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Three types of metal-doped ETS-10 zeolites including Ni-ETS-10, Al-ETS-10, and Ga-ETS-10 were successfully synthesized by one-pot template-free hydrothermal treatments. The effect of doping metals on the crystallinity, morphology, textural property, and basicity of the produced zeolites was systematically studied. It was found that doping with an appropriate amount of Ni could enhance the crystallinity and basicity of ETS-10 zeolites in comparison with Al and Ga, and the Ni species mainly existed in two forms of framework coordination and exchange site connection within Ni-ETS-10. The catalytic evaluation by the liquid Knoevenagel condensation reaction of benzaldehyde with ethyl cyanoacetate confirmed the superiority of ETS-10 and metal-doped ETS-10 in comparison with the contrast base zeolites of NaY and KY. And the 0.4Ni-ETS-10 catalyst exihibted the best performance with 75.6 % yield of ethyl ɑ-cyanocinnamate (ECC) among all the synthesized (metal-doped) ETS-10 zeolites. It is reasonable to expect that the demonstrated work has important implications for the design and facile synthesis of new-type high-performance base zeolite catalysts.

The effects of different complex shear stress conditions on grain refinement and texture evolution of Mg-13Gd-4Y-2Zn-0.5Zr alloy were investigated. With increasing strain rate, the average grain size of compression-shear (CS) and compression-torsion (CT) samples are decreased, and the grain size of dynamic recrystallization (DRX) grains is also decreased. This is because that the precipitation number of β phases is increased, and the hindering effect on grain growth can be significantly enhanced. The DRX fractions of CS and CT samples are decreased with increased strain rate. The low DRX fraction at high strain rate is related to the insufficient time for grains to nucleate. The DRX process can be promoted by the PSN mechanism of second phases, and the grain growth can be restricted by the pinning effect. At the same time, the texture strength is enhanced as the strain rate increased. Besides, the kinking degree of lamellar long-period stacking ordered (LPSO) phases is increased. Under complex shear stress conditions, non-basal slip, especially pyramidal slip, is easily activated and the texture is deflected greatly. Compared with the CS samples, CT samples have smaller average grain size, higher DRX fraction, and lower texture strength for a certain strain rate. This is because that the equivalent stress of the CT sample is larger, the stress triaxiality is smaller, so more serious dislocations are piled up near grain boundaries and second phases. At the same time, since CT sample was sheared with torsion, the dislocation movement path can be called “rotational dislocation accumulation”, and the longer distribution path of the CT sample is generated, so more sub-grains and low-angle grain boundaries (LAGBs) are formed. Compared with the CS sample, more huge-angle grain boundaries (HAGBs) and DRX grains are formed from grain boundary to grain interior, so better grain refinement effect is achieved.

ObjectivesTo investigate the characteristics of COVID-19 and its impact on patients with Takayasu’s arteritis (TAK).MethodsA web-based survey was administered to a TAK cohort and their co-residents in China during January 2023. Infection symptoms, post-acute sequelae of COVID-19 (PASC), potential impacts of COVID-19 on patients’ disease condition, treatment and immune-related parameters were analyzed. In addition, risk factors for COVID-19 and disease relapse after infection were explored.ResultsThe infection rate was significantly lower in patients with TAK than in co-residents (79.13% vs 90.67%, p=0.025). TAK patients were more prone to gastrointestinal symptoms (17.78% vs 5.88%, p=0.024), sleep problems (25.15% vs 10.29%, p=0.011), and symptoms involving more than 2 organs (58.90% vs 35.29%, p=0.001) after infection. Although only 2.45% of TAK patients were hospitalized and none progressed to life-threatening conditions, they were more likely to suffer from PASC (26.38% vs 13.24%, p=0.029), especially active patients. Active disease after the pandemic was significantly lower in infected patients than uninfected patients (21/163, 12.88% vs. 11/43, 25.58%, p=0.041). The presence of multiple system symptoms was a risk factor for active TAK after infection [OR: 3.62 (95% CI 1.06-12.31), p=0.040]. Moreover, csDMARDs treatment was a risk factor for COVID-19 infection [OR: 3.68 (95% CI 1.56-8.66), p=0.002].ConclusionAlthough TAK patients with COVID-19 have more acute and post-acute symptoms, there is no adverse outcome and the risk of disease relapse does not increase. Patients treated with csDMARDs may be at higher risk of infection and deserve more clinical attention.

Cisplatin resistance is a major therapeutic challenge in non-small cell lung cancer (NSCLC). Herein, the regulatory role of long non-coding RNA (lncRNA) ITGB2-AS1 in regulating NSCLC cisplatin resistance was investigated. NSCLC cisplatin resistance cells were constructed using A549 and H1975 cells. Cell viability and proliferation were detected by MTT assay and colony formation assay, respectively. Cell apoptosis and cell cycle were examined by flow cytometry. GSH, MDA, ROS, and Fe2+ levels were measured by the corresponding kits. The expressions of ferroptosis-negative regulation genes (GPX4 and SLC7A11) were determined by qRT-PCR and western blot. Molecular interactions were analyzed by RNA pull-down, RIP, ChIP, and dual-luciferase reporter assays. The effects of ITGB2-AS1 silencing on NSCLC cisplatin resistance in vivo were elevated by the tumor xenograft experiment. ITGB2-AS1 expression was increased in NSCLC patients and cisplatin-resistant NSCLC cells, which was positively correlated with ferroptosis-negative regulation genes. ITGB2-AS1 knockdown suppressed resistant cell proliferation and promoted cell apoptosis and ferroptosis. ITGB2-AS1 increased NAMPT expression by binding to FOSL2, thereby repressing p53 expression. The ITGB2-AS1 knockdown also inhibited NSCLC cisplatin resistance in vivo. ITGB2-AS1 promoted NSCLC cisplatin resistance by inhibiting p53-mediated ferroptosis via activating the FOSL2/NAMPT axis.

Regulable loading of Ni(OH)2 crystals by using three dimensionally ordered mesoporous carbon (3DOMC) as a support is achieved through a confined growth strategy accompanied by steam-assisted crystallization. Dual forms of high-crystalline nanosheet-like Ni(OH)2 severally distribute within mesopores or over the outer surface of 3DOMC particles depending on the loading amount (3% − 15%) of Ni(OH)2. Benefitted from the highly hybrid combination and efficient electrolyte diffusion, the obtained Ni(OH)2/carbon nanocomposites exhibit an excellent electrochemical performance, and the optimal sample of 6%_Ni(OH)2/3DOMC with confined extra-small Ni(OH)2 nanosheets as dominant shows the highest specific capacitance of 552.5F.g−1 at 1.0A·g−1, which is 330% higher than the contrast sample by using actived carbon as the support. Furthermore, the assembled hybrid supercapacitor by using 6%_Ni(OH)2/3DOMC and 3DOMC as positive and negative electrodes displays an energy density of 11.7 Wh.kg−1 at 288.1 W.kg−1 and a superior charge/discharge stability. It is expected that the flexible component, well-defined structure, and superior electrochemical performance could promote a great application potential of Ni(OH)2/3DOMC nanocomposites as supercapacitor electrodes and in other energy storage devices.

Abstract Background Takayasu arteritis (TAK) is a chronic granulomatous large vessel vasculitis with multiple immune cells involved. Chemokines play critical roles in recruitment and activation of immune cells. This study aimed to investigate chemokine profile in the peripheral blood and vascular tissue of patients with TAK. Methods A total of 58 patients with TAK and 53 healthy controls were enrolled. Chemokine array assay was performed in five patients with TAK and three controls. Chemokines with higher levels were preliminarily validated in 20 patients and controls. The validated chemokines were further confirmed in another group of samples with 25 patients and 25 controls. Their expression and distribution were also examined in vascular tissue from 8 patients and 5 controls. Correlations between these chemokines and peripheral immune cells, cytokines, and disease activity parameters were analyzed. Their serum changes were also investigated in these 45 patients after glucocorticoids and immunosuppressive treatment. Results Patients and controls were age and sex-matched. Twelve higher chemokines and 4 lower chemokines were found based on the chemokine array. After validation, increase of 5 chemokines were confirmed in patients with TAK, including CCL22, RANTES, CXCL16, CXCL11, and IL-16. Their expressions were also increased in vascular tissue of patients with TAK. In addition, levels of RANTES and IL-16 were positively correlated with peripheral CD3+CD4+ T cell numbers. Close localization of CCL22, CXCL11, or IL-16 with inflammatory cells was also observed in TAK vascular tissue. No correlations were found between these chemokines and cytokines (IL-6, IL-17, IFN-γ) or inflammatory parameters (ESR, CRP). No differences were observed regarding with these chemokines between active and inactive patients. After treatment, increase of CCL22 and decrease of RANTES and CXCL16 were found, while no changes were showed in levels of CXCL11 and IL-16. Conclusions CCL22, RANTES, CXCL16, CXCL11, and IL-16 were identified as the major chemokines involved in the recruitment of immune cells in the vascular tissue of patients with TAK. Additionally, the persistently high levels of CCL22, CXCL11, and IL-16 observed after treatment indicate their role in vascular chronic inflammation or fibrosis and demonstrate the need for developing more efficacious treatment options.

Background: Takayasu arteritis (TAK) is an immune-induced granulomatous vasculitis that occurs primarily in young Asian women. Our previous cohort studies have indicated that leflunomide (LEF), which can lead to rapid induction and might be a promising alternative treatment for TAK. Objectives: To compare the efficacy and safety of LEF versus placebo combined with prednisone for active TAK in a Chinese population. Design: This will be a multicenter, randomized, double-blinded controlled trial aiming to recruit 116 TAK patients with active disease. This study will last 52 weeks. Methods and analysis: Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to the intervention arm and a placebo tablet combined with prednisone will be given to the placebo arm. At the end of week 24, subjects who achieved clinical remission or partial clinical remission will proceed to maintenance therapy with LEF to the end of week 52; those who did not achieve clinical remission or partial clinical remission in the LEF intervention arm will drop out from the study, and those in the placebo control arm will switch to LEF treatment to week 52. The primary endpoint will be the clinical remission rate of LEF versus placebo at the end of week 24. The secondary endpoints will be the time to clinical remission, mean dose of prednisone, disease recurrence, time to recurrence, adverse events, as well as clinical remission in subjects who switched from the placebo control arm to LEF therapy after week 24. Intention to treat will be the primary analysis. Discussion: This is the first randomized double-blinded placebo-controlled trial to clarify the efficacy and safety of LEF in treating active TAK. The results will provide more evidence for TAK management. Registration: ClinicalTrials.gov identifier: NCT02981979

Objective: To elucidate the 3-year follow-up outcomes and risk factors associated with aortic regurgitation progression in Takayasu’s arteritis (TAK). Methods: This study was a prospective cohort study conducted among 77 patients with TAK at Zhongshan Hospital, Fudan University, China. All the participants were followed up and assessed with echocardiography for 3 years, and the baseline characteristics and dynamic changes in the aortic valve were recorded and investigated. A multivariable Cox model was used to explore the risk factors for aortic regurgitation progression. Results: The median onset age was 36.9 (26.0–44.4) years, and 57 patients (74.0%) were females. Fifty patients (64.9%) complained of aortic regurgitation, which was the most common valvular lesion at baseline. During the 3-year follow-up period, the progression of aortic regurgitation was observed in 29 (37.7%) patients with TAK. The progression group had higher baseline erythrocyte sedimentation rate (ESR; p = 0.013) and interleukin (IL)-6 ( p = 0.029) levels and lower early treatment remission rates ( p = 0.024). According to the Cox model, the elevated baseline IL-6 level [>13 pg/ml, hazard ratio (HR) = 2.4, 95% confidence interval (CI) = 1.0–5.8, p = 0.042] and absence of early treatment remission (HR = 3.3, 95% CI = 1.3–8.2, p = 0.010) were the independent risk factors for aortic regurgitation deterioration. Conclusion: About one-third of patients with TAK experienced aortic regurgitation progression within 3 years from first admission. Elevated IL-6 levels at baseline and absence of early treatment remission were the two important risk factors for subsequent aortic regurgitation progression.

Maria Feola et al., elucidate the compensatory role of pleckstrin-2 in ineffective erythropoiesis in β-thalassemic mice by reducing cofilin-mediated apoptosis and enhancing enucleation by activating RacGTPases. These findings could support future therapeutic interventions.

Abstract Background Takayasu arteritis (TA) is a rare disease, lacking convenient and feasible biomarkers to identify disease activity. We aimed to evaluate the value of complements in distinguishing active TA. Methods Consecutive patients were enrolled from the prospective East China TA cohort from April 2008 to June 2019. Patients were divided into two groups according to their baseline Kerr score. The value of complements and other biomarkers in identifying disease activity were analysed with cluster analysis, ROC curves, and combined tests. An independent group of patients from July 2019 to December 2019 were employed to validate the results. Results Of the enrolled 519 patients, 406 (72.2%) cases were identified as active disease. Higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), and complement 3 (C3) levels were observed in the active group. Elevated C3 (≥ 1.085 g/L) had a high value to identify active TA with a sensitivity of 69.9%, specificity of 66.7%, and AUC of 0.715. Combining the CRP (≥ 10.65 g/L; sensitivity, 50.7%; specificity, 82.4%) and C3, the sensitivity could be improved to 85.1% in parallel test and the specificity could be improved to 94.1% in serial test. Validation was further performed to confirm the value of C3 for disease activity assessment. The accuracy of the parallel test of CRP and C3 in external validation with independent 53 TA cases was 72.73% with the AUC of 0.721. Conclusion Elevated C3 could effectively evaluate the disease activity of TA, and C3 combining with CRP could further improve the disease activity evaluation.

BTB and CNC homology1 (BACH1), working as a transcriptional factor, is demonstrated to function on the regulation of epigenetic modifications by complex regulatory networks. Although BACH1 is reported as an oncogene, the overall analysis of its role remains lacking. In this study, we uncovered the capacity of BACH1 as a new pan-cancer therapeutic target. We found that BACH1 is highly expressed in abundant cancers and correlated with the poor prognosis of most cancers. The mutation sites of BACH1 varied in different cancer types and correlated to patients’ prognoses. The tumor mutation burden (TMB) in four cancer species and up to six tumor infiltrated immune cells had a significant relevance with BACH1. The enrichment analysis showed that the BACH1-associated genes were significantly enriched in the pathways of PD-1/L1 expression, ubiquitin-mediated proteolysis, T cell receptor, Th17 cell differentiation. We then demonstrated that BACH1 is positively correlated with the expression of many candidate genes, incluing SRPK2, GCLM, SLC40A1, and HK2 but negatively correlated with the expression of KEAP1 and GAPDH. Overall, our data shed light on BACH1’s effect on latent utility in cancer targeting therapy.

Abstract 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.

A real-time tuna detection network on mobile devices is a common tool for accurate tuna catch statistics. However, most object detection models have multiple parameters, and normal mobile devices have difficulties in satisfying real-time detection. Based on YOLOv3, this paper proposes a Tuna-YOLO, which is a lightweight object detection network for mobile devices. Firstly, following a comparison of the performance of various lightweight backbone networks, the MobileNet v3 was used as a backbone structure to reduce the number of parameters and calculations. Secondly, the SENET module was replaced with a CBAM attention module to further improve the feature extraction ability of tuna. Then, the knowledge distillation was used to make the Tuna-YOLO detect more accurate. We created a small dataset by deframing electronic surveillance video of fishing boats and labeled the data. After data annotation on the dataset, the K-means algorithm was used to get nine better anchor boxes on the basis of label information, which was used to improve the detection precision. In addition, we compared the detection performance of the Tuna-YOLO and three versions of YOLO v5-6.1 s/m/l after image enhancement. The results show that the Tuna-YOLO reduces the parameters of YOLOv3 from 234.74 MB to 88.45 MB, increases detection precision from 93.33% to 95.83%, and increases the calculation speed from 10.12 fps to 15.23 fps. The performance of the Tuna-YOLO is better than three versions of YOLO v5-6.1 s/m/l. Tuna-YOLO provides a basis for subsequent deployment of algorithms to mobile devices and real-time catch statistics.

An electrochemical lithium-ion battery model is well known to be suited for effectively describing the microstructure evolution in charging and discharging processes of a lithium-ion battery with practically realizable complexity. This paper presents a neural network-based parameter estimation scheme to identify the parameters of an electrochemical lithium-ion battery model in a near-optimal and real-time manner in order to consistently observe the electrochemical states of batteries. The network is first trained to learn the dynamics of the electrochemical lithium-ion battery model, and then, it is applied to estimate the parameters with available finite-time measurements of voltage, current, temperature, and state of charge. In order to efficiently learn the dynamic characteristics of a lithium-ion battery, a well-known recurrent neural network, called a long short-term memory model, is employed with other techniques such as batch normalization, dropout, and stochastic gradient descent with warm restarts for learning speed enhancement and regularization. Using synthetic and experimental data, we show that the proposed estimation scheme works well, finding parameters and recovering the voltage profiles within the root-mean-square error of 0.43% and 26 mV, respectively, even with measurements obtained within a sufficiently short interval of time.

ObjectivesTo 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).MethodsIn 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.ResultsIn 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).ConclusionsMacrophages 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.

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.

In order to accurately estimate the state of health (SOH) of a Li-ion battery, a reference performance test (RPT) needs to be conducted between several charging/discharging cycles for obtaining accurate data concerning the battery capacity and degradation. However, it is not practical to perform RPTs frequently because they are time-consuming and expensive; moreover, the Li-ion battery undergoes unnecessary degradation during test operations. Therefore, the RPTs should be performed as infrequently as possible. In this paper, a neural network-based SOH estimation scheme with reduced experimental data measured by the RPT is proposed for achieving economic efficiency and mitigating the dispensable degradation being caused by additional experiments. For the RPT-reduced experimental data, the continuous SOH estimation problem is formulated into a classification problem. The neural network learns how to estimate the SOH values using short time-series voltage and current data, labeled as the corresponding SOH values by the RPTs. Even in the SOH regions, where the data are not labeled as any given class and there is no prior knowledge on the corresponding SOH, the proposed SOH estimation scheme works well by performing regression with the class probability distribution.

Electrochemical models of lithium-ion batteries are derived according to the laws of physics; therefore, the parameters represent specific physical quantities such as lithium diffusivities, particle volume fractions, and ion intercalation rates. It is important to estimate these parameters to identify the internal states of a lithium-ion battery for efficient and safe management. Until now, parameter estimation algorithms for electrochemical lithium-ion battery models have been developed without considering the unequal identifiability among the target parameters. Thus, it is highly likely that existing algorithms exhibit inefficient exploration and lead to a slow convergence rate and even large parameter estimation error. For more accurate parameter estimation of an electrochemical lithium-ion battery model, we propose a new adaptive exploration harmony search (AEHS) scheme that provides a wide search space for a longer period of time when estimating parameters with low identifiability. The proposed algorithm is based on improved harmony search; its bandwidth parameters for determining the level of exploration are adjusted according to the individual and joint variabilities computed from the distributions of previously estimated parameters. Such adaptive bandwidth parameters can reduce inefficient exploration and enable fast convergence, allowing exploration that achieves global optimality. Simulation results show that the proposed parameter estimation algorithm produces the highest convergence rate and the smallest parameter estimation error compared with existing schemes. The performance of the proposed scheme is also validated using real data generated from experiments.

Iron overload results in significant morbidity and mortality in β-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in β-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbbth1/th1 (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes.

Background: The IL-6R antibody tocilizumab has been proven effective in treating Takayasu arteritis (TA). However, some patients show silent vascular stenosis progression (VSP) despite treatment with tocilizumab. The aim of the study was to explore the related risk factors of VSP in patients treated with tocilizumab., Methods: Patients receiving tocilizumab were enrolled from the prospective living ongoing East China Takayasu Arteritis cohort. Their medical information was uniformly recorded with a homogenized evaluation method. Magnetic resonant angiography or computed tomographic angiography was employed to monitor VSP during the follow-up period, and Cox regression analysis was performed to explore the related risk factors., Results: Thirty-eight patients were enrolled, among whom 18 (47.4%) experienced VSP, and seven and three patients experienced new and worsened vascular ischemic symptoms and events (VISE) during follow-up, respectively. The median period for VSP occurrence was 6.9 months during follow-up. Patients with VSP showed higher levels of baseline complement 3 (C3) than those in the patients without VSP. Multivariate Cox regression analysis revealed baseline C3 level (hazard ratio [HR] = 7.05, 95% confidence interval: 1.50-33.07, p = 0.013) was independently associated with VSP, with a cut-off value of 1.22 g/L., Conclusions: 47.4% of TA patients treated with tocilizumab would suffer VSP. A high C3 level is a risk factor for VSP in TA patients receiving tocilizumab, which may facilitate the option of tocilizumab in the future., (© 2023. The Author(s).)

Objectives: In IgG4-related disease, the relationship between pathological findings and relapse has not been well established. This study aimed to identify the clinical and pathological predictors of disease relapse in IgG4-RD., Methods: Patients with newly diagnosed IgG4-RD (n = 71) were enrolled between January 2011 and April 2020; all cases were pathologically confirmed. The clinical and pathological features were recorded in a database at baseline and each follow-up visit. Patients were followed up at least once a month via outpatient clinic examinations and telephone calls. Univariate and multivariate Cox regression analyses and receiver operating curve (ROC) analysis were used to identify the predictors of disease relapse and to assess their predictive value., Results: Over a median follow-up of 26 (range, 6-123) months, 3/71 (4.2%) patients died. Of the remaining 68 patients, 47 (69.1%) patients had achieved clinical remission and 21 (30.9%) had suffered relapse at the last follow-up. The independent predictors of relapse were IgG4 ≥ 6.5 g/L (HR = 2.84, 95% CI: 1.11-7.23), IgG ≥ 20.8 g/L (HR = 4.11, 95% CI: 1.53-11.06), IgG4-RD responder index (RI) ≥ 9 (HR = 3.82, 95% CI: 1.28-11.37), and severe IgG4 + plasma cell infiltration (HR = 6.32, 95% CI: 1.79-22.41). A prognostic score developed using three of the identified predictors (IgG ≥ 20.8 g/L, IgG4-RD RI ≥ 9, and severe IgG4 + plasma cell infiltration) showed good value for predicting impending relapse (AUC, 0.806)., Conclusions: In patients with IgG4-RD, IgG4 ≥ 6.5 g/L, IgG ≥ 20.8 g/L, IgG4-RD responder index (RI) ≥ 9, and severe IgG4 + plasma cell infiltration are predictors of relapse., (© 2022. The Author(s).)

Background: Hypertension occurred in 30-80% of Takayasu arteritis (TAK) patients around the world and the occurrence of hypertension might worsen the disease prognosis. This study aimed to investigate the clinical characteristics and imaging phenotypes, as well as their associations with events free survival (EFS) in Chinese TAK patients with hypertension., Methods: This current research was based on a prospectively ongoing observational cohort-the East China Takayasu Arteritis (ECTA) cohort, centered in Zhongshan Hospital, Fudan University. Totally, 204 TAK patients with hypertension were enrolled between January 2013 and December 2019. Clinical characteristics and imaging phenotypes of each case were evaluated and their associations with the EFS by the end of August 30, 2020, were analyzed., Results: Severe hypertension accounted for 46.1% of the entire population. Three specific imaging phenotypes were identified: Cluster 1: involvement of the abdominal aorta and/or renal artery (27.5%); Cluster 2: involvement of the ascending aorta, thoracic aorta, the aortic arch, and/or its branches (18.6%); and Cluster 3: combined involvement of Cluster 1 and 2 (53.9%). Clinical characteristics, especially hypertensive severity, differed greatly among the three imaging clusters. In all, 187 patients were followed up for a median of 46 (9-102) months; 72 events were observed in 60 patients (1-3 per person). The overall blood pressure control rate was 50.8%, and the EFS was 67.9% by the end of the follow-up. Multivariate Cox regression indicated that controlled blood pressure (HR = 2.13, 95% CI 1.32-3.74), Cluster 1 (HR = 0.69, 95% CI 0.48-0.92) and Cluster 3 (HR = 0.72, 95% CI 0.43-0.94) imaging phenotype was associated with the EFS. Kaplan-Meier curves showed that patients with controlled blood pressure showed better EFS (p = 0.043). Furthermore, using cases with Cluster 1 imaging phenotype and controlled blood pressure as reference, better EFS was observed in patients with Cluster 2 phenotype and controlled blood pressure (HR = 2.21, 95%CI 1.47-4.32), while the case with Cluster 1 phenotype plus uncontrolled blood pressure (HR = 0.64, 95%CI 0.52-0.89) and those with Cluster 3 phenotype and uncontrolled blood pressure (HR = 0.83, 95%CI 0.76-0.92) suffered worse EFS., Conclusion: Blood pressure control status and imaging phenotypes showed significant effects on the EFS for TAK patients with hypertension., (© 2021. The Author(s).)

Objective: To compare the clinical outcomes of patients with active immunoglobulin G (IgG) 4 related disease (IgG4-RD) receiving tocilizumab versus those receiving cyclophosphamide (CYC)., Methods: This IgG4-RD registry study was a prospective cohort study conducted among patients with active IgG4-RD hospitalized at Zhongshan Hospital, Fudan University. Patients who were treated with tocilizumab or CYC along with glucocorticoids (GCs) were enrolled. All participants were followed up at the hospital clinic at 3 and 6 months after discharge. Primary clinical outcomes were measured via the IgG4-RD responder index (RI), complete response (CR), and partial response (PR), as well as side effects., Results: From January 2015 to June 2020, 29 patients enrolled. Fourteen and 15 patients were treated with tocilizumab and CYC, respectively. At the 6-month follow-up, disease activity parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgG4, and IgG4-RD RI, decreased significantly in both groups. At 6 months, tocilizumab demonstrated its superiority, with 50% of patients achieving CR in the Tocilizumab group versus 20% in the CYC group. However, no statistical significance was identified ( p  = 0.128). The GC dosage at 6 months was significantly lower in the tocilizumab group than in the CYC group [10 (9.4-15) mg/d versus 15 (15-15) mg/d, p  = 0.025]. In the CYC group, two patients experienced lumbar vertebral compression fractures related to GCs. Other patients in both groups showed mild adverse effects., Conclusions: Tocilizumab could be a better steroid-sparing agent, with a comparable curative effect and tolerance, than CYC, in the treatment of IgG4-RD., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Objectives: Patients with IgG4-related disease (IgG4-RD) suffer high relapse rates during long-term treatment, but factors that predict relapse outcomes are not well established. In the present study, we aimed to identify predictive factors for treatment resistance and disease relapse in a Chinese IgG4-RD cohort., Methods: This study enrolled 102 patients newly diagnosed with IgG4-RD. Disease prognosis was determined by evaluating disease activity and dosage of glucocorticoids. Predictive factors for refractory and relapsed disease were identified by univariate analysis and Cox regression., Results: Among the 102 patients, 78 cases received medical treatment with regular follow-up (21 [6-111] months). During the follow-up period, 55 (70.5%) patients sustained clinical remission, and 23 (29.5%) patients suffered refractory or relapsed disease. The relapse rate of the patients with IgG4-RD was significantly higher among patients who stopped taking medicine than among those who continued treatment with glucocorticoids (GC) + immunosuppressor (IM). Serum TNF-α ≥ 13 pg/mL, sIL-2R ≥ 1010 U/mL, total cholesterol < 3.55 mmol/L, low-density lipoprotein < 2.0 mmol/L, IgG ≥ 20.2 g/L, and drug withdrawal were predictive factors for refractory and relapsed IgG4-RD. Multivariate Cox regression revealed that both sIL-2R and TNF-α were independent risk factors for refractory and relapsed disease. The combination of GC and IM treatment was an independent protective factor against refractory and relapsed IgG4-RD., Conclusions: High serum levels of sIL-2R and TNF-α may be informative risk factors for refractory and relapsed IgG4-RD. Our data suggest that a combination treatment of GC along with IM may be protective against refractory and relapsed IgG4-RD. Key Points • High sIL-2R and TNF-α levels are informative risk factors for refractory and relapsed IgG4-related disease. • Combination treatment of GC with IM protects against refractory and relapsed IgG4-related disease.

Background: The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. Objectives: To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). Methods: The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. Results: The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4 + plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. In vitro , IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. Conclusions: In vitro IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment., (Copyright © 2020 Zongfei, Rongyi, Xiaomeng, Lili, Lingying, Xiufang, Xiaomin, Zhuojun, Huiyong, Ying and Lindi.)

Background: Leflunomide (LEF) has been considered as an alternative treatment for Takayasu arteritis (TA); however, data on its efficacy are still scanty., Objective: To investigate the efficacy and safety of LEF versus cyclophosphamide (CYC) for initial-onset TA., Methods: Initial-onset TA patients with active disease were enrolled in this research. Patients enrolled from 1 January 2009 to 31 December 2015 were treated with glucocorticoids and CYC, while patients enrolled from 1 January 2016 to 31 October 2018 received glucocorticoids and LEF. Treatment response including complete remission (CR), partial remission (PR), and effectiveness rate (ER) and side effects were evaluated at 6 and 12 months., Results and Conclusion: In total, 92 patients were enrolled. A total of 47 patients were treated with LEF, while 45 patients were treated with CYC. The CR and ER rates were 75.55%, and 88.89% at 6 months, and 85.37% and 95.12% at 12 months in the LEF group. The CR and ER rates were 39.02% and 70.73% at 6 months, and 56.41% and 82.05% at 12 months in the CYC group. The CR rate was significantly higher in the LEF group than in the CYC group both at 6 months (75.61% versus 38.24%, p  < 0.01) and 12 months (77.42% versus 53.33%, p  < 0.05) after adjustment for propensity scores. The incidence of side effects in the LEF group was much lower than that in the CYC group (21.28% versus 44.44%). In conclusion, LEF provided a better treatment response, along with lower reproductive toxicity, compared with CYC in initial-onset TA., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)