Intervention time decides the status of autophagy, NLRP3 activity and apoptosis in macrophages induced by ox-LDL.

BACKGROUND: It has been determined through extensive studies that autophagy, the Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and apoptotic responses in macrophages jointly contribute to atherogenesis and its development in the presence of lipid abnormalities. Few studies have investigated in full-scale if the intervention time for lipids abnormality or NLRP3 activation have a significant effect on autophagy, NLRP3 or the apoptotic status in macrophages. METHODS: Human THP-1 monocyte-derived macrophages were established by challenging THP-1 monocytes with 80 µg/ml oxidized low-density lipoprotein (ox-LDL) for specific durations. Foam cell formation was observed by Oil Red O (ORO) staining. Western blots were employed to determine protein expression. Transmission electron microscope (TEM) and immunofluorescence microscopy were applied to observe the autophagic status of cells. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). RESULTS: The cells were treated with ox-LDL for 12 h and 36 h, which were considered to represent early and advanced stages of atherogenesis for this study. The results showed that inhibition of ox-LDL phagocytosis by cytochalasin D in the early stage improved autophagic status, reduced NLRP3 activation and the apoptotic response significantly. In contrast, cytochalasin D had little effect on blocking the detrimental effect of ox-LDL at the advanced stage. Moreover, the changes in autophagy, apoptosis and NLRP3 expression after treatment with small interfering (si) RNA targeting NLRP3 in the early and advanced stages of atherogenesis were consistent with the above data. CONCLUSIONS: Interventions against lipid disorders or inflammatory reactions in the early or advanced stages of atherogenesis may have different results depending on when they are applied during the process of atherosclerotic pathogenesis. These results may help improve therapeutic strategies for atherosclerosis prevention. Furthermore, a healthy lifestyle should still be recommended as the most important and inexpensive measure to prevent atherogenesis.

CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.

Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.

CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502-5p/KRAS and IGF2BP2/Myc axes.

BACKGROUND: Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. METHODS: High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502-5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. RESULTS: CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502-5p and interacting with IGF2BP2. CONCLUSION: Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

Breast lesions excised via vacuum-assisted system: could we get any clues for B3 lesions before excision biopsy?

BACKGROUND: The purpose of this study was to determine the validity of the ultrasound features as well as patient characteristics assigned to B3 (uncertain malignant potential) breast lesions before vacuum-assisted excision biopsy (VAEB). METHODS: This study population consisted of 2245 women with breast-nodular abnormalities, which were conducted ultrasound-guided VAEB (US-VAEB). Patient's clinical and anamnestic data and lesion-related ultrasonic feature variables of B3 captured before US-VAEB were compared with those of benign or malignant cases, using histopathological results as a benchmark. RESULTS: The proportions of benign, B3 and malignant breast lesions diagnosed post-US-VAEB were 88.5, 8.2 and 3.4% respectively. B3 high frequent occurred in BI-RADS-US grade 3 (7.7%), grade 4a (11.0%) and grade 4b (9.1%). The overall malignancy underestimation rate of B3 was 4.4% (8/183). Malignant lesions were found mostly in the range of BI-RADS grade 4b (27.3%), grade 4c (33.3%) and grade 5 (100%). Multivariate binary logistic regression analyses (B3 vs benign) showed that non-menopausal patients (95% CI 1.628-8.616, P = 0.002), single (95% CI 1.370-2.650, P = 0.000) or vascularity (95% CI 1.745-4.150, P = 0.000) nodules in ultrasonic features were significant risk factors for B3 occurrences. In addition, patients elder than 50 years (95% CI 3.178-19.816, P = 0.000), unclear margin (95% CI 3.571-14.119, P = 0.000) or suspicious calcification (95% CI 4.010-30.733, P = 0.000) lesions were significantly associated with higher risks of malignant potentials for B3 cases (malignant vs B3). CONCLUSION: The results of this study indicate that ultrasound findings and patients' characteristics might provide valuable information for distinguishing B3 lesions from benign breast abnormalities before VAEB, and help to reduce malignancy underestimation of B3.

Development and validation of a survival nomogram for patients with Siewert type II/III adenocarcinoma of the esophagogastric junction based on real-world data.

BACKGROUND: The clinical staging systems for adenocarcinoma of the esophagogastric junction (AEG) are controversial. We aimed to propose a prognostic nomogram based on real-world data for predicting survival of Siewert type II/III AEG patients after surgery. METHODS: A total of 396 patients with Siewert type II/III AEG diagnosed and treated at the Center for Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, from June 2009 to June 2017 were enrolled. The original data of 29 variables were exported from the electronic medical records system. The nomogram was established based on multivariate Cox regression coefficients, and its performance was measured using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curve analysis and calibration curve. RESULTS: A nomogram was constructed based on nine variables. The C-index for overall survival (OS) prediction was 0.76 (95% CI, 0.72 to 0.80) in the training cohort, in the validation-1 cohort was 0.79 (95% CI, 0.72 to 0.86), and 0.73 (95% CI, 0.67 to 0.80) in the validation-2 cohort. Time-dependent ROC curves and calibration curves in all three cohorts showed good prognostic predictive accuracy. We further proved the superiority of the nomogram in predictive accuracy for OS to pathological TNM (pTNM) staging system and other independent prognostic factors. Kaplan-Meier survival curves demonstrated the pTNM stage, grade of differentiation, positive lymph node, log odds of positive lymph node and organ invasion were prognostic factors with good discriminative ability. CONCLUSION: The established nomogram demonstrated a more precise prognostic prediction for patients with Siewert type II/III AEG.

The Association between the Participation of Quality Control Circle and Patient Safety Culture.

Promoting patient safety culture (PSC) is a critical issue for healthcare providers. Quality control circles program (QCCP) can be used as an effective tool to foster long-lasting improvements on the quality of medical institution. The effect of QCCP on PSC is still unknown. This was a retrospective study conducted with matching data. A safety attitudes questionnaire (SAQ) was used for the evaluation of PSC. The association between all scores of six subscales of SAQ and the participation QCCP were analyzed with both the Mann-Whitney and Kruskal-Wallis tests. A total of 2718 valid questionnaires were collected. Most participants of QCCP were females (78.9%), nurses (52.6%), non-supervisors (92.2%), aged <40 years old (64.8%), degree of specialist or university graduates (78%), and with work experience of <10 years (61.6%). Of all participants, the highest scores were in the dimension of safety climate (74.11 ± 17.91) and the lowest scores in the dimension of working conditions (68.90 ± 18.84). The participation of QCCP was associated with higher scores in four dimensions, namely: teamwork climate (p = 0.006), safety climate (p = 0.037), perception of management (p = 0.009), and working conditions (p = 0.015). The participation or not of QCCP had similar results in the dimension of job satisfaction and stress recognition. QCCP was associated with SAQ in subjects with the following characteristics: female, nurse, non-supervisor, aged >50 years old, higher education degrees and with longer working experiences in the hospital. In this first study on the association between each dimension of SAQ and the implementation of QCCP, we found that QCCP interventions were associated with better PSC. QCCP had no benefits in the dimensions of job satisfaction and stress recognition.

Long Non-coding RNA RP11-480I12.5 Promotes the Proliferation, Migration, and Invasion of Breast Cancer Cells Through the miR-490-3p-AURKA-Wnt/ß-Catenin Axis.

Background: RP11-480I12. 5 is a newly identified long non-coding RNA (lncRNA) that has never been studied in breast cancer (BC). The biological function of RP11-480I12.5 in breast carcinoma and its underlying mechanism are still unknown. Methods: We scanned The Cancer Genome Atlas (TCGA) database and identified RP11-480I12.5 as one of the most dysregulated lncRNAs. The level of RP11-480I12.5 was assessed in BC tissue samples and BC cell lines. The prognostic value of RP11-480I12.5 expression was assessed using the Kaplan-Meier method. The biological influence of RP11-480I12.5 on BC cell lines was studied using proliferation and Transwell migration and invasion assays. Results: RP11-480I12.5 expression was upregulated in data from both the TCGA database and our own database. Moreover, Kaplan-Meier and Cox proportional hazard analyses indicated that high RP11-480I12.5 expression was related to poor overall survival. Moreover, RP11-480I12.5 promoted the proliferation, migration, and invasion of BC. RP11-480I12.5 promoted the expression of AURKA and the activation of the downstream Wnt/ß-catenin pathway by sponging the microRNA (miRNA) miR-490-3p. Conclusion: Taken together, our results indicate that RP11-480I12.5 is associated with tumor progression in BCs. Our findings indicate that the lncRNA RP11-480I12.5 promotes the proliferation, migration, and invasion of BC cells through the miR-490-3p-AURKA-Wnt/ß-catenin axis, which may serve as a therapeutic target in the future.

BTB domain-containing 7 predicts low recurrence and suppresses tumor progression by deactivating Notch1 signaling in breast cancer.

PURPOSE: BTB domain-containing 7 (BTBD7) has been found to regulate epithelial tissue remodeling and branched organ formation and has been reported to modulate the biological behavior of several cancers. However, its role in breast cancer has not been identified. This study investigated the biological role and prognostic value of BTBD7 in breast cancer. METHODS: We identified the BTBD7 expression pattern using the GENT2 database and assessed its expression in breast cancer tissue and cell lines using quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry. We conducted a clinical relevance and survival analysis on a cohort of 121 breast cancer cases from our follow-up and validated it in a Kaplan-Meier plotter. The gain-loss effect of BTBD7 on cell proliferation, invasion, and migration was detected in vitro. We employed a xenograft mouse metastatic model for in vivo validation and performed a Cignal Finder Cancer 10-Pathway Reporter Array, western blot, immunofluorescence, Cell Counting Kit-8, and transwell invasion/migration assays to analyze the potential mechanism. RESULTS: BTBD7 was downregulated in human breast cancer cell lines and tissues. Decreased BTBD7 expression correlated with a positive lymph node status, lymphovascular invasion, and TNM stage, while high BTBD7 expression correlated with low breast cancer recurrence. BTBD7 suppressed cell proliferation, invasion/migration, and tumor metastasis in breast cancer. The mechanism studied suggested that the inhibitory role of BTBD7 was through the deactivation of Notch1 signaling in breast cancer. CONCLUSION: BTBD7 suppresses tumor progression, and its high expression correlates with low recurrence in breast cancer.

Mitochondrial fission regulator 2 (MTFR2) promotes growth, migration, invasion and tumour progression in breast cancer cells.

INTRODUCTION: Mitochondrial fission regulator 2 (MTFR2) belongs to the MTFR family, and 2 isoforms of MTFR2 are produced by alternative splicing. The role of MTFR2 in breast cancer (BC) remains unknown. RESULTS: MTFR2 was upregulated in BC tissues and was strongly associated with tumor characteristics. Moreover, Kaplan-Meier and Cox proportional hazards analyses indicated that high MTFR2 expression was related to poor overall survival. In addition, the capacity for migration and invasion decreased in two BC cell lines after knockdown of MTFR2. The epithelial-mesenchymal transition pathway was inhibited in MTFR2-silenced cells. MTFR2 can switch glucose metabolism from OXPHS to glycolysis in a HIF1α- and HIF2α-dependent manner. CONCLUSION: Taken together, our results indicate that increased expression of MTFR2 is associated with tumour progression in breast cancer cells through switching glucose metabolism from OXPHS to glycolysis in a HIF1α- and HIF2α-dependent manner. MATERIALS AND METHODS: We obtained data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to analyse MTFR2 expression in BC. The prognostic value of MTFR2 expression was assessed using the Kaplan-Meier method. The biological influence of MTFR2 on BC cell lines was studied using proliferation, Transwell migration, invasion and mitochondrial function assays.

Home-based cardiac rehabilitation improves quality of life, aerobic capacity, and readmission rates in patients with chronic heart failure.

BACKGROUND: Exercise tolerance and cardiac output have a major impact on the quality of life (QOL) of patients experiencing heart failure (HF). Home-based cardiac rehabilitation can significantly improve not only exercise tolerance but also peak oxygen uptake ((Equation is included in full-text article.)peak), and the QOL in patients with HF. The aim of this prospective study was to evaluate the beneficial effects of home-based cardiac rehabilitation on the quality of medical care in patients with chronic HF. METHODS: This study was a randomized prospective trial. HF patients with a left ventricular ejection fraction (LVEF) of less than 50% were included in this study. We randomly assigned patients to the control group (n = 18) and the interventional group (n = 19). Within the interventional group, we arranged individualized rehabilitation programs, including home-based cardiac rehabilitation, diet education, and management of daily activity over a 3-month period. Information such as general data, laboratory data, Cardiopulmonary Exercise Test (CPET) results, Six-minute Walk Test (6MWT) results, and the scores for the Minnesota Living with Heart Failure Questionnaire (MLHFQ) before and after the intervention, was collected from all patients in this study. RESULTS: Patients enrolled in the home-based cardiac rehabilitation programs displayed statistically significant improvement in (Equation is included in full-text article.)peak (18.2 ±â€Š4.1 vs 20.9 ±â€Š6.6 mL/kg/min, P = .02), maximal 6-Minute Walking Distance (6MWD) (421 ±â€Š90 vs 462 ±â€Š74 m, P = .03), anaerobic threshold (12.4 ±â€Š2.5 vs 13.4 ±â€Š2.6 mL/kg/min, P = .005), and QOL. In summary, patients receiving home-based cardiac rehabilitation experienced a 14.2% increase in (Equation is included in full-text article.)peak, a 37% increase in QOL score, and an improvement of 41 m on the 6MWD test. The 90-day readmission rate for patients reduced to 5% from 14% after receiving cardiac rehabilitation. CONCLUSION: Home-based cardiac rehabilitation offered the most improved results in functional capacity, QOL, and a reduced the rate of readmission within 90 days.

Over expression of GPR30, indicating poor prognosis and promoting proliferation, upregulates Beclin-1 expression via p38MAPK signaling in esophageal squamous cell carcinoma progression.

BACKGROUND: Beclin-1 and GPR30, both very important proteins, have been associated with tumor development. In our pre-experiment, the co-expression of GPR30 and Beclin-1 was observed in esophageal squamous cell carcinoma (ESCC), an observation not reported in other studies. The aim of our research was to investigate the relationship of these two proteins in the further progression of ESCC. METHODS: The over expression of GPR30 and Beclin-1 proteins was observed and confirmed by immunohistochemistry and immunofluorescence arrays. By interfering with GPR30 and p38 MAPK expression in EC-109, KYSE510, and KYSE3 cell lines, MTT and a scratch wound healing assay were used to investigate the impact of the GPR30 protein on the proliferative and migrative abilities of ESCC cells. A co-immunoprecipitation assay was used to observe the interaction between the p38 MAPK and Beclin-1 proteins; meanwhile, at a different time, in each group, the GPR30, MAPK, p ERK1/2, p38 MAPK, and Beclin-1 proteins were analyzed. The correlation between GPR30, Beclin-1 expression levels, and the clinical characteristics were evaluated by Mann-Whitney and chi-square tests. Using Kaplan-Meier plots and the Cox proportional hazard model analysis, we determined overall survival (OS) and progression free survival (PFS). RESULTS: GPR30 and Beclin-1 were over expressed significantly in ESCC (both p=0.0000) and were distributed into cytoplasms the most (the former p=0.0223, latter p=0.0018). In contrast to the non-agonist group, the abilities of GPR30 in promoting cell proliferation and metastasis were observed in the agonist group, and the effects could be blocked by p38MAPK inhibitors. In further assays, GPR30 agonists, via binding to GPR30, up-regulated Beclin-1, MAPK, and p38 MAPK expression, and Beclin-1 expression was reversed in the p38MAPK inhibitor group. In the GPR30 agonist group, an interaction between p38MARK and Beclin-1 was observed, but no similar results were observed in the non-agonist group. The high expression of both GPR30 and Beclin-1 was observed with p-stage and pT advancing (both p<0.0001). In a Kaplan-Meier analysis, compared to GPR30's negative expression, high expression identified a group of patients with the shortest overall survival (OS, p=0.0072) and progression free survival (PFS, p=0.0074). The Cox proportional hazard models revealed that they predicted a short time to OS (p=0.0125). CONCLUSION: Over expression of GPR30 up-regulated Beclin-1 expression and indicated a poor prognosis and may promote ESCC development via p38 MAPK in ESCC progression.

Up-regulation of Wnt7b rather than Wnt1, Wnt7a, and Wnt9a indicates poor prognosis in breast cancer.

Aberrant activation of Wnt/ß-catenin signaling is one of the most frequent abnormalities in human cancer, including breast cancer. The prognostic value of Wnt ligands has never been fully characterized. In this study, we focused on four Wnt ligands, namely Wnt1, Wnt7a, Wnt7b and Wnt9a, which were commonly studied and found pivotal in Wnt/ß-catenin signaling, but seldom explored for their prognostic value. We investigated the expression of Wnt1, Wnt7a, Wnt7b and Wnt9a in breast cancer tissues by using real-time PCR and immunohistochemical analysis, and further identified their prognostic significance. Results demonstrated that only Wnt7b expression level in breast cancer was significantly higher than that of benign breast. Spearman rank-correlation analysis revealed the expression level of Wnt1, Wnt7b and Wnt9a, but not Wnt7a, were all significantly associated with positive lymph nodes. The Kaplan-Meier survival curve demonstrated that patients with high Wnt7b expression had a shorter overall survival (OS) and recurrence-free survival (RFS) than those with low Wnt7b expression. Moreover, the univariate and multivariate analysis revealed that Wnt7b expression was an independent prognostic factor for both OS and RFS of breast cancer patients. In addition, the high expression of Wnt7b in breast cancer and its prognostic role were further validated by GENT (Gene Expression database of Normal and Tumor tissues) database and the Kaplan-Meier plotter database. Taken together, we identified that high expression of Wnt7b, rather than Wnt1, Wnt7a and Wnt9a, may serve as a prognostic biomarker for breast cancer.

miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy. METHODS: We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model. RESULTS: The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = -0.28, P = 3.88 × 10-3). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient. CONCLUSIONS: Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

Collagen triple helix repeat containing-1 negatively regulated by microRNA-30c promotes cell proliferation and metastasis and indicates poor prognosis in breast cancer.

BACKGROUND: Collagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. It was then found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors. However, the functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear. METHODS: CTHRC1 expressions in breast cancer tissues and cells were assessed by qRT-PCR, western blot and immunohistochemistry. The relative expression level of miR-134, miR-155, miR-30c and miR-630 in breast cancer cells respectively was detected by qRT-PCR. Wild type (Wt) and Mutant type (Mut) CTHRC1 3'UTR sequences were cloned into a psi-CHECK2 reporter vector, and the relative luciferase activity was detected by dual-luciferase reporter assay in indicated cells. The effect of ectopic expression of miR-30c or gain and loss of CTHRC1 on cell viability, cell proliferation, cell cycle progression and apoptosis, cell invasion and migration was respectively detected by CCK-8 assay, colony formation assay, flow cytometry analysis, transwell invasion/migration assay. Protein levels of ß-catenin, active ß-catenin, normal and phosphorylated form of GSK-3ß were detected by western blot in indicated cells. Immunofluorescence staining of ß-catenin was performed to observe nuclear localization. RESULTS: We found CTHRC1 was frequently up-regulated in human breast cancer cells and tissues. Then our cohort study and further meta-analysis validated high expression of CTHRC1 was associated with aggressive clinicopathological features and poor clinical outcome of breast cancer patients. In addition, CTHRC1 promoted cell proliferation, invasion and migration and suppressed cell apoptosis in breast cancer, which might be by activating GSK-3ß/ß-catenin signaling and inhibiting Bax/Caspase-9/Caspase-3 signaling respectively; and these biological functions of CTHRC1 could be directly negatively regulated by miR-30c. CONCLUSION: Taken together, we identified the role of miR-30c/CTHRC1 axis in breast cancer progression and demonstrated CTHRC1 may serve as a prognostic biomarker and therapeutic target for breast cancer.

Up-regulation of the tumor promoter Glyoxalase-1 indicates poor prognosis in breast cancer.

Glyoxalase 1 (Glo1) is an enzyme that plays a role to metabolize and inactivate methylglyoxal. Previous studies also have confirmed that Glo1 is closely related with tumorigenesis, metastasis, and drug-resistant, but its prognostic value in breast cancer has never been explored. In this study, we investigated the expression of Glo1 in breast cancer cell lines and tissues using real-time PCR, western blot and immunohistochemical analysis. We found Glo1 was frequently up-regulated in human breast cancer cells and tissues, and high expression of Glo1 was associated with positive lymph node, lymphovascular invasion, and TNM stage (all P<0.05). The Kaplan-Meier survival curve demonstrated that patients with high Glo1 expression had a shorter overall survival (OS) and recurrence-free survival (RFS) (Both P<0.001) than those with low Glo1 expression. Moreover, the univariate and further multivariate analysis revealed that Glo1 expression was an independent prognostic factor for both OS and RFS of breast cancer patients. Next, with CCK-8 assay, cell apoptosis analysis, colony formation assay, transwell invasion/migration assay, and wound-healing assay, we validated knock-down of Glo1 suppressed invasion and migration and promoted apoptosis of breast cancer cells. Taken together, we demonstrated the tumor-promoter Glo1 may serve as a prognostic biomarker for breast cancer.

Inhibition of mTOR sensitizes breast cancer stem cells to radiation-induced repression of self-renewal through the regulation of MnSOD and Akt.

The sensitization of breast cancer stem cells (BrCSCs) to the inhibitive effects of radiotherapy through adjuvant therapy which targets oncogenic pathways represents a prospective strategy for improving the effect of radiation in patients with triple-negative breast cancer (TNBC). Mammalian target of rapamycin (mTOR) activation is one of the most frequent events in human malignancies, and is critical for sustaining the self­renewing ability of cancer stem cells (CSCs); inhibition by rapamycin is an effective and promising strategy in anticancer treatments. In the present study, we found that mTOR activity was closely related to the self-renewal ability of BrCSCs, and in triple negative MDA-MB-453 and MDA-MB­468 cells, rapamycin repression of mTOR phosphorylation decreased the number of mammospheres and helped to sensitize the resistant CSCs to low-dose radiation therapy. By inhibiting mTOR and mitochondrial manganese superoxide dismutase (MnSOD), we confirmed that rapamycin functioned through the mTOR/MnSOD/reactive oxygen species (ROS) signaling pathway, and the existence of Akt governed the rapamycin­induced asymmetric division (AD) of stem cells in cases of radiation­treated breast cancer. The synergic effects of rapamycin and low-dose radiation induced the AD of stem cells, which then resulted in a decrease in the number of mammospheres, and both were mediated by MnSOD. Governed by Akt, the consequent inhibition of ROS formation and oxidative stress preserved the AD mode of stem cells, which is critical for an improved radiotherapy response in clinical treatment, as the tumor group is thus easier to eliminate with radiation therapy. We posit that an in-depth understanding of the interaction of radiation with CSCs has enormous potential and will make radiation even better and more effective.

Hsa-miR-1 suppresses breast cancer development by down-regulating K-ras and long non-coding RNA MALAT1.

MicroRNAs exert their functions by mainly regulating coding genes or long non-coding RNA expression. In the present study, we reported that hsa-miR-1 was down-regulated in breast cancer tissues. Restoration of miR-1 in breast cancer cells inhibited proliferation, motility and increased apoptosis in vitro. MiR-1 functioned as a tumor suppressor by targeting K-RAS and MALAT1. In addition, the effects of up-regulation of miR-1 were similar to that of silencing K-RAS and MALAT1 in breast cancer cells. In vivo study indicated that restoration of miR-1 inhibited tumor growth and metastasis. Patients with low miR-1 expression had poorer overall survival time than those with high miR-1 expression. Our findings emphasized the potential role of miR-1 as tumor suppressive miRNA in breast cancer.

Susceptibility and REF1 gene polymorphism towards colorectal cancer.

Published data on the relation between REF1 polymorphism and colorectal cancer risk showed inconclusive results. The aim of this study was to derive a comprehensive estimation of the association. Data on association between REF1 polymorphism and colorectal cancer risk were summarized. The association was estimated by calculating an odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) with the fixed effects model when P > 0.1 (from heterogeneity test) or with the random effects model when P < 0.1. No significant association was revealed in any genetic model assumed for the overall analysis (OR = 1.03, 95 % CI = 0.81-1.32 for Glu/Glu vs. Asp/Asp; OR = 1.05, 95 % CI = 0.96-1.15 for Glu/Glu + Asp/Glu vs. Asp/Asp; OR = 0.97, 95 % CI = 0.76-1.23 for Glu/Glu vs. Asp/Glu + Asp/Asp; OR = 1.03, 95 % CI = 0.92-1.16 for Glu vs. Asp; OR = 1.09, 95 % CI = 0.93-1.27 for Asp/Glu vs. Asp/Asp). In Caucasian population, nor did we find a significant association. This research indicates that REF1 polymorphism is unlikely to be associated with colorectal cancer risk.

Overexpression of collagen triple helix repeat containing 1 (CTHRC1) is associated with tumour aggressiveness and poor prognosis in human non-small cell lung cancer.

Collagen triple helix repeat-containing 1 (CTHRC1), a novel oncogene, was identified to be aberrantly overexpressed in several malignant tumors. However, the expression profile of CTHRC1 and its clinical significance in non-small cell lung cancer (NSCLC) remain unknown. In this study, we showed that CTHRC1 was evidently overexpressed in human NSCLC tissues and NSCLC cell lines at the protein and mRNA level. Ectopic up-regulation of CTHRC1 in cancer cells resulted in elevated invasive and proliferative abilities, which were attenuated by the specific CTHRC1 siRNA. The biological effect of CTHRC1 on metastasis and proliferation was mediated by the activation of the Wnt/ß-catenin pathway. Furthermore, CTHRC1 immunoreactivity was evidently overexpressed in paraffin-embedded NSCLC tissues (212/292, 72.60%) in comparison to corresponding adjacent non-cancerous tissues (6/66, 9.09%) (p<0.001). Clinicopathologic analysis showed that CTHRC1 expression was significantly correlated with differentiation degree (p<0.001), clinical stage (p<0.001), T classification (p<0.001), lymph node metastasis (p=0.013) and distant metastasis (p<0.001). Kaplan-Meier analysis revealed that patients with high CTHRC1 expression had poorer overall survival rates than those with low CTHRC1 expression. Multivariate analysis indicated that CTHRC1 expression was an independent prognostic factor for the overall survival of NSCLC patients. Collectively, CTHRC1 plays important roles in NSCLC progression, and the evaluation of CTHRC1 expression could serve as a potential marker for metastasis progression and prognosis in NSCLC patients.

Major food safety episodes in Taiwan: implications for the necessity of international collaboration on safety assessment and management.

The major food safety episodes that occurred in Taiwan during the past decade are briefly reviewed in this paper. Among the nine major episodes surveyed, with the exception of a U.S. beef (associated with Creutzfeldt-Jakob disease)-related incident, all the others were associated with chemical toxicants. The general public, which has a layperson attitude of zero tolerance toward food safety, may panic over these food-safety-associated incidents. However, the health effects and impacts of most incidents, with the exception of the melamine incident, were essentially not fully evaluated. The mass media play an important role in determining whether a food safety concern becomes a major incident. A well-coordinated and harmonized system for domestic and international collaboration to set up standards and regulations is critical, as observed in the incidents of pork with ractopamine, Chinese hairy crab with nitrofuran antibiotics, and U.S. wheat with malathion. In the future, it can be anticipated that food safety issues will draw more attention from the general public. For unknown new toxicants or illicit adulteration of food, the establishment of a more proactive safety assessment system to monitor potential threats and provide real-time information exchange is imperative.