Association of mucus eosinophil-derived neurotoxin levels with disease control status in patients with chronic rhinosinusitis.

OBJECTIVE: Identifying the biomarkers for uncontrolled chronic rhinosinusitis (CRS) is important for directing treatment decisions. Eosinophilia has been reported to be involved in the poor disease control of CRS and mucus eosinophil-derived neurotoxin (EDN) is potentially a biomarker of intense eosinophil activation. This study aimed to assess the relationship between mucus EDN levels, disease severity, and degree of CRS control. METHODS: A total of 150 adult patients with CRS and 25 healthy controls were prospectively enrolled. The nasal mucus and tissue specimens were collected to analyze EDN levels. Disease severity was assessed by Lund-Mackay score and 22-item Sino-Nasal Outcome Test (SNOT-22) score. Five CRS symptom severities during the prior month (nasal blockage, rhinorrhoea/postnasal drip, facial pain/pressure, smell, sleep disturbance or fatigue), use of rescue medications in the last six months, and the presence of diseased mucosa on nasal endoscopy were obtained. Consistent with the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 CRS control criteria, uncontrolled CRS was defined as meeting at least three items. RESULTS: 40% of patients with CRS presented with uncontrolled status. Patients with uncontrolled CRS had significantly higher nasal mucus EDN levels (P = 0.010), percentage of blood eosinophil (P = 0.015), SNOT-22 score (P < 0.001), Lund-Mackay score (P = 0.008), and a more eosinophilic dominant phenotype of CRS (P < 0.001) than patients with controlled CRS. Furthermore, mucus EDN levels were positively correlated with blood eosinophils (r = 0.541, P = 0.005), SNOT-22 score (r = 0.460, P = 0.021), and Lund-Mackay score (r = 0.387, P = 0.039). Mucus EDN levels were the significant parameter related to uncontrolled CRS in multivariable analysis after adjusting for patient demographics and comorbidities (odds ratio = 1.323; P = 0.004). CONCLUSIONS: Mucus EDN levels may be a potential biomarker for identifying the CRS control status.

Cuproptosis-associated hub gene identification and immune cell infiltration patterns in silicosis.

Recent research has hinted at a potential connection between silicosis, a fibrotic lung disease caused by exposure to crystalline silica particles, and cuproptosis. The aim of the study was to explore how cuproptosis-related genes (CRGs) may influence the development of silicosis and elucidate the underlying mechanisms. An analysis of genes associated with both silicosis and cuproptosis was conducted. Key gene identification was achieved through the application of two machine learning techniques. Additionally, the correlation between these key genes and immune cell populations was explored and the critical pathways were discerned. To corroborate our findings, the expression of key genes was verified in both a publicly available silica-induced mouse model and our own silicosis mouse model. A total of 12 differentially expressed CRGs associated with silicosis were identified. Further analysis resulted in the identification of 6 CRGs, namely LOX, SPARC, MOXD1, ALB, MT-CO2, and AOC2. Elevated immune cell infiltration of CD8 T cells, regulatory T cells, M0 macrophages, and neutrophils in silicosis patients compared to healthy controls was indicated. Validation in a silica-induced pulmonary fibrosis mouse model supported SPARC and MT-CO2 as potential signature genes for the prediction of silicosis. These findings highlight a strong association between silicosis and cuproptosis. Among CRGs, LOX, SPARC, MOXD1, ALB, MT-CO2, and AOC2 emerged as pivotal players in the context of silicosis by modulating CD8 T cells, regulatory T cells, M0 macrophages, and neutrophils.

Healthy lifestyles, systemic inflammation and breast cancer risk: a mediation analysis.

BACKGROUND: Despite the known association between healthy lifestyles and reduced risk of breast cancer, it remains unclear whether systemic inflammation, as a consequence of unhealthy lifestyles, may mediate the association. METHODS: A cohort study of 259,435 female participants in the UK Biobank was conducted to estimate hazard ratio (HR) for breast cancer according to 9 inflammation markers using Cox regression models. We further estimated the percentage of total association between healthy lifestyle index (HLI) and breast cancer that is mediated by these inflammation markers. RESULTS: During 2,738,705 person-years of follow-up, 8,889 cases of breast cancer were diagnosed among 259,435 women in the UK Biobank cohort. Higher level of C-reactive protein (CRP), systemic immune-inflammation index (SII), CRP-to-albumin Ratio (CAR), CRP-to-lymphocyte Ratio (CLR), monocyte-to-HDL-c ratio (MHR), and neutrophil-to-HDL-c ratio (NHR) were associated with increased breast cancer risk, while a higher lymphocyte-to-monocyte ratio (LMR) was associated with a lower risk. The inverse association between HLI and breast cancer was weakly mediated by CRP (8.5%), SII (1.71%), CAR (8.66%), CLR (6.91%), MHR (6.27%), and NHR (7.33%). When considering individual lifestyle factors, CRP and CAR each mediated 16.58% and 17.20%, respectively, of the associations between diet score and breast cancer risk, while the proportion mediated for physical activity and breast cancer were 12.13% and 11.48%, respectively. Furthermore, MHR was found to mediate 13.84% and 12.01% of the associations between BMI, waist circumference, and breast cancer. CONCLUSION: The association of HLI and breast cancer is weakly mediated by the level of inflammation, particularly by CRP and CAR. Systemic inflammatory status may be an intermediate in the biological pathway of breast cancer development.

Artificial intelligence-based diagnosis of standard endoscopic ultrasonography scanning sites in the biliopancreatic system: a multicenter retrospective study.

BACKGROUND: There are challenges for beginners to identify standard biliopancreatic system anatomical sites on endoscopic ultrasonography (EUS) images. Therefore, the authors aimed to develop a convolutional neural network (CNN)-based model to identify standard biliopancreatic system anatomical sites on EUS images. METHODS: The standard anatomical structures of the gastric and duodenal regions observed by EUS was divided into 14 sites. The authors used 6230 EUS images with standard anatomical sites selected from 1812 patients to train the CNN model, and then tested its diagnostic performance both in internal and external validations. Internal validation set tests were performed on 1569 EUS images of 47 patients from two centers. Externally validated datasets were retrospectively collected from 16 centers, and finally 131 patients with 85 322 EUS images were included. In the external validation, all EUS images were read by CNN model, beginners, and experts, respectively. The final decision made by the experts was considered as the gold standard, and the diagnostic performance between CNN model and beginners were compared. RESULTS: In the internal test cohort, the accuracy of CNN model was 92.1-100.0% for 14 standard anatomical sites. In the external test cohort, the sensitivity and specificity of CNN model were 89.45-99.92% and 93.35-99.79%, respectively. Compared with beginners, CNN model had higher sensitivity and specificity for 11 sites, and was in good agreement with the experts (Kappa values 0.84-0.98). CONCLUSIONS: The authors developed a CNN-based model to automatically identify standard anatomical sites on EUS images with excellent diagnostic performance, which may serve as a potentially powerful auxiliary tool in future clinical practice.

EML4-ALK fusion protein in Lung cancer cells enhances venous thrombogenicity through the pERK1/2-AP-1-tissue factor axis.

BACKGROUND: Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear. METHOD: High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS. RESULTS: Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression. CONCLUSION: EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Hematological and biochemical markers influencing breast cancer risk and mortality: Prospective cohort study in the UK Biobank by multi-state models.

BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer-related death among women. However, evidence concerning hematological and biochemical markers influencing the natural history of breast cancer from in situ breast cancer to mortality is limited. METHODS: In the UK Biobank cohort, 260,079 women were enrolled during 2006-2010 and were followed up until 2019 to test the 59 hematological and biochemical markers associated with breast cancer risk and mortality. The strengths of these associations were evaluated using the multivariable Cox regression models. To understand the natural history of breast cancer, multi-state survival models were further applied to examine the effects of biomarkers on transitions between different states of breast cancer. RESULTS: Eleven biomarkers were found to be significantly associated with the risk of invasive breast cancer, including mainly inflammatory-related biomarkers and endogenous hormones, while serum testosterone was also associated with the risk of in-situ breast cancer. Among them, C-reactive protein (CRP) was more likely to be associated with invasive breast cancer and its transition to death from breast cancer (HR for the highest quartile = 1.46, 95 % CI = 1.07-1.97), while testosterone and insulin-like growth factor-1 (IGF-1) were more likely to impact the early state of breast cancer development (Testosterone: HR for the highest quartile = 1.31, 95 % CI = 1.12-1.53; IGF-1: HR for the highest quartile = 1.17, 95 % CI = 1.00-1.38). CONCLUSION: Serum CRP, testosterone, and IGF-1 have different impacts on the transitions of different breast cancer states, confirming the role of chronic inflammation and endogenous hormones in breast cancer progression. This study further highlights the need of closer surveillance for these biomarkers during the breast cancer development course.

The interaction between systemic inflammatory markers and polygenic risk score in breast cancer risk: A cohort study in the UK Biobank.

BACKGROUND: Systemic inflammatory markers have been widely used in cancer prognosis prediction recently. However, there is limited knowledge regarding their impact on breast cancer risk and their interaction with polygenic risk scores. METHODS: A cohort study of 202,403 female participants from the UK Biobank were analyzed to estimate the hazard ratio (HR) for the incidence and mortality of breast cancer based on inflammatory markers using Cox regression models. Additionally, we stratified the analysis by polygenic risk scores (PRS) for breast cancer, and examined the interaction between these markers and PRS through likelihood ratio tests and relative excess risk due to interaction (RERI). RESULTS: Women in the highest tertile of neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and C-reactive protein (CRP) showed an increased risk of breast cancer [HR (95 %CI) = 1.10 (1.02-1.18), 1.09 (1.01-1.17) and 1.15 (1.05-1.25), respectively], as compared to those in the lowest tertile. Regarding breast cancer mortality, only NLR and CRP exhibited consistent results in the univariate model [HR (95 %CI) = 1.25 (0.99-1.58) and 1.39 (1.10-1.77), respectively]. When stratified by PRS, stronger associations between inflammatory markers and breast cancer risk were observed in the high PRS group. Furthermore, there was a significant additive interaction between CRP and PRS [RERI (95 % CI) = 0.30 (0.06-0.53)]. CONCLUSION: NLR and CRP are associated with breast cancer risk and mortality, and the effect of CRP is influenced by PRS. Systematic inflammatory markers, together with PRS, might be applied in combined screening for breast cancer.

Serum lncRNA LINC01535 as Biomarker of Diagnosis, Prognosis, and Disease Progression in Breast Cancer.

BACKGROUND: Breast cancer has become the world's leading cancer, the leading killer of women's health, with a high mortality rate. With the development of medical technology, lncRNAs are widely used in the diagnosis and prognosis of various tumors, so finding new specific molecular markers and targets is the key to prolonging the survival time of breast cancer patients. MATERIALS AND METHODS: The expressions of lncRNA LINC01535 and miR-214-3p in breast cancer were detected by quantitative real-time PCR (qRT-PCR). The diagnostic significance of LINC01535 in breast cancer was assessed by ROC curve. The prognostic value of LINC01535 was verified by Kaplan-Meier method. The regulation of low expression of LINC01535 on proliferation and other biological abilities of breast cancer cells was determined by CCK-8 and Transwell method. The luciferase activity report assays indicated the relationship between LINC01535 and miR-214-3p. RESULTS: LINC01535 was elevated in breast cancer, which was negatively correlated with miR-214-3p, and miR-214-3p expression was decreased. LINC01535 proved to be promising in the diagnosis and prognosis of breast cancer. Low expression of LINC01535 targeting miR-214-3p had regulatory significance on tumor progression, lymph node metastasis and TNM stage. CONCLUSION: Silencing LINC01535 inhibited the proliferation capacity, migration level and invasion of breast cancer cells in vitro. LINC01535 was likely to be the focus of continued attention as a diagnostic and prognosis marker for breast cancer in the future.

Olfactory cleft mucus eosinophil-derived neurotoxin better reflects olfactory loss than blood eosinophil counts in patients with chronic rhinosinusitis.

BACKGROUND: Eosinophils are associated with olfactory dysfunction in chronic rhinosinusitis (CRS) and eosinophil-derived neurotoxin (EDN) is a sensitive marker of intense eosinophil activation. This study aimed to analyze olfactory cleft mucus and olfactory mucosa EDN levels and their association with olfactory dysfunction in CRS. METHODS: We prospectively recruited 150 patients with CRS electing endoscopic sinus surgery and 25 healthy controls. Both superior turbinate biopsy specimens and olfactory cleft mucus were collected to analyze EDN levels. Sniffin' Sticks test scores, olfactory cleft computed tomography (CT) scores, and olfactory cleft endoscopy scale (OCES) were obtained. Multivariable logistic regression analysis was applied to analyze the predictability of EDN levels for olfactory dysfunction in CRS. RESULTS: Chronic rhinosinusitis with olfactory dysfunction presented significantly higher olfactory mucosa (p = 0.016) and olfactory cleft mucus (p < 0.001) EDN levels than CRS without olfactory dysfunction. Mucus EDN levels were positively correlated with blood eosinophils (r = 0.625, p = 0.002), olfactory cleft CT scores (r = 0.738, p < 0.001), and OCES (r = 0.605, p = 0.004) in CRS. Furthermore, mucus EDN levels were significantly negatively correlated with threshold, discrimination, and identification (TDI) (r = -0.688), olfactory threshold (r = -0.606), olfactory discrimination (r = -0.608), and olfactory identification (r = -0.697) scores. After adjusting for patient demographics and comorbidities, mucus EDN levels were significantly associated with olfactory dysfunction in CRS (odds ratio = 2.162; p = 0.027). Mucus EDN levels showed a significantly better performance for predicting olfactory dysfunction than blood eosinophil counts (area under the curve, 0.873 vs. 0.764, p = 0.024). CONCLUSION: Olfactory cleft mucus EDN level may be a better biomarker for predicting olfactory dysfunction in CRS than blood eosinophil counts.

Spatial patterns and the associated factors for breast cancer hospitalization in the rural population of Fujian Province, China.

BACKGROUND: Despite the known increasing incidence of breast cancer in China, evidence on the spatial pattern of hospitalization for breast cancer is scarce. This study aimed to describe the disparity of breast cancer hospitalization in the rural population of Southeast China and to explore the impacts of socioeconomic factors and heavy metal pollution in soil. METHODS: This study was conducted using the New Rural Cooperative Medical Scheme (NRCMS) claims data covering 20.9 million rural residents from 73 counties in Southeast China during 2015-2016. The associations between breast cancer hospitalization and socioeconomic factors and soil heavy metal pollutants were evaluated with quasi-Poisson regression models and geographically weighted Poisson regressions (GWPR). RESULTS: The annual hospitalization rate for breast cancer was 101.40/100,000 in the studied area and the rate varied across different counties. Overall, hospitalization for breast cancer was associated with road density (ß = 0.43, P = 0.02), urbanization (ß = 0.02, P = 0.002) and soil cadmium (Cd) pollution (ß = 0.01, P = 0.02). In the GWPR model, a stronger spatial association of Cd, road density and breast cancer hospitalization was found in the northeast regions of the study area while breast cancer hospitalization was mainly related to urbanization in the western regions. CONCLUSIONS: Soil Cd pollution, road density, and urbanization were associated with breast cancer hospitalization in different regions. Findings in this study might provide valuable information for healthcare policies and intervention strategies for breast cancer.

Toll-like receptor 4 deficiency in mice impairs venous thrombus resolution.

Objective: Toll-like receptor 4 (TLR4) is crucial to the development of sterile inflammatory responses. The deep venous thrombosis resolution (DVT) is similar to sterile inflammation, so we hypothesize that TLR4 is involved. Methods and Results: We evaluated the effects of TLR4 deficiency on thrombus lysis in vivo, and explored the mechanisms in vitro. DVT mouse model was established by inferior vena cava (IVC) ligation. After the IVC ligation (1, 3, and 7 d), the mice were euthanized to collect the venous thrombus. The Tlr4-/- mice had significantly elevated weight/length ratios of thrombi at 3 and 7 d and increased collagen content at 3 d after IVC ligation, in addition to significantly lesser intrathrombus infiltration of neutrophils and macrophages, lower monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) expression in thrombus tissue sections and homogenates, and lower pro-MMP-9 activity at 3 d after IVC ligation than wild-type mice. After 7 days of IVC ligation, VEGF, IFNß, and MCP-5 protein expression were decreased in venous thrombus from Tlr4-/- mice. 2 ml of 3% thioglycolate was injected intraperitoneally and peritoneal exudate was collected 3 days later from Tlr4-/- and wild type mice respectively. The intraperitoneal macrophages were isolated from adherent culture after centrifugation. Lipopolysaccharide (LPS) can activate TLR4/NF-κB signalling pathway in a concentration-dependent manner, initiated p65 nuclear translocation, IκBα phosphorylation and degradation, MMP-9 and MCP-1 transcription in WT intraperitoneal macrophages but not in Tlr4-/- intraperitoneal macrophages. Conclusion: TLR4 is involved in venous thrombosis resolution through NF-κB pathway. Loss of TLR4 in mice impairs the process.

Landscape analysis of m6A modification regulators related biological functions and immune characteristics in myasthenia gravis.

BACKGROUND: N6-methyladenosine (m6A) modification has been recognized to play fundamental roles in the development of autoimmune diseases. However, the implication of m6A modification in myasthenia gravis (MG) remains largely unknown. Thus, we aimed to systematically explore the potential functions and related immune characteristics of m6A regulators in MG. METHODS: The GSE85452 dataset with MG and healthy samples was downloaded from Gene Expression Omnibus (GEO) database. m6A modification regulators were manually curated. The targets of m6A regulators were obtained from m6A2Target database. The differential expressed m6A regulators in GSE85452 dataset were identified by "limma" package and were validated by RT-PCR. Function enrichment analysis of dysregulated m6A regulators was performed using "clusterProfiler" package. Correlation analysis was applied for analyzing the relationships between m6A regulators and immune characteristics. Unsupervised clustering analysis was used to identify distinct m6A modification subtypes. The differences between subtypes were analyzed, including the expression level of all genes and the enrichment degree of immune characteristics. Weighted gene co-expression network analysis (WGCNA) was conducted to obtain modules associated with m6A modification subtypes. RESULTS: We found that CBLL1, RBM15 and YTHDF1 were upregulated in MG samples of GSE85452 dataset, and the results were verified by RT-PCR in blood samples from19 MG patients and 19 controls. The targeted genes common modified by CBLL1, RBM15, and YTHDF1 were mainly enriched in histone modification and Wnt signaling pathway. Correlation analysis showed that three dysregulated m6A regulators were closely associated with immune characteristics. Among them, RBM15 possessed the strongest correlation with immune characteristics, including CD56dim natural killer cell (r = 0.77, P = 0.0023), T follicular helper cell (r = - 0.86, P = 0.0002), Interferon Receptor (r = 0.78, P = 0.0017), and HLA-DOA (r = 0.64, P = 0.0200). Further two distinct m6A modification patterns mediated by three dysregulated m6A regulators was identified. Bioinformatics analysis found that there were 3029 differentially expressed genes and different immune characteristics between two m6A modification patterns. Finally, WGCNA analysis obtained a total of 12 modules and yellow module was the most positively correlated to subtype-2. CONCLUSION: Our findings suggested that m6A RNA modification had an important effect on immunity molecular mechanism of MG and provided a new perspective into understanding the pathogenesis of MG.

Olfactory cleft mucus galectin-10 predicts olfactory loss in chronic rhinosinusitis.

BACKGROUND: Eosinophils have been reported to be involved in the pathogenesis of olfactory fluctuation in chronic rhinosinusitis (CRS). Galectin-10 is more frequently associated with type 2 inflammation and potentially a sign of intense eosinophil activation. OBJECTIVE: To explore olfactory cleft mucus and olfactory mucosa galectin-10 level and its association with olfactory dysfunction (OD) in CRS. METHODS: We prospectively enrolled 50 patients with CRS and 15 healthy controls. Olfactory cleft mucus and superior turbinate biopsy specimens were collected to analyze galectin-10 levels and quantify tissue eosinophils. Psychophysical olfactory testing, olfactory cleft endoscopy scale, and olfactory cleft computed tomography scores were obtained. The predictability of galectin-10 levels for OD in patients with CRS was analyzed by multivariable logistic regression analysis. RESULTS: Both olfactory cleft mucus and olfactory mucosa galectin-10 levels in patients with CRS with OD were significantly higher than those in patients with CRS without OD (all P < .001). Mucus galectin-10 levels were positively correlated with tissue eosinophils (r = 0.541, P = 0.002), olfactory cleft endoscopy scale (r = 0.498, P = 0.006), and olfactory cleft computed tomography scores (r = 0.432, P = 0.019) in patients with CRS. Mucus galectin-10 levels were negatively correlated threshold, discrimination, and identification (r = -0.589,  P = 0.001), olfactory threshold (r = -0.522, P = 0.003), olfactory discrimination (r = -0.488, P = 0.007), and olfactory identification (r = -0.466, P = 0.011) scores. After adjusting for patient demographics and comorbidities, mucus galectin-10 levels were significantly associated with OD in patients with CRS (odds ratio, 1.299; P = .008). Mucus galectin-10 levels greater than 8.975 ng/mL were the best predictor of OD in CRS. CONCLUSION: Olfactory cleft mucus galectin-10 is highly associated with OD in CRS.

VPS9D1-AS1 overexpression amplifies intratumoral TGF-ß signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer.

Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-ß pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-ß signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-ß, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-ß/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.

IL-17A promotes lung fibrosis through impairing mitochondrial homeostasis in type II alveolar epithelial cells.

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)-17A has been demonstrated to have a pro-fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL-17 receptor A (IL-17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)-induced PF murine model. We found that IL-17A knockout (IL-17A-/- ) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL-17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN-induced putative kinase 1 (PINK1)/Parkin signal-mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL-17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL-17A exerts its pro-fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1-mediated mitophagy, thereby leading to apoptosis of AECIIs.

Correlation between IFNAR1 expression in peripheral blood T lymphocytes and inflammatory cytokines, tumor-infiltrating lymphocytes, and chemosensitivity in patients with colorectal cancer.

IFN-α receptor (IFNAR) is critical for maintaining the crosstalk between cancer cells and lymphocytes. We investigated IFNAR1 expression in peripheral blood CD4+ and CD8+ T cells and explored their relationships with plasma cytokines, chemosensitivity and infiltrated T cells in the tumor microenvironment (TME) of colorectal cancer (CRC). The levels of IFNAR1, IFN-γ, and PD1 in peripheral T cells were tested using flow cytometry. Immunohistochemical staining of IFNAR1 in CRC tissues was performed. A cytometric bead array was used to determine the plasma concentrations of cytokines. In CRC patients, IFNAR1 levels were significantly increased in peripheral blood T cells, and plasma IL-6 levels were also significantly increased. Pearson correlation analysis revealed that IFNAR1 expression in CD8+ T cells was negatively associated with plasma IL-2, IFN-γ, and TNFα. IFNAR1 expression in CD4+ T cells was positively associated with TME infiltrated levels of CD8+ T cells. The levels of CD8+ T cells with IFNAR1 and plasma IFN-γ were associated with chemosensitivity. Collectively, IFNAR1 levels in CD4+ and CD8+ T cells were significantly upregulated in CRC patients and positively associated with T-cell infiltration. IFNAR1 may be a chemotherapy biomarker for predicting response.

lncRNA ACTA2-AS1 predicts malignancy and poor prognosis of triple-negative breast cancer and regulates tumor progression via modulating miR-532-5p.

BACKGROUND: Dysregulation of ACTA2-AS1 and miR-532-5p and their functions in various cancers have been widely reported. Their potential of serving as biomarkers in triple-negative breast cancer (TNBC) remains unknown. This study aimed to evaluate the function of ACTA2-AS1 and miR-532-5p and their potential of serving as biomarkers in TNBC. RESULTS: The TNBC tissues were collected from 119 patients, where the reduced level of ACTA2-AS1 and increased level of miR-532-5p were observed by PCR and showed a significantly negative correlation (P <  0.001). Both ACTA2-AS1 and miR-532-5p were closely associated with the malignant development and poor prognosis of TNBC patients. Moreover, in TNBC cell, overexpressing ACTA2-AS1 was found to suppress cell proliferation and metastasis, which was reversed by the upregulation of miR-532-5p. CONCLUSIONS: ACTA2-AS1 and miR-532-5p could act as biomarkers of TNBC predicting the progression and prognosis of patients. ACTA2-AS1 served as a tumor suppressor of TNBC which was mediated by miR-532-5p.

Bone mineral density and risk of breast cancer: A cohort study and Mendelian randomization analysis.

BACKGROUND: Estrogen is involved in both bone metabolism and breast cancer proliferation. However, evidence about the risk of breast cancer according to women's bone mineral density (BMD) is scarce, and little is known about their causal associations. METHODS: Women participating in the UK Biobank cohort were used to investigate the association between BMD and the risk of breast cancer using Cox regression models. Instrumental variants associated with estimated BMD (eBMD) were extracted from genome-wide association studies with European ancestry. Logistic regression was used to calculate the genetic association with breast cancer in the UK Biobank and 2-sample Mendelian randomization (MR) analyses to assess their causal associations with breast cancer. Finally, the pleiotropic conditional false discovery rate (cFDR) method was conducted to further detect common genetic variants between BMD and breast cancer. RESULTS: Compared with the general population, postmenopausal women with BMD T scores <-2.5 had a lower risk of breast cancer (hazard ratio [HR], 0.77; 95% CI, 0.59-1.00), and this effect was stronger in women with fracture (HR, 0.31; 95% CI, 0.12-0.82). In MR analysis, no causal associations between eBMD and breast cancer were observed. The cFDR method identified 63 pleiotropic loci associated with both BMD and breast cancer, of which CCDC170, ESR1, and FTO might play crucial roles in their pleiotropy. CONCLUSIONS: An association between BMD and the risk of postmenopausal breast cancer in the UK Biobank was observed, whereas no evidence supported their causal association. Instead, their association could be explained by pleiotropic genetic variants leading to the pathology of osteoporosis and breast cancer.

Selective, Stable Production of Ethylene Using a Pulsed Cu-Based Electrode.

Ethylene (C2H4) is an important product in carbon dioxide electroreduction (CO2RR) because of the essential role it plays in chemical industry. While several strategies have been proposed to tune the selectivity of Cu-based catalysts in order to achieve high C2H4 faradaic efficiency, maintaining high selectivity toward C2H4 in CO2RR remains an unresolved problem hampering the deployment of CO2 conversion technology due to the lack of stable electrocatalysts. Here, we develop a facile method to deposit a layer of Cu2O on Cu foil by an electrochemical pulsed potential treatment. This method is capable to easily scale up and synthesize multiple electrodes in one step. After the synthesis, the pulsed copper foil, denoted as P-Cu, exhibits good C2H4 faradaic efficiency of ∼50% in CO2RR at a potential around -1.0 V vs. RHE. The C2H4 selectivity is also found to be quantitatively correlated with the roughness factor (RF) of Cu-based catalysts. More importantly, for the first time, we demonstrate that the P-Cu electrode is quite durable in CO2RR to produce C2H4 for more than 6 months.

Cyclin B2 overexpression promotes tumour growth by regulating jagged 1 in hepatocellular carcinoma.

BACKGROUND: Our previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC). AIM OF THE STUDY: This study aimed to clarify the effect of CCNB2 gene silencing on tumorigenesis in nude mice and to detect the potential mechanism. METHODS: The effect of CCNB2 on HCC was tested in vivo. The downstream target genes of CCNB2 were predicted by proteomics and confirmed by western blot assay. The regulatory functions of CCNB2 in the proliferation and migration of HCC cells were determined through functional recovery experiments. The expression of the downstream target genes of CCNB2 was detected by immunohistochemistry. RESULTS: Knockdown of CCNB2 decreased tumour formation rate and tumour volume and weight and inhibited tumour proliferation. A total of 130 differentially expressed proteins were detected by proteomics, and Jagged 1 (JAG1) was predicted as the potential downstream target of CCNB2. Western blot assay revealed that CCNB2 and JAG1 expression was significantly correlated in HCC cells. The results of functional recovery experiments suggested that CCNB2 knockdown weakened the proliferation and migration ability of HCC cells, while JAG1 overexpression restored this ability of HCC cells that was weakened by CCNB2 knockdown. Immunohistochemistry showed that JAG1 expression was higher in HCC tissues than in paracancerous tissues and was related to tumour size and number and tumour thrombus formation. CONCLUSIONS: The proliferation of HCC cells in vivo was inhibited by CCNB2 knockdown. CCNB2 may accelerate the proliferation and metastasis of HCC cells by increasing JAG1 expression.