Comprehensive assessment of cellular senescence in the tumor microenvironment.

Cellular senescence (CS), a state of permanent growth arrest, is intertwined with tumorigenesis. Due to the absence of specific markers, characterizing senescence levels and senescence-related phenotypes across cancer types remain unexplored. Here, we defined computational metrics of senescence levels as CS scores to delineate CS landscape across 33 cancer types and 29 normal tissues and explored CS-associated phenotypes by integrating multiplatform data from ~20 000 patients and ~212 000 single-cell profiles. CS scores showed cancer type-specific associations with genomic and immune characteristics and significantly predicted immunotherapy responses and patient prognosis in multiple cancers. Single-cell CS quantification revealed intra-tumor heterogeneity and activated immune microenvironment in senescent prostate cancer. Using machine learning algorithms, we identified three CS genes as potential prognostic predictors in prostate cancer and verified them by immunohistochemical assays in 72 patients. Our study provides a comprehensive framework for evaluating senescence levels and clinical relevance, gaining insights into CS roles in cancer- and senescence-related biomarker discovery.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice.

AIMS: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. METHODS AND RESULTS: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. CONCLUSION: The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

Exploring value of CT coronary imaging combined with machine-learning methods to predict myocardial ischemia.

PURPOSE: To establish a machine-learning (ML) model based on coronary computed tomography angiography (CTA) images for evaluating myocardial ischemia in patients diagnosed with coronary atherosclerosis. METHODS: This retrospective analysis includes CTA images acquired from 110 patients. Among them, 58 have myocardial ischemia and 52 have normal myocardial blood supply. The patients are divided into training and test datasets with a ratio 7 : 3. Deep learning model-based CQK software is used to automatically segment myocardium on CTA images and extract texture features. Then, seven ML models are constructed to classify between myocardial ischemia and normal myocardial blood supply cases. Predictive performance and stability of the classifiers are determined by receiver operating characteristic curve with cross validation. The optimal ML model is then validated using an independent test dataset. RESULTS: Accuracy and areas under ROC curves (AUC) obtained from the support vector machine with extreme gradient boosting linear method are 0.821 and 0.777, respectively, while accuracy and AUC achieved by the neural network (NN) method are 0.818 and 0.757, respectively. The naive Bayes model yields the highest sensitivity (0.942), and the random forest model yields the highest specificity (0.85). The k-nearest neighbors model yields the lowest accuracy (0.74). Additionally, NN model demonstrates the lowest relative standard deviations (0.16 for accuracy and 0.08 for AUC) indicating the high stability of this model, and its AUC applying to the independent test dataset is 0.72. CONCLUSION: The NN model demonstrates the best performance in predicting myocardial ischemia using radiomics features computed from CTA images, which suggests that this ML model has promising potential in guiding clinical decision-making.

Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence.

Oxidative stress-induced DNA damage, the senescence-associated secretory phenotype (SASP), and impaired autophagy all are general features of senescent cells. However, the cross-talk among these events and processes is not fully understood. Here, using NIH3T3 cells exposed to hydrogen peroxide stress, we show that stress-induced DNA damage provokes the SASP largely via cytosolic chromatin fragment (CCF) formation, which activates a cascade comprising cGMP-AMP synthase (cGAS), stimulator of interferon genes protein (STING), NF-κB, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-κB signaling, promoting SASP and cellular senescence. We also present evidence that the persistent accumulation of CCFs in prematurely senescent cells is partially associated with a defect in DNA-degrading activity in autolysosomes and reduced abundance of activated DNase 2α. Intriguingly, we found that metformin- or rapamycin-induced activation of autophagy significantly lessened the size and levels of CCFs and repressed the activation of the cGAS-STING-NF-κB-SASP cascade and cellular senescence. These effects of autophagy activators indicated that autolysosomal function contributes to CCF clearance and SASP suppression, further supported by the fact that the lysosome inhibitor bafilomycin A1 blocked the role of autophagy-mediated CCF clearance and senescence repression.

Enhanced computed tomography radiomics-based machine-learning methods for predicting the Fuhrman grades of renal clear cell carcinoma.

OBJECTIVE: To develop and test an optimal machine learning model based on the enhanced computed tomography (CT) to preoperatively predict pathological grade of clear cell renal cell carcinoma (ccRCC). METHODS: A retrospective analysis of 53 pathologically confirmed cases of ccRCC was performed and 25 consecutive ccRCC cases were selected as a prospective testing set. All patients underwent routine preoperative abdominal CT plain and enhanced scans. Renal tumor lesions were segmented on arterial phase images and 396 radiomics features were extracted. In the training set, seven discrimination classifiers for high- and low-grade ccRCCs were constructed based on seven different machine learning models, respectively, and their performance and stability for predicting ccRCC grades were evaluated through receiver operating characteristic (ROC) analysis and cross-validation. Prediction accuracy and area under ROC curve were used as evaluation indices. Finally, the diagnostic efficacy of the optimal model was verified in the testing set. RESULTS: The accuracies and AUC values achieved by support vector machine with radial basis function kernel (svmRadial), random forest and naïve Bayesian models were 0.860±0.158 and 0.919±0.118, 0.840±0.160 and 0.915±0.138, 0.839±0.147 and 0.921±0.133, respectively, which showed high predictive performance, whereas K-nearest neighborhood model yielded lower accuracy of 0.720±0.188 and lower AUC value of 0.810±0.150. Additionally, svmRadial had smallest relative standard deviation (RSD, 0.13 for AUC, 0.17 for accuracy), which indicates higher stability. CONCLUSION: svmRadial performs best in predicting pathological grades of ccRCC using radiomics features computed from the preoperative CT images, and thus may have high clinical potential in guiding preoperative decision.

Short-chain fatty acid, acylation and cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), ß-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure.

Hepatic functional and pathological changes of type 1 diabetic mice in growing and maturation time.

To detect the changes in the liver function in both male and female OVE26 mice from young to adults for better understanding of type 1 diabetes-induced hepatic changes, OVE26 mice and wild-type FVB mice were raised in the same environment without any intervention, and then killed at 4, 12, 24 and 36 weeks for examining liver's general properties, including pathogenic and molecular changes. The influence of diabetes on the bodyweight of male and female mice was different. Both male and female OVE26 mice did not obtain serious liver injury or non-alcoholic fatty liver disease, manifested by mild elevation of plasma alanine transaminase, and less liver lipid content along with significantly suppressed lipid synthesis. Uncontrolled diabetes also did not cause hepatic glycogen accumulation in OVE26 mice after 4 weeks. Oxidative stress test showed no change in lipid peroxidation, but increased protein oxidation. Changed endoplasmic reticulum stress and apoptosis along with increased antioxidant capacity was observed in OVE26 mice. In conclusion, uncontrolled type 1 diabetes did not cause hepatic lipid deposition most likely because of reduced lipids synthesis in response to insulin deficiency. Enhanced antioxidant capacity might not only prevent the occurrence of severe acute liver injury but also the self-renewal, leading to liver dysfunction.

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. METHODS: Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. RESULTS: SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. CONCLUSIONS: SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.

Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm.

RATIONALE: Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown. OBJECTIVE: In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation. METHODS AND RESULTS: The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell-specific knockout of SIRT1 accelerated angiotensin II-induced formation and rupture of AAAs and AAA-related pathological changes, whereas vascular smooth muscle cell-specific overexpression of SIRT1 suppressed angiotensin II-induced AAA formation and progression in Apoe-/- mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl2)-induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II-induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression. CONCLUSIONS: These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.

Epigenetic Regulation of Vascular Aging and Age-Related Vascular Diseases.

Vascular aging refers to the structural and functional defects that occur in the aorta during the aging process and is characterized by increased vascular cell senescence, vascular dyshomeostasis, and vascular remodeling. Vascular aging is a major risk factor for vascular diseases. However, the current understanding of the biological process of vascular aging and age-related diseases is insufficient. Epigenetic regulation can influence gene expression independently of the gene sequence and mainly includes DNA methylation, histone modifications, and RNA-based gene regulation. Epigenetic regulation plays important roles in many physiological and pathophysiological processes and may explain some gaps in our knowledge regarding the interaction between genes and diseases. In this review, we summarize recent advances in the understanding of the epigenetic regulation of vascular aging and age-related diseases in terms of vascular cell senescence, vascular dyshomeostasis, and vascular remodeling. Moreover, the possibility of targeting epigenetic regulation to delay vascular aging and treat age-related vascular diseases is also discussed.

SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity.

AIMS: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. METHODS AND RESULTS: Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1.1 mg/kg/day). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analysed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-Tg mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. CONCLUSIONS: Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

Mitochondrial Sirtuins in cardiometabolic diseases.

Mitochondria are heterogeneous and essentially contribute to cellular functions and tissue homeostasis. Mitochondrial dysfunction compromises overall cell functioning, tissue damage, and diseases. The advances in mitochondrion biology increase our understanding of mitochondrial dynamics, bioenergetics, and redox homeostasis, and subsequently, their functions in tissue homeostasis and diseases, including cardiometabolic diseases (CMDs). The functions of mitochondria mainly rely on the enzymes in their matrix. Sirtuins are a family of NAD+-dependent deacylases and ADP-ribosyltransferases. Three members of the Sirtuin family (SIRT3, SIRT4, and SIRT5) are located in the mitochondrion. These mitochondrial Sirtuins regulate energy and redox metabolism as well as mitochondrial dynamics in the mitochondrial matrix and are involved in cardiovascular homeostasis and CMDs. In this review, we discuss the advances in our understanding of mitochondrial Sirtuins in mitochondrion biology and CMDs, including cardiac remodeling, pulmonary artery hypertension, and vascular dysfunction. The potential therapeutic strategies by targetting mitochondrial Sirtuins to improve mitochondrial function in CMDs are also addressed.

Application of 80-kVp tube voltage, low-concentration contrast agent and iterative reconstruction in coronary CT angiography: evaluation of image quality and radiation dose.

BACKGROUND AND AIM: To evaluate image quality and radiation dosage in coronary CT angiography using 80-kVp tube voltage combined with low-concentration contrast media (CM) and iterative reconstruction (IR) for coronary CT angiography (CCTA) and employing dual-source CT without heart-rate control. METHODS: 154 patients were randomly assigned to Group A (Control Group, 120-kVp tube voltage, high-concentration CM and filtered back projection reconstruction) and Group B (Low-Dose Group, 80 kVp, low-concentration CM and iterative construction). Two experienced radiologists double-blindly evaluated the following parameters: CT attenuation, signal-noise ratio (SNR), contrast-noise ratio (CNR), radiation dose, size-specific dose estimates (SSDE) and total iodine intake. Pearson correlation analysis was used to assess the relationship between SSDE and BMI. RESULTS: 98.1% vessel segments in Group A and 97.6% in Group B passed diagnostics, indicating no significant differences; the average aorta scores and CT attenuation values showed no significant differences between groups. Similar SNR and CNR results were obtained for the two groups, although values were slightly lower in Group A compared with Group B. The Effective Dose in Group B was 63% lower than that in Group A (P<.001). SSDE results were significantly different between the two groups (P<.001) but did not correlate with BMI. Finally, the total iodine intake in Group B was 22.9% lower than that in Group A. CONCLUSIONS: Coronary CTA conducted with a low tube voltage of 80 kVp, a low-concentration CM and IR without heart rate control can achieve images of similar quality to those obtained using standard procedures, significantly reducing the associated radiation dose and iodine intake.

What we talk about when we talk about spinal cord aging.

Spinal cord-associated disorders are common in the elderly population; however, the mechanisms underlying spinal aging remain elusive. In a recent Nature paper, Sun et al. systemically analyzed aged spines in nonhuman primates and identified a new cluster of CHIT1-positive microglia that drives motor neuron senescence and subsequent spine aging.

Predictive value of bilirubin and serum γ-glutamyltranspeptidase levels in type-2 diabetes mellitus patients with acute coronary syndrome.

BACKGROUND: Cardiovascular disease is a major complication of diabetes mellitus (DM). Type-2 DM (T2DM) is associated with an increased risk of cardiovascular events and mortality, while serum biomarkers may facilitate the prediction of these outcomes. Early differential diagnosis of T2DM complicated with acute coronary syndrome (ACS) plays an important role in controlling disease progression and improving safety. AIM: To investigate the correlation of serum bilirubin and γ-glutamyltranspeptidase (γ-GGT) with major adverse cardiovascular events (MACEs) in T2DM patients with ACS. METHODS: The clinical data of inpatients from January 2022 to December 2022 were analyzed retrospectively. According to different conditions, they were divided into the T2DM complicated with ACS group (T2DM + ACS, n = 96), simple T2DM group (T2DM, n = 85), and simple ACS group (ACS, n = 90). The clinical data and laboratory indices were compared among the three groups, and the correlations of serum total bilirubin (TBIL) levels and serum γ-GGT levels with other indices were discussed. T2DM + ACS patients received a 90-day follow-up after discharge and were divided into event (n = 15) and nonevent (n = 81) groups according to the occurrence of MACEs; Univariate and multivariate analyses were further used to screen the independent influencing factors of MACEs in patients. RESULTS: The T2DM + ACS group showed higher γ-GGT, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c) and lower TBIL and high-density lipoprotein cholesterol levels than the T2DM and ACS groups (P < 0.05). Based on univariate analysis, the event and nonevent groups were significantly different in age (t = 3.3612, P = 0.0011), TBIL level (t = 3.0742, P = 0.0028), γ-GGT level (t = 2.6887, P = 0.0085), LDL-C level (t = 2.0816, P = 0.0401), HbA1c level (t = 2.7862, P = 0.0065) and left ventricular ejection fraction (LEVF) levels (t=3.2047, P = 0.0018). Multivariate logistic regression analysis further identified that TBIL level and LEVF level were protective factor for MACEs, and age and γ-GGT level were risk factors (P < 0.05). CONCLUSION: Serum TBIL levels are decreased and γ-GGT levels are increased in T2DM + ACS patients, and the two indices are significantly negatively correlated. TBIL and γ-GGT are independent influencing factors for MACEs in such patients.

Endothelial H2S-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis.

Dysfunction of the vascular angiocrine system is critically involved in regenerative defects and fibrosis of injured organs. Previous studies have identified various angiocrine factors and found that risk factors such as aging and metabolic disorders can disturb the vascular angiocrine system in fibrotic organs. One existing key gap is what sense the fibrotic risk to modulate the vascular angiocrine system in organ fibrosis. Here, using human and mouse data, we discovered that the metabolic pathway hydrogen sulfide (H2S)-AMP-activated protein kinase (AMPK) is a sensor of fibrotic stress and serves as a key mechanism upregulating the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells to participate in lung fibrosis. Activation of the metabolic sensor AMPK was inhibited in endothelial cells of fibrotic lungs, and AMPK inactivation was correlated with enriched fibrotic signature and reduced lung functions in humans. The inactivation of endothelial AMPK accelerated lung fibrosis in mice, while the activation of endothelial AMPK with metformin alleviated lung fibrosis. In fibrotic lungs, endothelial AMPK inactivation led to YAP activation and overexpression of the angiocrine factor PAI-1, which was positively correlated with the fibrotic signature in human fibrotic lungs and inhibition of PAI-1 with Tiplaxtinin mitigated lung fibrosis. Further study identified that the deficiency of the antioxidative gas metabolite H2S accounted for the inactivation of AMPK and activation of YAP-PAI-1 signaling in endothelial cells of fibrotic lungs. H2S deficiency was involved in human lung fibrosis and H2S supplement reversed mouse lung fibrosis in an endothelial AMPK-dependent manner. These findings provide new insight into the mechanism underlying the deregulation of the vascular angiocrine system in fibrotic organs.

Multimodal data integration using machine learning to predict the risk of clear cell renal cancer metastasis: a retrospective multicentre study.

PURPOSE: To develop and validate a predictive combined model for metastasis in patients with clear cell renal cell carcinoma (ccRCC) by integrating multimodal data. MATERIALS AND METHODS: In this retrospective study, the clinical and imaging data (CT and ultrasound) of patients with ccRCC confirmed by pathology from three tertiary hospitals in different regions were collected from January 2013 to January 2023. We developed three models, including a clinical model, a radiomics model, and a combined model. The performance of the model was determined based on its discriminative power and clinical utility. The evaluation indicators included area under the receiver operating characteristic curve (AUC) value, accuracy, sensitivity, specificity, negative predictive value, positive predictive value and decision curve analysis (DCA) curve. RESULTS: A total of 251 patients were evaluated. Patients (n = 166) from Shandong University Qilu Hospital (Jinan) were divided into the training cohort, of which 50 patients developed metastases; patients (n = 37) from Shandong University Qilu Hospital (Qingdao) were used as internal testing, of which 15 patients developed metastases; patients (n = 48) from Changzhou Second People's Hospital were used as external testing, of which 13 patients developed metastases. In the training set, the combined model showed the highest performance (AUC, 0.924) in predicting lymph node metastasis (LNM), while the clinical and radiomics models both had AUCs of 0.845 and 0.870, respectively. In the internal testing, the combined model had the highest performance (AUC, 0.877) for predicting LNM, while the AUCs of the clinical and radiomics models were 0.726 and 0.836, respectively. In the external testing, the combined model had the highest performance (AUC, 0.849) for predicting LNM, while the AUCs of the clinical and radiomics models were 0.708 and 0.804, respectively. The DCA curve showed that the combined model had a significant prediction probability in predicting the risk of LNM in ccRCC patients compared with the clinical model or the radiomics model. CONCLUSION: The combined model was superior to the clinical and radiomics models in predicting LNM in ccRCC patients.

Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor).

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease (NAFLD), coupled with hepatitis and insulin resistance. Yet the details of the underlying mechanisms are not fully understood. Here, we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD. Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation (FAO), and induced insulin resistance. Conversely, hepatic Zbtb18 overexpression alleviated hepato-steatosis, insulin resistance, and hyperglycemia in mice fed on a high-fat diet (HFD) or in diabetic mice. Notably, in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor (FXR) mediated FAO and Clathrin Heavy Chain (CLTC) protein hinders NLRP3 inflammasome activity. This key mechanism by which hepatocyte's Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR's deletion and forced expression in mice and cultured mouse primary hepatocytes (MPHs). Moreover, CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages. Altogether, Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression, which inhibits NLRP3 inflammasome's activity alleviating inflammatory stress and insulin resistance, representing an attractive remedy for hepatic steatosis and fibrosis.