Inhibiting sEH suppresses NF-κB p65 signaling and reduces CXCL10 expression as a potential therapeutic target in HT.

BACKGROUND: Although Hashimoto's thyroiditis (HT) is one of most common autoimmune thyroid diseases, its treatment remains focused on symptom relief. The soluble epoxide hydrolase (sEH) shows potential functions as drug target in alleviating some autoimmune diseases, however, we seldom know its role in HT. METHODS: The protein expression of sEH and related downstream molecules were evaluated by immunohistochemistry, western blotting, enzyme linked immunosorbent assay or immunofluorescence staining. RNA sequencing of tissue samples was performed to analyze differential genes and dysregulated pathways in HT and controls. The thyroid follicular epithelial cells (TFECs) and rat HT model were used to verify the biological function of sEH and the inhibition role of adamantyl-ureido-dodecanoic acid (AUDA) in HT. RESULTS: The sEH was significantly up-regulated in HT patients compared with healthy individuals. Transcriptome sequencing showed cytokine-related pathways and chemokine expression, especially chemokine CXCL10 and its receptor CXCR3 were aberrant in HT patients. In TFECs and rat HT model, blocking sEH by AUDA inhibitor could effectively inhibit the autoantibody, pro-inflammatory NF-κB signaling, chemokine CXCL10/CXCR3 expression and type-1 helper CD4+ T cells. CONCLUSIONS: Our findings suggest that sEH/NF-κB p65/CXCL10-CXCR3 might be promising therapeutic targets for HT.

Combination of Breast Ultrasound With Magnetic Resonance Imaging in the Diagnosis of Non-mass-like Breast Lesions Detected on Ultrasound: A New Integrated Strategy to Improve Diagnostic Performance.

OBJECTIVE: The aim of the work described here was to evaluate the diagnostic performance of a new integrated strategy using breast ultrasound (US) combined with magnetic resonance imaging (MRI) to differentiate benign and malignant breast non-mass-like lesions (NMLs) detected on US. METHODS: From October 2017 to January 2021, 183 NMLs detected on US that had undergone MRI examinations were included in this respective study. Pathological results were used as the reference standard. The integrated diagnostic strategy of breast US combined with MRI based on a combination of MRI Breast Imaging Reporting and Data System (BI-RADS) with discriminant sonographic indicators highly associated with malignancy was established and validated in a cohort of 61 women. The diagnostic performances of US, MRI and the combined method were calculated and compared. RESULTS: In the training set, the area under the receiver operating characteristic curve (AUC), sensitivity and specificity of US, MRI and the integrated diagnostic strategy using US combined with MRI for NMLs were 0.730, 93.7% and 52.3%; 0.849, 94.7% and 75.0%; and 0.901, 92.6% and 87.5%, respectively. Compared with US or MRI alone, the integrated diagnostic strategy significantly increased the AUC (p < 0.001, p = 0.007) and specificity (p < 0.001, p = 0.034) while maintaining high sensitivity (p = 0.774, p = 0.551). In the validation set, the integrated strategy of US combined with MRI (AUC = 0.899) also had good performance compared with US (AUC = 0.728) or MRI (AUC = 0.838). CONCLUSION: The integrated diagnostic strategy of US combined with MRI exhibited good performance for breast NMLs compared with either modality used alone, which can improve the diagnostic specificity while maintaining high sensitivity.

Long-term outcomes in lean and non-lean NAFLD patients: a systematic review and meta-analysis.

BACKGROUND: Although nonalcoholic fatty liver disease (NAFLD) commonly occurs in overweight or obese individuals, it is increasingly being identified in the lean population. The association between lean and an increased risk of all-cause mortality among patients with NAFLD remains controversial. We aimed to perform a systematic review and meta-analysis of the literature to evaluate this association and compare the long-term outcomes of lean NAFLD patients and non-lean NAFLD patients. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, and Chinese Biomedical Literature Database (CBM) from inception to October 15, 2021, for relevant original research articles without any language restrictions. Our primary outcome was to compare the all-cause mortality in lean NAFLD patients and non-lean NAFLD patients by qualitative synthesis. Relative risks (RRs) and corresponding 95% confidential intervals (CIs) were pooled with a random effect model. Heterogeneity was evaluated using I-squared (I²) statistics while publication bias was determined using Egger's tests. Subgroup and sensitivity analyses were performed. As for secondary outcomes, we estimated total, cardiovascular, and liver-related mortality, as well as the incidence of diabetes, hypertension, cirrhosis, and cancer in lean and non-lean individuals with NAFLD by quantitative synthesis. Person-years of follow-up were used as the denominator to estimate the mortality and incidence. RESULTS: We identified 12 studies (n = 26,329), 7 of which (n = 7924) were used to evaluate the risk of all-cause mortality between lean and non-lean NAFLD patients. Lean patients with NAFLD were found to be at an elevated risk of death compared to non-lean patients (RR = 1.39, 95% CI 1.08-1.82, heterogeneity: I² = 43%). Among the lean NAFLD population, all-cause mortality was 13.3 (95% CI: 6.7-26.1) per 1000 person-years, 3.6 (95% CI: 1.0-11.7) for liver-related mortality, and 7.7 (95% CI: 6.4-9.2) for cardiovascular-related mortality. The incidence of new-onset diabetes was 13.7 (95% CI 8·2-22.7) per 1000 person-years, new-onset hypertension was 56.1 (95% CI: 40.2-77.9), cirrhosis was 2.3 (95% CI: 1.0-5.0), and cancer was 25.7 (95% CI: 20.3-32.4). CONCLUSIONS: Lean patients with NAFLD had a higher risk of all-cause death than non-lean patients. Body mass index (BMI) should not be used as a criterion to determine whether further observation and therapy of patients with NAFLD are warranted.

Determining whether the diagnostic value of B-ultrasound combined with contrast-enhanced ultrasound and shear wave elastography in breast mass-like and non-mass-like lesions differs: a diagnostic test.

Background: Mass-like (ML) and non-mass-like (NML) are two manifestations of breast lesions on ultrasound. Contrast-enhanced ultrasound (CEUS) can make up for the limitation of B-ultrasound (US) in the observation of focal blood flow, and shear wave elastography (SWE) can supplement the hardness information of the lesion. The present study aimed to analyze the characteristic manifestations of US, CEUS, and SWE in NML and ML breast and evaluate whether the diagnostic performance of these three ultrasound techniques differs in terms of differentiating between benign and malignant breast lesions. Methods: From January to August 2021, 382 patients (417 breast lesions) underwent US, CEUS, and SWE examinations. Of these, 204 women (218 breast lesions) were included in our study due to subsequent biopsy or surgery with pathological findings. The patients were divided into ML and NML groups according to the ultrasound characteristics, and the differences in multimodal ultrasound performance between benign and malignant NML and benign and malignant ML breast lesions were compared. The diagnostic performance of US, US + CEUS, US + SWE, US + CEUS + SWE for ML, NML and all breast lesions was evaluated by analyzing sensitivity, specificity and area under receiver operating characteristic (ROC) curve (AUC). Results: Pathologically, the 218 lesions included 96 malignant and 122 benign breast lesions. The sensitivity and specificity of US + CEUS + SWE in all lesion groups, ML group and NML group were 92.7% and 90.2%, 95.9% and 90.3%, 91.3% and 79.3%, respectively. In all breast group, AUCs of US + CEUS, US + SWE, US + CEUS + SWE were statistically different from AUC of US (P=0.0010, 0.0001, 0.0001). In the ML group, the AUC of US + CEUS, US + SWE, US + CEUS + SWE were statistically different from that of US (P=0.0120, 0.0008, 0.0002). In the NML group, there was a statistical difference between US + SWE and US AUC (P=0.0149). Conclusions: US, CEUS, and SWE have an important diagnostic value for benign and malignant ML and NML breast lesions. Multimodal ultrasound combined with US, CEUS, and SWE can improve the diagnostic efficacy in distinguishing between benign and malignant ML and NML lesions.

Diagnostic performance of contrast-enhanced ultrasound in breast lesions: what diagnostic models could be used for lesions of different sizes?

Background: Previous studies show the size of lesions could affect the diagnostic accuracy of contrast-enhanced ultrasound (CEUS). It is unclear whether CEUS has good diagnostic performance for lesions ≤2.0 and ≤1.0 cm. It is beneficial for the early diagnosis to explore the application of CEUS in breast lesions of different sizes. This study aims to analyze the diagnostic performance of CEUS and explore diagnostic models better suited to breast lesions of different sizes. Methods: A total of 1,059 lesions (656 benign and 403 malignant) examined by ultrasound and CEUS with definite pathological results were included in this retrospective study and divided into training (n=847) and validation (n=212) sets. All lesions were divided into three groups according to size. Diagnostic models (M0: all lesions; M1: ≤1.0 cm, M2: >1.0-2.0 cm, and M3: >2.0 cm) were developed through logistic regression analyses of CEUS features from the training set. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC) and validated in the validation set. Results: The median age of patients was 45±11 years (range, 18-80 years). The AUC values of M0 combined with the Breast Imaging Reporting and Data System (BI-RADS) in the training and validation sets were 0.921 and 0.922, respectively (P=0.893). The AUC values of M0 combined with BI-RADS in the three groups were 0.844, 0.936 and 0.928 respectively. M0 was less effective in diagnosing lesions ≤1.0 cm (0.844 vs. 0.921, P=0.029). The AUC of M1 combined with BI-RADS for lesions ≤1.0 cm was higher than that of M0 (0.893 vs. 0.844, P=0.047), and M2 and M3 had no statistical difference in diagnostic performance when compared with M0 (P=0.243; P=0.246). Conclusions: The diagnostic performance of CEUS was closely related to lesion size. Establishing a new diagnostic model for lesions ≤1.0 cm can improve the CEUS diagnostic performance for breast lesions ≤1.0 cm.

Efficacy and safety of percutaneous ultrasound-guided vacuum-assisted excision for the treatment of clinical benign breast lesions larger than 3 cm: a retrospective cohort study.

Background: Breast ultrasound-guided vacuum-assisted excision (US-VAE) has become a scarless solution for the removal of benign breast lesions. This procedure is now favored by more and more female patients for its satisfactory cosmetic outcome and few postoperative complications. However, controversy have been raised regarding its efficacy and safety in treating larger benign breast lesions. This study aimed to evaluate whether US-VAE is sufficient for the treatment of clinical benign breast lesions larger than 3 cm and to investigate the lesion features that affect the complete excision rate and hematoma occurrence rate. Methods: From January 2018 to July 2021, a total of 1,812 lesions in 1,367 patients underwent US-VAE at the Chinese People's Liberation Army General Hospital. A total of 89 benign breast lesions in 87 patients enrolled in this retrospective cohort study. The baseline clinical characteristics and ultrasonographic features of the lesions were recorded. Patients were followed up by US to record if there are any serious issues and the occurrence of hematoma and the recurrence of the lesions within 3 days and 6-12 months later, then at 1-year intervals. Lesions were classified to analyze the possible factors associated with complete excision rate and hematoma occurrence rate. Results: The mean age was 35.9±9.5 years (range, 18-54 years), and the median maximum size of benign breast lesions was 3.5 cm (range, 3.1-5.0 cm). The complete excision rate was 91.0% (81/89). Histopathology (P=0.002) and vascularity (P=0.032) of lesions showed statistically significant differences in groups with or without recurrent lesions. A total of 17 cases (17/89, 19.1%) presented with hematoma after the procedure. The maximum lesion size in patients with hematoma was significantly larger than that in those without hematoma (P<0.001). Conclusions: US-VAE is an effective and safe alternative method for the treatment of benign breast lesions larger than 3 cm, especially for fibroadenoma, adenosis, hamartoma. For benign phyllodes tumors and intraductal papillomas larger than 3 cm and lesions with hypervascularity, the possibility of recurrence after US-VAE should be noted. The size of lesions needs to be considered when evaluating the occurrence of hematoma after US-VAE.

Papillary breast lesions detected using conventional ultrasound and contrast-enhanced ultrasound: Imaging characteristics and associations with malignancy.

OBJECTIVE: This study aimed to evaluate the imaging features of papillary breast lesions detected using conventional ultrasonography (US) and contrast-enhanced ultrasound (CEUS) and to correlate the pathological results. Furthermore, the diagnostic efficiencies of these imaging features to predict the malignancy potential of papillary lesions were explored. METHODS: The findings of the conventional US and CEUS of 74 consecutive papillary breast lesions were assessed retrospectively. The obtained data were analyzed using univariate and multivariate logistic regressions to evaluate the ability of each parameter and combined parameters in distinguishing the benign and atypical or malignant papillary lesions. RESULTS: Among the imaging features of breast papillary lesions on conventional US and CEUS, two sonographic features (lesion size ≥1 cm and not circumscribed margin) on conventional US and four enhancement features (irregular enhancement, heterogeneous enhancement, enlargement of scope, and perfusion defect) on CEUS were found to be significantly different between the benign and atypical or malignant papillary lesions (P < 0.05). A multivariate logistic regression analysis further showed that only heterogeneous enhancement and enlarged enhancement scope were associated with malignancy. The sensitivity and specificity of heterogeneous enhancement, enlarged enhancement scope, and combined analysis for predicting atypical and malignant papillary lesions were 78.6 % and 39.1 %, 75 % and 37 %, and 75 % and 82.6 %, respectively. The combination of enhancement homogeneity and enhancement scope improved the diagnostic accuracy (AUC = 0.875). CONCLUSIONS: The results suggested that the imaging features on conventional US and CEUS could help in identifying benign and malignant papillary lesions and predict their malignancy potential.

CTRP13 attenuates the expression of LN and CAV-1 Induced by high glucose via CaMKKß/AMPK pathway in rLSECs.

OBJECTIVE: To investigate the effect and mechanism of CTRP13 on hepatic sinusoidal capillarization induced by high glucose in rat liver sinusoidal endothelial cells (rLSECs). RESULTS: CTRP13 was reduced in high glucose-treated rLSECs. High glucose increased LN and CAV-1 expression and inhibited CaMKKß and AMPK phosphorylation. CTRP13 overexpression protected rLSECs against high glucose-induced increase of LN and CAV-1 expression. Moreover, CTRP13 overexpression increased high glucose-induced inhibition of CaMKKß and AMPK activation in CTRP13-overexpressing rLSECs. Inhibition of CaMKKß and AMPK disturbed the protective effects of CTRP13 in high glucose-induced increase of LN and CAV-1. Hepatic steatosis was enhanced and basement membrane was thickened in liver of diabetic fatty liver rats. CONCLUSIONS: Our data identified the protective role of CTRP13 in hepatic sinusoidal capillarization induced by high glucose via activating CAMKKß/AMPK pathway. CTRP13 may be a potential target for screening and treating diabetic fatty liver. METHODS: Construct lentiviral CTRP13 overexpression vector and transfect rLSECs. Use STO-609 (a CaMKKß inhibitor) or Compound C (an AMPK inhibitor) to treat rLSECs. CTRP13, CaMKKß, AMPK, laminin (LN) and caveolin-1 (CAV-1) were detected by qRT-PCR and Western blotting. Establish rat model of diabetic fatty liver. Use immunohistochemistry, hematoxylin-eosin and silver staining to observe the histopathological features of liver.

Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms.

We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway.

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1.

Non-alcoholic fatty liver disease is associated with hepatic microangiopathy and liver inflammation caused by type 2 diabetes mellitus. Oxidised LDL (oxLDL) is involved in proinflammatory and cytotoxic events in various microcirculatory systems. The lectin-like oxLDL receptor 1 (LOX1) plays a crucial role in oxLDL-induced pathological transformation. However, the underlying mechanism of oxLDL's effects on liver microcirculation disturbances remains unclear. In this study, we investigated the effects of oxLDL on LOX1 (OLR1) expression and function, as well as on the fenestration features of human liver sinusoidal endothelial cells (HLSECs) in vitro. Primary HLSECs were obtained and cultured. The cells were treated with various concentrations of oxLDL (25, 50, 100 and 200  µg/ml), and the cytotoxicity and expression of LOX1 were examined. Furthermore, LOX1 knockdown was performed using siRNA technology, and the changes in intracellular reactive oxygen species (ROS), NFκB, p65, (p65), endothelin 1 (ET1 (EDN1)), eNOS (NOS3) and caveolin 1 (CAV1) levels were measured. Cells were treated with 100  µg/ml oxLDL, and the fenestra morphology was visualised using scanning electron microscopy. oxLDL significantly increased LOX1 expression at both the mRNA and protein levels in HLSECs in a dose- and time-dependent manner. oxLDL stimulation increased ROS generation and NFκB activation, upregulated ET1 and caveolin 1 expression, downregulated eNOS expression and reduced the fenestra diameter and porosity. All of these oxLDL-mediated effects were inhibited after LOX1 knockdown. These results reveal a mechanism by which oxLDL stimulates the production of LOX1 through the ROS/NFκB signalling pathway and by which LOX1 mediates oxLDL-induced endothelial injury and the defenestration of HLSECs.

Protection effect of endomorphins on advanced glycation end products induced injury in endothelial cells.

Endomorphins (EMs) have a very important bridge-function in cardiovascular, endocrinological, and neurological systems. This study is to investigate the effects of EMs on the synthesis and secretion of vasoactive substances induced by advanced glycation end products in primary cultured human umbilical vein endothelial cells (HUVECs). Firstly, HUVECs were stimulated with AGEs-bovine serum albumin (AGEs-BSA), bovine serum albumin (BSA), or both AGEs-BSA and EMs together, respectively. Then, HUVEC survival rate was calculated by MTT assay, the levels of NO, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) were detected by colorimetric analysis, and the contents of endothelin-1 (ET-1) were detected by ELISA. The mRNA levels of eNOS and ET-1 were measured by RT-PCR. The expression of p38 mitogen-activated protein kinase (p38 MAPK) was detected by immunofluorescence assay. The results showed that the mRNA expression and secretion of eNOS were significantly enhanced after incubation with EMs compared to those with AGEs-BSA, while the secretion of NO and iNOS, mRNA expression, and secretion of ET-1 had opposite changes. The fluorescence intensity of p38MAPK in nuclear was decreased after pretreatment with EMs compared to incubation with AGEs-BSA. Conclusion. The present study suggests that EMs have certain protection effect on AGEs-BSA-induced injury in HUVEC.