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To clarify the mechanisms underlying TRPV4 regulating angiogenesis by enhancing the activity of CACs, we detected the angiogenesis ability of HUVEC co-cultured with CACs, the effects of ILK on TRPV4 expression and CACs activity, and the impacts of TRPV4 agonist or inhibitor on cardio-protection of AMI rats with or without CAC transplantation. ILK overexpression or TRPV4 agonist promoted the angiogenesis in HUVEC co-cultured with CACs. ILK overexpression or activation upregulated TRPV4 expression in CACs, while TRPV4 agonist stimulation also regulated ILK expression. TRPV4 agonist effectively improved the myocardial function of AMI rats. Moreover, this effect could be strengthened when combined with CAC transplantation, as CAC transplantation dramatically upregulated the expression of ILK and TRPV4 in heart tissues of AMI rats. Thus, the application of TRPV4 agonist may maintain the activity of CACs to promote angiogenesis and microcirculation reconstruction in the area of myocardial infarction and substantially improve the therapeutic effect.

Background Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI. Methods We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state. Results We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro. Conclusion These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI.

We explored the effect of thrombin on human aortic smooth muscle cells (HASMCs) and further analyzed its role in the pathogenesis of atherosclerosis (AS). Thrombin-induced differentially expressed genes (DEGs) in HASMCs were identified by analyzing expression profiles from the GEO. Subsequently, enrichment analysis, GSEA, PPI network, and gene-microRNAs networks were interrogated to identify hub genes and associated pathways. Enrichment analysis results indicated that thrombin causes HASMCs to secrete various pro-inflammatory cytokines and chemokines, exacerbating local inflammatory response in AS. Moreover, we identified 9 HUB genes in the PPI network, which are closely related to the inflammatory response and the promotion of the cell cycle. Additionally, we found that thrombin inhibits lipid metabolism and autophagy of HASMCs, potentially contributing to smooth muscle-derived foam cell formation. Our study deepens a mechanistic understanding of the effect of thrombin on HASMCs and provides new insight into treating AS.

Background Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear. We aim to identify key transcription factor genes involved in diabetic tubulointerstitial injury. Methods A microarray dataset (GSE30122) from Gene Expression Omnibus (GEO) was downloaded. A total of 38 transcription factor genes based on 166 differentially expressed genes (DEGs) were identified by UCSC_TFBS. Results The regulatory network showed connections between the top 10 transcription factors and their target DEGs. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of targeted DEGs indicated that extracellular space, extracellular exosome, cell surface and complement and coagulation cascades were most significantly enriched. Utilizing Nephroseq v5 online platform, the mRNA expression pattern analysis of transcription factor genes demonstrated that mRNA expression of CDC5, CEBPA, FAC1, HFH1, IRF1, NFE2 and TGIF1 increased in renal tubulointerstitium of DN patients compared with normal controls while that of CEBPB and FOXO4 decreased in renal tubulointerstitium of DN patients compared with normal controls. Correlation analysis between mRNA expression of transcription factor genes in renal tubulointerstitium and clinical features showed that AP1, BACH1, CDC5, FAC1, FOXD1, FOXJ2, FOXO1, FOXO4, HFH1, IRF1, POU3F2, SOX5, SOX9, RSRFC4, S8 and TGIF1 may be related to diabetic tubulointerstitial injury. Conclusions (1) CDC5, FAC1, FOXO4, HFH1, IRF1 and TGIF1 may be key transcription factor genes. (2)Transcription factors involved in diabetic tubulointerstitial injury may become prospective targets for diagnosis and treatment of DN.

Rationale Chinese women topped the list of new breast cancers, the first diagnosed gastric metastasis and bone metastasis is extremely infrequent. The clinical and pathological diagnosis of metastatic breast cancer is difficult. To our knowledge, this is the first reported case of the first diagnosis of breast cancer with both gastric metastasis and bone metastasis. Case report The female patient was found to have abdominal distension for 15 days with nausea and vomiting. The patient underwent a gastroscopy at an outside hospital 4 days ago, showing: duodenal bulb changes, gastric retention and chronic non-atrophic gastritis. Gastroscopic biopsy showed chronic inflammation and edema of the duodenal mucosa with glandular hyperplasia. Conservative treatment was given with no relief of symptoms. She was seen in our hepatobiliary and pancreatic surgery department. After admission, palliative surgery was performed, and the swelling and surrounding involved tissues were taken for examination during surgery. The rapid pathological return could not exclude tumor lesions, and the postoperative pathology confirmed the diagnosis of invasive lobular carcinoma of the breast with gastric metastases, and the systemic examination revealed combined bone metastases. Diagnosis Pathology and immunohistochemistry(IHC), a whole-body bone scan confirmed the first diagnosis of breast cancer with both gastric and bone metastases. Interventions Palliative treatment with bisphosphonates and CDK4/6i (Palbociclib) in combination with AI (Exemestane) was administered. Outcomes The patient is currently under regular evaluation and is being followed up.

Study design This study was a retrospective review. Objective Bone mineral density (BMD) at the surgical site is associated with complications of surgical internal fixation, and it is very important to study the cervical BMD of patients with cervical spondylosis who need surgery and the related factors that affect cervical BMD. It is still unclear about the age-related influence of disease time, cervical alignment and range of motion (ROM) on cervical vertebral Hounsfield unit (HU) value. Methods This retrospective study was conducted on patients who underwent cervical surgery at one institution between January 2014 and December 2021. Age, sex, body mass index (BMI), disease type, comorbidities, neck pain, disease time, C2-7 Cobb angle (CA), cervical ROM and the C2-C7 vertebral HU value were recorded. The association between cervical HU value and each parameter of interest was assessed using the Pearson correlation coefficient. Multivariable linear regression analysis was performed to examine the relative influence of the multiple factors on cervical vertebral HU value. Results Among patients younger than 50 years old, the HU value of the cervical vertebral in females was higher than that of males, but after the age of 50 years, the value of females was lower than that of males and decreased significantly after 60 years old. In addition, cervical HU value was significantly correlated with the disease time, flexion CA and ROM. Our age-related subgroup of multivariate linear regression analyses shows that disease time and flexion CA negatively affected the C6-7 HU value in more than 60-year-old males and in more than 50-year-old females. Conclusions Disease time and flexion CA were negatively affecting the C6-7 HU values in more than 60-year-old males and in more than 50-year-old females. More attention should be paid to bone quality in cervical spondylosis patients with longer disease time and larger convex of flexion CA.

To explore the risk of fatty liver and type 2 diabetes with quantitative parameters of abdominal computed tomography (CT) in a non-obese population.A retrospective analysis of abdominal CT and hospitalization records of inpatients admitted from May 2019 to May 2021 were divided into a non-obese control group (n = 143 cases) and a non-obese diabetes group (n = 105 cases). The measured abdominal CT parameters included body width, liver and spleen CT values, and the ratio of the liver CT value to the spleen CT value (L/S ratio). Logistic regression was used to analyze the risk factors for diabetes in non-obese individuals.Three variables including body width (P 0.001), liver CT value (P = 0.013), and L/S ratio (P = 0.002) were significantly correlated with the presence of diabetes in non-obese individuals.Body width, liver CT value, and L/S ratio can be used to indicate the risk of type 2 diabetes in non-obese individuals.

The present study aimed to investigate the effects of an imbalance in the estrogen/androgen ratio on prostate fibrosis.Different concentrations of dihydrotestosterone (DHT) or estradiol (ECompared with the uncastrated control and corn oil injection groups, the collagen fiber content and collagen I and fibronectin expression were increased and elastin expression was decreased in the castrated rat prostate with corn oil injection group (p 0.01). Compared to castrated corn oil injection group, collagen fiber content, collagen I, and fibronectin expression were significantly decreased, and elastin expression was significantly increased in the castrated rat prostate 0.15 mg/kg DHT treatment group (p 0.01). Following treatment with 0.15 mg/kg DHT, the content of collagen fibers, and the expression of collagen I and fibronectin were increased, and the expression of elastin was decreased in the rat prostate with increasing concentrations of EAn imbalance in the estrogen/androgen ratio may affect prostate fibrosis. E

Multi-label feature selection, a crucial preprocessing step for multi-label classification, has been widely applied to data mining, artificial intelligence and other fields. However, most of the existing multi-label feature selection methods for dealing with mixed data have the following problems: (1) These methods rarely consider the importance of features from multiple perspectives, which analyzes features not comprehensive enough. (2) These methods select feature subsets according to the positive region, while ignoring the uncertainty implied by the upper approximation. To address these problems, a multi-label feature selection method based on fuzzy neighborhood rough set is developed in this article. First, the fuzzy neighborhood approximation accuracy and fuzzy decision are defined in the fuzzy neighborhood rough set model, and a new multi-label fuzzy neighborhood conditional entropy is designed. Second, a mixed measure is proposed by combining the fuzzy neighborhood conditional entropy from information view with the approximate accuracy of fuzzy neighborhood from algebra view, to evaluate the importance of features from different views. Finally, a forward multi-label feature selection algorithm is proposed for removing redundant features and decrease the complexity of multi-label classification. The experimental results illustrate the validity and stability of the proposed algorithm in multi-label fuzzy neighborhood decision systems, when compared with related methods on ten multi-label datasets.

In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune cells exacerbates the disease process and leads to the pathological development of pro-inflammatory cytokines, chemokines, and contact-killing compounds, causing the loss of dopaminergic neurons. So far, we have mainly focused on the role of the specific class of immune cells in PD while neglecting the impact of interactions among immune cells on the disease. Therefore, this review demonstrates the reciprocal interplays between microglia and T cells and the associated subpopulations through cytokine and chemokine production that impair and/or protect the pathological process of PD. Furthermore, potential targets and models of PD neuroinflammation are highlighted to provide the new ideas/directions for future research.

The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.

Background Alpha‐kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1β in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1β and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. Methods Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1β, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1β and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. Results The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1β in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1β, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. Conclusions Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.

It is widely accepted that financial data exhibit a long-memory property or a long-range dependence. In a continuous-time situation, the geometric fractional Brownian motion is an important model to characterize the long-memory property in finance. This paper thus considers the problem to estimate all unknown parameters in geometric fractional Brownian processes based on discrete observations. The estimation procedure is built upon the marriage between the bipower variation and the least-squares estimation. However, unlike the commonly used approximation of the likelihood and transition density methods, we do not require a small sampling interval. The strong consistency of these proposed estimators can be established as the sample size increases to infinity in a chosen sampling interval. A simulation study is also conducted to assess the performance of the derived method by comparing with two existing approaches proposed by Misiran et al. (International Conference on Optimization and Control 2010, pp. 573–586, 2010) and Xiao et al. (J. Stat. Comput. Simul. 85(2):269–283, 2015), respectively. Finally, we apply the proposed estimation approach in the analysis of Chinese financial markets to show the potential applications in realistic contexts.

There is increasing focus on applying deep learning methods to electrocardiograms (ECGs), with recent studies showing that neural networks (NNs) can predict future heart failure or atrial fibrillation from the ECG alone. However, large numbers of ECGs are needed to train NNs, and many ECGs are currently only in paper format, which are not suitable for NN training. We developed a fully-automated online ECG digitisation tool to convert scanned paper ECGs into digital signals. Using automated horizontal and vertical anchor point detection, the algorithm automatically segments the ECG image into separate images for the 12 leads and a dynamical morphological algorithm is then applied to extract the signal of interest. We then validated the performance of the algorithm on 515 digital ECGs, of which 45 were printed, scanned and redigitised. The automated digitisation tool achieved 99.0% correlation between the digitised signals and the ground truth ECG (n = 515 standard 3-by-4 ECGs) after excluding ECGs with overlap of lead signals. Without exclusion, the performance of average correlation was from 90 to 97% across the leads on all 3-by-4 ECGs. There was a 97% correlation for 12-by-1 and 3-by-1 ECG formats after excluding ECGs with overlap of lead signals. Without exclusion, the average correlation of some leads in 12-by-1 ECGs was 60–70% and the average correlation of 3-by-1 ECGs achieved 80–90%. ECGs that were printed, scanned, and redigitised, our tool achieved 96% correlation with the original signals. We have developed and validated a fully-automated, user-friendly, online ECG digitisation tool. Unlike other available tools, this does not require any manual segmentation of ECG signals. Our tool can facilitate the rapid and automated digitisation of large repositories of paper ECGs to allow them to be used for deep learning projects.

The research aimed to evaluate the effects of dietary fructooligosaccharide, probiotics and their combination on the growth performance, antioxidant enzymes and stress resistance of juvenile Eriocheir sinensis. Crabs (average weight: 9.90 ± 0.07 g) were randomly assigned into 4 groups (3 tanks per group) fed experimental diets: basal diet (control group), basal diet supplemented with 5 g/kg FOS, basal diet supplemented with 2 g/kg multi-strain probiotics (each gram contains Lactobacillus acidophilus 106 CFU + Bacillus subtilis 107 CFU + Saccharomyces cerevisiae 1010 CFU) and basal diet supplemented with symbiotic (5 g/kg FOS + 2 g/kg multi-strain probiotics) (designated as control, D1, D2 and D3, respectively). After 8 weeks of feeding trial, crabs were exposed to the transportation process (3 h). Cumulative mortality was recorded at 24 h, 48 h, 72 h and 96 h after transport stress, and pre-transport and post-transport sampling of hepatopancreas occurred for assay. The results indicated that crabs fed D3 had significantly higher weight gain (WG), specific growth rate (SGR) and lower feed conversion ratio (FCR) than crabs fed control diet. Before stress, compared to the control group, crabs fed D1 and D3 diet significantly increased catalase (CAT), superoxide dismutase (SOD) activities and decreased malondialdehyde (MDA) activities, the highest activities of pepsin, trypsin and chymotrypsin were observed in crabs fed D2 diet. After stress, there was a trend that the activities of antioxidants enzymes and proteases in all groups were significantly decreased. And compared to the control group, crabs fed D1 and D3 diet significantly improved SOD and CAT activities, the lowest MDA activity was observed in crabs fed D3 diet, no significant difference was obtained in activities of total antioxidant capacity (T-AOC) and three proteases among all groups (P > 0.05). At 96 h after transportation process, the lowest cumulative mortality was observed in crabs fed D3 diet, the difference among all groups before and at 24 h, 48 h and 72 h after stress was not significant (P > 0.05). In summary, a basal diet supplemented with synbiotic could improve the growth performance and protect the hepatopancreas of Eriocheir sinensis more effectively than singular supplementation with prebiotics or probiotics.

Microbiological confirmation is rare in children with active tuberculosis; therefore, a more accurate test is needed to detect pulmonary tuberculosis in children. In this multicenter study, we evaluated the utility of the Xpert MTB/RIF Ultra (Ultra) on sputum, an assay recommended by the World Health Organization to test for childhood tuberculosis in high-burden settings. Children with symptoms suggestive of tuberculosis were enrolled at three hospitals in China and categorized as having active tuberculosis or nontuberculosis. The sensitivity and specificity of Ultra were 42.1% (48/114) and 99.0% (208/210), respectively. Using three MTB culture results as the reference, the sensitivity of Ultra in the subset of 38 children with culture-positive and 76 children with culture-negative was 68.4% (26/38) and 28.9% (22/76), respectively(p

By utilizing wave velocity imaging technology, the uniaxial multi-stage loading test was conducted on siltstone to attain wave velocity imagings during rock fracture. Based on the time series parameters of acoustic emissions (AE), joint response characteristics of the velocity field and AE during rock fracture were analyzed. Moreover, the localization effect of damage during rock fracture was explored by applying wave velocity imagings. The experimental result showed that the wave velocity imagings enable three-dimensional (3-D) visualization of the extent and spatial position of damage to the rock. A damaged zone has a low wave velocity and a zone where the low wave velocity is concentrated tends to correspond to a severely damaged zone. AE parameters and wave velocity imagings depict the changes in activity of cracks during rock fracture from temporal and spatial perspectives, respectively: the activity of cracks is strengthened, and the rate of AE events increases during rock fracture; correspondingly, the low-velocity zones are gradually aggregated and their area gradually increases. From the wave velocity imagings, the damaged zones in rock were divided into an initially damaged zone, a progressively damaged zone, and a fractured zone. During rock fracture, the progressively damaged zone and the fractured zone both develop around the initially damaged zone, showing a typical localization effect of the damage. By capturing the spatial development trends of the progressively damaged zone and fractured zone in wave velocity imagings, the development of microfractures can be predicted, exerting practical significance for determining the position of the main fracture.

Purpose Some studies indicated that gender is associated with prognostic of cancer, However, currently the prognostic value of gender for gastric cardia adenocarcinoma (GCA) survival is unclear. The aim of our study is to reveal the influence of gender on the prognosis of patients with GCA. Patients and methods A total of 42,345 cases Chinese GCA patients were enrolled from our previously established GCA and esophageal cancer databases. The clinicopathological characteristics were retrieved from medical records in hospital. The follow-up was performed through letter, telephone or home interview. Among GCA patients, there were 32,544 (76.9%) male patients with the median age 62 years (range 17–97) and 9,801 (23.1%) female patients with the median age 61 years (range 17–95 years). The Chi-square test and Kaplan–Meier method were used to compare the continuous variables and survival. Cox proportional hazards model was used for competing risk analyses, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated. Results Men had shorter GCA-specific survival than women by multivariate analysis (HR 1.114; 95% CI 1.061 to 1.169; P vs. male, P vs. male, P vs. male, P = 0.035). It was worth noting that in patients with stages I, II, III, and IV, female patients survive longer than male patients (P = 0.049; P = 0.011; P P = 0.044, respectively). Conclusion Gender is an independent prognostic factor for patients with GCA. In comparison with men, women have a significantly better outcome. Smoking and drinking may be protective factors for male GCA patients.

Background Osteosarcoma (OS) is one of the malignant bone tumors with strong aggressiveness and poor prognosis. Leucine-rich repeats and immunoglobulin-like domains2 (LRIG2) is closely associated with the poor prognosis of a variety of tumors, but the role of LRIG2 in osteosarcoma and the underlying molecular mechanism remains unclear. Objective The aim of this study was to determine the function of LRIG2 in OS and the related molecular mechanism on cell proliferation, apoptosis and migration of OS. Methods The mRNA and protein expression of LRIG2 in OS tissues and cells was detected by qRT-PCR, western blot (WB) assay and immunohistochemistry (IHC). The cell counting Kit-8 (CCK-8), clone formation, transwell, TdT-mediated dUTP Nick-End Labeling (TUNEL) and WB assay were applied to determine the proliferation, migration and apoptosis abilities of OS cells and its molecular mechanisms. Spontaneous metastasis xenografts were established to confirm the role of LRIG2 in vivo. Results LRIG2 exhibited high expression in OS tissues and OS cell lines and the expression of which was significantly correlated with Enneking stage of patients, knockdown LRIG2 expression significantly inhibited OS cell proliferation, migration and enhanced apoptosis. Silencing LRIG2 also suppressed the growth of subcutaneous transplanted tumor in nude mice. Further, the mechanism investigation revealed that the protein level of cell proapoptotic proteins (Bax, caspase9 and caspase3) all increased attributed to LRIG2 deficiency, whereas expression of anti-apoptotic protein BCL2 decreased. LRIG2 silencing led to the decrease phosphorylation of AKT signaling, a decrease expression of vimentin and N-cadherin. Additionally, silencing LRIG2 significantly decreased the rate of tumor growth and tumor size. Conclusions LRIG2 acts as an oncogene in osteosarcoma, and it might become a novel target in the treatment of human OS.

Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Congenital heart disease (CHD) is the most common structural abnormality in patients with ARSA. We aimed to assess the prevalence of genetic abnormalities, particularly sequence variants, in fetuses with CHD and ARSA. By clinical phenotyping and genomic sequencing, we retrospectively reviewed all fetuses with a prenatal diagnosis of CHD combined with ARSA at a single center. As a result, we identified 30 fetuses with ARSA combined with CHD, with conotruncal anomalies being the most common (n = 12, 40%), followed by left ventricular outflow tract obstruction (n = 6, 20%) and atrioventricular septal defects (n = 6, 20%). Overall, 18 (60%) cases had a genetic diagnosis. Copy number variation sequencing analysis identified six (20%) fetuses with aneuploidy and seven (23%) with pathogenic copy-number variants. Whole-exome sequencing (WES) analysis of the remaining 17 cases revealed diagnostic genetic variants in five (29%) cases, indicating that the diagnostic yield of WES for the entire cohort was 17% (5/30). Our findings reveal the high burden of genetic abnormalities in fetal CHD with ARSA. Single-gene disorders contribute substantially to the genetic etiology of fetal CHD with ARSA.