The role of circRNAs and miRNAs in drug resistance and targeted therapy responses in breast cancer.

MicroRNAs (miRNAs) are small non-coding RNAs comprising 19-24 nucleotides that indirectly control gene expression. In contrast to other non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are defined by their covalently closed loops, forming covalent bonds between the 3' and 5' ends. circRNAs regulate gene expression by interacting with miRNAs at transcriptional or post-transcriptional levels. Accordingly, circRNAs and miRNAs control many biological events related to cancer, including cell proliferation, metabolism, cell cycle, and apoptosis. Both circRNAs and miRNAs are involved in the pathogenesis of diseases, such as breast cancer. This review focuses on the latest discoveries on dysregulated circRNAs and miRNAs related to breast cancer, highlighting their potential as biomarkers for clinical diagnosis, prognosis, and chemotherapy response.

The effect of robotic surgery on low anterior resection syndrome in patients with lower rectal cancer: a propensity score-matched analysis.

BACKGROUND: Many patients experience anorectal dysfunction after rectal surgery, which is known as low anterior resection syndrome (LARS). Robotic systems have many technical advantages that may be suitable for functional preservation after low rectal resection. Thus, the study aimed to explore whether robotic surgery can reduce the incidence and severity of LARS. METHODS: Patients undergoing minimally invasive sphincter-sparing surgery for low rectal cancer were enrolled between January 2015 and December 2020. The patients were divided into robotic or laparoscopic groups. The LARS survey was conducted at 6, 12 and 18 months postoperatively. Major LARS scores were analysed as the primary endpoint. In order to reduce confounding factors, one-to-two propensity score matches were used. RESULTS: In total, 342 patients were enrolled in the study. At 18 months postoperatively, the incidence of LARS was 68.7% (235/342); minor LARS was identified in 112/342 patients (32.7%), and major LARS in 123/342 (36.0%). After matching, the robotic group included 74 patients, and the laparoscopic group included 148 patients. The incidence of major LARS in the robotic group was significantly lower than that in the laparoscopic group at 6, 12, and 18 months after surgery. In multivariate logistic regression analysis, tumour location, laparoscopic surgery, intersphincteric resection, neoadjuvant therapy, and anastomotic leakage were independent risk factors for major LARS after minimally invasive sphincter-sparing surgery for low rectal cancer. Furthermore, a major LARS prediction model was constructed. Results of model evaluation showed that the nomogram had good prediction accuracy and efficiency. CONCLUSIONS: Patients with low rectal cancer may benefit from robotic surgery to reduce the incidence and severity of LARS. Our nomogram could aid surgeons in setting an individualized treatment program for low rectal cancer patients.

The clinical predictive value of geriatric nutritional risk index in elderly rectal cancer patients received surgical treatment after neoadjuvant therapy.

Objective: The assessment of nutritional status has been recognized as crucial in the treatment of geriatric cancer patients. The objective of this study is to determine the clinical predictive value of the geriatric nutritional risk index (GNRI) in predicting the short-term and long-term prognosis of elderly rectal cancer (RC) patients who undergo surgical treatment after neoadjuvant therapy. Methods: Between January 2014 and December 2020, the clinical materials of 639 RC patients aged ≥70 years who underwent surgical treatment after neoadjuvant therapy were retrospectively analysed. Propensity score matching was performed to adjust for baseline potential confounders. Logistic regression analysis and competing risk analysis were conducted to evaluate the correlation between the GNRI and the risk of postoperative major complications and cumulative incidence of cancer-specific survival (CSS). Nomograms were then constructed for postoperative major complications and CSS. Additionally, 203 elderly RC patients were enrolled between January 2021 and December 2022 as an external validation cohort. Results: Multivariate logistic regression analysis showed that GNRI [odds ratio = 1.903, 95% confidence intervals (CI): 1.120-3.233, p = 0.017] was an independent risk factor for postoperative major complications. In competing risk analysis, the GNRI was also identified as an independent prognostic factor for CSS (subdistribution hazard ratio = 3.90, 95% CI: 2.46-6.19, p < 0.001). The postoperative major complication nomogram showed excellent performance internally and externally in the area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analysis (DCA). When compared with other models, the competing risk prognosis nomogram incorporating the GNRI achieved the highest outcomes in terms of the C-index, AUC, calibration plots, and DCA. Conclusion: The GNRI is a simple and effective tool for predicting the risk of postoperative major complications and the long-term prognosis of elderly RC patients who undergo surgical treatment after neoadjuvant therapy.

Association between periodontal disease and oral squamous cell carcinoma: a systematic review and meta-analysis.

To investigate the relation between periodontal disease (PD) and oral squamous cell carcinoma (OSCC) we systematically searched records published up to August 2022. Odds ratios (OR) and relative risk (RR) with 95% confidence intervals (95% CI) were estimated to evaluate this relation, then sensitivity analysis was performed accordingly. Begg's test and Egger's test were used to detect publication bias. Out of 970 papers from several databases, 13 studies were included. Summary estimates showed that PD was positively associated with the prevalence of OSCC (OR = 3.28, 95% CI: 1.87 to 5.74), especially for severe PD (OR = 4.23, 95% CI: 2.92 to 6.13). No evident publication bias was revealed. No increased OSCC risk among patients with PD was shown according to the combined results (RR = 1.50, 95% CI: 0.93 to 2.42). Patients with OSCC exhibited significant differences in alveolar bone loss, clinical attachment loss, and bleeding on probing, when compared with controls. The systematic review and meta-analysis suggested that there was a positive association between PD and prevalence of OSCC. However, according to the current evidence, a causal relation is unclear.

Targeting tumor energy metabolism via simultaneous inhibition of mitochondrial respiration and glycolysis using biodegradable hydroxyapatite nanorods.

Tumor cells obtain energy supply from the unique metabolic pathways of mitochondrial respiration and glycolysis, which can be used interchangeably to produce adenosine triphosphate (ATP) for survival. To simultaneously block the two metabolic pathways and sharply cut off ATP supply, a multifunctional "nanoenabled energy interrupter" (called as HNHA-GC) was prepared by attaching glucose oxidase (GOx), hyaluronic acid (HA), and 10-hydroxycamptothecin (CPT) on the surface of degradable hydroxyapatite (NHA) nanorods. After targeted delivery of HNHA-GC to the tumor site by HA, the tumor-selective acid degradation of HNHA-GC as well as the subsequent deliveries of Ca2+, drug CPT, and GOx take place. The released Ca2+ and CPT induce mitochondrial dysfunction by Ca2+ overload and chemotherapy respectively, while the GOx-triggered glucose oxidation inhibits glycolysis by starvation therapy (exogenous effect). The generated H2O2 and released CPT increase the intracellular reactive oxygen (ROS) level. Moreover, the generated H+ and enhanced ROS promote Ca2+ overload by accelerating the degradation of HNHA-GC and preventing intracellular Ca2+ efflux, respectively (endogenous effect). As a result, the HNHA-GC displays a promising therapeutic modality for simultaneously cutting off mitochondrial and glycolytic ATP production through a combination of Ca2+ overload, chemotherapy, and starvation therapy.

Association between prior appendectomy and the risk and course of Crohn's disease: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The appendix has an important immune function in both health and disease, and appendectomy may influence microbial ecology and immune function. This meta-analysis aims to assess the association between appendectomy and the risk and course of Crohn's disease (CD). METHODS: PubMed, EMBASE, and the Cochrane Library were used to identify all studies published until June 2022. Data from studies evaluating the association between appendectomy and CD were reviewed. RESULTS: A total of 28 studies were included in the final analysis, comprising 22 case-control and 6 cohort studies. A positive relationship between prior appendectomy and the risk of developing CD was observed in both case-control studies (odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.22-2.08) and cohort studies (relative risk [RR]: 2.28, 95% CI: 1.66-3.14). The elevated risk of CD persisted 5 years post-appendectomy (RR = 1.24, 95% CI: 1.12-1.36). The risk of developing CD was similarly elevated regardless of the presence (RR = 1.64, 95% CI: 1.17-2.31) or absence (RR = 2.77, 95% CI: 1.84-4.16) of appendicitis in patients. Moreover, significant differences were found in the proportion of terminal ileum lesions (OR = 1.63; 95% CI: 1.38-1.93) and colon lesions (OR = 0.70; 95% CI: 0.5-0.84) between CD patients with appendectomy and those without appendectomy. CONCLUSIONS: The risk of developing CD following an appendectomy is significant and persists 5 years postoperatively. Moreover, the elevated risk of CD may mainly occur in the terminal ileum.

Seizure Outcome After Surgery for Refractory Epilepsy Diagnosed by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/MRI): A Systematic Review and Meta-Analysis.

OBJECTIVE: When magnetic resonance imaging (MRI) fails to detect an underlying epileptogenic lesion, the odds of a good outcome after epilepsy surgery are significantly lower (20%-65% compared with 60%-90% if a lesion is detected). We investigated the possible effects of introducing hybrid 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI into the decision algorithm for patients with lesioned and nonlesioned drug-resistant epilepsy. METHODS: Three databases were searched from January 1990 to October 2022. We registered the protocol with International Platform of Registered Systematic Review and Meta-analysis Protocols. Studies in which 18F-FDG PET/MRI was conducted with ≥12 months of postsurgical follow-up in patients with refractory epilepsy. Random-effects meta-analysis was used to calculate the proportion of patients with good outcomes. Metaregression was used to investigate sources of heterogeneity. RESULTS: We identified 8105 studies, of which 23 (1292 patients in total) were included. The overall good postoperative outcome rate was 71% (95% confidence interval 63.6-74.9). Good outcome was associated with the location of the refractory epileptic lesion (temporal lobe or extratemporal; risk ratio 1.27 [95% confidence interval 1.01-1.52], P = 0.009); Length of postoperative follow-up ≥40 months included in the same study accounted for 0.6% of the observed heterogeneity. CONCLUSIONS: Seventy-one percent of patients with refractory epilepsy and 18F-FDG PET/MRI epileptogenic lesion features had a good outcome of epilepsy after surgery. Our findings can be incorporated into routine preoperative consultations and emphasize the importance of the complete resection of the temporal lobe epileptogenic zone for 18F-FDG PET/MRI detection when safe and feasible.

Comparison of robotic versus laparoscopic lateral lymph node dissection for advanced lower rectal cancer: a retrospective study at two institutions.

BACKGROUND: Lateral lymph node dissection (LLND) represents a technically challenging procedure. This study aimed to evaluate the perioperative, genitourinary functional and mid-term oncological outcomes of laparoscopic lateral lymph node dissection (LLLND) and robotic lateral lymph node dissection (RLLND) for advanced lower rectal cancer (ALRC). METHODS: Between January 2015 and April 2021, consecutive patients who underwent RLLND and LLLND at two high-volume centres were enrolled. The perioperative outcomes, genitourinary function recovery and mid-term oncological outcomes of the patients were compared. A subgroup analysis of patients who underwent neoadjuvant chemoradiotherapy (nCRT) was performed. RESULTS: A total of 205 patients were included in the analysis, with 95 in the RLLND group and 110 in the LLLND group. The patients in the RLLND group had a longer operative time, less blood loss, and more harvested internal iliac lymph nodes than did those in the LLLND group. In postoperative complication, urinary retention was less frequent in the RLLND group than in the LLLND group. Additionally, the RLLND group had better genitourinary function recovery. Similar results were also observed from the nCRT subgroup analysis. Moreover, there was no significant difference in mid-term oncological outcomes between the two groups. Further subgroup analysis indicated that the patients who underwent nCRT + LLLND/RLLND had better local control than those who underwent only LLLND/RLLND. CONCLUSIONS: RLLND is safe and feasible for ALRC and is associated with more harvested internal iliac lymph nodes and better genitourinary function recovery. NCRT combined with minimally invasive LLND could constitute an improved strategy for ALRC.

Altered gut microbiome composition by appendectomy contributes to colorectal cancer.

Appendectomy impacts the homeostasis of gut microbiome in patients. We aimed to study the role of appendectomy in colorectal cancer (CRC) risk through causing gut microbial dysbiosis. Population-based longitudinal study (cohort 1, n = 129,155) showed a 73.0% increase in CRC risk among appendectomy cases throughout 20 years follow-up (Adjusted sub-distribution hazard ratio (SHR) 1.73, 95% CI 1.49-2.01, P < 0.001). Shotgun metagenomic sequencing was performed on fecal samples from cohort 2 (n = 314). Gut microbial dysbiosis in appendectomy subjects was observed with significant enrichment of 7 CRC-promoting bacteria (Bacteroides vulgatus, Bacteroides fragilis, Veillonella dispar, Prevotella ruminicola, Prevotella fucsa, Prevotella dentalis, Prevotella denticola) and depletion of 5 beneficial commensals (Blautia sp YL58, Enterococcus hirae, Lachnospiraceae bacterium Choco86, Collinsella aerofaciens, Blautia sp SC05B48). Microbial network analysis showed increased correlation strengths among enriched bacteria and their enriched oncogenic pathways in appendectomy subjects compared to controls. Of which, B. fragilis was the centrality in the network of the enriched bacteria. We further confirmed that appendectomy promoted colorectal tumorigenesis in mice by causing gut microbial dysbiosis and impaired intestinal barrier function. Collectively, this study revealed appendectomy-induced microbial dysbiosis characterized by enriched CRC-promoting bacteria and depleted beneficial commensals, signifying that the gut microbiome may play a crucial role in CRC development induced by appendectomy.

Development and validation of a new stage-specific nomogram model for predicting cancer-specific survival in patients in different stages of colon cancer: A SEER population-based study and external validation.

Background: The effects of laterality of the primary tumor on survival in patients in different stages of colon cancer are contradictory. We still lack a strictly evaluated and validated survival prediction tool, considering the different roles of tumor laterality in different stages. Methods: A total of 101,277 and 809 colon cancer cases were reviewed using the Surveillance, Epidemiology, and End Results database and the First Affiliated Hospital of Xi 'an Jiaotong University database, respectively. We established training sets, internal validation sets and external validation sets. We developed and evaluated stage-specific prediction models and unified prediction models to predict cancer-specific survival and compared the prediction abilities of these models. Results: Compared with right-sided colon cancers, the risk of cancer-specific death of left-sided colon cancer patients was significantly higher in stage I/II but was markedly lower in stage III patients. We established stage-specific prediction models for stage I/II and stage III separately and established a unified prediction model for all stages. By evaluating and validating the validation sets, we reported high prediction ability and generalizability of the models. Furthermore, the stage-specific prediction models had better predictive power and efficiency than the unified model. Conclusions: Right-sided colon cancer patients have better cancer-specific survival than left-sided colon cancer patients in stage I/II and worse cancer-specific survival in stage III. Using stage-specific prediction models can further improve the prediction of cancer-specific survival in colon cancer patients and guide clinical decisions.

Gasotransmitter H2S accelerates seed germination via activating AOX mediated cyanide-resistant respiration pathway.

Hydrogen sulfide (H2S) has been witnessed as a crucial gasotransmitter involving in various physiological processes in plants. H2S signaling has been reported to involve in regulating seed germination, but the underlying mechanism remains poorly understood. Here, we found that endogenous H2S production was activated in germinating Arabidopsis seeds, correlating with upregulated both the transcription and the activity of L-cysteine desulfhydrase (EC 4.4.1.28, LCD and DES1) responsible for H2S production. Moreover, seed germination could be significantly accelerated by exogenous NaHS (the H2S donor) fumigation and over-expressing DES1, while H2S-generation defective (lcd/des1) seeds exhibited decreased germination speed. We also confirmed that the alternative oxidase (AOX), a cyanide-insensitive terminal oxidase, can be stimulated by imbibition. Furthermore, exogenous H2S fumigation and over-expressing DES1 could significantly reinforced imbibition induced increase of both the AOX1A expression and AOX protein abundance, while this increase could be obviously weakened in lcd/des1. Additionally, exogenous H2S fumigation mediated post-translational modification to keep AOX in its reduced and active state, which might involve H2S induced improvement of the reduced GSH content and the cell reducing power. The promotive effect of H2S on germination was clearly impaired by inducing aox1a mutation, indicating that AOX acts downstream of H2S signaling to accelerate seed germination. Consequently, H2S signaling was activated during germination then acted as a trigger to induce AOX mediated cyanide-resistant respiration to accelerate seed germination. Our study correlates H2S signaling to cyanide-resistant respiration, providing evidence for more extensive studies of H2S signaling.

Development and External Validation of a Preoperative Nomogram for Predicting Lateral Pelvic Lymph Node Metastasis in Patients With Advanced Lower Rectal Cancer.

Background: The preoperative prediction of lateral pelvic lymph node (LPLN) metastasis is crucial in determining further treatment strategies for advanced lower rectal cancer patients. In this study, we established a nomogram model to preoperatively predict LPLN metastasis and then externally validated the accuracy of this model. Methods: A total of 287 rectal cancer patients who underwent LPLN dissection were included in this study. Among them, 200 patients from the Peking University First Hospital were included in the development set, and 87 patients from the First Affiliated Hospital of Xi'an Jiaotong University were included in the independent external validation set. Multivariate logistic regression analysis was used to develop the nomogram. The performance of the nomogram was assessed based on its calibration, discrimination, and clinical utility. Results: Five factors (differentiation grade, extramural vascular invasion, distance of the tumor from the anal verge, perirectal lymph node status, and largest short-axis diameter of LPLN) were identified and included in the nomogram. The nomogram developed based on the analysis showed robust discrimination with an area under the receiver operating characteristic curve (AUC) of 0.878 (95% CI, 0.824-0.932). The validation set showed good discrimination with an AUC of 0.863 (95% CI, 0.779-0.948). Decision curve analysis showed that the nomogram was clinically useful. Conclusions: The present study proposed a clinical-imaging nomogram with a combination of clinicopathological risk factors and imaging features. After external verification, the predictive power of the nomogram model was satisfactory, and it is expected to be a convenient, visual, and personalized clinical tool for assessing the risk of LPLN metastasis in advanced lower rectal cancer patients.

Molecular clustering based on gene set expression and its relationship with prognosis in patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a subtype of lung cancer with high morbidity and mortality. While genotyping is an important determinant for the prognosis of LUAD patients, there is a paucity of studies on gene set-based expression (GSE) typing for LUAD. This current study used GSE methodology to perform gene typing of LUAD patients. Methods: Clinical and genomic information of the LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Patients with LUAD were clustered into different molecular subtypes depending on the clinical and gene set expression characteristics. The survival rate and silhouette widths were compared between each molecular subtype. Differences in survival rate between gene sets were analyzed using Kaplan-Meier survival curves. Cox regression and Lasso regression were used to establish the prognostic gene set model based on the TCGA database, and the results were validated using the GEO dataset. Results: A total of 10 hub genes were finally identified and clustered into 3 subtypes with a mean contour width of 0.96. There were significant differences in survival rates among the 3 subtypes (P<0.05). Gene Ontology (GO) analysis indicated that the related biological processes (BP) were mainly involved in regulation of cell cycle, mitotic cell cycle phase transition, and proteasome-mediated ubiquitin-dependent protein catabolic process. The cellular components (CC) were related to the spindle, chromosomal region, and midbody. Molecular function (MF) mainly focused on ubiquitin-like protein ligase binding, translation regulator activity, and oxidation activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the main pathways included the Epstein Barr virus infection pathway of neurogeneration, the p53 signaling pathway, and the proteome pathways. In addition, the protein-protein interaction network was analyzed using the STRING and Cytospace software, and the top 9 hub genes identified were KIF2C, DLGAP5, KIF20A, PSMC1, PSMD1, PSMB7, SNAI2, FGF13, and BMP2. Conclusions: Patients with LUAD can be clustered into three subtypes based on the expression of gene sets. These findings contribute to understanding the pathogenesis and molecular mechanisms in LUAD, and may lead to potential individualized pharmacogenetic therapy for patients with LUAD.

Robot-assisted Total Mesorectal Excision and Lateral Pelvic Lymph Node Dissection for Locally Advanced Middle-low Rectal Cancer.

Since their approval for clinical use, da Vinci surgical robots have shown great advantages in gastrointestinal surgical operations, especially in complex procedures. The high-quality 3-D visual, multijoint arm and natural tremor filtration allow the surgeon to expose and dissect more accurately with minimal invasion. Total mesorectal excision is the standard surgical technique for the treatment of resectable rectal cancer. To reduce the lateral recurrence rate, lateral pelvic lymph node dissection can be performed, as it is a safe and feasible procedure for locally advanced middle-low rectal cancer with a high possibility of metastasis to the lateral lymph nodes. However, the complexity of the anatomic structures and the high postoperative complication rate limit its application. Recently, several surgeons have increasingly used robotic techniques for total mesorectal excision and lateral pelvic lymph node dissection. Compared with open and laparoscopic surgery, the robotic technique has several advantages, such as less blood loss, fewer blood transfusions, minimal trauma, shorter postoperative hospitalization, and quicker recovery. A robotic approach is generally regarded as a reasonable alternative for complicated procedures such as lateral pelvic lymph node dissection, although there are a limited number of high-quality prospective randomized controlled studies reporting direct evidence. Here, we provide the detailed steps of robot-assisted total mesorectal excision and lateral pelvic lymph node dissection performed at the First Affiliated Hospital of Xi'an Jiaotong University.

Lactobacillus rhamnosus GG defense against Salmonella enterica serovar Typhimurium infection through modulation of M1 macrophage polarization.

Lactobacillus rhamnosus GG (LGG), a model probiotic strain, plays an important role in immune regulatory activity to prevent and treat intestinal inflammation or diarrhea. However, the effect of the immune modulation of LGG on macrophages to prevent Salmonella infection has not been thoroughly studied. In this study, C57BL/6 mice were pre-administered LGG for 7 days continuously, and then infected with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium). The results of the in vivo study indicated that LGG could reduce body weight loss, death rate and intestinal inflammatory response caused by S. Typhimurium. LGG also limited S. Typhimurium dissemination to liver and spleen, and thereby protected against infection. In vitro study, we observed that LGG enhanced the phagocytic and bactericidal ability of macrophages and upregulated M1 macrophage characters (e.g. iNOS, NO and IL-12) against S. Typhimurium. In addition, LGG also elevated IL-10 secretion, which was helpful to ameliorate intestinal inflammatory injury caused by S. Typhimurium. In conclusion, LGG could modulate M1 macrophage polarization and offer protective effects against S. Typhimurium infection.

Expression of miR-129-5p and miR-433 in the serum of breast cancer patients and their relationship with clinicopathological features.

Expression of miR-129-5p and miR-433 was detected in breast cancer to explore the relationship with clinicopathological features of breast cancer. Seventy-eight patients with breast cancer diagnosed in Zhengzhou Central Hospital Affiliated to Zhengzhou University (Zhengzhou, China) from February 2016 to September 2017 were collected and enrolled into the research group. Additionally, 72 healthy people who underwent physical examination during the same period were selected as the control group. The expression levels of miR-129-5p and miR-433 in peripheral blood of the two groups were detected by fluorescence quantitative PCR (RT-PCR). The relationship between the expression of miR-129-5p, miR-433 and clinicopathological features, clinical stages of breast cancer, and the degree of differentiation were analyzed. Expression of miR-129-5p and miR-433 in the research group was significantly lower than that in the control group (P<0.05). Expression of miR-129-5p in the blood of breast cancer patients was correlated with tumor size, differentiation degree, lymph node metastasis, depth of invasion and clinical stages (P<0.05). Expression level of miR-433 was correlated with the degree of differentiation, lymph node metastasis, depth of invasion and clinical stages (P<0.05). miR-129-5p and miR-433 were positively correlated with differentiation degree (r=0.8507, r=0.7522; P<0.05), and negatively correlated with clinical stages (r=-0.6595, -0.8947; P<0.05). The sensitivity and area under curve (AUC) were higher in joint detection (87.5 and 0.95% respectively), compared with those in single detection. Patients were separated into high and low expression groups according to the median values of miR-129-5p and miR-433. The one-year survival rate of breast cancer patients was analyzed. Patients in the low expression groups had lower survival rates than patients in the high expression groups (P<0.05). In conclusion, the expression of miR-129-5p and miR-433 in peripheral blood of breast cancer patients is lower than that of healthy people, and the expression level is closely related to clinical stages and differentiation degree, which is expected to provide reference value for judging the state of breast cancer patients. The combined detection of miR-129-5p and miR-433 is of great significance in the diagnosis and treatment of breast cancer.

Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.

OBJECTIVE: MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated. APPROACH AND RESULTS: To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1ΔMac/ApoE-/-) mice and found that atherosclerosis was greater in MED1ΔMac/ApoE-/- mice than in MED1fl/fl/ApoE-/- littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1ΔMac/ApoE-/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1ΔMac mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPARγ (peroxisome proliferator-activated receptor γ) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPARγ and MED1 increased the binding of PPARγ or MED1 to the PPAR response elements of M2 marker genes. CONCLUSIONS: Our data suggest that MED1 is required for the PPARγ-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPARγ-regulated transactivation.

Periostin Enhances Migration, Invasion, and Adhesion of Human Endometrial Stromal Cells Through Integrin-Linked Kinase 1/Akt Signaling Pathway.

Although our previous study confirmed that periostin (PN) was overexpressed in the eutopic and ectopic endometrial stroma of women with endometriosis by immunohistochemitry, the role of PN in the pathophysiology of endometriosis remains unknown. Thus, we aimed to investigate the effects of PN on endometrial stromal cells (ESCs) migration, invasion, adhesion, and proliferation and to further study the mechanism under this process. Eutopic (EuSCs), ectopic (EcSCs), and normal ESCs (NSCs) were isolated and cultured. We evaluated the above-mentioned biology behaviors and the expression of PN, integrin-linked kinase 1 (ILK1), and phospho-Akt (p-Akt) in NSCs, EuSCs as well as EcSCs before and after receiving PN small-interfering RNA (siRNA). The protein and messenger RNA (mRNA) levels of PN were upregulated in EuSCs (P < .05; P = .2261 in proliferative phase and P = .3385 in secretory phase) and EcSCs (P < .001; P < .001 in proliferative phase and P < .05 in secretory phase) compared with NSCs, although there was no significant difference in PN mRNA between EuSCs and NSCs. In EcSCs, abilities of migration, invasion, and adhesion and the expressions of ILK1 and p-Akt were enhanced; and all of those were downregulated after PN siRNA interference. Thus, PN enhanced ESCs migration, invasion, and adhesion due to the ILK1/Akt signal pathway. As an agonist in the development and progression of endometriosis, PN may be a new clinical treatment target of endometriosis.

Celecoxib induces epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression.

PURPOSE: The purpose of our study was to investigate the therapeutic potential of Celecoxib for epithelial ovarian cancer, especially on cellular morphological changes, proliferation invasion and epithelial-mesenchymal transition (EMT). METHOD: The MTT and transwell assays were performed to evaluate the effect of Celecoxib on proliferation and invasion ability of ovarian cancer cell lines, respectively. Western blot was carried out to detect the expression of epithelial phenotypes, E-cadherin and Keratin, and mesenchymal phenotypes, N-cadherin and Vimentin, as well as p-AKT, p-ERK and ZEB1. ZEB1 small-interfering RNA (siRNA) was used to downregulate the expression of ZEB1 to further inquiring into the downstream of Celecoxib-induced EMT. RESULTS: Cellular morphological assessment revealed that both A2780 and SKOV3 cells gradually appeared in the morphology of mesenchymal cells after Celecoxib treatment. The MTT assay demonstrated that celecoxib had no effect on cell proliferation. Transwell assay showed that Celecoxib significantly increased the cell invasion ability. Western blot data proved that the expression of E-cadherin and keratin was elevated, whereas the expression of N-cadherin and Vimentin was decreased in a dose-dependent manner compared with the untreated cells, the expression of p-AKT, p-ERK and ZEB1 was also obviously elevated. However, ZEB1 siRNA reversed Celecoxib-induced E-cadherin expression and N-cadherin expression, as well as cellular invasiveness. CONCLUSION: Our results indicated that Celecoxib might induce EMT and increase cellular invasiveness in ovarian cancer cells in vitro, which also implied that it needed a comprehensive evaluation in preclinical researches before introducing Celecoxib into the clinical regimen.

Homocysteine reduces protein S-nitrosylation in endothelium.

Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular disease. The S-nitrosylation of proteins is involved in the regulation of cardiovascular functions. However, whether homocysteine (Hcy) impairs vascular functions through the inhibition of protein S-nitrosylation in the endothelium remains to be determined. The experiments were performed in human umbilical vein endothelial cells (HUVECs). Male Sprague­Dawley rats, with or without administration of L-methionine, were used for the in vivo validation of findings. S-nitrosylation was analyzed using immunofluorescence for nitrosocysteine, and further confirmed by the biotin switch method. The levels of reactive oxygen species (ROS) were detected by 2',7'-dichlorofluorescein diacetate (DCFH-DA) staining. The levels of nitric oxide (ΝΟ) were determined by the nitrate reduction method. Protein expression was analysed by western blot analysis. The activity of nuclear factor κB (NF-κB) was evaluated by an electrophoretic mobility shift assay (EMSA). The levels of plasma Hcy were measured by ELISA. The results showed that Hcy significantly reduced the levels of protein S-nitrosylation in HUVECs and endothelial S-nitrosylation of aorta. This reduction of protein S-nitrosylation was accompanied by increasing ROS, decreasing phosphorylation levels of Akt and endothelial nitric oxide synthase (eNOS), and reduced levels of nitric oxide in HUVECs. In addition, it was found that Hcy increased the protein expression of vascular cell adhesion molecule-1 by attenuating the cytoplasm S-nitrosylation of NF-κB (p65). These data suggested that Hcy impairs endothelial functions by inhibiting endothelial protein S-nitrosylation.