Genetic analysis of oligo-recurrence breast cancer: correlation with clinical outcomes.

BACKGROUND: We aimed to identify the relationship between the genomic characteristics and clinical outcomes of oligo-metastatic breast cancer. METHODS: Oligo-metastatic breast cancer diagnosed by pathology from January 2001 and August 2019 were reviewed and we matched the poly-metastatic patients based on the clinicopathological features of patients included. Clinicopathological values and data of genomic alterations were collected. Oligo-recurrence (oligo-R) was defined as a situation where disease progression occurred in less than 5 anatomical sites and other anatomic areas still suppressed by the ongoing therapy. RESULTS: A total of 26 breast cancer patients were enrolled in our study, including 14 patients with strict oligo-metastatic disease (oligo-R > 6 months) and 12 with simultaneous poly-metastatic disease. PIK3CA, TP53 and ERBB2 were the most common shared alterations identified in patients included. Based on the median time of oligo-R, we divided the patients with oligo-metastasis into longer oligo-R group (oligo-R > 31.04 months) and shorter oligo-R group (oligo-R ≤ 31.04 months). The analysis of PIK3CA mutation sites showed that H1047R mutation was closely associated with oligo-metastasis, rather than poly-metastasis. H1047R mutation also predicted a better prognosis (oligo-R > 31.04 months) in oligo-metastatic breast cancer. In addition, HER2 positive was more likely to be related to a good outcome in patients with oligo-metastasis. CONCLUSIONS: Through the genetic analysis of samples from oligo-metastasis, we found the prognostic values of PIK3CA H1047R and HER2 in oligo- and poly-metastasis. We improved the stratification of prognosis and provided new insights for biological behaviors of oligo-metastatic breast cancer.

Significant response to margetuximab in Chinese HER2-positive metastatic breast cancer patient who progressed after second-line targeted therapy.

Activation of the antibody-dependent cellular cytotoxicity is one of the key mechanisms of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody treatment. Margetuximab is a fragment C (Fc)-modified chimeric anti-HER2 immunoglobulin G1 monoclonal antibody that shares epitope specificity with trastuzumab. In this case, we reported that margetuximab plus chemotherapy was effective as later-line therapy in a postmenopausal Chinese woman with metastatic diseases, who was diagnosed with estrogen receptor -, progesterone receptor (PR)-, HER2+ invasive ductal carcinoma. This patient used paclitaxel-albumin plus trastuzumab and pertuzumab as the first-line therapy with progression-free survival (PFS) of 14 months, and pyrotinib in combined with vinorelbine as the second-line therapy with a PFS of 17 months. Then she received margetuximab plus capecitabine as the third-line treatment, the metastatic lesions in the liver were obviously shrunk, indicating clinical partial response and the PFS was 7 months. This case revealed that margetuximab plus chemotherapy may be an appropriate option for the patients who progressed after treating with anti-HER2 monoclonal antibodies and pyrotinib.

Long-term survival after sentinel lymph node biopsy or axillary lymph node dissection in pN0 breast cancer patients: a population-based study.

PURPOSE: Findings from randomized clinical trials have shown that survival in patients with sentinel lymph node (SLN)-negative breast cancer is noninferior with SLN biopsy (SLNB) alone versus further axillary lymph node dissection (ALND). However, the long-term outcome of these two surgical approaches in pN0 breast cancer patients in real-world setting remains uncertain. METHODS: We included patients diagnosed with pathologically staged T1-2N0M0 breast cancer between 2000 and 2015 in surveillance, epidemiology, and end results 18-registry database. Patients were considered to have undergone SLNB alone if they had ≤ 5 examined lymph nodes (ELNs), and ALND if they had ≥ 10 ELNs. The outcomes included overall survival (OS) and breast cancer-specific survival. Propensity score analyses by weighting and matching and multivariable Cox regression analysis were performed to minimize treatment selection bias. RESULTS: We included 309,430 patients (253,501 SLNB and 55,929 ALND). In the weighted cohort, ALND was associated with significantly lower OS (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.10-1.16) and BCSS (HR 1.16; 95% CI 1.10-1.22) compared with SLNB alone. Both the propensity score-matching model and multivariable Cox model demonstrated a survival benefit for SLNB when compared with ALND. Subgroup analyses for key variables did not change these findings. CONCLUSION: We found statistically significant differences in OS and BCSS between SLNB and ALND, though the magnitude of these differences was small. Our findings further support that SLNB alone should be the standard of care for patients who do not have metastatic lymph nodes identified during breast cancer surgery.

A Phase II Study of Fulvestrant 500 mg as Maintenance Therapy in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Patients with Advanced Breast Cancer After First-Line Chemotherapy.

LESSONS LEARNED: Fulvestrant 500 mg maintenance therapy showed a clinical benefit rate of 76% and median progression-free survival of 16.1 months in patients who achieved objective responses or disease control after first-line chemotherapy. Adverse events with fulvestrant maintenance therapy were consistent with the known safety profile of the drug. BACKGROUND: Evidence for maintenance hormonal therapy after chemotherapy for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is scarce. This study aimed to evaluate the efficacy of fulvestrant 500 mg maintenance therapy in patients after first-line chemotherapy. METHODS: We enrolled postmenopausal women with ER-positive/HER2-negative advanced breast cancer who attained tumor responses or disease control with four to eight cycles of chemotherapy as first-line treatment. Fulvestrant 500 mg was injected on days 1, 15, and 29 and every 28 (±3) days thereafter. The primary endpoint was the clinical benefit rate (CBR); the secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and safety. RESULTS: We included 58 patients; the median follow-up duration was 32.6 months. The CBR since commencing fulvestrant maintenance therapy was 76% (95% confidence interval [CI], 63%-86%), and ORR was 14% (95% CI, 6%-25%); eight patients achieved partial response. The median PFS for fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3-21.0 months). Thirty-nine patients (67%) reported at least one adverse event, of which most were grade 1/2, whereas three patients (5%) reported grade 3 adverse events. CONCLUSION: Fulvestrant 500 mg is a feasible and promising hormonal maintenance strategy in patients with ER-positive/HER2-negative advanced breast cancer who have no disease progression after first-line chemotherapy.

Bicalutamide plus Aromatase Inhibitor in Patients with Estrogen Receptor-Positive/Androgen Receptor-Positive Advanced Breast Cancer.

LESSONS LEARNED: Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)-resistant breast cancer are limited. Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage. BACKGROUND: Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR-positive triple-negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)-positive and AR-positive advanced breast cancer. METHODS: A Simon's two-stage, phase II, single-arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and tolerability. RESULTS: A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated. CONCLUSION: Bicalutamide in combination with another AI did not show synergistic activity in patients with ER-positive breast cancer and AI resistance. Results suggest that no more large-sample clinical trials should be conducted in this population for overcoming endocrine resistance.

Administration of Lapatinib with Food Increases Its Plasma Concentration in Chinese Patients with Metastatic Breast Cancer: A Prospective Phase II Study.

LESSONS LEARNED: Administration of lapatinib with food significantly increased its plasma concentration in Chinese patients with metastatic breast cancer. There were no serious adverse events during the study and no significant differences in lapatinib-related adverse events between the fasted and fed states. BACKGROUND: Lapatinib, a small molecular reversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2), was approved for use in combination with capecitabine to treat metastatic HER2-positive breast cancer. Administration of lapatinib in the fasted state was recommended; however, our preliminary phase II trial data showed that administration of lapatinib with food increased its concentration. METHODS: This study was a single-center, open-label, and prospective self-controlled clinical study. Ten Chinese patients with metastatic breast cancer were enrolled from June 2017 to April 2018. They were required to receive lapatinib plus physician's choice of chemotherapy. Patients were required to take lapatinib orally on an empty stomach continually for 10 days, and then take lapatinib with food continually for the next 10 days. Plasma concentration was measured by liquid chromatography on the 9th and 10th day of each state. RESULTS: Area under the concentration-time curve (AUC) of the fasted state and the fed state was 21.23 ± 8.91 mg*h/L (coefficient of variation (CV)% 42%) and 60.60 ± 16.64 mg*h/L (CV% 27%), respectively. The mean plasma concentration in the fasted state was 0.88 ± 0.39 mg/L (CV% 45%), and that in the fed state was 2.53 ± 0.77 mg/L (CV% 30%). Compared with taking lapatinib on an empty stomach, receiving lapatinib with food significantly increased the plasma concentration of lapatinib (Wilcoxon match-paired test, p = .005). In addition, there were no serious adverse events during the study or significant difference in lapatinib-related adverse events between the two states. CONCLUSION: Our study shows that receiving lapatinib with food can increase its plasma concentration with no significantly increased drug-related toxicity. We suggest that a larger-sample-size clinical trial is needed to fully understand the effect of administration of lapatinib with food.

Mucinous carcinoma with micropapillary features is morphologically, clinically and genetically distinct from pure mucinous carcinoma of breast.

Micropapillary features are seen in pure mucinous carcinoma of breast (PMC), which is termed mucinous carcinoma with micropapillary features (MPMC). However, whether MPMC can be identified as a morphologically, clinically or genetically distinct entity from PMC remains controversial. In this study, a retrospective review of 161 cases of breast mucinous carcinoma was conducted to assess the clinicopathologic features, prognostic implications, and genomic alterations of MPMC and PMC. MPMCs were identified in 32% of mucinous carcinomas showing an excellent interobserver agreement (ICC = 0.922). MPMCs occurred at a younger age and exhibited higher nuclear grade, more frequent lymph nodal metastasis, lymphovascular invasion, and HER2 amplification compared with PMCs. Survival analyses revealed that MPMCs show decreased progression-free survival compared with PMCs in both unmatched and matched cohorts. A similar outcome of distant disease-free survival was observed only in the unmatched cohort. However, no statistical difference in recurrence score was observed between MPMC and PMC using a 21-gene assay. Notably, both MPMCs and PMCs displayed low mutation burden, common mutations affecting TTN, GATA3, SF3B1, TP53, recurrent 6q14.1-q27 losses, and 8p11.21-q24.3 gains. GATA3, TP53, and SF3B1 were recurrently mutated in MPMCs, while PIK3CA mutations were exclusively detected in PMCs. Moreover, MPMCs harbored 17q and 20q gains as well as 17p losses, while PMCs displayed gains at 6p. PI3K-Akt, mTOR, ErbB, and focal adhesion pathways were more frequently deregulated in MPMCs than in PMCs, which may responsible for the aggressive tumor behavior of MPMCs. Our findings suggest that MPMC is morphologically, clinically, and genetically distinct from PMC.

Alleviation of cognitive deficits and high copper levels by an NMDA receptor antagonist in a rat depression model.

BACKGROUND: Major depressive disorder (MDD) is frequently associated with cognitive deficits and high copper levels. Dysfunction of N-methyl-d-aspartate (NMDA) receptors has been postulated to underlie MDD pathogenesis. This study sought to investigate the curative effect of the NMDA receptor antagonist memantine on cognitive deficits in depression and the underlying mechanisms. METHODS: Adult male Sprague-Dawley rats received corticosterone (CORT) (20 mg/kg) bi-weekly via subcutaneous injection and/or copper gluconate (7 mg/kg) via daily intragastric administration. After 3 weeks, sucrose preference tests and open field tests showed anhedonia and high anxiety in both the CORT and CORT+Cu groups. Memantine intervention (20 mg/kg daily via intragastric administration for 14 days) led to recovery of anhedonia and anxiety behaviors. Memantine also remarkably suppressed serum copper ion levels. Moreover, memantine treatment effectively rescued depression-related spatial memory deficits as shown by the Morris water maze task. RESULTS: Compared to the pre-memantine treatment results, the results of behavioral tests and cognitive function after memantine treatment were significantly normalized, and the copper concentration was decreased in all groups. CONCLUSIONS: Collectively, our findings suggest that the NMDA receptor antagonist memantine may improve symptoms of anhedonia and anxiety and the cognitive deficits associated with depression, likely be related to suppress serum copper ion levels.

Elevated vitreous Lipocalin-2 levels of patients with proliferative diabetic retinopathy.

BACKGROUND: Lipocalin-2 (LCN2) is a novel adipokine with potential roles in obesity, insulin resistance, and inflammation. This study aims to assess the concentrations of LCN2 and vascular endothelial growth factor (VEGF) expressed in the vitreous humors of patients with proliferative diabetic retinopathy (PDR). METHODS: The concentrations of LCN2 and VEGF were measured from the vitreous of 67 patients undergoing vitrectomy (20 controls and 47 PDR) via enzyme-linked immunosorbent assay (ELISA). Patients with non-ocular pathology that could elevate the LCN2 level in the vitreous were excluded. PDR activity and a history of panretinal photocoagulation were used for further grouping analysis. RESULTS: The vitreous concentration of LCN2 was statistically significantly higher in the PDR group compared to the control group (63,522 (30,009) pg/ml versus 1663 (1191) pg/ml, respectively; P < 0.001). VEGF level was also significantly higher in the PDR group than in the control group (1038 (1326) pg/ml versus 9 pg/ml, respectively; P < 0.001). The mean vitreous LCN2 and VEGF levels in active PDR patients were significantly higher than that of the inactive PDR patients. The mean LCN2 concentration in vitreous humor was significantly lower in the 28 PDR patients with a history of complete PRP (37,304 (16,651) pg/mL) in comparison with 19 PDR patients without preperformed panretinal photocoagulation or with preperformed incomplete panretinal photocoagulation (79,796 (24,391) pg/mL). A significant correlation between the vitreous LCN2 level and VEGF level was found in patients with PDR (R = 0.34; P = 0.019). CONCLUSIONS: This report shows a significant increase of LCN2 in the vitreous fluid of patients with PDR and present a significant correlation between LCN2 and VEGF, suggesting LCN2 might be involved in the pathogenesis of PDR.

ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1.

Diabetic retinopathy (DR), the most common cause of irreversible blindness in working-age adults, results in central vision loss that is caused by microvascular damage to the inner lining of the back of the eye, the retina. The aim of this work was to assess the temporal relationships between angiopoietin-like protein-4 (ANGPTL-4), a novel adipocytokine factor, and diabetic retinal inflammation and microvascular dysfunction. The downstream pathway(s) and upstream mediator(s) of ANGPTL-4 were then determined under high glucose (HG) conditions. Diabetic rats and control animals were randomly assigned to receive hypoxia inducible factor-1 alpha (HIF-1α) blockade (doxorubicin or shRNA) or vehicle for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were incubated with normal or high glucose, with or without blockade or recombinant proteins, for ANGPTL-4, HIF-1α, and vascular endothelial growth factor (VEGF). The levels of ANGPTL-4, profilin-1, HIF-1α, VEGF, interleukin 1 beta (IL-1ß), IL-6, and intercellular adherent molecule 1 (ICAM-1) in the rat retinas and HRMEC extracts were examined by Western blotting and real-time RT-PCR. The levels of ANGPTL-4, profilin-1, HIF-1α, and VEGF protein and mRNA were significantly higher in the diabetic rats and HG-exposed HRMECs. ANGPTL-4 was a potent modulator of increased inflammation, permeability, and angiogenesis via activation of the profilin-1 signaling pathway. Our results showed that ANGPTL-4 upregulation was induced by HG, which was dependent on HIF-1α activation that was also triggered by HG, both in vivo and in vitro. Our results suggest that targeting ANGPTL-4, alone or in combination with profilin-1, may be an effective therapeutic strategy and diagnostic screening biomarker for proliferative diabetic retinopathy and other vitreous-retinal inflammatory diseases.

Quantitative proteomics analysis of vitreous body from type 2 diabetic patients with proliferative diabetic retinopathy.

BACKGROUND: To compare the abundance of vitreous proteins between the patients with proliferative diabetic retinopathy (PDR) and idiopathic macular hole (IMH). METHODS: In this study, we performed mass spectrometry-based label-free quantitative proteomics analysis of vitreous samples from type 2 diabetic patients with PDR (n = 9) and IMH subjects (n = 9) and identified the abundance of 610 proteins. RESULTS: Out of 610 proteins, 64 proteins (Group A) were unique to PDR patients, while 212 proteins (Group B) could be identified in IMH vitreous only. Among the other 334 proteins that could be detected in both PDR and IMH eyes, 62 proteins differed significantly (p < 0.05, fold change > 2), which included 52 proteins (Group C) and 10 proteins (Group D) over- and under-expressed in PDR vitreous compared with the control. All proteins in these four groups were counted as significant proteins in our study. CONCLUSIONS: We identified and quantified 610 proteins in total, which included 338 significant proteins in our study. Protein distribution analysis demonstrated a clear separation of protein expression in PDR and IMH. The protein function analysis illustrated that immunity and transport related proteins might be associated with PDR.

Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline.

OBJECTIVE AND DESIGN: Chronic low-grade inflammation occurs in diabetic retinopathy (DR), but the underlying mechanism(s) remains (remain) unclear. NLRP3 inflammasome activation is involved in several other inflammatory diseases. Thus, we investigated the role of the NLRP3 inflammasome signaling pathway in the pathogenesis of DR. METHODS: Diabetes was induced in rats by streptozotocin treatment for 8 weeks. They were treated with NLRP3 shRNA or minocycline during the last 4 weeks. High glucose-exposed human retinal microvascular endothelial cells (HRMECs) were co-incubated with antioxidants or subjected to TXNIP or NLRP3 shRNA interference. RESULTS: In high glucose-exposed HRMECs and retinas of diabetic rats, mRNA and protein expression of NLRP3, ASC, and proinflammatory cytokines were induced significantly by hyperglycemia. Upregulated interleukin (IL)-1ß maturation, IL-18 secretion, and caspase-1 cleavage were also observed with increased cell apoptosis and retinal vascular permeability, compared with the control group. NLRP3 silencing blocked these effects in the rat model and HRMECs, confirming that inflammasome activation contributed to inflammation in DR. TXNIP expression was increased by reactive oxygen species (ROS) overproduction in animal and cell models, whereas antioxidant addition or TXNIP silencing blocked IL-1ß and IL-18 secretion in high glucose-exposed HRMECs, indicating that the ROS-TXNIP pathway mediates NLRP3 inflammasome activation. Minocycline significantly downregulated ROS generation and reduced TXNIP expression, subsequently inhibited NLRP3 activation, and further decreased inflammatory factors, which were associated with a decrease in retinal vascular permeability and cell apoptosis. CONCLUSIONS: Together, our data suggest that the TXNIP/NLRP3 pathway is a potential therapeutic target for the treatment of DR, and the use of minocycline specifically for such therapy may be a new avenue of investigation in inflammatory disease.

Expression of angiopoietin-like protein 8 correlates with VEGF in patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the vitreous and serum levels of angiopoietin-like protein 8 (ANGPTL-8) and vascular endothelial growth factor (VEGF) in patients with proliferative diabetic retinopathy (PDR). The serum levels of these factors were also analyzed in patients with diabetes and no diabetic retinopathy (NDR) and with non-proliferative diabetic retinopathy (NPDR), to detect the possible correlation between the ANGPTL-8 levels and hyperlipidemia. METHODS: Vitreous samples were obtained from 28 patients with PDR and from 12 patients without diabetes and with idiopathic macular hole (IMH). Serum samples were also obtained from 26 patients with NDR and 22 patients with NPDR. ANGPTL-8 levels and other factors were determined using an enzyme-linked immunosorbent assay. RESULTS: The ANGPTL-8 and VEGF levels in the vitreous and serum of the patients with PDR were higher than those in the patients with IMH, and were significantly correlated. The vitreous and serum ANGPTL-8 levels were more correlated with the triglyceride and low-density lipoprotein cholesterol levels than with the high-density lipoprotein cholesterol or total cholesterol levels in the patients with PDR. CONCLUSIONS: The vitreous and serum ANGPTL-8 levels were both upregulated in patients with PDR. There was an association between the elevation in the ANGPTL-8 levels and angiogenic and hyperlipidemic factors in the patients with PDR. These results suggest that ANGPTL-8 is a potential new diagnostic marker and therapeutic target for PDR treatment.

Increased levels of alphaB-crystallin in vitreous fluid of patients with proliferative diabetic retinopathy and correlation with vascular endothelial growth factor.

BACKGROUND: AlphaB-crystallin has been shown to have angiogenic properties. The purpose of this study was to determine the levels of alphaB-crystallin in the vitreous fluid of patients with proliferative diabetic retinopathy and to confirm the association between the expression level of alphaB-crystallin and vascular endothelial growth factor. METHODS: Vitreous samples were collected before vitrectomy from 46 eyes of 46 consecutive patients with proliferative diabetic retinopathy, and 19 patients without diabetes mellitus had vitrectomy for idiopathic macular hole. The concentrations of alphaB-crystallin and vascular endothelial growth factor were measured via enzyme-linked immunosorbent assay. RESULTS: The vitreous level (mean ± SD) of alphaB-crystallin was significantly higher in patients with proliferative diabetic retinopathy (317.3 ± 151.7 ng/mL) than in control patients (idiopathic macular hole, 8.3 ± 6.1 ng/mL) (P < 0.0001). The vitreous concentration of vascular endothelial growth factor was also significantly higher in patients with proliferative diabetic retinopathy (860.1 ± 566.4 pg/mL) than in control patients (9 pg/mL) (P < 0.0001). Meanwhile, both the expression levels of alphaB-crystallin and vascular endothelial growth factor were significantly higher in eyes with active proliferative diabetic retinopathy than in those with inactive proliferative diabetic retinopathy. Also, the vitreous concentration of alphaB-crystallin correlated significantly with that of vascular endothelial growth factor in vitreous fluid of proliferative diabetic retinopathy ([correlation coefficient], R = 0.78, P < 0.001). CONCLUSIONS: These results suggest a significant increase of alphaB-crystallin in the vitreous fluid of patients with proliferative diabetic retinopathy and present a crucial association between alphaB-crystallin and vascular endothelial growth factor with angiogenic activity in proliferative diabetic retinopathy.

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway.

AIMS/HYPOTHESIS: The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. METHODS: The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. RESULTS: High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. CONCLUSIONS/INTERPRETATION: These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucose-induced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.

Prognostic value of endocrine treatment-related symptoms in patients with breast cancer: a meta-analysis.

PURPOSE: Endocrine therapy is associated with improved disease-free survival (DFS) in hormone receptor-positive breast cancer, but it is also associated with many adverse events. The aim of this study was to clarify the association between endocrine treatment-related symptoms and treatment efficacy in patients receiving adjuvant endocrine therapy. METHOD: EMBASE, Web of Science, PubMed, and CENTRAL databases were searched for studies that compared treatment efficacy between patients in whom adverse events did and did not occur during hormone therapy. Hazard ratios (HRs) and associated 95 % confidence intervals (CIs) for DFS and overall survival were estimated and pooled using random-effects models. RESULTS: Of 4665 citations identified, ten studies incorporating 32,192 patients were included in the meta-analysis. The presence of endocrine treatment-related symptoms was associated with improved DFS (HR 0.76; 95 % CI 0.68-0.85). Similar results were observed in patients with vasomotor symptoms (HR 0.76; 95 % CI 0.66-0.87) or musculoskeletal symptoms (HR 0.75; 95 % CI 0.60-0.94), in patients taking an aromatase inhibitor (HR 0.69; 95 % CI 0.57-0.85) or tamoxifen (HR 0.74; 95 % CI 0.60-0.93), and in patients with symptoms at 3-month (HR 0.74; 95 % CI 0.66-0.83), 6-month (HR 0.80; 95 % CI 0.66-0.96), or 12-month follow-up visits (HR 0.75; 95 % CI 0.68-0.83). However, no significant difference in overall survival was observed between patients with or without endocrine treatment-related symptoms (HR 0.82; 95 % CI 0.60-1.11). Sensitivity analysis excluding studies with heterogeneous factors yielded consistent results. No evidence of publication bias was observed. CONCLUSION: In our meta-analysis, endocrine treatment-related symptoms were shown to correlate with superior DFS and may therefore be useful in predicting treatment efficacy in patients with breast cancer receiving hormone therapy.

ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the relationship between angiopoietin-like protein 4 (ANGPTL-4) and vascular endothelial growth factor (VEGF) in the serum and vitreous of eyes in patients with proliferative diabetic retinopathy (PDR). METHODS: Thirty-five eyes of 35 patients with PDR, 20 eyes of 20 patients with non-proliferative diabetic retinopathy, 20 eyes of 20 patients with diabetes but no diabetic retinopathy, and 14 eyes of 14 nondiabetic patients with an idiopathic macular hole (IMH) were recruited from Shanghai First People's Hospital. The ANGPTL-4 and VEGF concentrations were determined using enzyme-linked immunosorbent assays. Group means were compared using one-way analysis of variance with GraphPad Prism 4.0 and SPSS ver. 17.0. The research followed the tenets of the Declaration of Helsinki. RESULTS: The ANGPTL-4 and VEGF levels were significantly higher in the vitreous and serum of patients with PDR compared with patients with IMH. There were significant correlations between the ANGPTL-4 and VEGF levels in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated in patients with PDR. The ANGPTL-4 in both the vitreous and serum correlated with the serum triglyceride and high-density lipoprotein cholesterol levels. CONCLUSIONS: The ANGPTL-4 levels were markedly elevated and the ANGPTL-4 expression was directly correlated with the VEGF expression in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated with serum lipids in patients with PDR. Our results suggest that the ANGPTL-4 may be used as a new therapeutic target for the treatment of PDR.

RhoA/mDia-1/profilin-1 signaling targets microvascular endothelial dysfunction in diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a major cause of blindness in the working-age populations of developed countries, and effective treatments and prevention measures have long been the foci of study. Patients with DR invariably demonstrate impairments of the retinal microvascular endothelium. Many observational and preclinical studies have shown that angiogenesis and apoptosis play crucial roles in the pathogenesis of DR. Increasing evidence suggests that in DR, the small guanosine-5'-triphosphate-binding protein RhoA activates its downstream targets mammalian Diaphanous homolog 1 (mDia-1) and profilin-1, thus affecting important cellular functions, including cell morphology, motility, secretion, proliferation, and gene expression. However, the specific underlying mechanism of disease remains unclear. CONCLUSION: This review focuses on the RhoA/mDia-1/profilin-1 signaling pathway that specifically triggers endothelial dysfunction in diabetic patients. Recently, RhoA and profilin-1 signaling has attracted a great deal of attention in the context of diabetes-related research. However, the precise molecular mechanism by which the RhoA/mDia-1/profilin-1 pathway is involved in progression of microvascular endothelial dysfunction (MVED) during DR has not been determined. This review briefly describes each feature of the cascade before exploring the most recent findings on how the pathway may trigger endothelial dysfunction in DR. When the underlying mechanisms are understood, novel therapies seeking to restore the endothelial homeostasis comprised in DR will become possible.

Security load frequency control model of interconnected power system based on deception attack.

The interconnected power system connects the power grids of different regions through transmission lines, achieving power interconnection and resource sharing. However, data is transmitted through open power networks and is more susceptible to network attacks. To improve the stability of interconnected power systems under deception attacks, three scenarios of system security load frequency control were studied. Based on the construction of a dynamic model of load frequency control, an event-triggered strategy was used to reduce the communication frequency between nodes, resulting in a reduction in the amount of network transmission data. A sliding mode controller was constructed to solve the problem of event-triggered sliding mode security load frequency control. Elastic event-triggered sliding mode load frequency control for interconnected power systems under mixed attacks. The simulation results showed that using the load frequency control model triggered by events, the load frequency deviation of the interconnected power system can be stabilized at around 12 seconds, effectively saving the cost of network resources. Under the regulation of the load frequency control model based on sliding mode control, the interconnected power system stabilized in 10 seconds, reducing the load of network transmission. The elastic event-triggered sliding mode load frequency control model can ensure stable transmission of power data under various attacks and has good anti-interference performance. The results of this study have played an important role in achieving the stability of power resource supply. Compared with previous studies on individual power systems, this study solves the attack problem of interconnected power systems and considers the frequency control problem of system security loads under mixed attacks, enabling the system to recover stability faster.

Interplay of endothelial-mesenchymal transition, inflammation, and autophagy in proliferative diabetic retinopathy pathogenesis.

Background: Assessment and validation of endothelial-mesenchymal transition (EndoMT) in the retinal endothelium of patients with proliferative diabetic retinopathy (PDR) at the level of retinal and vitreous specimens, and preliminary discussion of its regulatory mechanisms. Methods: Transcriptome sequencing profiles of CD31+ cells from 9 retinal fibrovascular mem-branes (FVMs) and 4 postmortem retinas were downloaded from GEO databases to analyze EndoMT-related differentially expressed genes (DEGs). Then, 42 PDR patients and 34 idiopathic macular holes (IMH) patients were enrolled as the PDR and control groups, respectively. Vitreous humor (VH) samples were collected, and the expression of EndoMT-related proteins was quantified by enzyme-linked immunosorbent assay. Results: A total of 5845 DEGs were identified, and we subsequently focused on the analysis of 24 EndoMT-related marker genes, including the trigger of EndoMT, endothelial genes, mesenchymal genes, transcription factors, inflammatory factors, and autophagy markers. Six of these genes were selected for protein assay validation in VH, showing increased mesenchymal marker (type I collagen α 2 chain, COL1A2) and decreased endothelial marker (VE-cadherin, CDH5) accompanied by increased TGFß, IL-1ß, LC3B and P62 in PDR patients. In addition, anti-VEGF therapy could enhance EndoMT-related phenotypes. Conclusions: EndoMT may underlie the pathogenesis of PDR, and the induction and regulation correlate with autophagy defects and the inflammatory response.