An explainable machine learning-based model to predict intensive care unit admission among patients with community-acquired pneumonia and connective tissue disease.

BACKGROUND: There is no individualized prediction model for intensive care unit (ICU) admission on patients with community-acquired pneumonia (CAP) and connective tissue disease (CTD) so far. In this study, we aimed to establish a machine learning-based model for predicting the need for ICU admission among those patients. METHODS: This was a retrospective study on patients admitted into a University Hospital in China between November 2008 and November 2021. Patients were included if they were diagnosed with CAP and CTD during admission and hospitalization. Data related to demographics, CTD types, comorbidities, vital signs and laboratory results during the first 24 h of hospitalization were collected. The baseline variables were screened to identify potential predictors via three methods, including univariate analysis, least absolute shrinkage and selection operator (Lasso) regression and Boruta algorithm. Nine supervised machine learning algorithms were used to build prediction models. We evaluated the performances of differentiation, calibration, and clinical utility of all models to determine the optimal model. The Shapley Additive Explanations (SHAP) and Local Interpretable Model-Agnostic Explanations (LIME) techniques were performed to interpret the optimal model. RESULTS: The included patients were randomly divided into the training set (1070 patients) and the testing set (459 patients) at a ratio of 70:30. The intersection results of three feature selection approaches yielded 16 predictors. The eXtreme gradient boosting (XGBoost) model achieved the highest area under the receiver operating characteristic curve (AUC) (0.941) and accuracy (0.913) among various models. The calibration curve and decision curve analysis (DCA) both suggested that the XGBoost model outperformed other models. The SHAP summary plots illustrated the top 6 features with the greatest importance, including higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), lower level of CD4 + T cell, lymphocyte and serum sodium, and positive serum (1,3)-ß-D-glucan test (G test). CONCLUSION: We successfully developed, evaluated and explained a machine learning-based model for predicting ICU admission in patients with CAP and CTD. The XGBoost model could be clinical referenced after external validation and improvement.

A Nomogram for Predicting Mortality in Patients with Pneumonia-Associated Acute Respiratory Distress Syndrome (ARDS).

Background: There is no predictive tool developed for pneumonia-associated acute respiratory distress syndrome (ARDS) specifically so far, and the clinical risk classification of these patients is not well defined. Our study aims to construct an early prediction model for hospital mortality in patients with pneumonia-associated ARDS. Methods: In this single-center retrospective study, consecutive patients with pneumonia-associated ARDS admitted into intensive care units (ICUs) in West China Hospital of Sichuan University in China between January 2012 and December 2018 were enrolled. The least absolute shrinkage and selection operator (LASSO) regression and then multivariate logistic regression analysis were used to identify independent predictors which were used to develop a nomogram. We evaluated the performance of differentiation, calibration, and clinical utility of the nomogram. Results: The included patients were divided into the training cohort (442 patients) and the testing cohort (190 patients) with comparable baseline characteristics. The independent predictors for hospital mortality included age (OR: 1.04; 95% CI: 1.02, 1.05), chronic cardiovascular diseases (OR: 2.62; 95% CI: 1.54, 4.45), chronic respiratory diseases (OR: 1.87; 95% CI: 1.02, 3.43), lymphocytes (OR: 0.56; 95% CI: 0.39, 0.81), albumin (OR: 0.94; 95% CI: 0.90, 1.00), creatinine (OR: 1.00; 95% CI: 1.00, 1.01), D-dimer (OR: 1.06; 95% CI: 1.03, 1.09) and procalcitonin (OR: 1.14; 95% CI: 1.07, 1.22). A web-based dynamic nomogram (https://h1234.shinyapps.io/dynnomapp/) was constructed based on these factors. The concordance index (C index) of the nomogram was 0.798 (95% CI: 0.756, 0.840) in the training cohort and 0.808 (95% CI: 0.747, 0.870) in testing cohort. The precision-recall (PR) curves, calibration curves, decision curve analyses (DCA) and clinical impact curves showed that the nomogram has good predictive value and clinical utility. Conclusion: We developed and evaluated a convenient nomogram consisting of 8 clinical characteristics for predicting mortality in patients with pneumonia-associated ARDS.

Association between obstructive sleep apnea and low bone mass in adults: a systematic review and meta-analysis.

Introduction: This study aimed to synthesize existing evidence on the potential association between obstructive sleep apnea (OSA) and low bone mass in adults. Methods: Electronic searches of four main databases were performed. The inclusion criteria consisted of observational studies investigating the relationship between OSA and bone mass, osteoporosis, fractures, or bone metabolism markers in adult population. Bone mineral density (BMD) and T score of lumbar and femur neck, incidence of osteoporosis and fractures, bone metabolism marker levels were extracted as primary outcomes. Results: Among the 693 relevant publications, 10 studies consisting of 158,427 participants met with the inclusion and exclusion criteria. Meta-analysis showed a significant lower BMD of lumbar (mean difference (MD) = - 0.03; 95% CI - 0.05, - 0.01; I2 = 46%), femur neck (MD = - 0.06; 95% CI - 0.12, 0.00; I2 = 71%), and a significant lower T score of lumbar (MD = - 0.42; 95% CI - 0.79, - 0.05; I2 = 63%) in the OSA group. The results suggested that both male (odds ratio (OR) = 2.03; 95% CI 1.23, 3.35; I2 = 38%) and female (OR = 2.56; 95% CI 1.96, 3.34; I2 = 0%) had higher risk of osteoporosis in the OSA group. Besides, meta-analysis also showed that bone-specific alkaline phosphatase was significantly lower in OSA patients (MD = - 1.90; 95% CI - 3.48, - 0.32; I2 = 48%). Conclusions: A potential association between OSA and lower bone mass in adults is preliminarily proved. It also seems plausible that both male and female with OSA have a higher risk of osteoporosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00481-1.

Clinical profile analysis and nomogram for predicting in-hospital mortality among elderly severe community-acquired pneumonia patients: a retrospective cohort study.

BACKGROUND: Severe community-acquired pneumonia is one of the most lethal forms of CAP with high mortality. For rapid and accurate decisions, we developed a mortality prediction model specifically tailored for elderly SCAP patients. METHODS: The retrospective study included 2365 elderly patients. To construct and validate the nomogram, we randomly divided the patients into training and testing cohorts in a 70% versus 30% ratio. The primary outcome was in-hospital mortality. Univariate and multivariate logistic regression analyses were used in the training cohort to identify independent risk factors. The robustness of this model was assessed using the C index, ROC and AUC. DCA was employed to evaluate the predictive accuracy of the model. RESULTS: Six factors were used as independent risk factors for in-hospital mortality to construct the prediction model, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet, and BUN. The C index was 0.743 (95% CI 0.719-0.768) in the training cohort and 0.731 (95% CI 0.694-0.768) in the testing cohort. The ROC curves and AUC for the training cohort and testing cohort (AUC = 0.742 vs. 0.728) indicated a robust discrimination. And the calibration plots showed a consistency between the prediction model probabilities and observed probabilities. Then, the DCA demonstrated great clinical practicality. CONCLUSIONS: The nomogram incorporated six risk factors, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet and BUN, which had great predictive accuracy and robustness, while also demonstrating clinical practicality at ICU admission.

Markers of insulin resistance associated with non-alcoholic fatty liver disease in non-diabetic population.

Insulin resistance (IR) plays an important role in the development of non-alcoholic fatty liver disease (NAFLD). IR markers are divided into two types: (1) insulin-based IR marker, homeostatic model assessment of IR (HOMA-IR); and (2) non-insulin-based IR markers, such as triglyceride-glucose (TyG) index, TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-c), and metabolic score for IR (METS-IR). The non-insulin-based IR markers are often associated with lipids. The aim of this study was to analyse the association between IR markers and NAFLD in non-diabetic population. Baseline data of NAFLD and non-NAFLD groups were compared. Logistic regression was used to evaluate the relationship between five IR markers and NAFLD risk. The odds ratios (ORs) and 95% confidence intervals (CIs) of IR markers were calculated. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to evaluate the ability of different IR markers to detect NAFLD. Subgroup analyses were performed in obese and non-obese subgroups. This study found a positive correlation between NAFLD risk and elevation in five IR markers (HOMA-IR, TyG, TyG-BMI, TG/HDL-c, and METS-IR). In non-obese subjects, the AUC of TyG-BMI was larger than that of the other four IR markers to detect NAFLD. The AUC of HOMA-IR was larger than that of the other four IR markers to detect NAFLD in obese subjects. In non-diabetic population, the five IR markers are associated with the risk of NAFLD, including non-obese and obese NAFLD. TyG-BMI and HOMA-IR can be used to detect non-obese and obese NAFLD, respectively, with better detection ability compared with the other IR markers.

Genetic Association of Circulating Adipokines with Risk of Idiopathic Pulmonary Fibrosis: A Two-Sample Mendelian Randomization Study.

PURPOSE: The causal relationships between circulating adipokines and idiopathic pulmonary fibrosis (IPF) are yet to be established. We performed a two-sample Mendelian randomization (MR) study to investigate the causal roles of adipokines on IPF risk. METHODS: We analyzed the summary data from genome-wide association studies (GWAS), including adiponectin, leptin, resistin and monocyte chemoattractant protein-1 (MCP-1) and IPF. The inverse-variance weighted (IVW) method was considered as the major method and the MR-Egger, weighted median, simple mode and weighted mode were utilized as complementary methods. We also performed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test and leave-one-out analysis. RESULTS: The selected number of single nucleotide polymorphisms (SNPs) was 13 for adiponectin, 6 for leptin,12 for resistin, and 6 for MCP-1, respectively. The results showed a causal effect of the circulating adiponectin levels on the risk of IPF (OR 0.645, 95% CI 0.457-0.911, P = 0.013). However, we did not observe significant associations of genetic changes in serum leptin (OR 1.018, 95% CI 0.442-2.346, P = 0.967), resistin (OR 1.002, 95% CI 0.712-1.408, P = 0.993), and MCP-1 (OR 1.358, 95% CI 0.891-2.068, P = 0.155) with risk of developing IPF. There was no evidence of heterogeneity or horizontal pleiotropy. The sensitivity analyses confirmed that our results were stable and reliable. CONCLUSIONS: The increase in serum adiponectin was associated causally with a decreased risk of developing IPF. There is no evidence to support a causal association between leptin, resistin or MCP-1 with risk of IPF. Further studies are needed to confirm our findings.

Insight into the lncRNA-mRNA Co-Expression Profile and ceRNA Network in Lipopolysaccharide-Induced Acute Lung Injury.

Long non-coding RNAs (lncRNAs) participate in acute lung injury (ALI). However, their latent biological function and molecular mechanism have not been fully understood. In the present study, the global expression profiles of lncRNAs and mRNAs between the control and lipopolysaccharide (LPS)-stimulated groups of human normal lung epithelial cells (BEAS-2B) were determined using high-throughput sequencing. Overall, a total of 433 lncRNAs and 183 mRNAs were differentially expressed. A lncRNA-mRNA co-expression network was established, and then the top 10 lncRNAs were screened using topological methods. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis results showed that the key lncRNAs targeting mRNAs were mostly enriched in the inflammatory-related biological processes. Gene set variation analysis and Pearson's correlation coefficients confirmed the close correlation for the top 10 lncRNAs with inflammatory responses. A protein-protein interaction network analysis was conducted based on the key lncRNAs targeting mRNAs, where IL-1ß, IL-6, and CXCL8 were regarded as the hub genes. A competing endogenous RNA (ceRNA) modulatory network was created with five lncRNAs, thirteen microRNAs, and twelve mRNAs. Finally, real-time quantitative reverse transcription-polymerase chain reaction was employed to verify the expression levels of several key lncRNAs in BEAS-2B cells and human serum samples.

SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy.

Sirtuin6 (SIRT6) has been demonstrated to be involved in a range of physiological processes and diseases, while its role in acute respiratory distress syndrome (ARDS) remains unclear. Therefore, this study focused on the role and underlying mechanism of SIRT6 in ARDS with the aim of identifying potential therapeutic targets. In this study, we found that SIRT6 was significantly decreased in lipopolysaccharide (LPS)-induced A549 cells and a murine model. In vitro overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and alleviated cell apoptosis and inflammation, while knockdown of SIRT6 aggravated the loss of tight junction proteins (ZO-1 and occludin) and promoted cell apoptosis and inflammation in LPS-induced A549 cells. Furthermore, the overexpression of SIRT6 enhanced autophagy and inhibited the ERK1/2 pathway, while the knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 pathway. The autophagy activator rapamycin and the ERK1/2 inhibitor PD98059 rescued the effects of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. Mechanistically, SIRT6 deacetylated histone 3 at Lys9 to negatively regulate the ERK1/2 pathway. In vivo, the SIRT6-specific inhibitor OSS_128167 also significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis. Meanwhile, the SIRT6-specific inhibitor OSS_128167 also activated the ERK1/2 pathway and inhibited lung autophagy. These results suggested that SIRT6 could ameliorate the loss of tight junction proteins, inflammation, and apoptosis in LPS-induced ARDS by inhibiting the ERK1/ 2 pathway and enhancing autophagy, indicating that SIRT6 plays a beneficial role in ARDS and might be a potential therapeutic target for ARDS.

Nuclear SPHK2/S1P induces oxidative stress and NLRP3 inflammasome activation via promoting p53 acetylation in lipopolysaccharide-induced acute lung injury.

A bulk of evidence identified that macrophages, including resident alveolar macrophages and recruited macrophages from the blood, played an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). However, the molecular mechanisms of macrophages-induced acute lung injury (ALI) by facilitating oxidative stress and inflammatory responses remain unclear. Herein, we noticed that the levels of mitochondrial reactive oxygen species (mtROS), SPHK2 and activated NLRP3 inflammasome were higher in peripheral blood mononuclear cells (PBMCs) of ARDS patients than that in healthy volunteers. Similar observations were recapitulated in LPS-treated RAW264.7 and THP-1 cells. After exposure to LPS, the SPHK2 enzymatic activity, NLRP3 inflammasome activation and mtROS were significantly upregulated in macrophages. Moreover, knockdown SPHK2 via shRNA or inhibition SPHK2 could prominently decrease LPS-induced M1 macrophage polarization, oxidative stress and NLRP3 inflammasome activation. Further study indicated that upregulated SPHK2 could increase nuclear sphingosine-1-phosphate (S1P) levels and then restrict the enzyme activity of HDACs to facilitate p53 acetylation. Acetylation of p53 reinforced its binding to the specific region of the NLRP3 promoter and drove expression of NLRP3. In the in vivo experiments, it was also observed that treating with Opaganib (ABC294640), a specific SPHK2 inhibitor, could observably alleviate LPS-induced ALI, evidencing by lowered infiltration of inflammatory cells, increased M2 macrophages polarization and reduced oxidative damage in lung tissues. Besides, SPHK2 inhibition can also decrease the accumulation of acetylated p53 protein and the activation of NLRP3 inflammasome. Taken together, our results demonstrated for the first time that nuclear S1P can regulate the acetylation levels of non-histone protein through affecting HDACs enzyme activities, linking them to oxidative stress and inflammation in response to environmental signals. These data provide a theoretical basis that SPHK2 may be an effective therapeutic target of ARDS.

Regulated cell death in cancer: from pathogenesis to treatment.

ABSTRACT: Regulated cell death (RCD), including apoptosis, pyroptosis, necroptosis, and ferroptosis, is regulated by a series of evolutionarily conserved pathways, and is required for development and tissue homeostasis. Based on previous genetic and biochemical explorations of cell death subroutines, the characteristics of each are generally considered distinctive. However, recent in-depth studies noted the presence of crosstalk between the different forms of RCD; hence, the concept of PANoptosis appeared. Cancer, a complex genetic disease, is characterized by stepwise deregulation of cell apoptosis and proliferation, with significant morbidity and mortality globally. At present, studies on the different RCD pathways, as well as the intricate relationships between different cell death subroutines, mainly focus on infectious diseases, and their roles in cancer remain unclear. As cancers are characterized by dysregulated cell death and inflammatory responses, most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells. In this review, we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression. The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised. We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds, immune checkpoint inhibitors, and nanoparticles. Together, these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.

A prediction model for hospital mortality in patients with severe community-acquired pneumonia and chronic obstructive pulmonary disease.

BACKGROUND: No personalized prediction model or standardized algorithm exists to identify those at high risk of death among severe community-acquired pneumonia (SCAP) patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the risk factors and to develop a useful nomogram for prediction of mortality in those patients. METHODS: We performed a retrospective, observational, cohort study in the intensive care unit (ICU) of West China Hospital, Sichuan University with all consecutive SCAP patients with COPD between December 2011 and December 2018. The clinical data within 24 h of admission to ICU were collected. The primary outcome was hospital mortality. We divided the patients into training and testing cohorts (70% versus 30%) randomly. In the training cohort, univariate and multivariate logistic regression analysis were used to identify independent risk factors applied to develop a nomogram. The prediction model was assessed in both training and testing cohorts. RESULTS: Finally, 873 SCAP patients with COPD were included, among which the hospital mortality was 41.4%. In training cohort, the independent risk factors for hospital mortality were increased age, diabetes, chronic renal diseases, decreased systolic blood pressure (SBP), and elevated fibrinogen, interleukin 6 (IL-6) and blood urea nitrogen (BUN). The C index was 0.840 (95% CI 0.809-0.872) in training cohort and 0.830 (95% CI 0.781-0.878) in testing cohort. Furthermore, the time-dependent AUC, calibration plots, DCA and clinical impact curves indicated the model had good predictive performance. Significant association of risk stratification based on nomogram with mortality was also found (P for trend < 0.001). The restricted cubic splines suggested that estimated associations between these predictors and hospital mortality were all linear relationships. CONCLUSION: We developed a prediction model including seven risk factors for hospital mortality in patients with SCAP and COPD. It can be used for early risk stratification in clinical practice after more external validation.

Clinical profile analysis and nomogram for predicting in-hospital mortality among elderly severe community-acquired pneumonia patients with comorbid cardiovascular disease: a retrospective cohort study.

BACKGROUND: Researchers have linked cardiovascular disease (CVD) with advancing age; however, how it drives disease progression in elderly severe community acquired pneumonia (SCAP) patients is still unclear. This study aims to identify leading risk predictors of in-hospital mortality in elderly SCAP patients with CVD, and construct a comprehensive nomogram for providing personalized prediction. PATIENTS AND METHODS: The study retrospectively enrolled 2365 elderly patients identified SCAP. Among them, 413 patients were found to have CVD. The LASSO regression and multivariate logistic regression analysis were utilized to select potential predictors of in-hospital mortality in elderly SCAP patients with CVD. By incorporating these features, a nomogram was then developed and subjected to internal validations. Discrimination, calibration, and clinical use of the nomogram were assessed via C-index, calibration curve analysis, and decision plot. RESULTS: Compared with patients without CVD, elderly SCAP patients with CVD had a significant poor outcome. Further analysis of the CVD population identified 7 independent risk factors for in-hospital mortality in elderly SCAP patients, including age, the use of vasopressor, numbers of primary symptoms, body temperature, monocyte, CRP and NLR. The nomogram model incorporated these 7 predictors showed sufficient predictive accuracy, with the C-index of 0.800 (95% CI 0.758-0.842). High C-index value of 0.781 was obtained in the internal validation via bootstrapping validation. Moreover, the calibration curve indicative a good consistency of risk prediction, and the decision curve manifested that the nomogram had good overall net benefits. CONCLUSION: An integrated nomogram was developed to facilitate the personalized prediction of in-hospital mortality in elderly SCAP patients with CVD.

Resveratrol attenuates inflammation and apoptosis through alleviating endoplasmic reticulum stress via Akt/mTOR pathway in fungus-induced allergic airways inflammation.

BACKGROUND: Resveratrol has shown pleiotropic effects against inflammation and oxidative response. The present study aimed to investigate the effects and mechanisms of resveratrol on fungus-induced allergic airway inflammation. METHODS: Female BALB/c mice were injected intraperitoneally with Aspergillus fumigatus (Af) extract emulsified with aluminum on day 0 and 7 and intranasally challenged with Af extracts on day 14 and 15. Resveratrol or dexamethasone or a vehicle was injected intraperitoneally 1 h before each challenge. Mice were sacrificed for serum, bronchoalveolar lavage fluid (BALF), and lungs 24 h after the last challenge. The control group was administered with saline. BEAS-2B was used for the experiments in vitro that Af-exposed airway epithelial cells. RESULTS: Resveratrol and dexamethasone attenuated the airway inflammation and eosinophilia, and reduced not only the production of IL-4, IL-5, and IL-13 in the BALF and lung tissues but also the mRNA levels of lung IL-6, TNF-α, and TGF-ß induced by Af challenge (P < 0.05). Furthermore, Af-induced lung endoplasmic reticulum (ER) stress-related proteins PERK, CHOP, and GRP78 and the apoptosis markers including cleaved caspase-3 and cleaved caspase-7 were both suppressed significantly by resveratrol (P < 0.05). In vitro, activation of ER stress and the Akt/mTOR pathway in Af-exposed BEAS-2B cells were effectively ameliorated by resveratrol. Inhibition of the Akt/mTOR pathway using LY294002 suppressed the ER stress while ER stress inhibitor 4-PBA decreased the apoptosis in Af-exposed BEAS-2B cells. CONCLUSIONS: Our findings collectively revealed that resveratrol alleviated the Af-exposed allergic inflammation and apoptosis through inhibiting ER stress via Akt/mTOR pathway, exerting therapeutic effects on the fungus-induced allergic lung disorder.

Clinical characteristics and risk factors associated with mortality in patients with severe community-acquired pneumonia and type 2 diabetes mellitus.

BACKGROUND: The present study was performed to investigate the impacts of type 2 diabetes mellitus (T2DM) on severe community-acquired pneumonia (SCAP) and to develop a novel prediction model for mortality in SCAP patients with T2DM. METHODS: This was a retrospective observational study conducted in consecutive adult patients with SCAP admitted to the intensive care unit (ICU) of West China Hospital, Sichuan University, China, between September 2011 and September 2019. The primary outcome was hospital mortality. A propensity score matching (PSM) analysis model with a 1:2 ratio was used for the comparisons of clinical characteristics and outcomes between T2DM and nondiabetic patients. The independent risk factors were identified via univariate and then multivariable logistic regression analysis and were then used to establish a nomogram. RESULTS: In total, 1262 SCAP patients with T2DM and 2524 matched patients without T2DM were included after PSM. Patients with T2DM had longer ICU length of stay (LOS) (13 vs. 12 days, P = 0.016) and higher 14-day mortality (15% vs. 10.8%, P < 0.001), 30-day mortality (25.7% vs. 22.7%, P = 0.046), ICU mortality (30.8% vs. 26.5%, P = 0.005), and hospital mortality (35.2% vs. 31.0%, P = 0.009) than those without T2DM. In SCAP patients with T2DM, the independent risk factors for hospital mortality were increased numbers of comorbidities and diabetes-related complications; elevated C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), brain natriuretic peptide (BNP) and blood lactate; as well as decreased blood pressure on admission. The nomogram had a C index of 0.907 (95% CI: 0.888, 0.927) in the training set and 0.873 (95% CI: 0.836, 0.911) in the testing set, which was superior to the pneumonia severity index (PSI, AUC: 0.809, 95% CI: 0.785, 0.833). The calibration curve and decision curve analysis (DCA) also demonstrated its accuracy and applicability. CONCLUSIONS: SCAP patients with T2DM had worse clinical outcomes than nondiabetic patients. The nomogram has good predictive performance for hospital mortality and might be generally applied after more external validations.

CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop.

Circular RNA (circRNA), a closed continuous loop formed by back-splicing, has been confirmed to be implicated in a variety of human diseases including cancers. However, the underlying molecular mechanism of circRNA regulating the progression of renal cell carcinoma (RCC) remains largely unclear. In the present study, we identified a novel circular RNA, circESRP1, that derived from the ESRP1 gene locus at 8q22.1 exons. Lower expression of circESRP1 was found in clear cell RCC (ccRCC) tissues and cell lines. Besides, circESRP1 expression level showed inversely correlated with the advanced tumor size, TNM stage and distant metastasis of ccRCC. The expression level of circESRP1 exhibited a positive correlation with CTCF protein but negatively correlated with miR-3942 in 79 ccRCC tissues. In vivo experiments, we found that overexpression of circESRP1 effectively repressed xenograft tumor growth and inhibited c-Myc-mediated EMT progression. CircESRP1 acted as a sponge to competitively bind with miR-3942 as confirmed through RNA pull-down, RIP and dual-luciferase reporter assays. Moreover, CTCF, a downstream target of miR-3942, was validated to specifically promote the circESRP1 transcript expression and regulated by circESRP1/miR-3942 pathway to form a positive feedback loop. We also revealed that the circESRP1/miR-3942/CTCF feedback loop regulated the ccRCC cell functions via c-Myc mediated EMT process. This study provides a novel regulatory model of circRNA via forming a positive-feedback loop that perpetuates the circESRP1/miR-3942/CTCF axis, suggesting that this signaling may serve as a novel target for the treatment of ccRCC.

Accumulation of LDL/ox-LDL in the necrotic region participates in osteonecrosis of the femoral head: a pathological and in vitro study.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a common but intractable disease that appears to involve lipid metabolic disorders. Although numerous studies have demonstrated that high blood levels of low-density lipoprotein (LDL) are closely associated with ONFH, there is limited evidence to explain the pathological role of LDL. Pathological and in vitro studies were performed to investigate the role of disordered metabolism of LDL and oxidized LDL (ox-LDL) in the femoral head in the pathology of ONFH. METHODS: Nineteen femoral head specimens from patients with ONFH were obtained for immunohistochemistry analysis. Murine long-bone osteocyte Y4 cells were used to study the effects of LDL/ox-LDL on cell viability, apoptosis, and metabolism process of LDL/ox-LDL in osteocytes in normoxic and hypoxic environments. RESULTS: In the pathological specimens, marked accumulation of LDL/ox-LDL was observed in osteocytes/lacunae of necrotic regions compared with healthy regions. In vitro studies showed that ox-LDL, rather than LDL, reduced the viability and enhanced apoptosis of osteocytes. Pathological sections indicated that the accumulation of ox-LDL was significantly associated with impaired blood supply. Exposure to a hypoxic environment appeared to be a key factor leading to LDL/ox-LDL accumulation by enhancing internalisation and oxidation of LDL in osteocytes. CONCLUSIONS: The accumulation of LDL/ox-LDL in the necrotic region may contribute to the pathology of ONFH. These findings could provide new insights into the prevention and treatment of ONFH.

Hypoxic TAM-derived exosomal miR-155-5p promotes RCC progression through HuR-dependent IGF1R/AKT/PI3K pathway.

Hypoxic tumor-associated macrophages (TAMs) are related to poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). Exosomes are small lipid-bilayer vesicles that implicated in tumor progression and metastasis. However, whether hypoxic TAM-derived exosomes affect RCC progression within the hypoxic tumor microenvironment has not been elucidated. GSE analysis identified miR-155-5p was upregulated in RCC. Moreover, we quantified levels of miR-155-5p using RT-qPCR, performed immunohistochemical staining in 79 pairs of primary RCC specimens and related them to clinicopathological parameters. Higher miR-155-5p levels were related to more CD163 + TAM infiltration and elevated HIF-1a expression in our cohort. In the in vitro studies, we initially purified and characterized the exosomes from the supernatant of TAMs subjected to normoxia or hypoxia, and then transfected antagomiR-155-5p or control into these TAMs to produce corresponding exosomes. Gain and loss-of-function studies further investigated the effect of transferred hypoxic exosomal miR-155-5p on the cross-talk between TAMs and RCC cells in xenograft model and in vitro co-culture experiments. The results of RNA immunoprecipitation analyses elucidated that miR-155-5p could directly interact with human antigen R (HuR), thus increasing IGF1R mRNA stability. Mechanistically, hypoxic TAM-Exo transferred miR-155-5p promoted RCC progression partially through activating IGF1R/PI3K/AKT cascades. Taken together, transfer of miR-155-5p from hypoxic TAMs by exosomes to renal cancer cells explains the oncogenic manner, in which M2 macrophages confer the malignant phenotype to RCC cells by enhancing HuR-mediated mRNA stability of IGF1R.

NLRP3 Deficiency Protects Against Intermittent Hypoxia-Induced Neuroinflammation and Mitochondrial ROS by Promoting the PINK1-Parkin Pathway of Mitophagy in a Murine Model of Sleep Apnea.

Obstructive sleep apnea (OSA) associated neurocognitive impairment is mainly caused by chronic intermittent hypoxia (CIH)-triggered neuroinflammation and oxidative stress. Previous study has demonstrated that mitochondrial reactive oxygen species (mtROS) was pivotal for hypoxia-related tissue injury. As a cytosolic multiprotein complex that participates in various inflammatory and neurodegenerative diseases, NLRP3 inflammasome could be activated by mtROS and thereby affected by the mitochondria-selective autophagy. However, the role of NLRP3 and possible mitophagy mechanism in CIH-elicited neuroinflammation remain to be elucidated. Compared with wild-type mice, NLRP3 deficiency protected them from CIH-induced neuronal damage, as indicated by the restoration of fear-conditioning test results and amelioration of neuron apoptosis. In addition, NLRP3 knockout mice displayed the mitigated microglia activation that elicited by CIH, concomitantly with elimination of damaged mitochondria and reduction of oxidative stress levels (malondialdehyde and superoxide dismutase). Elevated LC3 and beclin1 expressions were remarkably observed in CIH group. In vitro experiments, intermittent hypoxia (IH) significantly facilitated mitophagy induction and NLRP3 inflammasome activation in microglial (BV2) cells. Moreover, IH enhanced the accumulation of damaged mitochondria, increased mitochondrial depolarization and augmented mtROS release. Consistently, NLRP3 deletion elicited a protective phenotype against IH through enhancement of Parkin-mediated mitophagy. Furthermore, Parkin deletion or pretreated with 3MA (autophagy inhibitor) exacerbated these detrimental actions of IH, which was accompanied with NLRP3 inflammasome activation. These results revealed NLRP3 deficiency acted as a protective promotor through enhancing Parkin-depended mitophagy in CIH-induced neuroinflammation. Thus, NLRP3 gene knockout or pharmacological blockage could be as a potential therapeutic strategy for OSA-associated neurocognitive impairment.

Diagnostic accuracy of the Berlin questionnaire and therapeutic effect of nasal continuous positive airway pressure in OSAHS patients with glucose metabolic dysfunction.

PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with alterations in glucose metabolism. The Berlin questionnaire (BQ) is effective in identifying subjects with high risk of OSAHS. However, its validity in patients with glucose metabolic dysfunction remains unclear. Our study aims to examine the diagnostic efficacy of the BQ in detecting OSAHS in patients with glucose metabolic dysfunction and to explore the effect of nasal CPAP on glucose metabolism. METHODS: Patients with glucose metabolic dysregulation were first asked to complete the BQ and then recruited for polysomnogram (PSG). The diagnostic accuracy of the BQ and the relationships between groups with normal glucose tolerance (NGT), elevated fasting blood glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM) were analyzed. Subjects with both OSAHS and glucose dysregulation received CPAP treatment and underwent an oral glucose tolerance test. Changes in apnea-hypopnea indices (AHI) and glycemic parameters were calculated to determine the efficacy of CPAP. RESULTS: Glycosylated hemoglobin and insulin levels were statistically different between the high-risk and low-risk groups according to the BQ. For diagnosis of subjects with OSAHS who also had glucose metabolic dysfunction, the sensitivity and specificity of the BQ using AHI cut-off values at 5 events per hour were 73% and 67%. CPAP therapy effectively reduced the blood glucose, HOMA-IR, and insulin levels. CONCLUSIONS: The BQ can be considered to be an effective and economical screening tool for patieints with OSAHS who also have glucose metabolic dysfunction. Treatment with CPAP may improve glycemic parameters.