scCRT: a contrastive-based dimensionality reduction model for scRNA-seq trajectory inference.

Trajectory inference is a crucial task in single-cell RNA-sequencing downstream analysis, which can reveal the dynamic processes of biological development, including cell differentiation. Dimensionality reduction is an important step in the trajectory inference process. However, most existing trajectory methods rely on cell features derived from traditional dimensionality reduction methods, such as principal component analysis and uniform manifold approximation and projection. These methods are not specifically designed for trajectory inference and fail to fully leverage prior information from upstream analysis, limiting their performance. Here, we introduce scCRT, a novel dimensionality reduction model for trajectory inference. In order to utilize prior information to learn accurate cells representation, scCRT integrates two feature learning components: a cell-level pairwise module and a cluster-level contrastive module. The cell-level module focuses on learning accurate cell representations in a reduced-dimensionality space while maintaining the cell-cell positional relationships in the original space. The cluster-level contrastive module uses prior cell state information to aggregate similar cells, preventing excessive dispersion in the low-dimensional space. Experimental findings from 54 real and 81 synthetic datasets, totaling 135 datasets, highlighted the superior performance of scCRT compared with commonly used trajectory inference methods. Additionally, an ablation study revealed that both cell-level and cluster-level modules enhance the model's ability to learn accurate cell features, facilitating cell lineage inference. The source code of scCRT is available at https://github.com/yuchen21-web/scCRT-for-scRNA-seq.

Efficacy of revascularization in CTO patients based on hibernating myocardium therapy.

BACKGROUND: The effectiveness of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still uncertain, especially for patients with ischemic left ventricular dysfunction. This study aimed to assess hibernating myocardium (HM), as determined by single-photon emission computed tomography (SPECT) and 18F-FDG positron emission tomography (PET), and to compare the benefits of PCI and optimal medical therapy (OMT). METHODS: A retrospective study collected data from 332 patients with CTO and ischemic left ventricular dysfunction. The study compared patients who underwent PCI or OMT via propensity score matching (PSM) analysis which was performed with a 1:2 matching protocol using the nearest neighbour matching algorithm. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE), defined as a composite of cardiac death, readmission for worsening heart failure (WHF), revascularization and myocardial infarction (MI). RESULTS: After PSM, there were a total of 246 individuals in the PCI and OMT groups. Following Cox regression, hibernating myocardium/total perfusion defect (HM/TPD) was identified as an independent risk factor (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.008-1.052, p = .007). The cut-off value of HM/TPD was 38%. The results of the subgroup analysis suggest that for patients with HM/TPD >38%, the OMT group had a greater risk of MACE (p = .035). A sensitivity analysis restricting patients with single-vessel CTO lesions, HM/TPD remained an independent predictor (HR 1.025, 95% CI 1.008-1.043, p = .005). CONCLUSION: HM/TPD is an independent predictor of MACE, and for patients with HM/TPD > 38%, CTO-PCI had a lower risk of MACE compared with OMT. However, further validation is still needed through large-scale studies.

Machine learning-based coronary artery calcium score predicted from clinical variables as a prognostic indicator in patients referred for invasive coronary angiography.

OBJECTIVES: Utilising readily available clinical variables, we aimed to develop and validate a novel machine learning (ML) model to predict severe coronary calcification, and further assessed its prognostic significance. METHODS: This retrospective study enrolled patients who underwent coronary CT angiography and subsequent invasive coronary angiography. Multiple ML algorithms were used to train the models for predicting severe coronary calcification (cardiac CT-measured coronary artery calcium [CT-CAC] score ≥ 400). The ML-based CAC (ML-CAC) score derived from the ML predictive probability was stratified into quartiles for prognostic analysis. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: Overall, 5785 patients were divided into training (80%) and test sets (20%). For clinical practicability, we selected the nine-feature support vector machine model with good and satisfactory performance regarding both discrimination and calibration based on five repetitions of the 10-fold cross-validation in the training set (mean AUC = 0.715, Brier score = 0.202), and based on the test in the test set (AUC = 0.753, Brier score = 0.191). In the test set cohort (n = 1137), the primary endpoint was observed in 50 (4.4%) patients during a median 2.8 years' follow-up. The ML-CAC system was significantly associated with an increased risk of the primary endpoint (adjusted hazard ratio for trend 2.26, 95% CI 1.35-3.79, p = 0.002). There was no significant difference in the prognostic value between the ML-CAC and CT-CAC systems (C-index, 0.67 vs. 0.69; p = 0.618). CONCLUSION: ML-CAC score predicted from clinical variables can serve as a novel prognostic indicator in patients referred for invasive coronary angiography. CLINICAL RELEVANCE STATEMENT: In patients referred for invasive coronary angiography who have not undergone preoperative CT-measured coronary artery calcium scoring, machine learning-based coronary artery calcium score assessment can serve as an alternative for predicting the prognosis. KEY POINTS: • The coronary artery calcium (CAC) score, a solid prognostic indicator, can be predicted using non-CT methods. • We developed a machine learning (ML)-CAC model utilising nine clinical variables to predict severe coronary calcification. • The ML-CAC system offers significant prognostic value in patients referred for invasive coronary angiography.

Comparison of intravascular lithotripsy versus rotational atherectomy for the treatment of severe coronary artery calcification.

BACKGROUND: Calcified lesions are one of the most challenging cases for PCI, where optimal angiographic results and satisfying outcomes are hard to achieve. METHODS: We evaluated the baseline clinical, procedures characteristics and outcomes of patients with severe coronary artery calcification (CAC) who underwent coronary intravascular lithotripsy (IVL) and rotational atherectomy (RA). RESULTS: Respectively 152 and 238 patients who underwent IVL and RA are enrolled from January 2023 to November 2023. Regarding demographic characteristics, the gender proportion, medical history of PCI and smoke history among groups reach statistical significance. Left anterior descending and right coronary artery were the main vessels treated in both groups. The 2.5 and 3.0 mm IVL balloons and 1.5 mm burr were the most commonly used. 99.3% cases were successfully implanted drug-eluting stents after IVL balloon pre-treatment, which was higher than in the group treated with RA. During hospitalization, there were no serious adverse events in the IVL group, but there were two adverse events in the RA group. Procedural complications were higher in the RA group than the IVL group (5.5% vs. 0.7%, P = 0.027). CONCLUSIONS: IVL appears to be safe and effective for the treatment of severe CAC lesions compared to RA.

Efficacy and safety of drug-coated balloons in chronic total coronary occlusion recanalization: a systematic review and meta-analysis.

BACKGROUND: With advancements in chronic total coronary occlusion (CTO) recanalization techniques and concepts, the success rate of recanalization has been steadily increasing. However, the current data are too limited to draw any reliable conclusions about the efficacy and safety of drug-coated balloons (DCBs) in CTO percutaneous coronary intervention (PCI). Herein, we conducted a meta-analysis to confirm the efficacy of DCB in CTO PCI. METHODS: We systematically searched PubMed, Web of Science and Embase from inception to July 25, 2023. The primary outcome was major advent cardiovascular events (MACE), including cardiac death, nonfatal myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). The follow-up angiographic endpoints were late lumen enlargement (LLE), reocclusion and restenosis. RESULTS: Five studies with a total of 511 patients were included in the meta-analysis. Across studies, patients were predominantly male (72.9-85.7%) and over fifty years old. The summary estimate rate of MACE was 13.0% (95% CI 10.1%-15.9%, I2 = 0%, p = 0.428). The summary estimate rates of cardiac death and MI were 2.2% (95% CI 0.7%-3.7%, I2 = 0%, p = 0.873) and 1.2% (95% CI -0.2-2.6%, I2 = 13.7%, p = 0.314), respectively. Finally, the pooled incidences of TLR and TVR were 10.1% (95% CI 5.7%-14.5%, I2 = 51.7%, p = 0.082) and 7.1% (95% CI 3.0%-11.2%, I2 = 57.6%, p = 0.070), respectively. Finally, the summary estimate rates of LLE, reocclusion and restenosis were 59.4% (95% CI 53.5-65.3%, I2 = 0%, p = 0.742), 3.3% (95% CI 1.1-5.4%, I2 = 0%, p = 0.865) and 17.5% (95% CI 12.9-22.0%, I2 = 0%, p = 0.623), respectively. CONCLUSION: Accordingly, DCB has the potential to be used as a treatment for CTO in suitable patients.

Development of a Novel Nomogram to Predict Major Adverse Cardiac Events in Patients with Chronic Total Occlusion.

Objectives: To create a nomogram using single photon emission computed tomography (SPECT) myocardial perfusion imaging and 18F-FDG positron emissions tomography (PET) gated myocardial metabolism imaging to forecast major adverse cardiovascular events (MACE) in chronic total occlusion (CTO) patients treated with optimal medical therapy (OMT). Methods: A total of 257 patients who received OMT between January 2016 and December 2021 were included in this retrospective study. Patients were randomly divided into development (n=179) and validation (n=78) cohorts. A thorough evaluation was conducted, encompassing clinical features and imaging analysis, which involved assessing myocardial perfusion and metabolism. Independent risk factors were identified using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses. Calibration curves and decision curve analysis (DCA) were used to evaluate the clinical usefulness. Results: In the development cohort, 53 patients (29.6%) experienced MACE out of 179 patients, while in the validation cohort, MACE occurred in 23 (29.5%) patients out of 78. The PET-left ventricular end-systolic volume (P-ESV) (HR 1.01; 95% CI 1.003-1.017; p=0.003), hibernating myocardium / total perfusion defect (HM/TPD) (HR 1.053; 95% CI 1.038-1.069; p<0.001), PET-left ventricular ejection fraction (P-LVEF) (HR 0.862; 95% CI 0.788-0.943; p=0.001), and left anterior descending branch (LAD) (HR 2.303; 95% CI 1.086-4.884; p=0.03) were significantly associated with MACE and were used to develop the nomogram. The nomogram demonstrated excellent discrimination with C-indexes of 0.931 and 0.911 in the development and validation cohorts. DCA determined that the model exhibited a considerably superior net advantage in predicting MACE. Conclusion: A new nomogram integrating clinical factors and imaging features was created to predict the risk of MACE in patients with CTO.

Global burden of diseases attributable to intimate partner violence: findings from the Global Burden of Disease Study 2019.

PURPOSE: Our study aims to evaluate the global burden of disease attributable to IPV from 1990 to 2019 at global, regional, national, and socio-demographic index (SDI) levels. Our research question is: What is the global burden of disease attributable to intimate partner violence (IPV) from 1990 to 2019, and how does it vary at global, regional, national, and socio-demographic index (SDI) levels? METHODS: Data parameters for the number of deaths, disability-adjusted life years (DALYs), and age-standardized rate were obtained from the Global Burden of Disease Study 2019. We calculated the percentage change and population attributable fraction with 95% uncertainty intervals. RESULTS: IPV directly accounted for 0.14% [95% UI 0.09%, 0.21%] and 0.32% [95% UI 0.17%, 0.49%] of global all-cause deaths and DALYs in 2019, respectively. The age-standardized deaths and DALYs rates of IPV increased by 12.83% and 4.00% respectively from 1990 to 2019. Women aged 35-39 and 30-34 had the highest deaths and DALYs rate respectively. The highest age-standardized rates of IPV-related deaths and DALYs were observed in Southern Sub-Saharan. Both of deaths and DALYs were high in low-socio-demographic Index (SDI) quintile in 2019. CONCLUSIONS: A higher level of deaths and DALYs attributable to IPV were reported in younger women, in the early 2000s, in Southern Sub-Saharan regions and in low SDI regions. Our study provides policymakers with up-to-date and comprehensive information.

Drug-Loaded Mesoporous Silica Nanoparticles Enhance Antitumor Immunotherapy by Regulating MDSCs.

Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.

Fibroblast growth factor 21 inhibits vascular calcification by ameliorating oxidative stress of vascular smooth muscle cells.

Vascular calcification is very common in clinical. Severe vascular calcification is related to the occurrence of adverse events. Oxidative stress (OS) plays a pathophysiological role in the formation of vascular calcification. Previous studies have demonstrated that fibroblast growth factor 21(FGF21) could inhibit vascular calcification both in vivo and in vitro. FGF21 has also been proved to promote the recovery of superoxide dismutase (SOD) and thereby alleviate OS. Thus, our assumption was that FGF21 inhibit vascular calcification partly by restoring the level of antioxidant SOD and reducing OS. In this study, we established the vascular calcification by 5/6 nephrectomy plus high phosphate diet chronic kidney disease (CKD) model. The results showed the receptor of FGF21, fibroblast growth factor receptor 1 (FGFR1) and ßKlotho in the aorta increased in CKD group, and mainly located in the media of the artery. Ulteriorly, immunofluorescence (IF) and IHC staining showed that FGFR1 and ßKlotho mainly existed in arterial vascular smooth muscle cells (VSMCs). When FGF21 was knock out, the calcification was more severe in FGF21 KO + CKD mice, compared to wild type (WT)+ CKD mice. The transcriptional level of vascular calcification-related genes was significantly higher in FGF21 KO mice than control group. The dihydroethidium (DHE) staining reactive oxygen species (ROS) level in the CKD group was higher compared to the control group, but lower in FGF21 KO + CKD group, and the transcriptional level of SOD1 and SOD2 in FGF21 KO + CKD group was significantly higher than that in CKD group. In conclusion, FGF21 could inhibit vascular calcification, partly by restoring the level of antioxidant SOD and reducing vascular oxidative stress. This study provides further evidence for FGF21 as a candidate drug for cardiovascular protective agents.

Procedural Characteristics and Clinical Outcomes Associated with Chronic Total Occlusion Percutaneous Coronary Intervention in Patients with a History of Prior Coronary Artery Bypass Graft: A Meta-Analysis.

Background: Owing to advances in procedural techniques and the training of interventional staff in catheterization labs, recent work has demonstrated the safety of percutaneous coronary intervention (PCI) as a treatment for patients suffering from chronic total occlusion (CTO). However, there has been little research focused on systematic comparisons of PCI outcomes in CTO patients that did or did not exhibit a history of previous coronary artery bypass grafting (CABG). Methods: Electronic databases were systematically searched for all studies comparing CTO-PCI outcomes for patients with and without a history of CABG, with event rates subsequently being compared via random-effects models with forest plots and odds ratios with 95% confidence intervals (CI), owing to the assumption of between-studies heterogeneity. Results: In total, 8 observational studies enrolling 13,509 CTO patients were identified, including 3389 and 10,120 patients with and without a history of prior CABG, respectively. Patients were enrolled in these studies from 1999-2018. Pooled analyses indicated that CABG history was not linked to a lower proportion of radial access 24 (95% CI 0.52-1.03, p = 0.08), and a prior CABG history was linked to a greater contrast volume (95% CI 0.12-0.44, p < 0.001), higher radiation dose (95% CI 0.27-0.40, p < 0.001), longer fluoroscopy time (95% CI 0.42-0.61, p < 0.001), longer procedural time (95% CI 0.38-0.64, p < 0.001), a higher number of implanted stents (95% CI 0.41-0.60, p < 0.001), longer total stent length (95% CI 0.21-0.60, p < 0.001), higher technical failure rates (95% CI 1.46-1.85, p < 0.001), and higher rates of procedural failure (95% CI 1.42-1.79, p < 0.001). The in-hospital mortality (95% CI 1.50-4.03, p < 0.001) and periprocedural mortality (95% CI 1.63-3.73, p < 0.001) of patients with a history of CABG were also higher. While stroke incidence was comparable in both groups (95% CI 0.80-4.47, p = 0.15), periprocedural major adverse cardiovascular and cerebrovascular events (MACCE) rates were significantly higher among patients exhibiting a history of CABG (95% CI 1.66-2.94, p < 0.001). Conclusions: These results suggest that CTO-PCI procedures may be more challenging and associated with lower rates of success in CABG patients relative to procedures performed in patients without any history of CABG. Moreover, in-hospital outcomes including MACCE and mortality were worse for patients that had undergone prior CABG.

Towards Efficient Federated Learning: Layer-Wise Pruning-Quantization Scheme and Coding Design.

As a promising distributed learning paradigm, federated learning (FL) faces the challenge of communication-computation bottlenecks in practical deployments. In this work, we mainly focus on the pruning, quantization, and coding of FL. By adopting a layer-wise operation, we propose an explicit and universal scheme: FedLP-Q (federated learning with layer-wise pruning-quantization). Pruning strategies for homogeneity/heterogeneity scenarios, the stochastic quantization rule, and the corresponding coding scheme were developed. Both theoretical and experimental evaluations suggest that FedLP-Q improves the system efficiency of communication and computation with controllable performance degradation. The key novelty of FedLP-Q is that it serves as a joint pruning-quantization FL framework with layer-wise processing and can easily be applied in practical FL systems.

The predictive value of the triglyceride-glucose index for cardiovascular events in patients with coronary chronic total occlusion.

BACKGROUND: Chronic total occlusion (CTO) of the coronary artery is a difficult problem in clinical practice. The triglyceride-glucose (TyG) index is an effective risk predictor of cardiovascular risk. However, the relationship between the TyG index and the prognosis of CTO patients remains unstudied. Thus, the present study aimed to investigate the relationship between the TyG index and cardiovascular risk in CTO patients. METHODS: This was a single-centre, retrospective cohort study. We retrospectively enrolled 652 patients with CTO lesions diagnosed by angiography and who underwent revascularization through PCI. Patients were routinely followed up for 24 months unless meeting the endpoint. The primary endpoint was the composite of all-cause death, nonfatal myocardial infarction, unplanned revascularization, and nonfatal ischaemic stroke. To test the association of the TyG index with cardiovascular risk, the categorized TyG index and Cox proportional hazards regression models were utilized. RESULTS: A total of 652 patients were enrolled in the final analysis (male: 83.7%, age: 58.2 ± 10.49 years). The average TyG index was 8.8 ± 0.57. CTO PCIs were procedurally successfully completed in 503 (77.15%) patients. During the follow-up period of 22.8 ± 3.84 months, 73 (11.19%) major adverse cardiovascular and cerebral events (MACCEs) occurred. When fully adjusted, there was a 2.09-fold risk for MACCEs among patients with the highest TyG index compared with those with the lowest TyG index [T2 vs. T1: hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.65-2.38, P = 0.057; T3 vs. T1: HR 2.09, 95% CI 1.14-3.86, P = 0.018; P for trend = 0.036]. The restricted cubic spline (RCS) analysis showed that the HR for MACCEs increased as the TyG index increased over 8.71 [HR per standard deviation (SD) 1.740, 95% CI 1.23-2.46, P = 0.002]. The risk of MACCEs increased with increasing tertiles of TyG index in successful CTO PCI patients and nondiabetes mellitus (DM) patients (P < 0.05) but not in patients with failed CTO PCI and DM patients. CONCLUSION: The study revealed that the TyG index had significant relevance to cardiovascular risk in CTO patients and suggests that the TyG index is feasible for predicting cardiovascular risk in CTO patients.

Establishment of a Risk Scoring Model for Perioperative Unex-Plained Shock during Percutaneous Coronary Intervention for the Treatment of Chronic Total Occlusion.

Background: Several complications can contribute to the risk of shock during the chronic total occlusion (CTO) percutaneous coronary intervention (PCI) procedure. However, some patients that develop shock do not exhibit any apparent complications, and few studies to date have discussed the risk of unexplained perioperative shock in patients undergoing CTO PCI. Accordingly, this study was designed with the goal of defining perioperative risk factors linked to the odds of unexplained shock during CTO PCI. Methods: In total, this study analyzed data from 924 patients that underwent CTO PCI without any in-hospital complications from January 2016-August 2021. Cardiologists collected data pertaining to patient clinical characteristics, laboratory findings, angiographic findings, and procedural characteristics. Patients were separated into two groups based upon whether or not they experienced perioperative shock. The relationship between specific variables and perioperative shock incidence was assessed via a multivariable stepwise logistic regression approach. A risk-scoring nomogram was then designed for use as a tool to guide patient risk assessment efforts during PCI procedural planning. Results: Overall, 4.8% of these patients (44/924) experienced unexplained perioperative shock. Independent predictors associated with unexplained shock during CTO PCI included baseline systolic pressure (odds ratio (OR) 0.968, 95% confidence interval (CI): 0.945-0.991), baseline heart rate (OR 1.055, 95% CI: 1.020-1.091), baseline hemoglobin (OR 0.970, 95% CI: 0.947-0.994), procedure duration (OR 1.008, 95% CI: 1.002-1.015), J-CTO score (OR 1.521, 95% CI: 1.021-2.267), and use of a retrograde approach (OR 3.252, 95% CI: 1.426-7.415). The unbiased C-index estimate was 0.859, and this model exhibited excellent calibration. Conclusions: The risk of unexplained shock is an important consideration for clinicians performing the CTO PCI procedure. These analyses revealed unexplained shock risk to be independently related to lower baseline systolic pressure, higher baseline heart rate, lower baseline hemoglobin, more procedure time, higher J-CTO score, and more use of a retrograde approach.

Possible effects of fibroblast growth factor 21 on vascular calcification via suppressing activating transcription factor 4 mediated apoptosis and osteogenic transformation in rats.

Vascular calcification (VC), a significant risk factor of many cardio-cerebral vascular diseases, is a perplexing issue with no effective treatment in clinical work up to now. Endoplasmic reticulum stress (ERS) mediated apoptosis has been proved to be a significant mechanism for initiating VC process. Activating transcription factor 4 (ATF4), a key transcription factor of ERS, is most closely associated with VC. Fibroblast growth factor 21 (FGF21), an atypical member of the FGFs family, has a protective biological function in various metabolic diseases by ERS pathways. However, the possible effects of FGF21 on VC by regulating ERS, especially through the ATF4 pathway, is still unclear. Our research provides the first evidence that exogenous FGF21 treatment can alleviate the vitamin D3 plus nicotine-induced VC at least in part via suppressing ATF4 mediated apoptosis and osteogenic transformation in rats.

[Fibroblast growth factor 21 plays a protective role in cardiovascular diseases by inducing autophagy].

Fibroblast growth factor 21 (FGF21) is a growth factor with endocrine function in the fibroblast growth factor family. Previous reports have shown that FGF21 is involved in the regulation of energy metabolism and plays a protective role in cardiovascular diseases such as coronary heart disease, diabetes, non-alcoholic fatty liver disease and so on. Recent studies have found that FGF21 can induce autophagy in a variety of tissues and organs, and autophagy is involved in many pathological processes of cardiovascular diseases, including vascular calcification, atherosclerosis, and myocardial ischemia-reperfusion injury. Therefore, FGF21 may play a protective role in a variety of cardiovascular diseases by regulating autophagy. This article reviews the research progress on the protective role of FGF21 in cardiovascular diseases by inducing autophagy.

Flat-Band Electronic Structure and Interlayer Spacing Influence in Rhombohedral Four-Layer Graphene.

The stacking order of multilayer graphene significantly influences its electronic properties. The rhombohedral stacking sequence is predicted to introduce a flat band, which has high density of states and the enhanced Coulomb interaction between charge carriers, thus possibly resulting in superconductivity, fractional quantum Hall effect, and many other exotic phases of matter. In this work, we comprehensively study the effect of the stacking sequence and interlayer spacing on the electronic structure of four-layer graphene, which was grown on a high crystalline quality 3C-SiC(111) crystal. The number of graphene layers and coverage were determined by low energy electron microscopy. First-principles density functional theory calculations show distinctively different band structures for ABAB (Bernal), ABCA (rhombohedral), and ABCB (turbostratic) stacking sequences. By comparing with angle-resolved photoelectron spectroscopy data, we can verify the existence of a rhombohedral stacking sequence and a nearly dispersionless electronic band (flat band) near the Fermi level. Moreover, we find that the momentum width, bandgap, and curvature of the flat-band region can be tuned by the interlayer spacing, which plays an important role in superconductivity and many other exotic phases of matter.

Fibroblast growth factor 21 ameliorates vascular calcification by inhibiting osteogenic transition in vitamin D3 plus nicotine-treated rats.

FGF21, a special member of FGF superfamily, has been proven to have pleiotropic metabolic effects and many potential therapeutic action in various metabolic disorders. Vascular calcification (VC), a perplexing clinical issue, is a major risk factor for many cardiovascular diseases, especially for patients with some metabolic diseases. However, the role of FGF21 on VC in vivo remains unclear. Thus, in this study, we observed the effect and mechanism of FGF21 on VC induced by vitamin D3 plus nicotine (VDN) treated rats. After four weeks' treatment, the calcium overload is mainly manifested in the increased blood pressure, aortic calcium content and ALP activity. Also, the HE and Alizarin-red S staining showed the structural damage of calcified vessel walls. In addition, the level of endogenous FGF21/ß-Klotho/FGFR1 axis was up-regulated in the aortas of VC rats. Furthermore, exogenous FGF21 treatment significantly ameliorated the aortic injury and calcification in VC rats, and the level of ß-Klotho and FGFR1 were furtherly increase. Moreover, FGF21 inhibited the osteogenic transition of VSMCs by down-regulating the expression of bone-associated proteins such as osteopontin (OPN), osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2), together with restored the expression of SM22α and SM α-actin, which are two of lineage markers in VSMCs. We provide the first evidence that FGF21 can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs in rats. FGF21 might be an efficient endogenous vasoprotective factor for calcification.

Identifying colon cancer risk modules with better classification performance based on human signaling network.

Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer.

[Effects and mechanism of fibroblast growth factor 21 on rat vascular smooth muscle cells calcification].

OBJECTIVE: To observe the effect and mechanism of fibroblast growth factor 21 (FGF21) on rat vascular smooth muscle cells (VSMCs) calcification in vitro. METHODS: VSMCs was treated with calcification medium containing calcium chloride and ß-glycerophosphate to induce rat VSMCs calcification in vitro. VSMCs were divided into 5 groups: the control group (cultured in normal medium), the calcification group (incubated in calcified medium), the FGF21 group (cultured in calcified medium and FGF21), the PD166866 group (cultured in calcified medium and FGF21 and PD166866, inhibitor of fibroblast growth factor receptor-1 (FGFR1)), the GW9662 group (cultured in calcified medium and FGF21 and GW9662, inhibitor of peroxisome proliferators activated receptor-γ (PPAR-γ)). The calcification of VSMCs was detected by calcium content, alkaline phosphatase activity and alizarin red staining. The protein and mRNA expression of FGFR1, ß-Klotho, osteocalcin and smooth muscle 22α (SM22α) were determined by western blot analysis and realtime-PCR, respectively. RESULTS: (1) The mRNA (P < 0.01) and protein expressions of ß-Klotho and FGFR1 were significantly downregulated in calcification group compared with control group (P < 0.05 or 0.01). (2) The protein levels and mRNA expression of calcium content, alkaline phosphatase activity and osteocalcin were significantly downregulated, while the protein levels and mRNA of SM22α were significantly increased in FGF21 group compared with calcification group (all P < 0.05). Moreover, alizarin red staining verified positive red nodules on calcified VSMCs was significantly reduced in FGF21 group than in calcification group. (3) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between PD166866 group and calcification group (all P > 0.05). (4) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between GW9662 group and calcification group (all P > 0.05). CONCLUSION: The inhibition of VSMCs calcification by FGF21 is mediated by further downregulating FGFR1 and ß-Klotho while activating PPAR-γ pathways.

Machine learning predictions of the adverse events of different treatments in patients with ischemic left ventricular systolic dysfunction.

This study aimed to develop several new machine learning models based on hibernating myocardium to predict the major adverse cardiac events(MACE) of ischemic left ventricular systolic dysfunction(LVSD) patients receiving either percutaneous coronary intervention(PCI) or optimal medical therapy(OMT). This study included 329 LVSD patients, who were randomly assigned to the training or validation cohort. Least absolute shrinkage and selection operator(LASSO) regression was used to identify variables associated with MACE. Subsequently, various machine learning models were established. Model performance was compared using receiver operating characteristic(ROC) curves, the Brier score(BS), and the concordance index(C-index). A total of 329 LVSD patients were retrospectively enrolled between January 2016 and December 2021. Utilizing LASSO regression analysis, five factors were selected. Based on these factors, RSF, GBM, XGBoost, Cox, and DeepSurv models were constructed. In the development and validation cohorts, the C-indices were 0.888 vs. 0.955 (RSF). The RSF model (0.991 vs. 0.982 vs. 0.980) had the highest area under the ROC curve (AUC) compared with the other models. The BS (0.077 vs. 0.095vs. 0.077) of RSF model were less than 0.25 at 12, 18, and 24 months. This study developed a novel predictive model based on RSF to predict MACE in LVSD patients who underwent either PCI or OMT.