Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation.

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1ß (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

A new proposal for phenotypic classification and outcome assessment of dermatomyositis based on clinical manifestations and serological testing.

BACKGROUND: Dermatomyositis (DM) is an infrequent disease subgroup of idiopathic inflammatory myopathies characterized by distinct skin lesions. However, high heterogeneity makes clinical diagnosis and treatment of DM very challenging. OBJECTIVES: Unsupervised classification in DM patients and analysis of key factors related to clinical outcomes. METHODS: This retrospective study was conducted between 2017 and 2022 at the Department of Rheumatology, Xiangya Hospital, Central South University. 162 DM patients were enrolled for unsupervised hierarchical cluster analysis. In addition, we divided the clinical outcomes of DM patients into four subgroups: withdrawal, stabilization, aggravation, and death, and compared the clinical profiles amongst the subgroups. RESULTS: Out of 162 DM patients, three clusters were defined. Cluster 1 (n = 40) was mainly grouped by patients with prominent muscular involvement and mild Interstitial Lung Disease (ILD). Cluster 2 (n = 72) grouped patients with skin rash, anti-Melanoma Differentiation Associated protein 5 positive (anti-MDA5+), and Rapid Progressive Interstitial Lung Disease (RP-ILD). Cluster 3 (n = 50) grouped patients with the mildest symptoms. The proportion of death increased across the three clusters (cluster 3 < cluster 1 < cluster 2). STUDY LIMITATIONS: The number of cases was limited for the subsequent construction and validation of predictive models. We did not review all skin symptoms or pathological changes in detail. CONCLUSIONS: We reclassified DM into three clusters with different risks for poor outcome based on diverse clinical profiles. Clinical serological testing and cluster analysis are necessary to help clinicians evaluate patients during follow-up and conduct phenotype-based personalized care in DM.

An investigation of the risk factors of chronic obstructive pulmonary disease in natural population-based cohorts in China - a nested case-control study.

Background: Chronic obstructive pulmonary disease (COPD) has become one of the most significant chronic diseases in China. According to conventional wisdom, smoking is the pathogenic factor. However, current research indicates that the pathophysiology of COPD may be associated with prior respiratory system events (e.g., childhood hospitalization for pneumonia, chronic bronchitis) and environmental exposure (e.g., dust from workplace, indoor combustion particles). Dyspnea, persistent wheezing, and other respiratory symptoms further point to the need for pulmonary function tests in this population. Reducing the burden of chronic diseases in China requires a thorough understanding of the various factors that influence the occurrence of COPD. Methods: Using a cohort from the natural population, this study used nested case-control analysis. We carried out a number of researches, including questionnaire surveys and pulmonary function testing, in the Northwest and Southeast cohorts of China between 2014 and 2021. After removing any variations in the baseline data between patients and control subjects using propensity score matching analysis, the risk factors were examined using univariate or multivariate regression. Result: It was discovered that prior history of chronic bronchitis, long-term wheezing symptoms, and environmental exposure-including smoking and biofuel combustion-were risk factors for COPD. Dyspnea, symptoms of mobility limitation, organic matter, and a history of hospitalization for pneumonia at an early age were not significant in the clinical model but their incidence in COPD group is higher than that in healthy population. Discussion: COPD screening effectiveness can be increased by looking for individuals with chronic respiratory symptoms. Smokers should give up as soon as they can, and families that have been exposed to biofuels for a long time should convert to clean energy or upgrade their ventilation. Individuals who have previously been diagnosed with emphysema and chronic bronchitis ought to be extra mindful of the prevention or advancement of COPD.

Case report: 177Lu DOTA-TATE: a new scheme for the treatment of prostate neuroendocrine cancer.

Background: Most instances of small cell carcinoma originate from the lungs, while the gastrointestinal tract serves as a secondary site. Only a minuscule proportion of cases manifest within the urogenital system. Prostate small cell carcinoma (SCCP) represents an exceedingly uncommon pathological subtype within the realm of prostate cancer, displaying significant rarity in clinical settings. This scarcity has resulted in a paucity of adequate foundational and clinical research for SCCP treatment. While investigations have unveiled a certain therapeutic efficacy of radiotherapy and chemotherapy for SCCP, clinical practice has revealed suboptimal treatment outcomes. We hereby present a case report detailing the utilization of 177Lu-DOTA-TATE in the treatment of SCCP, aiming to investigate the therapeutic efficacy of 177Lu-DOTA-TATE for SCCP. Case presentation: A male patient in his 80s presented with elevated prostate-specific antigen (PSA) levels and underwent a biopsy that revealed prostate adenocarcinoma. The patient received CAB (bicalutamide + goserelin) therapy. One year later, disease progression was detected, and a second biopsy confirmed the presence of prostate small cell carcinoma. Following the diagnosis of prostate small cell carcinoma, the patient underwent two cycles of 177Lu-DOTA-TATE treatment. Subsequent to the treatment, the original lesions showed shrinkage, metastatic lesions disappeared, and there was significant improvement, approaching complete remission. Conclusion: SCCP exhibits a high degree of malignancy and aggressive invasiveness, currently lacking effective therapeutic modalities. The treatment course of this patient serves as compelling evidence for the efficacy of 177Lu-DOTA-TATE in managing SCCP, thereby opening new avenues for future SCCP treatments.

The associations of alcoholic liver disease and nonalcoholic fatty liver disease with bone mineral density and the mediation of serum 25-Hydroxyvitamin D: A bidirectional and two-step Mendelian randomization.

BACKGROUND: Reduced bone mineral density (BMD) and osteoporosis are common in chronic liver diseases. However, the causal effect of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) on BMD remains uncertain. OBJECTIVES: This study uses a two-sample Mendelian randomization (MR) design to evaluate the genetically predicted effect of ALD and NAFLD on BMDs using summary data from publically available genome-wide association studies (GWASs). METHODS: The GWAS summary statistics of ALD (1416 cases and 213,592 controls) and NAFLD (894 cases and 217,898 controls) were obtained from the FinnGen consortium. BMDs of four sites (total body, n = 56,284; femoral neck, n = 32,735; lumbar spine, n = 28,498; forearm, n = 8143) were from the GEnetic Factors for OSteoporosis Consortium. Data for alcohol consumption (n = 112,117) and smoking (n = 33,299) and serum 25-Hydroxyvitamin D (25-OHD) level (n = 417,580) were from UK-biobank. We first performed univariate MR analysis with the Inverse Variance Weighted (IVW) method as the primary analysis to investigate the genetically predicted effect of ALD or NAFLD on BMD. Then, multivariate MR and mediation analysis were performed to identify whether the effect was mediated by alcohol consumption, smoking, or serum 25-OHD level. RESULTS: The MR results suggested a robust genetically predicted effect of ALD on reduced BMD in the femoral neck (FN-BMD) (IVW beta = -0.0288; 95% CI: -0.0488, -0.00871; P = 0.00494) but not the other three sites. Serum 25-OHD level exhibited a significant mediating effect on the association between ALD and reduced FN-BMD albeit the proportion of mediation was mild (2.21%). No significant effects of NAFLD, alcohol consumption, or smoking on BMD in four sites, or reverse effect of BMD on ALD or NAFLD were detected. CONCLUSION: Our findings confirm the genetically predicted effect of ALD on reduced FN-BMD, and highlight the importance of periodic BMD and serum 25-OHD monitoring and vitamin D supplementation as needed in patients with ALD. Future research is required to validate our results and investigate the probable underlying mechanisms.

Cardiovascular mortality by cancer risk stratification in patients with localized prostate cancer: a SEER-based study.

Purpose: The risk of cardiovascular disease (CVD) mortality in patients with localized prostate cancer (PCa) by risk stratification remains unclear. The aim of this study was to determine the risk of CVD death in patients with localized PCa by risk stratification. Patients and methods: Population-based study of 340,806 cases in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with localized PCa between 2004 and 2016. The proportion of deaths identifies the primary cause of death, the competing risk model identifies the interaction between CVD and PCa, and the standardized mortality rate (SMR) quantifies the risk of CVD death in patients with PCa. Results: CVD-related death was the leading cause of death in patients with localized PCa, and cumulative CVD-related death also surpassed PCa almost as soon as PCa was diagnosed in the low- and intermediate-risk groups. However, in the high-risk group, CVD surpassed PCa approximately 90 months later. Patients with localized PCa have a higher risk of CVD-related death compared to the general population and the risk increases steadily with survival (SMR = 4.8, 95% CI 4.6-5.1 to SMR = 13.6, 95% CI 12.8-14.5). Conclusions: CVD-related death is a major competing risk in patients with localized PCa, and cumulative CVD mortality increases steadily with survival time and exceeds PCa in all three stratifications (low, intermediate, and high risk). Patients with localized PCa have a higher CVD-related death than the general population. Management of patients with localized PCa requires attention to both the primary cancer and CVD.

Comparison of Laparoscopic Percutaneous Extraperitoneal Internal Ring Closure by Two-Hook Hernia Needle and Open Repair for Pediatric Inguinal Hernia.

Purpose: In children, pediatric inguinal hernia (PIH) is a prevalent condition. PIH is currently more frequently managed by laparoscopic closure of the hernia sac. We improved this minimally invasive technique; that is, laparoscopic two-hook hernia needle percutaneous extraperitoneal internal ring closure. Safety and effectiveness were evaluated by comparing the differences between laparoscopic repair (LR) and open repair (OR) in terms of operation time, surgical complications, contralateral metachronous hernia incidence, and recurrence rate. Methods: A retrospective clinical data analysis was performed on pediatric patients who had hernia surgery utilizing the LR or OR method between June 2019 and June 2021. Medical records of all of the children were gathered, and clinical traits, information about the procedure, and follow-up were all analyzed. Results: A total of 370 patients' inguinal hernias were repaired. For 136 patients undergoing OR and 234 patients undergoing LR, all procedures were completed satisfactorily. There were 98 cases of bilateral hernias and 272 cases of unilateral hernias (180 on the right side and 92 on the left). In the LR group, 58 patients who had been initially diagnosed with unilateral hernias developed contralateral occult hernias intraoperatively. Inguinal hernia operations took an average of 13.82 (LR) and 32.07 (OR) minutes for unilateral cases, and 21.00 (LR) and 54.85 (OR) minutes for bilateral cases. For LR and OR, the average follow-up time was 22.41 months and 23.10 months, respectively. The perioperative complications included peritoneal rupture in 3 patients, scrotal edema or hematoma in 5, hydrocele in 3, and groin pain in 6. In the LR group, 1 patient experienced the postoperative recurrence, whereas 8 individuals in the OR group did. Conclusions: Our initial research showed that laparoscopic two-hook hernia needle percutaneous extraperitoneal internal ring closure inguinal hernia repair is a safe and effective procedure. The LR method has the benefits of concealing the incision, a quicker procedure, having a lower risk of complications, and finding contralateral patent processus vaginalis. Therefore, promoting and using this surgical technique in clinical practice are merited. Clinical Trial Registration number: Medical Association of Xiangtan (2022-xtyx-28).

The impact of tumor characteristics on cardiovascular disease death in breast cancer patients with CT or RT: a population-based study.

Background: Previous studies focused on the impact of cardiovascular diseases (CVD) risk factors in breast cancer patients with chemotherapy (CT) or radiotherapy (RT). This study aimed to identify the impact of tumor characteristics on CVD death in these patients. Methods: Data of female breast cancer patients with CT or RT between 2004 and 2016 were included. The risk factors of CVD death were identified using Cox regression analyses. A nomogram was constructed to evaluate the predicted value of tumor characteristics, and then validated by the concordance indexes (C-index) and calibration curves. Result: A total of 28,539 patients were included with an average follow-up of 6.1 years. Tumor size > 45 mm (adjusted HR = 1.431, 95% CI = 1.116-1.836, P = 0.005), regional (adjusted HR = 1.278, 95% CI = 1.048-1.560, P = 0.015) and distant stage (adjusted HR = 2.240, 95% CI = 1.444-3.474, P < 0.001) were risk factors of CVD death for breast cancer patients with CT or RT. The prediction nomogram of tumor characteristics (tumor size and stage) on CVD survival was established. The C-index of internal and external validation were 0.780 (95% Cl = 0.751-0.809), and 0.809 (95% Cl = 0.768-0.850), respectively. The calibration curves showed consistency between the actual observation and nomogram. The risk stratification was also significant distinction (P < 0.05). Conclusion: Tumor size and stage were related to the risk of CVD death for breast cancer patients with CT or RT. The management of CVD death risk in breast cancer patients with CT or RT should focus not only on CVD risk factors but also on tumor size and stage.

Development and validation of nomogram including high altitude as a risk factor for COPD: A cross-sectional study based on Gansu population.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a common and harmful disease that requires an effective tool to early screen high-risk individuals. Gansu has unique environments and customs, leading to the different prevalence and etiology of COPD from other regions. The association between altitude and COPD once attracted epidemiologists' attention. However, the prevalence in Gansu and the role of altitude are still unclarified. Methods: In Gansu, a multistage stratified cluster sampling procedure was utilized to select a representative sample aged 40 years or older. The questionnaire and spirometry examination were implemented to collect participants' information. The diagnosis and assessment of COPD were identified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, while post-bronchodilator FEV1/FVC < LLN was for sensitivity analysis. Furthermore, the effect of high altitude on COPD was evaluated by the logistic regression model after propensity score matching (PSM). Finally, the participants were randomly divided into training and validation sets. The training set was used to screen the relative factors and construct a nomogram which was further assessed by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) in the two sets. Results: There were 2,486 eligible participants in the final analysis, of which 1,584 lived in low altitudes and 902 lived in high altitudes. Based on the GOLD criterion, the crude and standardized prevalences in Gansu were 20.4% (18.7-22.0) and 19.7% (17.9-21.6). After PSM, the logistic regression model indicated that high altitude increased COPD risk [PSM OR: 1.516 (1.162-1.978)]. Altitude, age, sex, history of tuberculosis, coal as fuel, and smoking status were reserved for developing a nomogram that demonstrated excellent discrimination, calibration, and clinical benefit in the two sets. Conclusions: COPD has become a serious public health problem in Gansu. High altitude is a risk factor for COPD. The nomogram has satisfactory efficiency in screening high-risk individuals.

Non-cancer-specific survival in patients with primary central nervous system lymphoma: A multi-center cohort study.

Objective: The study aimed to evaluate the non-cancer-specific death risk and identify the risk factors affecting the non-cancer-specific survival (NCSS) in patients with primary central nervous system lymphoma (PCNSL). Methods: This multi-center cohort study included 2497 patients with PCNSL in the Surveillance, Epidemiology and End Results (SEER) database from 2007 to 2016, with a mean follow-up of 4.54 years. The non-cancer-specific death risk in patients with PCNSL and primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) was evaluated using the proportion of deaths, standardized mortality ratio (SMR), and absolute excess risk (AER). Univariate and multivariate competing risk regression models were utilized to identify the risk factors of NCSS. Results: PCNSL was the most frequent cause of death in PCNSL patients (75.03%). Non-cancer-specific causes constituted a non-negligible portion of death (20.61%). Compared with the general population, PCNSL patients had higher risks of death from cardiovascular disease (CVD) (SMR, 2.55; AER, 77.29), Alzheimer's disease (SMR, 2.71; AER, 8.79), respiratory disease (SMR, 2.12; AER, 15.63), and other non-cancer-specific diseases (SMR, 4.12; AER, 83.12). Male sex, Black race, earlier year of diagnosis (2007-2011), being unmarried, and a lack of chemotherapy were risk factors for NCSS in patients with PCNSL and PCNS-DLBCL (all P < 0.05). Conclusion: Non-cancer-specific causes were important competing causes of death in PCNSL patients. More attention is recommended to non-cancer-specific causes of death in the management of PCNSL patients.

Construction and validation of a fatty acid metabolism-related gene signature for predicting prognosis and therapeutic response in patients with prostate cancer.

Background: Reprogramming of fatty acid metabolism is a newly-identified hallmark of malignancy. However, no studies have systematically investigated the fatty acid metabolism related-gene set in prostate cancer (PCa). Methods: A cohort of 381 patients with gene expression and clinical data from The Cancer Genome Atlas was used as the training set, while another cohort of 90 patients with PCa from GEO (GSE70769) was used as the validation set. Differentially expressed fatty acid metabolism-related genes were subjected to least absolute shrinkage and selection operator (LASSO)-Cox regression to establish a fatty acid metabolism-related risk score. Associations between the risk score and clinical characteristics, immune cell infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE) score, and response to chemotherapy were analyzed. Finally, the expression level of genes included in the model was validated using real-time PCR. Results: A prognostic risk model based on five fatty acid metabolism related genes (ALDH1A1, CPT1B, CA2, CROT, and NUDT19) were constructed. Tumors with higher risk score were associated with larger tumor size, lymph node involvement, higher Gleason score, and poorer biochemical recurrence (BCR)-free survival. Furthermore, the high- and low-risk tumors exhibited distinct immune cell infiltration features and immune-related pathway activation. High-risk tumors were associated with favorable response to immunotherapy as indicated by high TMB and low TIDE score, but poor response to bicalutamide and docetaxel chemotherapy. Conclusion: This study established a fatty acid metabolism-related gene signature which was predictive of BCR and response to chemotherapy and immunotherapy, providing a novel therapeutic biomarker for PCa.

Metastatic patterns and prognosis of patients with primary malignant cardiac tumor.

Background: Distant metastases are independent negative prognostic factors for patients with primary malignant cardiac tumors (PMCT). This study aims to further investigate metastatic patterns and their prognostic effects in patients with PMCT. Materials and methods: This multicenter retrospective study included 218 patients with PMCT diagnosed between 2010 and 2017 from Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was utilized to identify metastatic risk factors. A Chi-square test was performed to assess the metastatic rate. Kaplan-Meier methods and Cox regression analysis were used to analyze the prognostic effects of metastatic patterns. Results: Sarcoma (p = 0.002) and tumor size¿4 cm (p = 0.006) were independent risk factors of distant metastases in patients with PMCT. Single lung metastasis (about 34%) was the most common of all metastatic patterns, and lung metastases occurred more frequently (17.9%) than bone, liver, and brain. Brain metastases had worst overall survival (OS) and cancer-specific survival (CSS) among other metastases, like lung, bone, liver, and brain (OS: HR = 3.20, 95% CI: 1.02-10.00, p = 0.046; CSS: HR = 3.53, 95% CI: 1.09-11.47, p = 0.036). Conclusion: Patients with PMCT who had sarcoma or a tumor larger than 4 cm had a higher risk of distant metastases. Lung was the most common metastatic site, and brain metastases had worst survival among others, such as lung, bone, liver, and brain. The results of this study provide insight for early detection, diagnosis, and treatment of distant metastases associated with PMCT.

Diagnostic and Prognostic Nomograms for Lung Metastasis in Triple-Negative Breast Cancer.

Background: The lungs are one of the common sites of metastasis of triple-negative breast cancer (TNBC). Patients with lung metastases (LM) have a shorter duration of survival. This study is aimed at determining the prognostic factors of patients with TNBC with LM and constructing two nomograms to assess the risk of LM and the prognosis of patients with TNBC with LM. Methods: Clinicopathological and follow-up data of patients with TNBC between 2010 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were used to screen for independent predictors of LM in patients with TNBC and identify the independent prognostic factors of patients with TNBC with LM. The two nomograms were appraised using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results: A total of 27,048 patients with TNBC were included in this study. Age, tumour size, T stage, and N stage were identified as independent risk factors for LM in patients with TNBC. Histological type, marital status, prior surgery, chemotherapy, bone metastases, brain metastases, and LM were confirmed as independent prognostic factors for patients with TNBC with LM. The area under the ROC curve (AUC) of the diagnostic nomogram was 0.838 (95% confidence interval 0.817-0.860) in the training cohort and 0.894 (95% confidence interval 0.875-0.917) in the verification cohort. The AUC values of the 6-, 12-, and 18-month prognostic nomograms in the training cohort were 0.809 (95% confidence interval 0.771-0.868), 0.779 (95% confidence interval 0.737-0.834), and 0.735 (95% confidence interval 0.699-0.811), respectively, and the corresponding AUC values in the validation cohort were 0.735(95% confidence interval 0.642-0.820), 0.672 (95% confidence interval 0.575-0.758), and 0.705 (95% confidence interval 0.598-0.782), respectively. According to the calibration curves and data analysis, both nomograms exhibited good performance. Conclusion: We successfully constructed and verified two valuable nomograms for predicting the incidence of LM and prognosis of patients TNBC with LM.

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration.

BACKGROUND: Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). METHODS: Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. RESULTS: The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes. CONCLUSION: This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.

TREM-1 aggravates chronic obstructive pulmonary disease development via activation NLRP3 inflammasome-mediated pyroptosis.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major cause of death globally. Inflammation plays a crucial role in COPD development. Pyroptosis, an inflammatory form of cell death, may involve in the pathogenesis of COPD. This study aims to explore the role and action mechanism of triggering receptor expressed on myeloid cells 1 (TREM-1) in COPD. METHODS: Here, cigarette smoke stimulation was used to establish COPD model in mice. Cigarette smoke extract combined with lipopolysaccharide was used to stimulate RAW264.7 cells for COPD model in vitro. QRT-PCR and Western blot were performed to detect the expression of mRNA and proteins, respectively, in the lung tissues and cells. Concentration of cytokines was measured using ELISA. H&E staining was used to analyze the pathological changes in lung tissues. The number of infiltrated macrophage was examined using immunofluorescence. LP17 was used to silence the expression of TREM-1. RESULTS: The results showed that TREM-1 was highly expressed in COPD. In vivo, inhibition of TREM-1 effectively improved the injury in lung tissues of COPD mouse, and reduced the infiltration of macrophages. Moreover, inhibition of TREM-1 in vivo and in vitro notably suppressed the activation of NLRP3 inflammasome and pyroptosis. Rescue experiment demonstrated that TREM-1 activated pyroptosis via regulating NLRP3 inflammasome. CONCLUSION: Overall, our results proved that TREM-1 promoted the lung injury and inflammation in COPD mouse through activation of NLRP3 inflammasome-mediated pyroptosis. Our data indicated a novel mechanism of TREM-1 in COPD development, and maybe provide a novel therapeutic target for COPD treatment.

Guideline for the diagnosis, treatment and long-term management of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.

Correlations Between the Characteristics of Alternative Splicing Events, Prognosis, and the Immune Microenvironment in Breast Cancer.

OBJECTIVE: Alternative splicing (AS) is the mechanism by which a few genes encode numerous proteins, and it redefines the concept of gene expression regulation. Recent studies showed that dysregulation of AS was an important cause of tumorigenesis and microenvironment formation. Therefore, we performed a systematic analysis to examine the role of AS in breast cancer (Breast Cancer, BrCa) progression. METHODS: The present study included 993 BrCa patients from The Cancer Genome Atlas (TCGA) database in the genome-wide analysis of AS events. We used differential and prognostic analyses and found differentially expressed alternative splicing (DEAS) events and independent prognostic factors related to patients' overall survival (OS) and disease-free survival (DFS). We divided the patients into two groups based on these AS events and analyzed their clinical features, molecular subtyping and immune characteristics. We also constructed a splicing factor (SF) regulation network for key AS events and verified the existence of AS events in tissue samples using real-time quantitative PCR. RESULTS: A total of 678 AS events were identified as differentially expressed, of which 13 and 10 AS events were independent prognostic factors of patients' OS and DFS, respectively. Unsupervised clustering analysis based on these prognostic factors indicated that the Cluster 1 group had a better prognosis and more immune cell infiltration. SFs were significantly related to the expression of AS events, and AA-RPS21 was significantly upregulated in tumors. CONCLUSION: Alternative splicing expands the mechanism of breast cancer progression from a new perspective. Notably, alternative splicing may affect the patient's prognosis by affecting the infiltration of immune cells. Our research provides important guidance for subsequent studies of AS in breast cancer.

Cigarette smoke extract-treated airway epithelial cells-derived exosomes promote M1 macrophage polarization in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a persistent respiratory disorder that is primarily caused by exposure to cigarette smoke (CS). Exosomes have emerged as crucial mediators of intercellular communication, but their role in CS-induced COPD is not fully understood. Here, we investigated whether exosomes derived from cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs) promote M1 macrophage polarization by upregulating triggering receptor expressed on myeloid cells-1 (TREM-1) expression during COPD pathogenesis. The exosomes isolated from PBS- or CSE-treated MAECs were named as ExoPBS or ExoCSE, respectively. Macrophages were transfected with si-TREM-1 to explore the role of TREM-1 in ExoCSE-induced M1 macrophage polarization. The lentivirus expressing shTREM-1 was injected into COPD model mice by intranasal instillation, which was carried out to explore the in vivo role of TREM-1 in ExoCSE-induced M1 macrophage polarization and CS-induced lung injury. We isolated ExoPBS and ExoCSE successfully, and found that ExoCSE promoted M1 macrophage polarization. Furthermore, we found that the promotion of ExoCSE to M1 macrophage polarization was partly reversed by TREM-1 knockdown. The results of animal experiments showed that ExoCSE administration aggravated CS-induced impairment in pulmonary function, lung injury and M1 macrophage polarization, which were partly rescued by TREM-1 silencing. Overall, ExoCSE promoted M1 macrophage polarization by upregulating TREM-1 expression, thereby aggravating the development of COPD.

An induced pluripotent stem cell line (CSUi004-A) from skin fibroblasts of a healthy individual.

We established an induced pluripotent stem cell (iPSC) reprogrammed from dermal fibroblasts of a 53-year-old healthy man. Retroviruses expressing Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) were employed to initiate the reprogramming and were silenced in iPSCs. The generated iPSCs were pluripotent as determined by immunostaining and expression of pluripotency markers. They were further induced as embryoid bodies in vitro and teratomas in vivo, reminiscent of their full capacity of differentiating into three germ layers. They are with a normal karyotype and genetically identical to donor fibroblasts. This iPSC line provides excellent cell sources for studying and modeling human-specific physiology.

Establishment of an induced pluripotent stem cell line (CSUi003-A) from fibroblasts of a healthy elderly individual.

Skin fibroblasts derived from a 71-year-old healthy woman were reprogrammed into induced pluripotent stem cells (iPSCs) by the transduction of retroviruses expressing OCT4, SOX2, KLF4 and c-MYC, respectively. The generated iPSCs maintained a normal karyotype and expressed various pluripotency markers. Moreover, they could be induced to form embryoid bodies in vitro and teratomas in vivo, indicating the full capacity of differentiating into three germ layers. This iPSC line could be differentiated into multiple cell subtypes for cellular modeling and drug discovery.