The landscape of immune checkpoint-related long non-coding RNAs core regulatory circuitry reveals implications for immunoregulation and immunotherapy responses.

Long non-coding RNAs (lncRNAs) could modulate expression of immune checkpoints (ICPs) by cooperating with immunity genes in tumor immunization. However, precise functions in immunity and potential for predicting ICP inhibitors (ICI) response have been described for only a few lncRNAs. Here we present an integrated framework that leverages network-based analyses and Bayesian network inference to identify the regulated relationships including lncRNA, ICP and immunity genes as ICP-related LncRNAs mediated Core Regulatory Circuitry Triplets (ICP-LncCRCTs) that can make robust predictions. Hub ICP-related lncRNAs such as MIR155HG and ADAMTS9-AS2 were highlighted to play central roles in immune regulation. Specific ICP-related lncRNAs could distinguish cancer subtypes. Moreover, the ICP-related lncRNAs are likely to significantly correlated with immune cell infiltration, MHC, CYT. Some ICP-LncCRCTs such as CXCL10-MIR155HG-ICOS could better predict one-, three- and five-year prognosis compared to single molecule in melanoma. We also validated that some ICP-LncCRCTs could effectively predict ICI-response using three kinds of machine learning algorithms follow five independent datasets. Specially, combining ICP-LncCRCTs with the tumor mutation burden (TMB) improves the prediction of ICI-treated melanoma patients. Altogether, this study will improve our grasp of lncRNA functions and accelerating discovery of lncRNA-based biomarkers in ICI treatment.

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.

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.

Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study.

PURPOSE: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION: Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

Identifying immune checkpoint-related lncRNA biomarkers for immunotherapy response and prognosis in cancers.

Long non-coding RNAs (lncRNAs) could modulate expression of immune checkpoints (ICPs) in tumor-immune. However, precise functions in immunity and potential for predicting ICP inhibitors (ICI) response have been described for only a few lncRNAs. Here, a multiple-step pipeline was developed to identify cancer- and immune-context ICP and lncRNA cooperative regulation pairs (ICPaLncCRPs) across cancers. Immune-related ICPs and lncRNAs were extracted follow immune cell lines and immunologic constant of rejection groups. ICPaLncCRP networks were constructed, which likely to modulate tumor-immune by specific patterns. Common and specific hub ICPaLncs such as MIR155HG, TRG-AS1 and PCED1B-AS1 maybe play central roles in prognosis and circulating. Moreover, these hub ICPaLncs were significantly correlated with immune cell infiltration based on bulk and single-cell RNA sequencing data. Some ICPaLncCRPs such as IDO1-MIR155HG could predict three- and five-year prognosis of melanoma in two independent datasets. We also validated that some ICPaLncCRPs could effectively predict ICI-response follow six independent datasets. Collectively, this study will enhance our understanding of lncRNA functions and accelerate discovery of lncRNA-based biomarkers in ICI treatment.

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.

The prognostic significance of skin involvement in breast cancer patients with chest wall recurrence.

PURPOSE: To assess the prognostic significance of skin involvement in breast cancer patients with chest wall recurrence (CWR). METHODS: We retrospectively analyzed the clinicopathological data of breast cancer patients with CWR who were diagnosed pathologically between January 2000 and April 2020. Disease-free survival (DFS) was the time from radical resection for CWR to disease recurrence. Progression-free survival (PFS) was defined as the time from the diagnosis of locally unresectable CWR to the first sign of disease progression. Persistent chest wall progression was defined as three consecutive chest wall progressions with no distant organ involvement. RESULTS: A total of 476 patients with CWR were included in this study. Skin involvement was confirmed in 345 patients. Skin involvement was significantly correlated with a high T stage (p = 0.003), more positive nodes at initial examination (p < 0.001) and lymphovascular invasion (p < 0.001). Kaplan-Meier analysis showed that skin involvement was a predictor of shorter DFS (p < 0.001), including both local disease progression (p < 0.001) and distant disease progression (p = 0.022). Multivariate analysis showed that skin involvement was an independent biomarker for DFS (p = 0.043). Patients with skin involvement were more likely to experience persistent chest wall progression (p = 0.040). After eliminating the potential deviation caused by an insufficient follow-up time, persistent chest wall progression was more likely to be associated with a high N stage (p = 0.002), negative progesterone receptor (PR; p = 0.001) and positive human epidermal growth factor receptor 2 (HER2; p = 0.046) of the primary site, and negative oestrogen receptor (ER; p = 0.027) and PR (p = 0.013) of the chest wall lesion and skin involvement (p = 0.020). CONCLUSION: Skin involvement was a predictor of poor disease control in patients with CWR and was closely related to persistent chest wall progression. We stratified the prognosis of individualized treatment for breast cancer patients with CWR to provide new insights into the biological behaviours of the disease.

Skin involvement is a predictor of poor local disease control in breast cancer patients with CWR and a factor contributing to persistent chest wall progression after CWR. We stratified the prognosis of individualized treatment for breast cancer patients with CWR.

Subcutaneous pedicled propeller flap technique for microscopic reconstruction of eyelid defects.

AIM: To describe the subcutaneous pedicled propeller flap technique for the microscopic reconstruction of eyelid defects and evaluate its outcomes. METHODS: The clinical data of 23 patients (23 eyes) who underwent microscopic reconstruction of eyelid defects with the subcutaneous pedicled propeller flap technique were retrospectively analyzed. All patients underwent eyelid tumor resection and one-stage microscopic reconstruction with the subcutaneous pedicled propeller flap for anterior- or posterior-layer eyelid defects. The survival rate of the propeller flap, eyelid function and appearance, tumor recurrence rate, and patient satisfaction were evaluated after the surgery. RESULTS: The patients consisted of 12 men and 11 women, aged 31-82y (mean, 58.9y). The longest follow-up time was 5y, and the shortest was 3mo. All the propeller flaps survived well. There was no significant difference in color and luster between the flap and adjacent tissues, and there was no dog ear phenomenon. No obvious scarring was observed. There were no obvious abnormalities of eyelid morphology or function, and no adverse complications such as exposure keratitis, entropion, ectropion, ptosis, and eyelid retraction. No tumor recurrence was found at the time of the last follow-up. All patients were satisfied with the surgical results. CONCLUSION: The subcutaneous pedicled propeller flap technique for the microscopic reconstruction of eyelid defects has satisfactory outcomes in terms of eyelid function and esthetics, and merits clinical application.

[Acupuncture regulates autophagy in hippocampal neurons of cerebral ischemia/reperfusion injured rats by activating type â ¢ PI3K/Beclin-1 pathway].

OBJECTIVE: To observe the effects of acupuncture on the expression of type Ⅲ phosphatidylinositol 3-hydroxykinase (PI3K) and Beclin-1 in hippocampus of rats with cerebral ischemia/reperfusion injury (CI/RI), so as to explore the mechanism of acupuncture in regulating type Ⅲ PI3K pathway to activate autophagy in the hippocampal neurons of CI/RI rats. METHODS: SD rats were randomly divided into sham operation group (n=11) and operation group. Then after successful modeling, rats in the operation group were randomly divided into model, acupuncture, model+3-MA and acupuncture+3-MA groups, with 11 rats in each group. The model of CI/RI was established by occlusion of the middle cerebral artery. Rats in the model+3-MA and acupuncture+3-MA groups were injected with 3-MA (400 nmol/ 5 µL) 5 µL into the lateral ventricle 30 min before reperfusion. Rats in the acupuncture and acupuncture+3-MA groups were punctured with filiform needles at "Dazhui" (GV14), "Shuigou" (GV26) and "Baihui" (GV20) and stimulated manually once every 15 min. The acupuncture intervention was conducted for 30 min each time, once every 12 h for a total of 7 times. The degree of neurological impairment was evaluated 2 h after reperfusion and after intervention by Garcia score. After intervention, the percentage of cerebral ischemic area was observed by TTC staining, the protein expression levels of type Ⅲ PI3K, Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B), lysosome associated membrane protein 2 (Lamp2) and P62 in ischemic hippocampal tissue were detected by Western blot, the ultrastructure of neurons in ischemic hippocampus was observed by transmission electron microscopy (TEM). RESULTS: Compared with the sham operation group, the Garcia score was decreased (P<0.01), the percentage of cerebral ischemic area was increased (P<0.01), the expression levels of type Ⅲ PI3K, Beclin-1, LC3B-Ⅱ/Ⅰ, Lamp2 proteins were decreased (P<0.01), and the expression level of P62 protein was increased (P<0.01) in ischemic hippocampal tissue in the model group. Compared with the model group, the Garcia score was increased (P<0.01), the percentage of cerebral ischemic area was decreased (P<0.01), the expression levels of type Ⅲ PI3K, Beclin-1, LC3B-Ⅱ/Ⅰ, Lamp2 proteins were increased (P<0.01, P<0.05) and the expression level of P62 was decreased (P<0.01) in ischemic hippocampal tissue in the acupuncture group； the percentage of cerebral ischemic area was increased (P<0.05), the expressions of type Ⅲ PI3K and Beclin-1 were decreased (P<0.01) and the expression level of P62 protein was increased (P<0.05) in ischemic hippocampal tissue in the mo-del+3-MA group. Compared with the model +3-MA group, the Garcia score was increased (P<0.05), the percentage of cerebral ischemic area was decreased (P<0.01), the expression levels of type Ⅲ PI3K, Beclin-1, LC3B-Ⅱ/Ⅰ in ischemic hippo-campal tissue were increased (P<0.01, P<0.05) in the acupuncture+3-MA group. Compared with the acupuncture group, the Garcia score was decreased, the percentage of cerebral ischemic area was increased (P<0.05, P<0.01), the expression levels of type Ⅲ PI3K, Beclin-1, Lamp2 proteins were decreased (P<0.01, P<0.05) and P62 protein was increased (P<0.05) in ischemic hippocampal tissue in the acupuncture+3-MA group. The results of TEM showed that the edema of neurons was heavier, and few hypolysosomes existed in the model group; there was no obvious damage to neuronal structure, intracellular matrix was abundant, and a few lysosomes existed in the acupuncture group; the neuronal cells had mild edema and primary lysosomes were present in the acupuncture +3-MA group. CONCLUSION: Acupuncture can improve the symptoms of neurological impairment and reduce the percentage of cerebral ischemic area in rats with CI/RI. The mechanism may be related to regulating type Ⅲ PI3K/Beclin-1 pathway, up-regulating the expressions of autophagy related factors LC3B-Ⅱ and Lamp2, and down-regulating the expression of P62.

An update on the role of thioredoxin-interacting protein in diabetic kidney disease: A mini review.

Thioredoxin-interacting protein (TXNIP) was first isolated from Vitamin D3-exposed HL60 cells. TXNIP is the main redox-regulating factor in various organs and tissues. We begin with an overview of the TXNIP gene and protein information, followed by a summary of studies that have shown its expression in human kidneys. Then, we highlight our current understanding of the effect of TXNIP on diabetic kidney disease (DKD) to improve our understanding of the biological roles and signal transduction of TXNIP in DKD. Based on the recent review, the modulation of TXNIP may be considered as a new target in the management of DKD.

A Prediction Nomogram for Recurrent Retinal Detachment.

Purpose: Recurrent retinal detachment (re-RD) is one of the complications in rhegmatogenous retinal detachment patients who underwent surgical treatment. We investigated the risk factors for re-RD and developed a nomogram for estimating clinical risk. Methods: Univariate and multivariable logistic regression models were performed to determine the association between variables and re-RD, and a nomogram was then developed for re-RD. The nomogram performance was assessed based on its discrimination, calibration, and clinical usefulness. Results: This study analyzed 15 potential variables of re-RD in 403 rhegmatogenous retinal detachment patients who underwent initial surgical treatment. Axial length, inferior breaks, retinal break diameter, and surgical methods were independent risk factors for re-RD. A clinical nomogram incorporating these four independent risk factors was constructed. The diagnostic performance of the nomogram was excellent (area under the curve = 0.892, 95% CI: 0.831-0.953). Our study further validated this nomogram by bootstrapping for 500 repetitions. The area under the curve of the bootstrap model was 0.797 (95% CI: 0.712-0.881). This model showed good calibration curve fitting and a positive net benefit in decision curve analysis. Conclusion: Axial length, inferior breaks, retinal break diameter, and surgical methods could be risk factors for re-RD. We have developed a prediction nomogram of re-RD for rhegmatogenous retinal detachment following initial surgical treatment.

The prognostic value and immune microenvironment association of AR in HER2+ nonmetastatic breast cancer.

This study aimed to investigate the prognostic value of AR in HER2+ nonmetastatic breast invasive ductal carcinoma (IDC) and its relationship with the immune microenvironment. HER2+ nonmetastatic breast IDC patients diagnosed by pathology who underwent surgery at Sun Yat-sen University Cancer Center from 2016 to 2017 were included. AR+ and AR- breast IDC samples were matched 1:1 in age, T stage, and N stage for immune infiltration analysis. A total of 554 patients with HER2+ nonmetastatic breast cancer were included in this retrospective study, regardless of HR status. The cut-off value for AR was set at 10%. ER+ (p < 0.001) and PR+ (p < 0.001) were associated with positive AR expression. Kaplan-Meier survival curve analysis suggested that AR was closely correlated with overall survival (OS) (p = 0.001) but not disease-free survival (DFS) (p = 0.051). After eliminating the potential impact caused by HR, AR also predicted longer OS (p = 0.014) and was an independent predictive factor for OS of HER2+HR- nonmetastatic breast IDC patients, as revealed by multivariate analysis (p = 0.036). For AR+ and AR- matched HER2+HR- patients, TILs (p = 0.043) and PD-L1 (p = 0.027) levels were significantly lower in AR+ patients. The strongest negative correlation was observed between AR and PD-L1 (Pearson's r = -0.299, p = 0.001). AR+ status was markedly related to better OS in HER2+HR- nonmetastatic breast cancer patients, while a negative correlation was observed between AR and PD-L1/TILs. We provide new insights into the prognostic value of AR and its association with the immune microenvironment to optimize treatment strategies in HER2+ nonmetastatic breast IDCs.

Construction and validation of a macrophage polarization-related prognostic index to predict the overall survival in patients with early-stage triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and the current prognostic system cannot meet the clinical need. Interactions between immune responsiveness and tumor cells plays a key role in the progression of TNBC and macrophages are vital component of immune cells. A prognostic model based on macrophages may have great accuracy and clinical utility. Methods: For model development, we screened early stage (without metastasis) TNBC patients from The Cancer Genome Atlas (TCGA) database. We extracted messenger RNA (mRNA) expression data and clinical data including age, race, tumor size, lymph node status and tumor stage. The follow up time and vital status were also retrieved for overall survival calculation. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was used to calculate the immune cell composition of each sample. Weighted gene co-expression network analysis (WGCNA) was used to identify M1-like macrophage-related genes. Combining least absolute shrinkage and selection operator (LASSO) with multivariate Cox regression, the M1-like macrophage polarization-related prognostic index (MRPI) was established. We obtained TNBC patients in Gene Expression Omnibus (GEO) database through PAM50 method and retrieved the mRNA expression data and survival data. The Harrell's concordance index (CI), the area under the receiver operating characteristic (ROC) curves (AUCs) and the calibration curve were used to evaluate the developed model. Results: We obtained 166 early TNBC cases and 113 normal tissue cases for model building, along with 76 samples from GSE58812 cohort for model validation. CIBERSORT analysis suggested obvious infiltration of macrophages, especially M1-like macrophages in early TNBC. Four genes were eventually identified for the construction of MPRI in the training set. The AUCs at 2 years, 3 years, and 5 years in the training cohort were 0.855, 0.881 and 0.893, respectively; and the AUCs at 2 years, 3 years, and 5 years in the validation cohort were 0.887, 0.792 and 0.722, respectively. Calibration curves indicated good predictive ability and high consistency of our model. Conclusions: MRPI is a promising biomarker for predicting the prognosis of early-stage TNBC, which may indicate personalized treatment and follow-up strategies and thus may improve the prognosis.

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.

Current Situation of Diagnosis and Treatment of HER2-Positive Metastatic Breast Cancer Patients in China: A Nationwide Cross-Sectional Survey of Doctors.

BACKGROUND: The Advanced Breast Cancer Alliance conducted a nationwide investigation to understand the current situation of the diagnosis and treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients. METHODS: In 2019, electronic questionnaires including basic information about respondents, characteristics of patients, and the present status of diagnosis and treatment were sent to 495 doctors from 203 medical centers covering 28 provinces. RESULTS: The factors that influenced treatment plans included the disease process, the performance status, and the economic status of patients. Regimens and response to neoadjuvant/adjuvant chemotherapy were important factors in the decision of the first-line treatment. Overall, 54% of doctors retained trastuzumab and replaced chemotherapy drugs in second-line treatment regimens for patients with progression-free survival (PFS) ≥ 6 months in the first-line setting, while 52% of participants chose pyrotinib plus capecitabine for patients with PFS < 6 months. Economic factors played an important role in doctors' decision-making and the varying treatment options for respondents in first-tier, second-tier, and other cities. CONCLUSIONS: This large-scale survey regarding the diagnosis and treatment of HER2-positive MBC patients revealed that clinical decisions made by Chinese doctors followed the guidelines, but their choices were constrained by economic factors.

Procyanidin B2 Protects TR-iBRB2 Cells Against Hyperglyc emia Stress by Attenuating Oxidative Stress and Inflammasome Activation via Regulation of Redoxosomes/NF-kB Signaling.

BACKGROUND: Microvascular dysfunction is a hallmark of diabetic retinopathy (DR), which may lead to visual impairment and blindness. Procyanidin B2 (PB2) is a subclass of flavonoids and is widely known due to its anti-oxidant and antiinflammatory effects. However, little is known about the effect of PB2 on hyperglycemia stress-induced retinal microvascular dysfunction. OBJECTIVE: The purpose of this study was to investigate the effect of PB2 against hyperglycemia stress in rat retinal capillary endothelial cells (TR-iBRB2) as well as the underpinning mechanism. METHODS: Cell viability was determined using MTT assay. ROS, NOX activity analysis, Western blot analysis, and immunofluorescence analysis were applied in the study. RESULTS: The results showed that PB2 pre-treatment significantly reduced high glucose- induced cytotoxicity in TR-iBRB2 cells by suppressing oxidative stress and inflammasome activation. Mechanistical study revealed that redoxosomes were formed and activated in TR-iBRB2 cells upon hyperglycemia stress, resulting in activation of NF- κB and thus induction of oxidative stress and inflammasomes activation. However, PB2 pre-treatment dose-dependently attenuated the above events, indicating the protective effect of PB2 against hyperglycemia stress was achieved by regulating redoxosomes/ NF-kB signaling. CONCLUSION: Our findings may contribute to the potential clinical use of PB2 in treating DR and suggest redoxosomes/NF-kB signaling may be a potential therapeutic target of this disease.

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.

Trends and Disparities in the Incidence of Intraocular Foreign Bodies 1990-2019: A Global Analysis.

Objectives: This study aims to provide trends and disparities in the incidence of intraocular foreign bodies (IOFBs) from 1990 to 2019 in 204 countries by region, country, socio-demographic index (SDI), age, and sex. Methods: The global, regional and national number of incident cases as well as age-standardized incidence rate (ASIR) of IOFBs were attained from the Global Burden of Disease Study 2019 (GBD 2019). To estimate the trend of ASIR of IOFBs, the estimated annual percentage change (EAPC) was calculated from 1990 to 2019. Results: Globally, although ASIR of IOFBs decreased with an EAPC of -0.93% [95% uncertainty interval (UI) -1.1 to -0.76] from 1990 to 2019, ASIR of IOFBs increased from 2008 to 2019. From 35.79 million (95% UI 23.62-50.89) in 1990 to 46.63 million (95% UI 32.45-64.45) in 2019, the number of IOFB incident cases worldwide increased by 30.29% (95% UI 19.63-43.55). The incidence of IOFBs varied by region and country, and it was closely related to socio-economic development. Furthermore, while ASIR of IOFBs was high in the young population aged 15-49 years, we observed a significant increase in the number of IOFB incident cases in older adults when compared to other age groups. In terms of sex, males accounted for the vast majority of IOFB incident cases. Conclusions: The global ASIR of IOFBs is on the rise, with an increase in incident cases, designating IOFBs as a global health challenge. The incidence of IOFBs cases is directly related to geographic location, socio-economic status, age, sex, and other factors. Our findings could be useful for the control and prevention of IOFBs.

[Acupuncture mediated miR-34c-5p regulates the autophagy of hippocampal neurons in rats with cerebral ischemia/reperfusion injury].

OBJECTIVE: To observe the effect of acupuncture on the expression of miR-34c-5p, autophagy-related proteins and apoptosis rate in hippocampus of rats with cerebral ischemia/reperfusion injury (CI/RI), so as to explore its mechanism in regulating autophagy in hippocampal neurons in CI/RI rats. METHODS: SD rats were randomly divided into sham operation, model, medication and acupuncture groups, with 20 rats in each group. The rat model of CI/RI was established by occlusion of the middle cerebral artery. In the acupuncture group, "Dazhui" (GV14), "Baihui" (GV20) and "Shuigou" (GV26) were punctured with filiform needles and stimulated manually once every 15 min, for 30 min. The rats of the medication group were intraperito-neally injected with edaravone (5 mg/kg). The treatment was conducted once every 12 h for a total of 7 times. The neurological de-ficit score of all the rats were evaluated according to Garcia's methods, and TTC staining was employed to assess the cerebral ischemic area (percentage of cerebral infarct area, CIA). Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of hippocampal neurons. The expression of hippocampal miR-34c-5p was measured by real-time PCR, and the protein expressions of hippocampal LC3B, Beclin1 and p62 were measured by Western blot. The apoptosis rate of ischemic brain tissue was observed by TUNEL staining. RESULTS: Compared with the sham operation group, the neurological deficit score, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly decreased (P<0.01, P<0.05), and the CIA and the apoptosis rate significantly increased (P<0.01) in the model group. Compared with the model group, the neurological deficit scores, the expressions of miR-34c-5p, Beclin1, p62 and LC3B-Ⅱ/LC3B-Ⅰ were significantly increased (P<0.01, P<0.05), and the CIA and the apoptosis rate significantly decreased (P<0.01) in the medication and acupuncture groups. Compared with the medication group, the expression of miR-34c-5p was significantly increased (P<0.01). The results of electron microscope showed that the neurons in the acupuncture and medication groups were less damaged than those in the model group, the cells showed mild edema, and the structures were relatively complete. Some normal organelles could be seen, and autophagy bodies, autophagy lysosomes and their encapsulated organelles could still be observed. CONCLUSION: Acupuncture can improve the neurological deficit and reduce the area of cerebral infarction in CI/RI rats, which is closely with its effect in promoting hippocampal neuronal autophagy and anti-apoptosis via up-regulating the expression of miR-34c-5p.

Similarities and differences in working memory and neurometabolism of obsessive-compulsive disorder and major depressive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) both showed cognitive impairment, and the altered neurometabolic may associate with cognitive impairment. However, there are limited comparative working memory (WM) and neuroimaging studies on these two disorders. Therefore, we investigated the characteristics of WM and neurometabolic changes in patients with OCD and MDD. METHODS: A total of 64 unmedicated patients (32 OCD and 32 MDD), and 33 healthy controls (HC) were included to conduct WM assessment comprising Digit Span Test (DST), 2-back task and Stroop Color and Word Test (SCWT). Additionally, all subjects underwent protons magnetic resonance spectroscopy (1H-MRS) to collect neurometabolic ratios of N-acetyl aspartate (NAA) and choline-containing compounds (Cho) to creatine (Cr) in the prefrontal cortex (PFC) and lentiform nucleus (LN). Finally, differential and correlation analysis were conducted to investigate their characteristics and relationships. RESULTS: Compared with HC, both OCD and MDD patients exhibited a lower accuracy rate in the 2-back task, and only MDD patients performed worse in DST scores and longer reaction times in SCWT (all p < 0.05). Both OCD and MDD patients had lower NAA/Cr ratios in bilateral PFC (all p < 0.05). And the decreased NAA/Cr ratios in right PFC were positively correlated to DST scores in MDD group (r = 0.518, p = 0.003). CONCLUSIONS: Both OCD and MDD showed WM impairment and neurometabolic alterations in PFC. Besides, MDD performed more severe and broader WM impairment compared to OCD. Moreover, the dysfunction of PFC may underlie the neural basis of WM impairment in MDD.