gastric cancer and will contribute to the treatment strategy of this disease.

PGC-1ß cooperating with FOXA2 inhibits proliferation and migration of breast cancer cells.

BACKGROUND: Breast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics. Peroxisome gamma coactivator-1ß (PGC-1ß) has long been identified to be involved in this type of tumorigenesis. However, the mechanisms of PGC-1ß in human breast cancer have not been fully understood and the function requires to be further elucidated. METHODS: mRNA and protein expression of PGC-1ß and FOXA2 in breast cancer tissues and cell lines were determined by qRT-PCR and Western Blotting, respectively. To further visualize the expression and localization of PGC-1ß and FOXA2, immunochemistry and immunofluorescence staining methods were employed. The effect of PGC-1ß and FOXA2 on cell proliferation and migration were evaluated by CCK8, clone formation, transwell and wound-healing assays, which has been done either with stable PGC-1ß knockdown or FOXA2 overexpression in vitro. Xenografts model of nude mice were used to evaluate tumor growth in vivo. In addition, proteins expression of the PI3K-AKT-mTOR signaling pathway involved in the regulation of breast cancer were detected by Western Blotting. RESULTS: Our results showed that PGC-1ß was upregulated and FOXA2 was downregulated in breast cancer tissues and cell lines. These two proteins can be interacted with each other to form the complex. Also, we found the combination of PGC-1ß interference with FOXA2 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth in vivo. We further identified that PGC-1ß and FOXA2 strongly correlated with the PI3K-AKT-mTOR signaling pathway, and they exerted their biological functions by activating this pathway. CONCLUSIONS: We demonstrated that downregulation of PGC-1ß combined with overexpression of FOXA2 obviously inhibited the function of breast cancer cells through regulating the PI3K-AKT-mTOR pathway.

TSPAN9 and EMILIN1 synergistically inhibit the migration and invasion of gastric cancer cells by increasing TSPAN9 expression.

BACKGROUND: Globally, the incidence and mortality rates of gastric cancer are high, and its poor prognosis is closely related to tumor recurrence and metastasis. Therefore, the molecular mechanisms associated with the migration and invasion of gastric cancer cells are important for gastric cancer treatment. Previously, TSPAN9 has been reported to inhibit gastric cancer cell migration; however, the underlying molecular mechanism remains unclear. METHODS: Human gastric adenocarcinoma cell lines, SGC7901 and AGS, were cultured in vitro. TSPAN9 expression was determined by RT-PCR, western blot analysis, and immunohistochemistry in gastric cancer and tumor-adjacent tissues. Following the over-expression and knockdown of TSPAN9, wound healing and cell invasion assays were performed and EMT-related protein expression was evaluated to analyze the invasion and migration of gastric cancer cells. TSPAN9 expression and the invasion and metastasis of gastric cancer cells were observed by the functional assays following EMILIN1 over-expression. RESULTS: Inhibiting TSPAN9 expression significantly promoted the migration and invasion of gastric cancer cells. In addition, immunofluorescence co-localization and co-immunoprecipitation analysis revealed closely related expression of EMILIN1 and TSPAN9. Moreover, EMILIN1 can synergistically boost the tumor suppressive effect of TSPAN9, which may be produced by promoting TSPAN9 expression. CONCLUSIONS: We have demonstrated that EMILIN1 induces anti-tumor effects by up-regulating TSPAN9 expression in gastric cancer. Hence, membrane proteins TSPAN9 and EMILIN1 may represent novel therapeutic targets for the treatment of gastric cancer.

FOXO3 Inhibits Human Gastric Adenocarcinoma (AGS) Cell Growth by Promoting Autophagy in an Acidic Microenvironment.

BACKGROUND/AIMS: Previous studies have shown that FOXO3, a member of the forkhead box O (FOXO) family, regulates autophagy in various cells. To date, whether the induction of autophagy in gastric cancer (GC) cells is triggered by an acidic microenvironment is unclear. Little is known about the relationship between FOXO3 and acidic microenvironments in GC. The aims of our study were to investigate the roles of FOXO3 and the acidic microenvironment in autophagy and to determine how FOXO3 and the acidic microenvironment regulate GC cell growth through autophagy. METHODS: We cultured human gastric adenocarcinoma (AGS) cells in media with different pH values in vitro, transfected the cells with FOXO3a plasmids and then detected autophagy in the cells under different conditions. In addition, we also performed cell counting kit 8 (CCK8), wound and cell invasion assays to test cell viability and invasion, respectively. We employed real-time PCR, western blotting and mRFP-GFP-LC3 vectors to detect the expression of various autophagy indicators. RESULTS: We found that cells treated with FOXO3 and exposed to an acidic microenvironment displayed suppressed growth compared with control cells. We also found that the protein expression levels of several autophagy makers, such as LC3I, LC3II and Beclin-1, were higher in FOXO3 plasmid-transfected AGS cells cultured in an acidic microenvironment than in control cells, while P62 protein expression levels were clearly decreased in FOXO3 plasmid-transfected cells compared with control cells. Moreover, we observed autophagic flux in AGS cells overexpressing FOXO3 and exposed to low pH conditions. CONCLUSION: These findings suggest that FOXO3 inhibits AGS cell growth by promoting autophagy in an acidic microenvironment. Furthermore, the results showed that anticancer therapies targeting FOXO3 and low pH conditions may be useful in the treatment of GC.

N-Acetyl-Glucosamine Sensitizes Non-Small Cell Lung Cancer Cells to TRAIL-Induced Apoptosis by Activating Death Receptor 5.

BACKGROUND/AIMS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer agent due to its selective toxicity. However, many human non-small cell lung cancer (NSCLC) cells are partially resistant to TRAIL, thereby limiting its clinical application. Therefore, there is a need for the development of novel adjuvant therapeutic agents to be used in combination with TRAIL. METHODS: In this study, the effect of N-acetyl-glucosamine (GlcNAc), a type of monosaccharide derived from chitosan, combined with TRAIL was evaluated in vitro and in vivo. Thirty NSCLC clinical samples were used to detect the expression of death receptor (DR) 4 and 5. After GlcNAc and TRAIL co-treatment, DR expression was determined by real-time PCR and western blotting. Cycloheximide was used to detect the protein half-life to further understand the correlation between GlcNAc and the metabolic rate of DR. Non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to detect receptor clustering, and the localization of DR was visualized by immunofluorescence under a confocal microscope. Furthermore, a co-immunoprecipitation assay was performed to analyze the formation of death-inducing signaling complex (DISC). O-linked glycan expression levels were evaluated following DR5 overexpression and RNA interference mediated knockdown. RESULTS: We found that the clinical samples expressed higher levels of DR5 than DR4, and GlcNAc co-treatment improved the effect of TRAIL-induced apoptosis by activating DR5 accumulation and clustering, which in turn recruited the apoptosis-initiating protease caspase-8 to form DISC, and initiated apoptosis. Furthermore, GlcNAc promoted DR5 clustering by improving its O-glycosylation. CONCLUSION: These results uncovered the molecular mechanism by which GlcNAc sensitizes cancer cells to TRAIL-induced apoptosis, thereby highlighting a novel effective agent for TRAIL-mediated NSCLC-targeted therapy.

Short- and long-term outcomes of laparoscopic hepatectomy in elderly patients with hepatocellular carcinoma.

PURPOSE: To compare short- and long-term outcomes of laparoscopic hepatectomy (LH) in elderly and non-elderly patients with hepatocellular carcinoma (HCC). METHODS: Clinical and follow-up data of patients with HCC who underwent LH in our Institute from January 2011 to December 2016 were retrospectively analyzed. The patients were divided into elderly (48 cases, 70 years old or older) or non-elderly group (97 cases, <70 years) according to their age at the time of operation. The short- and long-term outcomes of both groups were compared. RESULTS: The Charlson comorbidity index and American Society of Anesthesiologists (ASA) score of patients in the elderly group were higher than those of patients in the nonelderly group, and the rates of hepatitis virus infection and cirrhosis in the elderly group were lower than those in the non-elderly group. The rest of the preoperative data showed no statistical significance. Short-term outcomes, including operation time, intraoperative blood loss, transfer rate, length of hospital stay, incidence of complications and their severity within 30 days after surgery, and pathological findings, showed no significant difference between the elderly and non-elderly groups. Recurrence rates, treatment of the recurrence, overall survival (OS) rates, and disease-free survival (DFS) rates were similar in both groups. Multivariate analysis showed that age was not an independent predictor of OS and DFS. CONCLUSIONS: LH in elderly patients can achieve short- and long-term outcomes similar to those in non-elderly patients with liver cancer. Old age is not a contraindication for LH in patients with HCC.

Association of Toll-like receptor 3 gene polymorphism with the severity of enterovirus 71 infection in Chinese children.

Enterovirus 71 (EV71) infection has become one of the major threats to children globally in recent years. Toll-like receptor 3 (TLR3) plays an essential role in host defense against EV71 infection. This study was designed to assess the possible association between the TLR3c.1377C/T polymorphism and disease severity in Chinese children with EV71 infection. The TLR3c.1377C/T gene polymorphism was identified in EV71-infected patients (n = 177), including mild cases (n = 99) and severe cases (n = 78) as well as healthy controls (n = 225), using improved multiplex ligation detection reaction (iMLDR) technology. Serum levels of IFN-γ and IL-4 were measured using enzyme-linked immunosorbent assays. The presence of the TT genotype (p = 0.030) and the T allele (OR, 1.8; 95% CI, 1.2-2.8; p = 0.010) was significantly more frequent in severe cases. The plasma levels of IFN-γ and the IFN-γ/IL-4 ratio were significantly lower with the TT (102.0 ± 24.2 pg/mL, p < 0.01 and 14.2 ± 2.8, p < 0.001) and CT genotypes (114.1 ± 26.2 pg/mL, p < 0.05 and 18.0 ± 3.1, p < 0.001) than with the CC genotype (135.5 ± 36.8 pg/mL and 24.9 ± 4.7), but the plasma levels of IL-4 with the TT (7.3 ± 1.7 pg/mL, p < 0.01) and CT genotypes (6.4 ± 1.3 pg/mL, p < 0.05) were significantly higher than with the CC genotype (5.5 ±1.3 pg/mL). These findings suggest that the TLR3c.1377T allele is associated with susceptibility to severe EV71 infection in Chinese children.

miR-155 Promotes ox-LDL-Induced Autophagy in Human Umbilical Vein Endothelial Cells.

As an evolutionarily conserved metabolic process, autophagy is involved in the process of atherosclerosis (AS). MicroRNA-155 (miR-155), a multifunctional miRNA, plays an important role in many physiological and pathological conditions, including AS and autophagy. However, the effect of miR-155 on the regulation of autophagy in endothelial cells has not been reported to date. Therefore, the objective of our study was to investigate the role of miR-155 in autophagy induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs). Our results demonstrated that ox-LDL induced autophagy in HUVECs and increased the expression of miR-155 significantly. Overexpression of miR-155 improved autophagic activity, whereas low expression of miR-155 inhibited autophagic activity. Therefore, the data demonstrated that miR-155 has a modulating effect on the autophagy of vascular endothelial cells.

MiR-200b expression in breast cancer: a prognostic marker and act on cell proliferation and apoptosis by targeting Sp1.

MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells. In the present study, we investigated the roles and mechanisms of miR-200b in human breast cancer (BC). MiR-200b expression was carried out by qRT-PCR in human BC cell lines and clinical samples and the prognostic potential of miR-200b expression was further evaluated. In vitro, effects of miR-200b on BC cell proliferation, apoptosis and cell cycle distribution were tested by CCK-8 kit, flow cytometric analysis respectively. Luciferase assay and Western blot analysis were performed to validate the potential targets of miR-200b after the preliminary screening by employing open access software. We found that miR-200b was significantly down-regulated in both BC tissues and cell lines. The low expression of miR-200b was correlated with late TNM stage, negative oestrogen receptor and positive HER-2 status. Multivariate analysis showed that miR-200b expression was an independent prognostic predictor for BC patients. Integrated analysis identified Sp1 as a direct and functional target of miR-200b. Knockdown of Sp1 inhibited cell proliferation, induce apoptosis and act on cell cycle resembling that of miR-200b high expression. Our data demonstrates that miR-200b has potential to serve as prognostic biomarker and tumour suppressor for BC patients. As a direct and functional target of miR-200b, Sp1 and miR-200b both could be an exciting target for BC treatment strategy.

Overexpression of CUGBP1 is associated with the progression of non-small cell lung cancer.

The multifunctional RNA-binding protein CUGBP1 regulates multiple aspects of nuclear and cytoplasmic messenger RNA (mRNA) processing, including splicing, stabilization, and translation of mRNAs. Previous studies have shown that CUGBP1 is overexpressed in non-small-cell lung cancer (NSCLC) tissues, but the pathological functions of CUGBP1 in tumorigenesis and development are unknown. Here, we provide the first evidence demonstrating the clinicopathological significance of CUGBP1 in NSCLC. Using immunohistochemistry, the levels of CUGBP1 expression in NSCLC tissues and adjacent non-cancerous tissues were examined and determined to be associated with differentiation. Short hairpin RNA-induced downregulation of CUGBP1 promoted apoptosis and decreased proliferation in the A549 NSCLC cell line. Moreover, Western blot analysis indicated that the depletion of CUGBP1 increased the protein levels of cyclin D1, BAD, BAX, Jun D, and E-cadherin, while the cyclin B1 level decreased. Knockdown of CUGBP1 decreased ß-catenin and vimentin levels and increased E-cadherin expression, suggesting that CUGBP1 may contribute significantly to epithelial to mesenchymal transition (EMT) progression. These results demonstrate the importance of CUGBP1 in the biological and pathological functions of NSCLC and indicate its potential as a therapeutic target for NSCLC.

[Surgical treatment of intracranial aneurysms via the pterional keyhole approach].

OBJECTIVE: Modify the pterional approach for intracranial aneurysms clipping with minimally invasive concept to reduce the risk of iatrogenic surgical trauma. METHODS: A 4.0 cm skin incision was made along the temporal hairline and centered on the pterion, temporal muscle was incised along the sylvian fissure.A bone flap with 2.0 to 2.5 cm in diameter was milled after a bone hole was drilled just on the sphenoid ridge, which was drilled off as needed then.Aneurysms were exposed after dissection of sylvian fissure and cistern, as well as cerebrospinal fluid releasing.A total of 123 cases with 140 intracranial aneurysms were treated surgically via the pterional keyhole approach, including 6 large aneurysms, 4 giant aneurysms, and 17 cases with multiple aneurysms (34 aneurysms). Of 3 cases with bilateral aneurysms, 2 were treated via bilateral approach as well as 1 via unilateral approach. Contralateral approach was used in 1 case with ophthalmic artery aneurysm, which pointed medial. Concomitant intracranial tumors were removed simultaneously in 2 cases, and one of them was diagnosed with middle cerebral artery aneurysm and tuberculum sellae meningioma, the other one with posterior communicating artery aneurysm and middle cranial fossa menigioma. RESULTS: Of the 140 aneurysms, 139 aneurysms were clipped and 1 was trapped.Postoperative image showed 4 cases had residual of aneurysm neck. 3 cases had incomplete dysfunction of oculomotor nerve and 1 had mild hemiplegia after surgery and recovered eventually. 4 cases presented with aggravated disturbance of consciousness, of whom 3 cases were caused by ischemia and 1 by brain edema.Unusual ipsilateral hemiplegia occurred in 1 case in Hunt&Hess grade IV, which caused by contralateral vasospasm. Postoperative courses in other cases were uneventful. CONCLUSIONS: As a minimally invasive and effective approach, the pterional keyhole approach is applicable to intracranial aneurysms clipping for patients without any necessary for decompressive craniectomy. Surgical related complications and operative duration can be reduced significantly.

FOXM1 mediates resistance to docetaxel in gastric cancer via up-regulating Stathmin.

Docetaxel is commonly used as an effective chemotherapeutic drug for gastric cancer patients recently. With the increasing emergence of docetaxel resistance nowadays, identification of suitable biomarkers for predicting chemosensitivity to docetaxel may be a key role for improving therapeutic effects for gastric cancer patients. In this study, we investigated the correlation between the expression of transcription factor forkhead box protein M1 (FOXM1) and chemotherapy response to docetaxel in gastric cancer, the possible mechanism for which was further explored. As a result, FOXM1 overexpression was shown to mediate resistance to docetaxel in gastric cancers. It altered microtubule dynamics to protect tumour cells from docetaxel-induced apoptosis. Mechanistic investigations revealed that tubulin-destabilizing protein Stathmin, which mediated docetaxel resistance in FOXM1-silenced gastric cancer cells, is a direct down-stream target of FOXM1, whereas another microtubule dynamics protein mitotic centromere-associated kinesin (MCAK), shown to be related to docetaxel resistance in gastric cancer cells, is not associated with FOXM1 expression significantly. These results were further provided by immunohistochemical analysis, indicating that FOXM1 and Stathmin expression levels were correlated in 103 post-operational gastric cancer specimens. Moreover, when we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers was found to be reversed, simultaneously with the down-regulation of FOXM1 and Stathmin. Therefore, FOXM1 can be a useful marker for predicting and monitoring docetaxel response. Through the inhibition of FOXM1, docetaxel resistance can be reversed, and thus FOXM1 could be a new therapeutic target in docetaxel-resistant gastric cancer.

[Heart rate variability study based on a novel RdR RR Intervals Scatter Plot].

On the basis of Poincare scatter plot and first order difference scatter plot, a novel heart rate variability (HRV) analysis method based on scatter plots of RR intervals and first order difference of RR intervals (namely, RdR) was proposed. The abscissa of the RdR scatter plot, the x-axis, is RR intervals and the ordinate, y-axis, is the difference between successive RR intervals. The RdR scatter plot includes the information of RR intervals and the difference between successive RR intervals, which captures more HRV information. By RdR scatter plot analysis of some records of MIT-BIH arrhythmias database, we found that the scatter plot of uncoupled premature ventricular contraction (PVC), coupled ventricular bigeminy and ventricular trigeminy PVC had specific graphic characteristics. The RdR scatter plot method has higher detecting performance than the Poincare scatter plot method, and simpler and more intuitive than the first order difference method.