Generation of KCNH2 heterozygous knockout induced pluripotent stem cell (iPSC) line (Long and Short QT Syndrome).

KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member) encodes a voltage-activated potassium channel role as rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential. Mutations in this gene can cause long QT syndrome and short QT syndrome. Transcript variants encoding distinct isoforms were also identified. In this study, we generated induced pluripotent stem cells (iPSC) from a healthy individual by electroporation of peripheral blood mononuclear cells and generated a KCNH2 heterozygous knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had a normal karyotype, were free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Two-dimensional heavy fermions in the van der Waals metal CeSiI.

Heavy-fermion metals are prototype systems for observing emergent quantum phases driven by electronic interactions1-6. A long-standing aspiration is the dimensional reduction of these materials to exert control over their quantum phases7-11, which remains a significant challenge because traditional intermetallic heavy-fermion compounds have three-dimensional atomic and electronic structures. Here we report comprehensive thermodynamic and spectroscopic evidence of an antiferromagnetically ordered heavy-fermion ground state in CeSiI, an intermetallic comprising two-dimensional (2D) metallic sheets held together by weak interlayer van der Waals (vdW) interactions. Owing to its vdW nature, CeSiI has a quasi-2D electronic structure, and we can control its physical dimension through exfoliation. The emergence of coherent hybridization of f and conduction electrons at low temperature is supported by the temperature evolution of angle-resolved photoemission and scanning tunnelling spectra near the Fermi level and by heat capacity measurements. Electrical transport measurements on few-layer flakes reveal heavy-fermion behaviour and magnetic order down to the ultra-thin regime. Our work establishes CeSiI and related materials as a unique platform for studying dimensionally confined heavy fermions in bulk crystals and employing 2D device fabrication techniques and vdW heterostructures12 to manipulate the interplay between Kondo screening, magnetic order and proximity effects.

Transition Metal Functionalized C30N12S6 as High-Performance Trifunctional Catalysts with Integrated Descriptors toward Hydrogen Evolution, Oxygen Evolution, and Oxygen Reduction Reactions: A Case of High-Throughput First-Principles Screening within the Framework of TM-N2@C30N10S6.

In energy conversion and storage technologies, the design of highly efficient trifunctional electrocatalysts integrating with the high hydrogen evolution reaction (HER) and oxygen evolution/reduction reaction (OER/ORR) activities is highly desirable. Herein, utilizing first-principles computations, a novel periodically ordered macropore C30N12S6 monolayer was proposed, and the stability analysis attests to its good stability. Single transition metal (TM) atom anchored onto this newly proposed C30N12S6 monolayer to form single-atom catalysts, as achieved by TM-N2@C30N10S6, among which the Co-N2@C30N10S6 is the most promising multifunctional catalyst toward HER/OER/ORR with low overpotential of 0.01/0.59/0.3 V; meanwhile, the Rh-N2@C30N10S6 can be used as a bifunctional OER/ORR catalyst with low overpotential of 0.37/0.44 V, overmatching the landmark Pt (111) and IrO2/RuO2 catalysts. Particularly, the TM-d orbital in TM@CNS is remarkably hybridized with the O-p orbital of oxygenated intermediates, so that the lone electrons initially located at the antibonding orbital pair up and fill the downward bonding orbital, allowing OH* to be suitably adsorbed on TM@CNS, enhancing the catalytic performance. The relevant attributes, such as good stabilities and metallic features, ensured their applications in ambient conditions. Moreover, multilevel descriptors were constructed to clarify the origin of activity on TM@CNS, such as ΔGOH* (Gibbs free energy of OH*), εd (d-band center), COHP (crystal orbital Hamilton population), Nd/Nd + s (number of d/d + s electrons) and φ (descriptor), among which the filling of outer d-electrons of TM atom significantly affects the value of ΔGOH* that can determine the overpotential and, thus, become a key descriptor.

Time-reversal symmetry breaking superconductivity between twisted cuprate superconductors.

Twisted interfaces between stacked van der Waals (vdW) cuprate crystals present a platform for engineering superconducting order parameters by adjusting stacking angles. Using a cryogenic assembly technique, we construct twisted vdW Josephson junctions (JJs) at atomically sharp interfaces between Bi2Sr2CaCu2O8+x crystals, with quality approaching the limit set by intrinsic JJs. Near 45° twist angle, we observe fractional Shapiro steps and Fraunhofer patterns, consistent with the existence of two degenerate Josephson ground states related by time-reversal symmetry (TRS). By programming the JJ current bias sequence, we controllably break TRS to place the JJ into either of the two ground states, realizing reversible Josephson diodes without external magnetic fields. Our results open a path to engineering topological devices at higher temperatures.

Comprehensive physiological, transcriptomic, and metabolomic analysis of the key metabolic pathways in millet seedling adaptation to drought stress.

Drought is one of the leading environmental constraints that affect the growth and development of plants and, ultimately, their yield and quality. Foxtail millet (Setaria italica) is a natural stress-resistant plant and an ideal model for studying plant drought resistance. In this study, two varieties of foxtail millet with different levels of drought resistance were used as the experimental material. The soil weighing method was used to simulate drought stress, and the differences in growth, photosynthetic physiology, metabolite metabolism, and gene transcriptional expression under drought stress were compared and analyzed. We aimed to determine the physiological and key metabolic regulation pathways of the drought-tolerant millet in resistance to drought stress. The results showed that drought-tolerant millet exhibited relatively stable growth and photosynthetic parameters under drought stress while maintaining a relatively stable level of photosynthetic pigments. The metabolomic, transcriptomic, and gene co-expression network analysis confirmed that the key to adaptation to drought by millet was to enhance lignin metabolism, promote the metabolism of fatty acids to be transformed into cutin and wax, and improve ascorbic acid circulation. These findings provided new insights into the metabolic regulatory network of millet adaptation to drought stress.

The role of plateletcrit in Takayasu arteritis: A potential biomarker for disease activity and 6-month treatment response.

OBJECTIVES: To determine the role of plateletcrit as a potential biomarker for disease activity and treatment response in Takayasu arteritis (TAK). METHODS: Totally, 215 newly diagnosed TAK patients were consecutively enrolled. Demographic data, clinical manifestations, laboratory and imaging examinations, and treatment strategy were recorded at baseline and at each visit during the 6-month treatment period. Normal plateletcrit (0.1%-0.4%) and hyper-plateletcrit (>0.4%) observed at baseline were used as group criteria. RESULTS: At baseline, the overall plateletcrit was 0.32 (0.24-0.38)%, with a normal and high level observed in 172 (80.00%) and 43 (20.00%) patients, respectively. Baseline plateletcrit was significantly higher in patients with active disease and associated with inflammatory biomarkers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin (IL)-6 (all p < .01). At 6 months, complete remission was achieved in 171 (79.53%) patients, and a significant decrease in plateletcrit was observed in these cases (p < .01). Patients with a normal baseline plateletcrit were more likely to achieve complete remission compared to those with a high baseline plateletcrit (HR = 4.65, 95% CI: 2.38-19.08, p < .01). In addition, ESR (p = .01) and IL-6 (p = .02) levels were still higher in patients with a high baseline plateletcrit at 6 months. Progression of vascular lesions was indicated in 18 (8.37%) patients at 6 months, and these patients also had significantly higher baseline plateletcrit (p = .03). CONCLUSION: Plateletcrit levels were positively related to disease activity and inflammatory index in TAK. Importantly, patients with high baseline plateletcrit levels may show a worse treatment response at 6 months.

Kagome-like BiP3 Monolayer: An Emerging Quasi-Direct Auxetic Semiconductor Coupled with High Anisotropic Mobility toward Visible-Light-Driven Photoelectrocatalytic pH-Robust Overall Water-Splitting.

Two-dimensional (2D) Janus materials exhibit an outstanding potential that can meet the rigorous requirements of photocatalytic water splitting resulting from their unique atomic arrangement. However, these materials are quite scarce. Through ab initio density functional theory calculations, we introduce a kagome topology into the honeycomb lattice of blue phosphorene using phosphorus and bismuth atoms to build a hybrid honeycomb-like kagome lattice, realized by a hitherto unknown kagome-like Janus-like BiP3 monolayer with robust stability. Excitingly, the out-of-plane asymmetry benefiting from kagome and honeycomb topologies gives rise to a significantly negative out-of-plane Poisson's ratio and an obvious built-in electric field pointing from the sublayer of the P atom to the sublayer of the Bi atom. In conjunction with the investigations that encompass semiconducting properties, such as a quasi-direct gap, suitable band-edge positions, effective visible-light absorption, and high carrier mobility, the BiP3 monolayer achieves overall water splitting at pH 0-14 regardless of strain. Moreover, this intrinsic electric field provides a sufficient photogenerated carrier driving force for water splitting. The bare BiP3 comprises P and Bi atoms that function as catalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) active sites, respectively. Upon exposure to light, the reaction of water into H2 and O2 can be observed across a pH range of 0-14. Meanwhile, by designing a transition-metal single-atom catalyst (TM@BiP3), our investigations have shown that embedding a single TM on BiP3 is a feasible route to improving the HER/OER activity by reducing the overpotentials to -0.039 and 0.58 eV for Mo and Os atoms, respectively. In this case, the positive value of the external potential acts as a sufficient OER driving force, i.e., in the light environment, the Os@BiP3 system can promote water molecules spontaneously oxidized into O2 at pH 0-14.

Exogenous hydrogen sulfide alleviates hepatic endoplasmic reticulum stress via SIRT1/FoxO1/PCSK9 pathway in NAFLD.

High-fat-induced endoplasmic reticulum (ER) stress has been the main reason for the occurrence and development of nonalcoholic fatty liver disease (NAFLD). Hydrogen sulfide (H2 S) produces a marked effect on regulating lipid metabolism and antioxidation, whose effects on ER stress of NAFLD are still unclear. Here, we studied the influence of exogenous H2 S on NAFLD and its potential mechanism. In vivo, NAFLD model was induced by high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of exogenous H2 S intervention for 4 weeks. HepG2 cells exposure to lipid mixture (LM) were used as vitro model to explore the potential mechanism. We found exogenous H2 S significantly inhibited the hepatic ER stress and improved the liver fat deposition of HFD-fed mice. These similar results were also observed in HepG2 cells dealt with LM after exogenous H2 S treatment. Further mechanism studies showed exogenous H2 S strengthened the combination of FoxO1 with the PCSK9 promoter gene through SIRT1-mediated deacetylation, thereby inhibiting the PCSK9 expression to relieve the hepatic ER stress. However, SIRT1 knockout eliminated the effects of exogenous H2 S on FoxO1 deacetylation, PCSK9 inhibition, and remission of hepatic ER stress and steatosis. In conclusion, exogenous H2 S improved NAFLD by inhibiting hepatic ER stress through SIRT1/FoxO1/PCSK9 pathway. Exogenous H2 S and ER stress may be potential drug and target for the treatment of NAFLD, respectively.

Identification of ferroptosis and drug resistance related hub genes to predict the prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Currently, overcoming the drug resistance in HCC is a critical challenge and ferroptosis has emerged as a promising therapeutic option for cancer. We aim to construct a new gene signature related to ferroptosis and drug resistance to predict the prognosis in HCC. The RNA-seq data of HCC patients was obtained from the Cancer Genome Atlas database. Using least absolute shrinkage and selection operator cox regression, Kaplan-Meier analysis, and differential analysis, we constructed a prognostic model consisting of six hub genes (TOP2A, BIRC5, VEGFA, HIF1A, FTH1, ACSL3) related to ferroptosis and drug resistance in HCC. Functional enrichment, pathway enrichment and GSEA analysis were performed to investigate the potential molecular mechanism, and construction of PPI, mRNA-miRNA, mRNA-RBP, mRNA-TF and mRNA-drugs interaction networks to predict its interaction with different molecules. Clinical prognostic characteristics were revealed by univariate, multivariate cox regression analysis and nomogram. We also analyzed the relationship between the signature, immune checkpoints, and drug sensitivity. The expression of the gene signature was detected in HCC cell lines and HPA database. Our prognostic model classified patients into high and low-risk groups based on the risk scores and found the expression level of the genes was higher in the high-risk group than the low-risk group, demonstrating that high expression of the hub genes was associated with poor prognosis in HCC. ROC analysis revealed its high diagnostic efficacy in both HCC and normal tissues. The proportional hazards model and calibration analysis confirmed that the model's prediction was most accurate for 1- and 3-years survival. QRT-PCR showed the high expression level of the gene signature in HCC. Our study built a novel gene signature with good potential to predict the prognosis of HCC, which may provide new therapeutic targets and molecular mechanism for HCC diagnosis and treatment.

A Mesoscale Study on the Dilation of Actively Confined Concrete under Axial Compression.

The confinement of concrete enhances its strength and ductility by restraining lateral dilation. The accuracy of a confinement model depends on how well it captures the dilation of concrete. In the current paper, a mesoscale model is established to study the dilation properties of concrete in active confinement, where the heterogeneity of concrete is considered. The stress-strain and lateral-axial strain curves of concrete in active confinement were used to demonstrate the validity of the mesoscale model. Subsequently, the distribution of lateral strain and the influences of the strength grade and confinement ratio on the dilation of concrete were investigated in a simulation. The results show that the distribution of the lateral strain along the radial or longitudinal directions is not uniform on the specimen when compressive failure occurs. The confinement ratio has a more significant influence on the concrete's transverse dilation than the strength grade. Finally, an expression of the lateral-axial strain relationship of concrete in active confinement is proposed. The proposed formula can reflect the simulation results of the mesoscale model and is in good agreement with the prediction of existing formulas.

The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin.

Hematological and neurological expressed 1 (HN1) is closely associated with the proliferation and metastasis of various tumors. However, the physiological functions and clinical significance of HN1 in hepatocellular carcinoma (HCC) remain indistinct. In this study, we investigated the role of HN1 in the pathogenesis of HCC and the underlying mechanism using clinical data from HCC patients, in vitro experiments utilizing HCC cell lines and in vivo animal models. We demonstrated that the overexpressed HN1 in HCC was correlated with patients' adverse outcomes. The gain and loss of function experiments indicated that HN1 could promote the proliferation, migration, and invasion of HCC cells in vitro. Furthermore, we found that HN1 knockdown sensitized HCC cells to oxaliplatin. Mechanically, HN1 prevented HMGB1 protein from ubiquitination and degradation via the autophagy-lysosome pathway, which was related to the interaction between HN1 protein and TRIM28 protein. In the nucleus, the downregulation of HMGB1 followed by HN1 knockdown resulted in increased DNA damage and cell death in the oxaliplatin-treated HCC cells. In the cytoplasm, HN1 regulated autophagy via HMGB1. Furthermore, HN1 knockdown in combination with HMGB1 overexpression restored the aggressive phenotypes of HCC cells and the sensitivity of these cells to oxaliplatin. HN1 knockdown inhibited the tumor growth and metastasis, and promoted the anticancer efficiency of oxaliplatin in vivo. In conclusion, our data suggest that the HN1/HMGB1 axis plays an important role in the development/progression and chemotherapy of HCC. Our findings indicate that the HN1/HMGB1 axis may be a promising therapeutic target for HCC treatment.

A novel model to assess disease activity in Takayasu arteritis based on 18F-FDG-PET/CT: a Chinese cohort study.

OBJECTIVE: To investigate the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in assessing disease activity in Takayasu arteritis (TA). METHODS: Ninety-one patients with TA were recruited from a Chinese cohort. Clinical data, acute-phase reactants and 18F-FDG-PET/CT findings were simultaneously recorded. The value of using 18F-FDG-PET/CT to identify active disease was evaluated, using ESR as a reference. Disease activity assessment models were constructed and concordance index (C-index), net reclassification index (NRI), and integrated discrimination index (IDI) were evaluated to compare the benefits of the new modes with ESR and the Kerr score. RESULTS: In total, 64 (70.3%) cases showed active disease. Higher levels of ESR and CRP, and lower IL-2 receptor (IL-2R) levels were observed in active cases. 18F-FDG-PET/CT parameters measured by determining the standard uptake value (SUV), including SUVmean, SUVratio1, SUVratio2, sum of SUVmean and sum of SUVmax, were significantly higher in active disease groups. The C-index threshold of ESR to indicate active disease was 0.78 (95% CI: 0.69, 0.88). The new activity assessment model combining ESR, sum of SUVmean and IL-2R showed significant improvement in C-index over the ESR method (0.96 vs 0.78, P < 0.01; NRI 1.63, P < 0.01; and IDI 0.48, P < 0.01). The new model also demonstrated modest superiority to the Kerr score assessment (0.96 vs 0.87, P = 0.03; NRI 1.19, P < 0.01; and IDI 0.33, P < 0.01). CONCLUSIONS: A novel 18F-FDG-PET/CT-based method that involves combining the sum of SUVmean with ESR score and IL-2R levels demonstrated superiority in identifying active TA compared with conventional methods.

Potential Role of Macrophage Phenotypes and CCL2 in the Pathogenesis of Takayasu Arteritis.

Objectives: To investigate vascular macrophage phenotype as well as vascular and peripheral chemokine (C-C motif) ligand 2 (CCL2) expression during different stages of disease progression in patients with Takayasu Arteritis (TA). Methods: In this study, 74 patients with TA and 50 controls were recruited. TA disease activity was evaluated with Kerr scores. Macrophage phenotype and CCL2 expression were examined by immunohistochemistry in vascular specimens from 8 untreated and 7 treated TA patients, along with 4 healthy controls. Serum CCL2 were quantified by enzyme-linked immune-absorbent assay from TA patients at baseline (n=59), at 6-months (n=38), and from 46 healthy volunteers. Vascular macrophage phenotype, vascular CCL2 expression and serum CCL2 levels during different stages, as well as the relationship between serum CCL2 and disease activity or other inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin 6 (IL-6)) were investigated. Results: In untreated patients, vascular M1 macrophages and CCL2 showed increased expression, mainly in the adventitia. In contrast, in treated patients, vascular adventitial M1 and CCL2 expression were decreased, while vascular medial M2 macrophages and CCL2 levels were increased. Distribution of macrophages and CCL2 was consistent within the TA vascular lesions regardless of the disease stage. Furthermore, peripheral CCL2 was elevated in patients with TA (TA: 160.30 ± 120.05 vs. Control: 65.58 ± 54.56 pg/ml, P < 0.001). CCL2 levels were found to correlate with ESR, CRP, and IL-6 (all R values between 0.55 and 0.6, all P < 0.001). Receiver operating curve analysis demonstrated that CCL2 (at the cut-off value of 100.36 pg/ml) was able to predict disease activity (area under the curve = 0.74, P = 0.03). Decrease in CCL2 level was observed in patients with clinical remission (CR), but not in patients without CR, after 6 months of treatment (CR patients: baseline 220.18 ± 222.69 vs. post-treatment 88.71 ± 55.89 pg/ml, P = 0.04; non-CR patients: baseline 142.45 ± 104.76 vs. post-treatment 279.49 ± 229.46 pg/ml, P = 0.02). Conclusions: Macrophages contribute to vascular pathological changes in TA by undergoing phenotype transformation. CCL2 is an important factor for recruiting macrophages and a potential biomarker for disease activity.

Effectiveness and safety of tocilizumab in patients with refractory or severe Takayasu's arteritis: A prospective cohort study in a Chinese population.

OBJECTIVE: To assess the effectiveness and safety of tocilizumab (TCZ) in treating severe/refractory Takayasu's arteritis (TAK). METHODS: A prospective cohort study was started on 1 November 2013 and terminated on 10 June 2020. Thirty-seven patients diagnosed as severe/refractory TAK, treated with TCZ combined with or without immunosuppressors were enrolled. Treatment response (complete remission (CR) and partial remission (PR)), imaging progression and side effects were analyzed at 6-month treatment. Disease flare was analyzed during the remaining follow-up. RESULTS: The CR and RR rates were 70% and 88% at 6 months of TCZ treatment, respectively. Glucocorticoids was tapered from 30.0 (20.0-40.0) to 15.0 (10.0-15.0) mg/day at 6 months. Younger patients (≤26 years) (OR=14.6, 95% CI 1.27-170.4, P<0.05) and those with involvement of bilateral carotid arteries or vertebral arteries (OR=14.6, 95% CI 1.27-169.1, P<0.05) might show a better response to TCZ at 6 months. Combined therapy of immunosuppressors had no significant effects on the effectiveness of TCZ at 6 months. Among the total 23 patients with CR at 6 months, 14 cases discontinued TCZ therapy after 6 months, and disease flare was observed in six ones (43%), with medium flare at 7 (7-9.8) months. One patient (11%) who continued TCZ therapy suffered disease flare at 8 months. Infections were the most commonly observed side effects (38%), with four patients discontinuing TCZ treatment due to severe infections. CONCLUSION: TCZ treatment achieved a favorable response with acceptable adverse effects for TAK.

Effectiveness and safety of methotrexate versus leflunomide in 12-month treatment for Takayasu arteritis.

AIMS: The study investigates the effectiveness and safety of methotrexate (MTX) versus leflunomide (LEF) in 12-month treatment of Takayasu arteritis (TAK). METHODS: This was a cohort study. Patients diagnosed with TAK between 1 January 2013 and 1 January 2019 were enrolled from First Hospital of China Medical University and Zhongshan Hospital of Fudan University. Patients had active disease and were treated with glucocorticoid combined with LEF or MTX. Treatment response, imaging assessment and side-effects were evaluated during 12-month follow-up. RESULTS: In total, 68 patients were enrolled (40 cases treated with LEF and 28 treated with MTX). At baseline, age, sex, disease duration and disease activity index showed no significant differences between groups. Prevalence of complete remission (CR) at 6 months was significantly higher in the LEF group than that in the MTX group (LEF versus MTX: 72.50% versus 53.57%, p = 0.04), though the CR prevalence at 9 months and 12 months showed no significant differences between groups. At 9 months, the prevalence of treatment resistance was much lower in the LEF group compared with MTX group (5.41% versus 11.54%, p = 0.03). Furthermore, prevalence of disease relapse in the LEF group was lower than that in MTX group at 12 months (7.24% versus 16.67%, p = 0.03). Patients with high baseline C-reactive protein levels (⩾15 mg/L) carried a higher risk of treatment resistance (OR = 1.36, 95% CI 1.07-13.41, p = 0.06) and disease relapse (HR = 2.51, 95% CI 1.36-12.98, p = 0.04). CONCLUSION: LEF might provide a quicker treatment response with lower prevalence of disease relapse compared with that elicited in MTX during 12 months follow-up for TAK.

Potential risk of hyperuricemia: leading cardiomyocyte hypertrophy by inducing autophagy.

BACKGROUND: Clinical studies have shown that hyperuricemia is associated with many cardiovascular diseases; however, the mechanisms involved remain unclear. In this study, we investigated the effect of uric acid on cardiomyocytes and the underlying mechanism. METHODS AND RESULTS: H9c2 cardiomyocytes were treated with various concentrations of uric acid. 3-Methyladenine (3-MA) or Compound C was added before treatment with uric acid. The expression of myocardial hypertrophy-related genes was measured using polymerase chain reaction (PCR). The cell surface area was calculated using ImageJ Software. Western blotting was used to measure the protein levels. Uric acid increased the gene expression of Nppa, Nppb, and Myh5, which are involved in myocardial hypertrophy, and the relative cell surface area of cardiomyocytes in a dose-dependent manner. Consistently, the ratio of LC3II/I, which is a biomarker of autophagy, increased dose-dependently, whereas the protein level of p62, a protein that is degraded by autophagy, decreased. 3-MA, an autophagy inhibitor, rescued uric acid-induced myocardial hypertrophy. Treatment with uric acid increased the level of phosphorylated adenosine monophosphate kinase (AMPK), as well as its downstream effector unc-51-like kinase (ULK1). Pharmacological inhibition of AMPK by Compound C attenuated the uric acid-induced activation of autophagy and myocardial hypertrophy. CONCLUSIONS: Uric acid induces myocardial hypertrophy by activating autophagy via the AMPK-ULK1 signaling pathway. Decreasing the serum uric acid level may therefore be clinically beneficial in alleviating cardiac hypertrophy.

Effectiveness and safety of leflunomide compared with cyclophosphamide as induction therapy in Takayasu's arteritis: an observational study.

AIMS: The objective of this study was to investigate the outcomes of leflunomide (LEF) compared with those of cyclophosphamide (CYC) as induction against active Takayasu's arteritis (TA) in Chinese patients. METHODS: This was an observational study based on a prospective cohort that included TA patients diagnosed in large third-level first-class general hospitals in East China from January 2009 to September 2018. LEF- or CYC-induced active patients were enrolled for comparative effectiveness analysis. One-to-more paired cohorts of LEF versus CYC were derived by propensity-score matching (PSM). The primary outcome was complete remission (CR) at 9-month follow up, and secondary endpoints included partial remission (PR) and effectiveness rate (ER). Multivariable logistic regression was used to identify statistical significance. RESULTS: A total of 131 enrolled patients with at least 3-months treatment included 53 receiving a regimen of glucocorticoid (GC) and LEF and 78 receiving GC and CYC. Compared with the CYC group, the LEF group showed higher CR rate {LEF versus CYC: 84.6% [95% confidence interval (CI) 74.5-94.8%] versus 59.0% (47.8-70.1%); relative risk (RR) = 0.3 (0.1-0.6), p = 0.002} and lower daily GC dose [10.0 (5.0-12.5) versus 12.5 (10.0-15.0) mg, p = 0.043] at the end of the 9-month induction. In the matched analysis, the LEF group (n = 23) still indicated a higher CR rate than the CYC group (n = 54) after PSM [RR = 0.1 (0.0-0.6), p = 0.003]. Four LEF-treated patients had mild side effects, and one died unrelated to LEF. CONCLUSION: LEF could be an alternative induction therapy against TA, showing good effectiveness and tolerance compared with CYC.

Involvement of the pulmonary arteries in patients with Takayasu arteritis: a prospective study from a single centre in China.

BACKGROUND: Takayasu arteritis (TA) is a large vessel vasculitis that can involve pulmonary arteries (PAs). We studied multiple clinical characteristics related to pulmonary artery involvement (PAI) in TA patients. METHODS: We enrolled 216 patients with TA from a large prospective cohort. PAI was assessed in each patient based on data from magnetic resonance angiography/computed tomography angiography. Pulmonary hypertension, cardiac function, and pulmonary parenchymal lesions were evaluated further in patients with PAI based on echocardiography, the New York Heart Association Functional Classification, and pulmonary computed tomography, respectively. These abnormalities related to PAI were followed up to evaluate treatment effects. RESULTS: PAI was detected in 56/216 (25.93%) patients, which involved the pulmonary trunk, main PAs, and small vessels in the lungs. Among patients with PAI, 28 (50%) patients were accompanied by pulmonary hypertension, which was graded as 'severe' in 9 (16.07%), 'moderate' in 10 (17.86%), and mild in 9 (16.07%). Twenty-six (46.43%) patients showed advanced NYHA function (III, 20, 35.71%; IV, 6, 10.71%). Furthermore, 21 (37.50%) patients presented with abnormal pulmonary parenchymal lesions in the area corresponding to PAI (e.g. the mosaic sign, infarction, bronchiectasis). During follow-up, two patients died due to heart failure and pulmonary thrombosis. In the remaining patients, the abnormalities mentioned above improved partially after routine treatment. CONCLUSIONS: PAI is common in TA patients. PAI can cause pulmonary hypertension, cardiac insufficiency, and pulmonary parenchymal lesions, which worsen patients' prognosis.

The value of interleukin-6 in predicting disease relapse for Takayasu arteritis during 2-year follow-up.

OBJECTIVE: To evaluate the value of interleukin-6 (IL-6) in predicting long-term disease prognosis for Takayasu arteritis (TA). METHODS: Sixty-seven TA patients, who had IL-6 levels detected at the first visit and had a regular follow-up of at least 2 years, were enrolled. Data recorded up to March 31, 2019, including clinical presentations, laboratory indices, treatments, and radiological images were collected and used for analysis. The value of IL-6 in predicting disease relapse and imaging progression was analyzed. RESULTS: IL-6 levels were positively related with disease activity index, including Kerr scores, C-reactive protein (CRP) levels. Patients were divided into three groups according to baseline serum IL-6 levels: low group (< 5.4 pg/mL, n = 29), medium group (5.4-11.5 pg/mL, n = 20), and high group (> 11.5 ng/mL, n = 18). Patients in the medium and high group had higher disease activity than those in the low group (p < 0.01). Baseline IL-6 levels were correlated with luminal stenosis (p < 0.05), although no significant correlations with long-term imaging progression were observed. Patients with more than 2 episodes of disease relapses were most commonly seen in the medium group (p < 0.05). Multivariate Cox proportional hazard regression analysis indicated that medium and high IL-6 levels were positive predictors for disease relapse (HR 4.3, 95%CI 1.3-18.7 p = 0.07 for medium group; HR 2.1, 95% CI 0.7-48.9, p = 0.19 for high group) with disease status and treatment adjusted. CONCLUSIONS: IL-6 may be a valuable predictor of TA disease relapse during long-term follow-up. Treatments targeted at IL-6 pathways might reduce disease relapse and have better prognostic effects for TA. Key Points • Positive relationships between IL-6 levels and disease activity index, including Kerr scores, C-reactive protein (CRP) levels, etc. were indicated. • Medium and high baseline IL-6 levels were valuable for predicting disease relapse during the 2-year follow-up. • Baseline IL-6 levels were positively correlated with luminal stenosis on imaging.

CYR61/TGF-ß axis promotes adventitial fibrosis of Takayasu's arteritis in the IL-17 mediated inflammatory microenvironment.

OBJECTIVES: Takayasu's arteritis (TAK) is characterised by inflammation and fibrosis in the aortas, but its pathogenesis remains unclear. The aim of the study is to demonstrate the role of cysteine-rich protein 61 (CYR61), a novel proinflammatory factor, in the inflammation and fibrosis of TAK vessels. METHODS: CYR61 expression in the aortic vessel was compared between TA tissues and healthy samples by immunohistochemistry staining. The effect of CYR61 on the proliferation, migration and activation of adventitial fibroblasts (AFs) in the IL-17-mediated inflammatory microenvironment was studied in vitro. RESULTS: Here we found higher expression of CYR61 in the aortic adventitia in TAK patients than in healthy donors by immunohistochemistry staining. In vitro, recombinant human CYR61 (rhCYR61) significantly upregulated the proliferation of primary human aortic adventitial fibroblasts (AFs) and their expression of extracellular matrix (ECM) proteins such as collagen I, collagen III and fibronectin at the mRNA and protein levels, but rhCYR61 partly inhibited the migration of AFs. The integrin αvß1 was identified as a membrane receptor of CYR61 in AFs, and its downstream Erk1/2 pathway was found activated by detecting its phosphorylation level. Pretreatment with PD98059, an inhibitor of Erk1/2, down-regulated the mRNA and protein expression of ECM proteins in the rhCYR61-stimulated AFs. Furthermore, rhCYR61 up-regulated the expression of TGF-ß, and TGF-ß siRNA transfection obviously attenuated the profibrotic effect ofrhCYR61. Finally, to clarify the cooperation between CYR61 and classical proinflammatory factors, IL-17 was chosen as a co-stimulator in the culture of AFs. rhIL-17 promoted the mRNA and protein expression of CYR61 in AFs, and the collaboration of rhIL-17 and rhCYR61 dramatically boosted the synthesis of ECM and TGF-ß. CONCLUSIONS: Our findings suggest that CYR61 played a profibrotic role through the TGF-ß pathway and it enhanced IL-17-mediated inflammation and fibrosis in the mechanism of vascular impairment in TAK.