Assessment of relationships between frailty and chronic pain: a bidirectional two-sample Mendelian randomisation study.

BACKGROUND: Previous observational studies have indicated a complex association between chronic pain and frailty. This study aimed to examine the bidirectional causal relationship between frailty and chronic pain and to quantify mediating effects of known modifiable risk factors. METHODS: A bidirectional two-sample Mendelian randomisation (MR) analysis was applied in this study. Summary genome-wide association statistics for frailty, as defined by both frailty index (FI) and Fried Frailty Score (FFS), pain at seven site-specific chronic pain (SSCP) (headache, facial, neck/shoulder, stomach/abdominal, back, hip and knee) and multisite chronic pain (MCP) were extracted from populations of European ancestry. Genetic instrumental variables strongly correlated with each exposure were selected. The inverse-variance-weighted method was the primary method used in the MR, supplemented by a range of sensitivity and validation analyses. Two-step MR analysis was undertaken to evaluate the mediating effects of several proposed confounders. RESULTS: Genetically predicted higher FI and FFS were associated with an increased risk of MCP and specific types of SSCP, including neck/shoulder pain, stomach/abdominal pain, back pain, hip pain and knee pain. In the reverse direction analysis, genetic liability to MCP was found to be associated with increased FI and FFS. These results remained consistent across sensitivity and validation assessments. Two-step MR suggested a mediating role for body mass index, smoking initiation, physical inactivity, educational attainment and depression. CONCLUSIONS: Our research provided genetic evidence that the association between frailty and chronic pain was bidirectional where the coexistence of both conditions will exacerbate each other.

LNX2 involves in the role of ghrelin to promote the neuronal differentiation of adipose tissue-derived mesenchymal stem cells.

Adipose tissue-derived mesenchymal stem cells (ADSCs) have promising effects on nerve repair due to the differentiation ability to neural cells. Ghrelin has been shown to promote the neural differentiation of ADSCs. This work was designed to explore its underlying mechanism. Herein, we found high expression of LNX2 in ADSCs after neuronal differentiation. Knockdown of LNX2 might block neuronal differentiation of ADSCs, as evidenced by the decreased number of neural-like cells and dendrites per cell, and the reduced expressions of neural markers (including ß-Tubulin III, Nestin, and MAP2). We also demonstrated that LNX2 silencing suppressed the nuclear translocation of ß-catenin in differentiated ADSCs. Luciferase reporter assay indicated that LNX2 inhibited wnt/ß-catenin pathway by reducing its transcriptional activity. In addition, results showed that LNX2 expression was increased by ghrelin, and its inhibition diminished the effects of ghrelin on neuronal differentiation. Altogether, the results suggest that LNX2 is involved in the role of ghrelin to facilitate neuronal differentiation of ADSCs.

The development and validation of a nomogram to determine neurological outcomes in cardiac arrest patients.

OBJECTIVES: This study aimed to investigate the variables that influence neurological functional restoration in cardiac arrest patients and construct a nomogram to predict neurofunctional prognosis. PATIENTS AND METHODS: We extracted the data from the Dryad database. Associations between patient variables and neurological outcomes were examined by logistic regression models. On the basis of these predictors, a prognostic nomogram was constructed. The identification and calibration of the prognostic nomogram were evaluated through the receiver operating characteristic (ROC) curve, the calibration curve, and the concordance index (C-index). RESULTS: A total of 374 cardiac arrest individuals were recruited in the research. Sixty percent of the participants had an adverse neurological result. The multivariable logistic regression analysis for poor neurological recovery, which showed patient age ≥ 65 years, previous neurological disease, witnessed arrest, bystander cardio-pulmonary resuscitation(CPR), cardiac arrest presenting with a non-shockable rhythm, total epinephrine dose ≥ 2.5 mg at the time of resuscitation and acute kidney injury(AKI) remained independent predictors for neurological outcomes. CONCLUSIONS: The novel nomogram based on clinical characteristics is an efficient tool to predict neurological outcomes in cardiac arrest patients, which may help clinicians identifying high-risk patients and tailoring personalized treatment regimens.

Nomogram for prediction of prolonged postoperative ileus after colorectal resection.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a major complication in patients undergoing colorectal resection. The aim of this study was to analyze the risk factors contributing to PPOI, and to develop an effective nomogram to determine the risks of this population. METHODS: A total of 1,254 patients with colorectal cancer who underwent radical colorectal resection at Fujian Cancer Hospital from March 2016 to August 2021 were enrolled as a training cohort in this study. Univariate analysis and multivariate logistic regressions were performed to determine the correlation between PPOI and clinicopathological characteristics. A nomogram predicting the incidence of PPOI was constructed. The cohort of 153 patients from Fujian Provincial Hospital were enrolled as a validation cohort. Internal and external validations were used to evaluate the prediction ability by area under the receiver operating characteristic curve (AUC) and a calibration plot. RESULTS: In the training cohort, 128 patients (10.2%) had PPOI after colorectal resection. The independent predictive factors of PPOI were identified, and included gender, age, surgical approach and intraoperative fluid overload. The AUC of nomogram were 0.779 (95% CI: 0.736-0.822) and 0.791 (95%CI: 0.677-0.905) in the training and validation cohort, respectively. The two cohorts of calibration plots showed a good consistency between nomogram prediction and actual observation. CONCLUSIONS: A highly accurate nomogram was developed and validated in this study, which can be used to provide individual prediction of PPOI in patients after colorectal resection, and this predictive power can potentially assist surgeons to make the optimal treatment decisions.

Comparison of prolonged postoperative ileus between laparoscopic right and left colectomy under enhanced recovery after surgery: a propensity score matching analysis.

BACKGROUND: There were differences in the recovery of bowel function and prolonged postoperative ileus (PPOI) between laparoscopic right colectomy (RC) and left colectomy (LC) under the guidance of enhanced recovery after surgery. METHODS: We selected 870 patients who underwent elective laparoscopic colectomy from June 2016 to December 2021, including 272 patients who had RC and 598 who had LC. According to 1:1 proportion for propensity score matching and correlation analysis, 247 patients who had RC and 247 who had LC were finally enrolled. RESULTS: The incidence of PPOI in all patients was 13.1%. Age, sex, smoking habit, preoperative serum albumin level, operation type, and operation time were the important independent risk factors based on multivariate logistic regression and correlation analysis for PPOI (p<0.05). Age, sex, body mass index, preoperative serum albumin level, operation time, and degree of differentiation between the two groups were significantly different before case matching (p<0.05). There were no statistically significant differences in baseline characteristics and preoperative biochemical parameters between the two groups after case matching (p>0.05). The incidence of PPOI in patients who had RC was 21.9%, while that in patients who had LC was 13.0%. The first flatus, first semi-liquid, and length of stay in LC patients were lower than those in RC patients (p<0.05). CONCLUSION: The return of bowel function in LC was faster than that in RC, and the incidence of PPOI was relatively lower. Therefore, caution should be taken during the early feeding of patients who had laparoscopic RC.

Linc-OIP5 in the breast cancer cells regulates angiogenesis of human umbilical vein endothelial cells through YAP1/Notch/NRP1 signaling circuit at a tumor microenvironment.

BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.

MicroRNA-34a induces transdifferentiation of glioma stem cells into vascular endothelial cells by targeting Notch pathway.

The function of microRNA-34a (miR-34a) in transdifferentiation of glioma stem cells (GSCs) into vascular endothelial cells (VECs) was explored by focusing on Notch ligand Delta-like 1 (Dll1). MiR-34a mimics was transfected into CD133 + glioma cell U251. The angiogenesis feature of miR-34a transfected U251 cells was investigated and the expressions of CD31, CD34, Vwf, Notch 1, and Dll1 were quantified. Length of branching vessel-like structures in the miR-34a transfected U251 cells was significantly higher than control cells. The VEC feature of miR-34a overexpressed U251 cells was further confirmed by the expressions of CD31, CD34, and vWF. Transfection of miR-34a decreased the expression of Notch 1 and Dll1. Furthermore, the miR-34a overexpression-enhanced tube formation of GSCs was suppressed when the decreased expression of Dll1 was restored. The current study highlighted the potential of miR-34a as an inducer in GSCs' transdifferentiation into VECs by targeting Dll1.

Decreased miR-208 induced ischemia myocardial and reperfusion injury by targeting p21.

Aberrant expression of miR-208 was previously reported in cardiomyocytes after cardiac ischemia reperfusion (CIR) injury. However, the underlying mechanism has never been elucidated. In the current study, the relative level of miR-208 was determined in the hearts of CIR injury mice models using real time PCR. The effect of miR-208 on cardiomyocytes apoptosis was determined by Hoechst staining and annexin V-PI staining. Meanwhile, caspase3 activity was explored using an assay kit. To identify left ventricular fraction and relative wall thickness, the two-dimensional echocardiography was applied. Dual luciferase assay was applied to determine the target gene of miR-208. Compared with normal control, the level of miR-208 was significantly reduced in the hearts of CIR injury mouse models. Further studies revealed that reduction of miR-208 contributed to reactive oxygen species (ROS) production in the cardiomyocytes. We also found that inhibition of miR-208 prompted cardiomyocyte apoptosis. More importantly, the phosphorylation level of Akt and p38 was enhanced in primary cardiomyocytes transfected with miR-208 inhibitor, indicating a potential stress-response after CIR injury in primary cardiomyocytes. Dual luciferase assay and western blot analysis showed that transfection with miR-208 markedly suppressed the protein expression of p21, suggesting p21 was a target gene of miR-208. To conclude, we showed that reduced miR-208 level enhanced cardiomyocyte apoptosis mainly by targeting p21.

Development of an individualized model for predicting postoperative delirium in elderly patients with hepatocellular carcinoma.

Postoperative delirium (POD) is a common complication in older patients with hepatocellular carcinoma (HCC) that adversely impacts clinical outcomes. We aimed to evaluate the risk factors for POD and to construct a predictive nomogram. Data for a total of 1481 older patients (training set: n=1109; validation set: n=372) who received liver resection for HCC were retrospectively retrieved from two prospective databases. The receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA) were used to evaluate the performance. The rate of POD was 13.3% (148/1109) in the training set and 16.4% (61/372) in the validation set. Multivariate analysis of the training set revealed that factors including age, history of cerebrovascular disease, American Society of Anesthesiologists (ASA) classification, albumin level, and surgical approach had significant effects on POD. The area under the ROC curves (AUC) for the nomogram, incorporating the aforementioned predictors, was 0.798 (95% CI 0.752-0.843) and 0.808 (95% CI 0.754-0.861) for the training and validation sets, respectively. The calibration curves of both sets showed a degree of agreement between the nomogram and the actual probability. DCA demonstrated that the newly established nomogram was highly effective for clinical decision-making. We developed and validated a nomogram with high sensitivity to assist clinicians in estimating the individual risk of POD in older patients with HCC.

PDGFRß triggered by bFGF promotes the proliferation and migration of endothelial progenitor cells via p-ERK signalling.

We have examined the effects of bFGF (basic fibroblast growth factor) on p-ERK (phosphorylated extracellular signal-regulated kinase) through PDGFRß (platelet-derived growth factor receptor ß) in the proliferation and migration of EPCs (endothelial progenitor cells). EPC migration was detected using the Transwell system. The expression of PDGFRß mRNA and protein, total ERK and p-ERK proteins was respectively assessed by real-time PCR and Western blottings. bFGF promote the proliferation and migration of EPCs, the effects of bFGF being implemented by activating ERK signalling through the expression of PDGFRß, whereas an anti-bFGF antibody and inhibitor of PDGF (platelet-derived growth factor) receptor kinase (AG1296) could respectively decrease the expression of PDGFRß mRNA and protein and p-ERK protein. Total ERK protein did not change under the same experimental conditions, and an inhibitor of p-ERK (PD98059) inhibited the proliferation and migration of EPCs. The findings strongly suggest that a PDGFRß/p-ERK signalling pathway triggered by bFGF plays an important role in the proliferation and migration of EPCs.

A predictive nomogram model for low anterior resection syndrome after rectal cancer resection.

BACKGROUND: The aim of this study was to identify risk factors associated with the low anterior resection syndrome (LARS) and to construct a nomogram capable of predicting the risk of LARS in patients who undergo rectal cancer resection. METHODS: About 538 patients who had undergone anterior resection were recruited as a development set. In addition, 114 patients with rectal cancer were analysed as a validation set to test the new nomogram. Patients in the development set were grouped into two separate cohorts: those with major LARS and those with minor or no LARS. Multiple logistic regression was conducted to detect risk factors for major LARS. RESULTS: The prevalence of major LARS was 40.7%, of minor LARS was 28.6% and the proportion with no LARS was 30.7% in the development set. In multivariate analysis, female gender, preoperative chemoradiation, low tumour height, diverting ileostomy, postoperative anastomotic leakage were shown to be independently associated with major LARS occurring in patients after rectal cancer resection. The area under the curve (AUC) values of the nomogram were 0.726 (95% CI: 0.682-0.769) and 0.750 (95% CI: 0.655-0.845) in the development and validation sets, respectively. The calibration curves and Hosmer-Lemeshow goodness of fit tests showed that the model was acceptably accurate. CONCLUSION: A nomogram model based on risk factors could be valuable as a predictor of the probability of major LARS after rectal cancer surgery, and provides a guide that clinical staff can use to take preventive measures for high-risk patients.

Lumbar Sympathetic Ganglion Block for Cancer-Associated Secondary Lower Limb Lymphedema: A Retrospective Study.

BACKGROUND: Although lower limb lymphedema (LLL) is more or equally as frequent and harmful as upper limb lymphedema after cancer treatment, there are only a few studies on this topic. Cancer-related secondary LLL not only has physical implications, but also affects quality of life among patients who underwent gynecological cancer treatment. Despite numerous studies of various therapies, the optimal treatment for cancer-related LLL is still unknown. OBJECTIVES: We aimed to investigate the efficacy of lumbar sympathetic ganglion block (LSGB) in patients with secondary LLL in the present study. STUDY DESIGN: This study is a retrospective study. SETTING: A single academic hospital, outpatient setting. METHODS: A total of 30 patients with secondary unilateral LLL and failed complex decongestive treatment,  from January 2017 through May 2021, were reviewed for inclusion in this study. The patients underwent fluoroscopy-guided LSGB 2 times with the help of digital subtraction angiography at 3-day intervals. Leg circumference was measured, and the volume of the leg was calculated before surgery, on the first day after the first surgery, on the first day after the second surgery, and on the seventh day after the second surgery. The World Health Organization Quality of Life Instrument Questionnaire scores were monitored before and after LSGB. RESULTS: The leg circumference and volume decreased significantly from baseline after the treatment (P < 0.001). One week after 2 rounds of LSGB, the physical health score, psychological score, and social relationships score were higher than those before treatment (all P < 0.05). There was no difference in the environmental health score (P = 0.2731). LIMITATIONS: This study was limited by its sample size and retrospective observational design. CONCLUSIONS: LSGB can be a safe and effective treatment option for patients with secondary LLL after gynecological cancer treatment.

MicroRNA-9-5p increases the sensitivity of colorectal cancer cells to 5-fluorouracil by downregulating high mobility group A2 expression.

Chemotherapy drug 5-fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC); however, 5-FU resistance decreases CRC therapeutic efficiency. A previous study revealed that microRNA (miR)-9-5p serves an antitumor effect in CRC. However, the effect of miR-9-5p in CRC chemoresistance remains unknown. In the present study, two CRC cell lines, including HT-29 and HCT-116 cells, were used to investigate the impact of miR-9-5p in overcoming 5-FU resistance. The results revealed that treatment with 5-FU decreased CRC cell viability and upregulated miR-9-5p expression in both CRC cells. Knockdown of miR-9-5p decreased HCT-116 cell sensitivity to 5-FU and inhibited apoptosis. By contrast, miR-9-5p overexpression enhanced the sensitivity of HT-29 cells to 5-FU and induced apoptosis. Additionally, it was confirmed that miR-9-5p directly targeted high mobility group A2 (HMGA2). HMGA2 overexpression reversed miR-9-5p-induced HT-29 apoptosis. The present study indicated that miR-9-5p enhanced the sensitivity of CRC cells to 5-FU via downregulating HMGA2 expression.

Protective effects of miR-155-5p silencing on IFN-γ-induced apoptosis and inflammation in salivary gland epithelial cells.

Previous studies have demonstrated that microRNAs (miRNAs/miRs) serve a vital role in the pathogenesis of Sjögren's syndrome (SS). The present study aimed to investigate the role of miR-155-5p in SS and determine its underlying molecular mechanism. An inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) with interferon-γ (IFN-γ). The apoptosis of SGECs was measured by using flow cytometry. Levels of proinflammatory factors were detected by reverse transcription-quantitative PCR and ELISA, respectively. Immunofluorescence was used for p65 staining. Dual-luciferase reporter assay was performed to verify the interaction between miR-155-5p and arrestin ß2 (ARRB2). The protein levels in the NF-κB signaling pathway were assessed by western blotting. The results of the present study demonstrated that treatment with IFN-γ increased miR-155-5p expression, in addition to inducing apoptosis and inflammation in SGECs. Furthermore, overexpression of miR-155-5p promoted IFN-γ-induced apoptosis and inflammation in SGECs. Overexpression of miR-155-5p also increased Bax protein expression, enzyme activities of caspase 3 and caspase 9, release of inflammatory cytokines interleukin-6 and tumor necrosis factor-α, and decreased Bcl-2 protein expression in IFN-γ-treated SGECs. By contrast, all of the effects aforementioned were reversed following miR-155-5p knockdown. These results demonstrated that miR-155-5p activated the NF-κB signaling pathway, where treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, reversed the effects of miR-155-5p overexpression on the inflammatory factors in IFN-γ-induced SGECs. miR-155-5p was demonstrated to target ARRB2 and negatively regulated its expression levels, such that overexpression of ARRB2 reversed the effects of miR-155-5p overexpression on the inflammatory response, apoptosis and the NF-κB signaling pathway in IFN-γ-treated SGECs. Collectively, results from the present study suggest that miR-155-5p may activate the NF-κB signaling pathway by negatively regulating ARRB2 to promote salivary gland damage during SS pathogenesis. This suggests that miR-155-5p may serve to be a potential target for the treatment of SS.

Lycium barbarum polysaccharides attenuate kidney injury in septic rats by regulating Keap1-Nrf2/ARE pathway.

Lycium barbarum polysaccharides (LBP) are derived from Wolfberry and have antioxidant activities. This study aimed to evaluate the efficacy of LBP for kidney injury in a rat model of sepsis. Male rats were divided randomly to control group (Con), LPS group (LPS), ulinastatin group (ULI), low dose LBP group (LBP-1), middle dose LBP group (LBP-2) and high dose LBP group (LBP-3). After intraperitoneal injection of LPS (5 mg/kg) to make sepsis model (LPS group), 10,000 U/kg ulinastatin were given in ULI group, and 200, 400 and 800 mg/kg LBP was given in LBP-1, -2, -3 group, respectively. Serum IL-1ß, IL-6, IL-8, TNF-α and NF-κB levels were measured by ELISA. Nrf2, Keap1, NF-κB, HO-1 and NQO1 expression levels were detected by PCR and Western blot analysis. We found that LBP decreased the levels of NF-κB and pro-inflammatory cytokines while attenuated kidney injury. In addition, LBP regulated Keap1-Nrf2/ARE signaling pathway in the kidney. In conclusion, LBP attenuates inflammation injury in the kidney via possible regulation of Keap1-Nrf2/ARE signaling.

Abnormal DNA methylation in the lumbar spinal cord following chronic constriction injury in rats.

Pathogenesis of neuropathic pain is complex and not clearly understood. Glutamate decarboxylase 67 (GAD 67) is a key synthetic enzyme for the main inhibitory transmitter gamma-aminobutyric acid (GABA), and diminishes in the spinal dorsal horn in rats following chronic constriction injury (CCI). GAD 67 is coded by gene GAD 1. DNA methylation can regulate the expression of GAD 67 by regulating the methylation of GAD 1 promoter in the psychotic brain. DNA methylation is primarily mediated by DNA methyltransferases (DNMTs) and methyl-DNA binding domain proteins (MBDs). In this study, in order to discover whether DNA methylation regulates GAD 67 expression in the spinal cord in CCI rats and is involved in neuropathic pain, we examined mRNA levels of DNMTs, MBDs and GAD 67 with real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), and methylation of GAD 1 promoter with Pyromark CpG Assays in the lumbar spinal cord in CCI rats on day 14 after surgery. Our results showed that DNMT3a, DNMT3b and methyl-CpG binding protein 2 (MeCP2) expression increased, MBD2 expression decreased, and DNMT1, MBD1 and MBD3 expression hardly changed in the lumbar spinal cord in CCI rats on day 14 after surgery. GAD 67 expression decreased, and methylation of GAD 1 promoter increased in the lumbar spinal cord in CCI rats on day 14 after surgery. These results indicate that decreased GAD 67 may be associated with increased GAD 1 promoter methylation, which may be mediated by DNMT3a, DNMT3b, MeCP2 and MBD2 in CCI rats. These indicate that abnormal DNA methylation may be highly involved in CCI-induced neuropathic pain.

Linc-OIP5 in the breast cancer cells regulates angiogenesis of human umbilical vein endothelial cells through YAP1/Notch/NRP1 signaling circuit at a tumor microenvironment

BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.