TV-circRGPD6 Nanoparticle Suppresses Breast Cancer Stem Cell-Mediated Metastasis via the miR-26b/YAF2 Axis.

Metastatic tumor is a major contributor to death caused by breast cancer. However, effective and targeted therapy for metastatic breast cancer remains to be developed. Initially, we exploited a feasible biological rationale of the association between metastatic status and tumor-initiating properties in metastatic breast cancer stem cells (BCSCs). Further, we explored that circular RNA RANBP2-like and GRIP domain-containing protein 6 (circRGPD6) regulates the maintenance of stem cell-like characteristics of BCSCs. Targeted expression of circRGPD6 via human telomerase reverse transcriptase (hTERT) promoter-driven VP16-GAL4-woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)-integrated systemic amplifier delivery composite vector (TV-circRGPD6) significantly inhibited expression of stem-cell marker CD44 and increased expression of the DNA damage marker p-H2AX. Furthermore, we determined TV-circRGPD6, alone or synergized with docetaxel, displays significant therapeutic responses on metastatic BCSCs. Mechanistic analyses exploited that TV-circRGPD6 suppresses BCSC-mediated metastasis via the microRNA (miR)-26b/YAF2 axis. Clinically, for the first time, we observed that expressions of circRGPD6 and YAF2 predict a favorable prognosis in patients with breast cancer, whereas expression of miR-26b is an unfavorable prognostic factor. Overall, we have developed a TV-circRGPD6 nanoparticle that selectively expresses circRGPD6 in metastatic BCSCs to eradicate breast cancer metastasis, therefore providing a novel avenue to treat breast cancers.

Night-shift work, breast cancer incidence, and all-cause mortality: an updated meta-analysis of prospective cohort studies.

OBJECTIVES: Night-shift work exposure is proposed to link to a wide range of health issues, especially cancer incidence, cancer-specific death, and all-cause death. However, the epidemiological associations among night-shift work exposure, breast cancer, breast cancer-specific death, and all-cause mortality remain inconclusive. METHODS: We performed an updated systematic review and meta-analysis to confirm potential associations among night-shift work exposure, breast cancer, and all-cause mortality. RESULTS: A total of 31 prospective cohort studies, involving 9.3 million participants, 31,244 incident breast cancer cases, 12,728 cancer-related deaths, 7882 cardiovascular deaths, and 30,807 all-cause mortalities were included. Overall, the summary RR of incident breast cancer in females for an increase of night-shift work was 1.029 (95% CI 1.003-1.055). Compared with standard day workers, night-shift workers had a statistically significantly increased RR (1.086, 95% CI 1.032-1.142) for breast cancer incidence in the subgroup of > 10 years exposure. Furthermore, a positive association was revealed in subgroup studies of rotating night-shift work (RR = 1.053, 95% CI 1.018-1.090). A significant increased risk of cardiovascular mortality was demonstrated in the night-shift work group (RR = 1.031; 95% CI 1.006-1.057). CONCLUSION: Our systematic review and meta-analysis provided convincing evidence supporting positive associations among night-shift work exposure, breast cancer incidence, and cardiovascular mortality. Taken together, night-shift work exposure significantly increased the risk of breast cancer morbidity by 2.9% for total, 8.6% for the subgroup of more than 10 years night-shift work, and 5.3% for rotating night-shift work. In addition, night-shift work increased the risk of cardiovascular mortality by 3.1%.

POMC maintains tumor-initiating properties of tumor tissue-derived long-term-cultured breast cancer stem cells.

The identification and understanding of the molecular network of cancer stem cells (CSCs) have had a profound impact on our view of carcinogenesis and treatment strategy. Unfortunately, a major problem is that serial passages of CSCs from clinical solid tumor specimens currently are not available in any lab, and thus, reported data are difficult to confirm and intensively interrogated. Here, we have generated two tumor tissue-derived breast CSC (BCSC) lines that showed prolonged maintenance over 20 serial passages in vitro, while retaining their tumor-initiating biological properties. We then deciphered the intrinsic mechanism using analyses of mRNA expression array profiles. It has been determined that pro-opiomelanocortin (POMC) is closely related with protein phosphorylation mediated by G-protein-coupled estrogen receptor (GPER) in BCSC. Following, knockdown of POMC inhibits properties of mammosphere formation, CD44+ CD24- population, CD44 expression, and clonogenicity ability in BCSC. We found that inhibition of POMC attenuates phosphorylation of AKT2 and GSK3ß in BCSC. Further in vivo investigations demonstrated that POMC interference regulates proliferation of BCSC-bearing tumors. Combination of the clinical results that POMC positive expression is frequently upregulated in human breast cancer and POMC positivity correlated with a poor prognosis, POMC is a potential therapeutic target for BCSC. In conclusion, we have successfully established two long-term-cultured BCSC from clinical specimens. We further indicated that POMC acts as a potential therapeutic target and prognostic marker for future treatment of BCSC.

Diabetes Increases Morbidities of Colonic Diverticular Disease and Colonic Diverticular Hemorrhage: A Systematic Review and Meta-Analysis.

Colonic diverticular disease (CDD) and colonic diverticular hemorrhage (CDH) are the most common disorders in hospital admissions and outpatient health clinic visits. However, risk factors of CDD and CDH are complicated and need to be discussed. Diabetes mellitus (DM) has been related with CDD and CDH, but the associations remain ambiguous. Therefore, we performed a literature search for studies involving the associations among DM, morbidity of CDD, and incidence of CDH. Relative risks or odds ratios with their corresponding 95% confidence intervals (CIs) were combined and weighted to produce summary effect size. Sensitivity analysis and subgroup analysis were further performed. We selected 17 studies that involved a total of 8212 patients with diabetes, 381,579 controls without diabetes. We found that patients with DM had approximately 1.201 times higher CDD morbidity in prospective studies (95% CI, 1.135-1.270) with no significant heterogeneity (Q = 0.42, P = 0.519, I = 0%). DM was associated with a 52.8% increase in risk of CDH (95% CI, 14%-104%); we did not find significant heterogeneity among these studies (Q = 12.94, P = 0.114, I = 38.2%). This meta-analysis confirms that DM is an important risk factor for morbidities of CDD and CDH.

Diabetes and risk of anastomotic leakage after gastrointestinal surgery.

BACKGROUND: Anastomotic leakage (AL) is one of the most common and lethal complications in gastrointestinal surgery. However, the relationship between AL risk and diabetes mellitus (DM) remains ambiguous. This meta-analysis was to evaluate the association between DM and AL risk in patients after gastrointestinal resection. METHODS: Odds ratios (OR) estimate with their corresponding 95% confidence intervals (CIs) were combined and weighted to produce pooled OR using the fixed-effects model. Relative risks were calculated in subgroup analysis of prospective studies. We calculated publication bias by Begg rank correlation test and Egger linear regression test. RESULTS: DM was significantly and independently associated with an increased risk of AL morbidity in colorectal patients, 1.661 times in total patients (95% CIs = 1.266-2.178), 1.995 times in a subgroup of case-control studies, 1.581 times in cohort investigations, 1.688 times in retrospective trials, and 1.562 times in prospective designs. After adjusting for the factor of obesity and/or body mass index in the subgroup analyses of colorectal surgery, DM patients without obesity experienced a significantly increased risk of AL (OR = 1.572, 95% CIs = 1.112-2.222). Furthermore, when obesity had not been adjusted, DM patients endured a dramatical increase of AL incidence (OR = 1.812, 95% CIs = 1.171-2.804). Perforation incidence after gastric resection showed borderline association with DM (OR = 2.170, 95% CIs = 0.956-4.926). CONCLUSIONS: The present meta-analysis provides strong evidence for the first time that DM is significantly and independently associated with an increased risk of AL mortality in colorectal surgery.

Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer.

BACKGROUND: MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated the role of miR-124 in breast cancer and clarified the regulation of flotillin-1 (FLOT1) by miR-124. METHODS: The expression levels of miR-124 were examined in breast cancer cell lines and patient specimens using quantitative reverse transcription-PCR. The clinicopathological significance of the resultant data was later analyzed. Next, we explored the function of miR-124 to determine its potential roles on cancer cell growth and migration in vitro. A luciferase reporter assay was conducted to confirm the target gene of miR-124, and the results were validated in cell lines and patient specimens. RESULTS: We found that miR-124 expression was significantly downregulated in breast cancer cell lines and patient specimen compared with normal cell lines and paired adjacent normal tissues (P < 0.0001), respectively. MiR-124 was also associated with tumor node metastasis (TNM) stage (P = 0.0007) and lymph node metastasis (P = 0.0004). In breast cancer cell lines, the ectopic expression of miR-124 inhibited cell growth and migration in vitro. Moreover, we identified the FLOT1 gene as a novel direct target of miR-124, and miR-124 ectopic expression significantly inhibited FLOT1. Luciferase assays confirmed that miR-124 could directly bind to the 3' untranslated region of FLOT1 and suppress translation. Moreover, FLOT1 was widely upregulated, and inversely correlated with miR-124 in breast cancer tissues. Consistent with the effect of miR-124, the knockdown of FLOT1 significantly inhibited breast cancer cell growth and migration. We also observed that the rescue expression of FLOT1 partially restored the effects of miR-124. CONCLUSIONS: Our study demonstrated that miR-124 might be a tumor suppressor in breast cancer via the regulation of FLOT1. This microRNA could serve as a potential diagnostic marker and therapeutic target for breast cancer.

Technique Success, Technique Efficacy and Complications of HIFU Ablation for Palliation of Pain in Patients With Bone Lesions: A Meta-Analysis of 28 Feasibility Studies.

Several feasibility studies have reported that high-intensity focused ultrasound (HIFU) ablation can be applied to ease patients' bone pain. However, the effect of HIFU ablation to palliate bone pain remains unclear. To evaluate the technique's success, efficacy, minor complication and major complication on patients suffering from bone pain, we searched the PubMed, MEDLINE, EMBASE and Cochrane Library databases from January 1998 to March 2019. Clinical studies that have assessed the association between bone pain and HIFU ablation were involved. We filtered out 28 feasibility studies, which reported the association between HIFU ablation and bone pain, including a total of 717 patients and 736 bone lesions. Overall, our results indicate that the rate of technique success of HIFU ablation was 93% (95% confidence interval [CI] 89%-96%) for patients with bone lesions. The technique efficacy rate of HIFU ablation for palliation of pain from bone lesions was 80% (95% CI 74%-87%) in all the patients, 96% (91%-100%) in the subgroup of retrospective studies and 77% (69%-85%) in the subgroup of prospective studies. In regard to HIFU ablation treatment safety, the hazard ratio for minor complication was 12% (95% CI 7%-17%), and the hazard ratio for major complication was 2% (95% CI 1%-3%). In conclusion, the summary rates for various considerations of using HIFU ablation for the palliation of bone pain are as follows: technique success is 93%, technique efficacy is 77%, minor complication is 12% and major complication is 2%. Our results suggest that extracorporeal HIFU ablation is a promising method for palliation of pain in bone lesions, with high technique success and efficacy, but low adverse events.

A clinical rule for the difficulty prediction on scalp intravenous access in infants (SIAI) from emergency room.

Infant intravenous access poses a significant challenge to the operator. Scalp vein is the ideal location for emergency medical staff to perform intravenous access for administration of fluids or medications. To tackle this challenge, we developed a clinical rule for the difficulty prediction on scalp intravenous access in infants (SIAI) conducting a prospective cohort study in a pediatric emergency room. A total of 658 infant patients who underwent SVI from January 2017 to September 2018 were recruited in this study. The failure rate of SIAI on the first attempt was 20.2%. Five variables, including dehydration condition, obesity, vein invisibility, vein impalpability and hyperactive status of infant, were independently and statistically associated with failure rate of SIAI. Furthermore, we indicated that any one alone of the above five variables did not significantly lead to greater than 50% failure rate of indwelling needle SIAI (p > 0.05). However, summary effects of more than one of these five variables were statistically significant associated with greater than 50% failure rate of SIAI (p < 0.05). When employing the five-variable model, validation cohort subjects displayed dehydration, obesity, vein invisibility, vein impalpability and hyperactive status had a 67.5% likelihood of failed first attempt on SIAI (C = 0.675; 95% CI: 0.622-0.727; p < 0.001). For the first time, we developed the difficult model for SIAI. We found that dehydration, obesity, vein invisibility, vein impalpability and hyperactive status of the infant patients are the independent and significant predictors associated with SIAI failure. Our predicted model indicates that infant patients with combination of more than one of the five variables contribute to greater than 50% failure rate of indwelling needle in SIAI.

Nanoparticle Delivery of miR-34a Eradicates Long-term-cultured Breast Cancer Stem Cells via Targeting C22ORF28 Directly.

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning protocol. Tissue microarray analysis has been used to study 217 cases of clinical breast cancer specimens. Results: Here, we have successfully established four long-term maintenance BCSC that retain their tumor-initiating biological properties. Our analyses of microarray and qRT-PCR explored that miR-34a is the most pronounced microRNA for investigation of BCSC. We establish hTERT promoter-driven VISA delivery of miR-34a (TV-miR-34a) plasmid that can induce high throughput of miR-34a expression in BCSC. TV-miR-34a significantly inhibited the tumor-initiating properties of long-term-cultured BCSC in vitro and reduced the proliferation of BCSC in vivo by an efficient and safe way. TV-miR-34a synergizes with docetaxel, a standard therapy for invasive breast cancer, to act as a BCSC inhibitor. Further mechanistic investigation indicates that TV-miR-34a directly prevents C22ORF28 accumulation, which abrogates clonogenicity and tumor growth and correlates with low miR-34 and high C22ORF28 levels in breast cancer patients. Conclusion: Taken together, we generated four long-term maintenance BCSC derived from either clinical specimens or cell lines, which would be greatly beneficial to the research progress in breast cancer patients. We further developed the non-viral TV-miR-34a plasmid, which has a great potential to be applied as a clinical application for breast cancer therapy.

Diabetes increases morbidity and mortality rates in peptic ulcer bleeding: An updated systematic review and meta-analysis.

BACKGROUND/AIMS: To elucidate the relationship between diabetes mellitus (DM) and the risk of peptic ulcer complications. MATERIALS AND METHODS: Fixed effects and random effects models were used for calculating pooled relative risks (RRs) and/or odds ratios (ORs). Subgroup and sensitivity analyses were also performed. RESULTS: Nineteen high-quality investigations were included in the present study. In an analysis of morbidity rates in primary peptic ulcer bleeding (PUB), we calculated a summary OR of 1.433 (95% CI=1.280-1.604) in the random effects model comparing incidence in diabetes patients and in those without diabetes. In addition, a meta-analysis using the fixed effects model indicated a higher 30-day mortality in PUB in DM patients (OR=1.442, 95% CI=1.245-1.671) than in patients without DM. Further subgroup analyses demonstrated that DM patients in prospective cohort studies had an increased risk of 30-day mortality in PUB (RR=1.407, 95% CI=1.177-1.681). A similar result was obtained in a retrospective cohort subgroup, in which DM significantly increased mortality rates in PUB (OR=1.521, 95% CI=1.171-1.976). CONCLUSION: We provided convincing evidence by a meta-analysis that DM was associated with a 43.3% increase in morbidity rates in PUB and a 44.2% increase in the risk of 30-day mortality in PUB patients.

Meta-analysis of randomized controlled trials comparing latanoprost with other glaucoma medications in chronic angle-closure glaucoma.

PURPOSE: To evaluate the efficacy and safety of latanoprost compared with other glaucoma medications in the treatment of chronic angle-closure glaucoma (CACG) and to provide the basis for clinical medication. METHODS: Major literature databases were searched for randomized controlled trials (RCT) involving latanoprost among patients with CACG. Primary outcome measures were absolute changes in intraocular pressure (IOP) and incidence of ocular adverse events. Statistical analyses included the calculation of standardized mean difference (SMD) and relative risk (RR). The statistical analysis was performed using STATA version 12.0 software. RESULTS: Ten RCT involving 1096 patients were included in this meta-analysis. Analysis showed that latanoprost was not significantly different from other glaucoma medications in reducing IOP (SMD = 0.29, 95% confidence interval [CI] -0.02 to 0.59, p=0.069). Further subgroup analysis revealed that latanoprost was superior compared with timolol (SMD = 0.64, 95% CI 0.46 to 0.82, p<0.001) and marginally inferior to travoprost and bimatoprost (SMD = -0.19, 95% CI -0.35 to -0.02, p = 0.026). As for conjunctival hyperemia, latanoprost caused a higher proportion than timolol (RR = 2.36, 95% CI 1.27 to 4.37, p = 0.007). However, latanoprost was associated with lower incidence of conjunctival hyperemia (RR = 0.42, 95% CI 0.30 to 0.59, p<0.001), and with fewer occurrence of other ocular side effects (excluding conjunctival hyperemia) than travoprost and bimatoprost (RR = 0.61, 95% CI 0.48 to 0.78, p<0.001). CONCLUSIONS: Travoprost and bimatoprost are superior in IOP control than latanoprost, but latanoprost is better tolerated in patients with CACG.

Efficacy of corneal collagen cross-linking for treatment of keratoconus: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy of corneal collagen cross-linking (CXL) for the treatment of keratoconus. METHODS: We performed a literature search for randomized controlled trials that assessed the effect of CXL in slowing progression of keratoconus. The primary outcome measures included changes of topographic parameters, visual acuity, and refraction. Efficacy estimates were evaluated by weighted mean difference (WMD) and 95% confidence interval (CI) for absolute changes of the interested outcomes. RESULTS: Significant decrease in mean keratometry value, maximum keratometry value and minimum keratometry value were demonstrated in the CXL group compared with the control group (WMD = -1.65; 95% CI: -2.51 to -0.80; P < 0.00001; WMD = -2.05; 95% CI: -3.10 to -1.00; P < 0.00001; WMD = -1.94; 95% CI: -2.63 to -1.26; P < 0.00001; respectively). Best spectacle-corrected visual acuity improved significantly in CXL group (WMD = -0.10; 95% CI: -0.15 to -0.05; P < 0.00001), whereas uncorrected visual acuity did not differ statistically. Manifest cylinder error decreased significantly in patients undergoing CXL procedure compared with control patients in sensitivity analysis (WMD = -0.388; 95% CI: -0.757 to -0. 019; P = 0.04). The changes in central corneal thickness and intraocular pressure were not statistically significant. CONCLUSION: CXL may be an effective option in stabilizing keratoconus. Further long-term follow-up studies will be necessary to assess the persistence of CXL.

Night-shift work increases morbidity of breast cancer and all-cause mortality: a meta-analysis of 16 prospective cohort studies.

Night-shift work (NSW) has previously been related to incidents of breast cancer and all-cause mortality, but many published studies have reported inconclusive results. The aim of the present study was to quantify a potential dose-effect relationship between NSW and morbidity of breast cancer, and to evaluate the association between NSW and risk of all-cause mortality. The outcomes included NSW, morbidity of breast cancer, cardiovascular mortality, cancer-related mortality, and all-cause mortality. Sixteen investigations were included, involving 2,020,641 participants, 10,004 incident breast cancer cases, 7185 cancer-related deaths, 4820 cardiovascular end points, and 2480 all-cause mortalities. The summary risk ratio (RR) of incident breast cancer for an increase of NSW was 1.057 [95% confidence interval (CI) 1.014-1.102; test for heterogeneity p = 0.358, I(2) = 9.2%]. The combined RR (95% CI) of breast cancer risk for NSW vs daytime work was: 1.029 (0.969-1.093) in the <5-year subgroup, 1.019 (1.001-1.038) for 5-year incremental risk, 1.025 (1.006-1.044) for 5- to 10-year exposure times, 1.074 (1.010-1.142) in the 10- to 20-year subgroup, and 1.088 (1.012-1.169) for >20-year exposure lengths. The overall RR was 1.089 (95% CI 1.016-1.166) in a fixed-effects model (test for heterogeneity p = 0.838, I(2) = 0%) comparing rotating NSW and day work. Night-shift work was associated with an increased risk of cardiovascular death (RR 1.027, 95% CI 1.001-1.053), and all-cause death 1.253 (95% CI 0.786-1.997). In summary, NSW increased the risk of breast cancer morbidity by: 1.9% for 5 years, 2.5% for 5-10 years, 7.4% for 10-20 years, and 8.8% for >20-years of NSW. Additionally, rotating NSW enhanced the morbidity of breast cancer by 8.9%. Moreover, NSW was associated with a 2.7% increase in cardiovascular death.

MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer.

Triple-negative breast cancer is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of both miR-101 and MCL-1 in the sensitivity of human triple-negative breast cancer (TNBC) to paclitaxel. We found that the expression of miR-101 was strongly decreased in triple-negative breast cancer tissues and cell lines. The expression of miR-101 was not associated with clinical stage or lymph node infiltration in TNBC. Ectopic overexpression of miR-101 inhibit growth and induced apoptosis in vitro and suppressed tumorigenicity in vivo. MCL-1 was significantly overexpressed in most of the TNBC tissues and cell lines. Luciferase assay results confirmed MCL-1 as a direct target gene of miR-101. MiR-101 inhibited MCL-1 expression in TNBC cells and transplanted tumors. There was a negative correlation between the level of expression of miR-101 and MCL-1 in TNBC tissues. Suppression of MCL-1 enhanced the sensitivity of MDA-MB-435 cells to paclitaxel. Furthermore, miR-101 increased paclitaxel sensitivity by inhibiting MCL-1 expression. Our findings provide significant insight into the molecular mechanisms of TNBC carcinogenesis and may have clinical relevance for the development of novel, targeted therapies for TNBC.

Up-regulation and worse prognostic marker of cytoplasmic TARBP2 expression in obstinate breast cancer.

Expression of trans-activation-responsive-RNA-binding protein 2 (TARBP2) varied from normal cell lines to various cancer cell lines. The discussion of TARBP2 serve as tumor suppressor or tumor promotor goes on. However, its expression in breast cancer remains unknown. The aim of present study was to assess the expression of cytoplasm TARBP2 as potential prognostic marker in breast cancer. We further investigated cytoplasm TARBP2 could be a novel target in treatment for late-stage breast cancer and triple-negative breast cancer (TNBC). A total of patients with breast cancer were involved in our cohort. Immunohistochemical staining for TARBP2 on tissue microarray and western blot were used. Immunohistochemistry showed that cytoplasm TARBP2 was frequently up-regulated in breast carcinoma. This finding was in line with the result of western blot analysis. Further investigation showed that cytoplasm TARBP2 expression in non-TNBC was higher than that of their adjacent normal breast tissues (NBT), and TNBC was the highest of the three groups. The positive expression of cytoplasm TARBP2 in stage III breast cancer, stage I-II breast cancer, and NBT decreased gradually. In addition, univariate and multivariate survival analysis revealed cytoplasm TARBP2 was an independent prognostic factor for breast cancer. Breast cancer patients with cytoplasm TARBP2 expression had poorer disease-free survival and overall survival, and similar results were obtained in TNBC group and stage III breast cancer group. Our results provide convincing evidence for the first time that the expression of cytoplasm TARBP2 is up-regulated in breast cancer. Breast cancer patients with TARBP2 cytoplasm expression have unfavorable prognosis. Patients of TNBC and late-stage breast cancer with higher cytoplasm TARBP2 expression have an unfavorable prognosis.