Interaction of human dendritic cell receptor DEC205/CD205 with keratins.

DEC205 (CD205) is one of the major endocytic receptors on dendritic cells and has been widely used as a receptor target in immune therapies. It has been shown that DEC205 can recognize dead cells through keratins in a pH-dependent manner. However, the mechanism underlying the interaction between DEC205 and keratins remains unclear. Here we determine the crystal structures of an N-terminal fragment of human DEC205 (CysR∼CTLD3). The structural data show that DEC205 shares similar overall features with the other mannose receptor family members such as the mannose receptor and Endo180, but the individual domains of DEC205 in the crystal structure exhibit distinct structural features that may lead to specific ligand binding properties of the molecule. Among them, CTLD3 of DEC205 adopts a unique fold of CTLD, which may correlate with the binding of keratins. Furthermore, we examine the interaction of DEC205 with keratins by mutagenesis and biochemical assays based on the structural information and identify an XGGGX motif on keratins that can be recognized by DEC205, thereby providing insights into the interaction between DEC205 and keratins. Overall, these findings not only improve the understanding of the diverse ligand specificities of the mannose receptor family members at the molecular level but may also give clues for the interactions of keratins with their binding partners in the corresponding pathways.

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Artificial and Biosynthetic Nanoparticles Boost Bioelectrochemical Reactions via Efficient Bidirectional Electron Transfer of Shewanella loihica.

Bioelectrochemical reactions using whole-cell biocatalysts are promising carbon-neutral approaches because of their easy operation, low cost, and sustainability. Bidirectional (outward or inward) electron transfer via exoelectrogens plays the main role in driving bioelectrochemical reactions. However, the low electron transfer efficiency seriously inhibits bioelectrochemical reaction kinetics. Here, a three dimensional and artificial nanoparticles-constituent inverse opal-indium tin oxide (IO-ITO) electrode is fabricated and employed to connect with exoelectrogens (Shewanella loihica PV-4). The above electrode collected 128-fold higher cell density and exhibited a maximum current output approaching 1.5 mA cm-2 within 24 h at anode mode. By changing the IO-ITO electrode to cathode mode, the exoelectrogens exhibited the attractive ability of extracellular electron uptake to reduce fumarate and 16 times higher reverse current than the commercial carbon electrode. Notably, Fe-containing oxide nanoparticles are biologically synthesized at both sides of the outer cell membrane and probably contributed to direct electron transfer with the transmembrane c-type cytochromes. Owing to the efficient electron exchange via artificial and biosynthetic nanoparticles, bioelectrochemical CO2 reduction is also realized at the cathode. This work not only explored the possibility of augmenting bidirectional electron transfer but also provided a new strategy to boost bioelectrochemical reactions by introducing biohybrid nanoparticles.

Magnetic resonance imaging-based radiomics was used to evaluate the level of prognosis-related immune cell infiltration in breast cancer tumor microenvironment.

PURPOSE: The tumor immune microenvironment is a valuable source of information for predicting prognosis in breast cancer (BRCA) patients. To identify immune cells associated with BRCA patient prognosis from the Cancer Genetic Atlas (TCGA), we established an MRI-based radiomics model for evaluating the degree of immune cell infiltration in breast cancer patients. METHODS: CIBERSORT was utilized to evaluate the degree of infiltration of 22 immune cell types in breast cancer patients from the TCGA database, and both univariate and multivariate Cox regressions were employed to determine the prognostic significance of immune cell infiltration levels in BRCA patients. We identified independent prognostic factors for BRCA patients. Additionally, we obtained imaging features from the Cancer Imaging Archive (TCIA) database for 73 patients who underwent preoperative MRI procedures, and used the Least Absolute Shrinkage and Selection Operator (LASSO) to select the best imaging features for constructing an MRI-based radiomics model for evaluating immune cell infiltration levels in breast cancer patients. RESULTS: According to the results of Cox regression analysis, M2 macrophages were identified as an independent prognostic factor for BRCA patients (HR = 32.288, 95% CI: 3.100-357.478). A total of nine significant features were selected to calculate the radiomics-based score. We established an intratumoral model with AUCs (95% CI) of 0.662 (0.495-0.802) and 0.678 (0.438-0.901) in the training and testing cohorts, respectively. Additionally, a peritumoral model was created with AUCs (95% CI) of 0.826 (0.710-0.924) and 0.752 (0.525-0.957), and a combined model was established with AUCs (95% CI) of 0.843 (0.723-0.938) and 0.744 (0.491-0.965). The peritumoral model demonstrated the highest diagnostic efficacy, with an accuracy, sensitivity, and specificity of 0.773, 0.727, and 0.818, respectively, in its testing cohort. CONCLUSION: The MRI-based radiomics model has the potential to evaluate the degree of immune cell infiltration in breast cancer patients, offering a non-invasive imaging biomarker for assessing the tumor microenvironment in this disease.

Bacillus subtilis: current and future modification strategies as a protein secreting factory.

Bacillus subtilis is regarded as a promising microbial expression system in bioengineering due to its high stress resistance, nontoxic, low codon preference and grow fast. The strain has a relatively efficient expression system, as it has at least three protein secretion pathways and abundant molecular chaperones, which guarantee its expression ability and compatibility. Currently, many proteins are expressed in Bacillus subtilis, and their application prospects are broad. Although Bacillus subtilis has great advantages compared with other prokaryotes related to protein expression and secretion, it still faces deficiencies, such as low wild-type expression, low product activity, and easy gene loss, which limit its large-scale application. Over the years, many researchers have achieved abundant results in the modification of Bacillus subtilis expression systems, especially the optimization of promoters, expression vectors, signal peptides, transport pathways and molecular chaperones. An optimal vector with a suitable promoter strength and other regulatory elements could increase protein synthesis and secretion, increasing industrial profits. This review highlights the research status of optimization strategies related to the expression system of Bacillus subtilis. Moreover, research progress on its application as a food-grade expression system is also presented, along with some future modification and application directions.

Enhancing Ni/Co Activity by Neighboring Pt Atoms in NiCoP/MXene Electrocatalyst for Alkaline Hydrogen Evolution.

Density functional theory (DFT) calculations demonstrate neighboring Pt atoms can enhance the metal activity of NiCoP for hydrogen evolution reaction (HER). However, it remains a great challenge to link Pt and NiCoP. Herein, we introduced curvature of bowl-like structure to construct Pt/NiCoP interface by adding a minimal 1 ‰-molar-ratio Pt. The as-prepared sample only requires an overpotential of 26.5 and 181.6 mV to accordingly achieve the current density of 10 and 500 mA cm-2 in 1 M KOH. The water dissociation energy barrier (Ea) has a ~43 % decrease compared with NiCoP counterpart. It also shows an ultrahigh stability with a small degradation rate of 10.6 µV h-1 at harsh conditions (500 mA cm-2 and 50 °C) after 3000 hrs. X-ray photoelectron spectroscopy (XPS), soft X-ray absorption spectroscopy (sXAS), and X-ray absorption fine structure (XAFS) verify the interface electron transfer lowers the valence state of Co/Ni and activates them. DFT calculations also confirm the catalytic transition step of NiCoP can change from Heyrovsky (2.71 eV) to Tafel step (0.51 eV) in the neighborhood of Pt, in accord with the result of the improved Hads at the interface disclosed by in situ electrochemical impedance spectroscopy (EIS) and scanning electrochemical microscopy (SECM) tests.

Scalable Manufacturing of Environmentally Stable All-Solid-State Plant Protein-Based Supercapacitors with Optimal Balance of Capacitive Performance and Mechanically Robust.

The development of advanced biomaterial with mechanically robust and high energy density is critical for flexible electronics, such as batteries and supercapacitors. Plant proteins are ideal candidates for making flexible electronics due to their renewable and eco-friendly natures. However, due to the weak intermolecular interactions and abundant hydrophilic groups of protein chains, the mechanical properties of protein-based materials, especially in bulk materials, are largely constrained, which hinders their performance in practical applications. Here, a green and scalable method is shown for the fabrication of advanced film biomaterials with high mechanical strength (36.3 MPa), toughness (21.25 MJ m-3 ), and extraordinary fatigue-resistance (213 000 times) by incorporating tailor-made core-double-shell structured nanoparticles. Subsequently, the film biomaterials combine to construct an ordered, dense bulk material by stacking-up and hot-pressing techniques. Surprisingly, the solid-state supercapacitor based on compacted bulk material shows an ultrahigh energy density of 25.8 Wh kg-1 , which is much higher than those previously reported advanced materials. Notably, the bulk material also demonstrates long-term cycling stability, which can be maintained under ambient condition or immersed in H2 SO4 electrolyte for more than 120 days. Thus, this research improves the competitiveness of protein-based materials for real-world applications such as flexible electronics and solid-state supercapacitors.

Association between triglyceride glucose-body mass index and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a retrospective study.

BACKGROUND: The triglyceride glucose-body mass index (TyG-BMI index) has been considered a reliable surrogate measure of insulin resistance; however, its ability to predict the incidence of cardiovascular disease in individuals with coronary artery disease (CAD) remains uncertain. The aim of this study was to demonstrate the correlation between the TyG-BMI index and cardiovascular incidence. METHODS: A total of 2533 consecutive participants who underwent percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation were included. Data from 1438 patients was analyzed in the study. The endpoint was defined as a composite of acute myocardial infarction, repeat revascularization, stroke, and all-cause mortality (major adverse cardiac and cerebrovascular events, MACCEs) at 34-month follow-up. The formula for calculating the TyG-BMI index is ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. RESULTS: Among the 1438 participants, 195 incident patient cases of MACCEs were ascertained. The incidence of MACCEs showed no statistically significant differences in the TyG-BMI index tertiles in the overall population. Further exploratory subgroup analysis and multivariable logistic regression analysis revealed a linear relationship between the TyG-BMI index (per 1 SD increased) and MACCEs in the elderly patients (OR = 1.22, 95% CI 1.011-1.467, p = 0.038) and in the female patients (OR = 1.33, 95% CI 1.004-1.764, p = 0.047). The addition of the TyG-BMI index to traditional risk factor models in elderly and female patients did not improve risk prediction for MACCEs. CONCLUSION: A higher TyG-BMI index was proportionally related to an increased incidence of MACCEs in the elderly or female patients. However, the inclusion of the TyG-BMI index did not provide better predictive performance for MACCEs in the elderly, specifically in female patients.

Soliton and bound-state soliton mode-locked fiber laser based on polarization-dependent grating.

We demonstrate the generation of solitons and bound-state solitons in a passively mode-locked fiber laser based on the nonlinear polarization rotation effect by polarization-dependent helical grating. The CO2-laser-inscribed grating has a high polarization-dependent loss of 24.4 dB at 1558.4 nm, which has facilitated the achievement of stable mode locking. The soliton laser could generate 548.9 fs pulses at 1560.59 nm with a spectrum bandwidth of 5.45 nm and a signal-to-noise ratio of 75.2 dB. Through adjustment of the polarization controller and pump power, a bound-state soliton mode-locked pulse with a spectral modulation period of 3.11 nm was achieved and the temporal interval between the two solitons was 2.19 ps. Furthermore, its repetition rate can be easily manipulated by varying the pump power. The results indicated that the polarization-dependent helical grating is an excellent polarizer that could be applied in an ultrafast fiber laser.

Evaluating Upstaging in Ductal Carcinoma In Situ Using Preoperative MRI-Based Radiomics.

BACKGROUND: About 20%-40% of patients diagnosed with ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) will develop invasive cancer at the time of excision. Improving the preoperative diagnosis of DCIS is important for surgical planning. PURPOSE: To establish an MRI-based radiomics nomogram for preoperatively evaluating the upstaging of DCIS patients and help with risk stratification. STUDY TYPE: Retrospective. POPULATION: A total of 227 patients (50.5 ± 9.7 years; 67 upstaged DCIS) were divided into training (n = 109), internal (n = 47), and external (n = 71) validation cohort. FIELD STRENGTH/SEQUENCE: 1.5-T or 3-T, dynamic contrast-enhanced (DCE) imaging, and diffusion-weighted imaging (DWI). ASSESSMENT: DCIS lesions were manually segmented using ITK-SNAP software and 1304 radiomic features were extracted from DCE, DWI, and apparent diffusion coef-ficient (ADC) maps, respectively. A radscore was calculated by a random forest algo-rithm based on DCIS upstaging-related radiomic features, which selected by a coarse-to-fine method including interclass correlation coefficient, single-factor anal-ysis, and the least absolute shrinkage and selection operator (LASSO) method. Uni-variate and multivariate logistic regression was used to analyze the independent risk factors, including age, location, lesion size, estrogen receptor (ER) status, and other clinico-pathologic factors. Finally, Mann-Whitney U tests were performed to com-pare the differences in radscore between low/intermediate and high nuclear grade groups for pure DCIS patients. STATISTICAL TESTS: Student's t-tests or Mann-Whitney U tests, chi-square-tests, or Fisher's-tests, univariate and multivariate logistic regression analysis, calibration curve, Youden index, the area under the curve (AUC), Delong test, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Eight important radiomic features (two from ADC, three from DWI, and three from DCE) were selected for calculating radscore. Clinical model including age and ER was established with AUCs of 0.747 and 0.738 in the internal and external validation cohorts, respectively. A combined model integrating age, estrogen receptor (ER), and radscore were also constructed with AUCs of 0.887 and 0.881. Further subgroup analysis showed that pure DCIS patients with different nuclear grade have significant differences in radscore. DATA CONCLUSION: Multisequence MRI radiomics may preoperatively evaluate the upstaging of DCIS and might provide personalized image-based clinical decision support. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Discovery of 3-phenyl-1,2,4-oxadiazole derivatives as a new class of SARS-CoV-2 main protease inhibitors.

The ongoing COVID-19 pandemic has led to massive infections and deaths and caused tremendous grief among the people. Although vaccines have played an important role in fighting COVID-19, the situation that the protective effect of current vaccines significantly decreases against mutated strains reminds us of the pressing need for developing effective antiviral therapeutics. The main protease (Mpro) is a key enzyme for SARS-CoV-2 viral replication and transcription and an attractive target for drug development. In this research, we report a new series of Mpro inhibitors containing 3-phenyl-1,2,4-oxadiazole. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, 16d, which showed an IC50 value of 5.27 ± 0.26 µM. Collectively, we obtained a new small molecular inhibitor targeting SARS-CoV-2 Mpro, which contains a new scaffold. This compound could be taken as a lead compound for subsequent drug discovery against SARS-CoV-2.

Research progress on the degradation mechanism and modification of keratinase.

Keratin is regarded as the main component of feathers and is difficult to be degraded by conventional proteases, leading to substantial abandonment. Keratinase is the only enzyme with the most formidable potential for degrading feathers. Although there have been in-depth studies in recent years, the large-scale application of keratinase is still associated with many problems. It is relatively challenging to find keratinase not only with high activity but could also meet the industrial application environment, so it is urgent to exploit keratinase with high acid and temperature resistance, strong activity, and low price. Therefore, researchers have been keen to explore the degradation mechanism of keratinases and the modification of existing keratinases for decades. This review critically introduces the basic properties and mechanism of keratinase, and focuses on the current situation of keratinase modification and the direction and strategy of its future application and modification. KEY POINTS: •The research status and mechanism of keratinase were reviewed. •The new direction of keratinase application and modification is discussed. •The existing modification methods and future modification strategies of keratinases are reviewed.

Static and Dynamic Plantar Pressure Distribution in 94 Patients with Different Stages of Unilateral Knee Osteoarthritis Using the Footscan® Platform System: An Observational Study.

BACKGROUND Plantar pressure analysis is widely used in the study of knee osteoarthritis (KOA). The present study aimed to investigate the static and dynamic plantar pressure distribution in patients with different stages of unilateral KOA using the Footscan® platform system. MATERIAL AND METHODS We recruited 94 patients aged 61.75±7.23 years old with different stages of unilateral KOA for static and dynamic analysis using the Footscan® platform system. The static pressure (%) of the left, right, anterior, posterior, and the pelvic rotation (°) was assessed. The peak pressure (PP, kPa) was investigated in 10 areas of the foot: medial heel (MH), lateral heel (LH), midfoot (MF), first to fifth metatarsals (M1-M5), hallux (T1), and toes 2-5 (T2-5). The correlation between KOA stages and plantar pressure distributions was investigated. RESULTS The results revealed that static pressure on the unaffected side and pelvic rotation were positively correlated with KOA stages. In addition, there was a positive correlation between KOA stages and PP of M5, MF, and LH zones on the affected side and PP of M2, M3, and M4 zones on the unaffected side, and a negative correlation between KOA stages and PP of T1 and T2-5 zones on the affected side. CONCLUSIONS With the progression of KOA, static plantar pressure tends to distributed on the unaffected side, and the dynamic plantar pressure tends to be distributed laterally on both feet. The plantar pressure distributions in unilateral KOA patients are abnormal and are closely related to the severity of KOA.

Correction of Error of Airborne Anemometers Caused by Self-Excited Air Turbulence.

An airborne anemometer, which monitors wind on the basis of Meteorological Multi-rotor UAVs (Unmanned Aerial Vehicles), is important for the prevention of catastrophe. However, its performance will be affected by the self-excited air turbulence generated by UAV rotors. In this paper, for the purpose of the correction of an error, we developed a method for the elimination of the influence of air turbulence on wind speed measurement. The corresponding correction model is obtained according to the CFD (Computational Fluid Dynamics) simulation of a six-rotor UAV which is carried out with the sliding grid method and the S-A turbulence model. Then, the model is applied to the developed prototype by adding the angle of attack compensation model of the airborne anemometer. It is shown by the actual application that the airborne anemometer can maintain the original measurement accuracy at different ascent speeds.

A Pure Electric Driverless Crawler Construction Machinery Walking Method Based on the Fusion SLAM and Improved Pure Pursuit Algorithms.

Driverless technology refers to the technology that vehicles use to drive independently with the help of driverless system under the condition of unmanned intervention. The working environment of construction machinery is bad, and the working conditions are complex. The use of driverless technology can greatly reduce the risk of driver operation, reduce labor costs and improve economic benefits.Aiming at the problem of the GPS positioning signal in the working environment of construction machinery being weak and not able to achieve accurate positioning, this paper uses the fusion SLAM algorithm based on improved NDT to realize the real-time positioning of the whole vehicle through reconstruction of the scene. Considering that the motion characteristics of crawler construction machinery are different from those of ordinary passenger cars, this paper improves the existing pure pursuit algorithm. Simulations and real vehicle tests show that the algorithm combined with the fusion SLAM algorithm can realize the motion control of driverless crawler construction machinery well, complete the tracking of the set trajectory perfectly and have high robustness. Considering that there is no mature walking method of driverless crawler construction machinery for reference, the research of this paper will lay a foundation for the development of driverless crawler construction machinery.

Efficient butyrate production from rice straw in an optimized cathodic electro-fermentation process.

Butyrate production from renewable biomass shows great potential against climate change and over-consumption of fossil fuels. Herein, key operational parameters of a cathodic electro-fermentation (CEF) process were optimized for efficient butyrate production from rice straw by mixed culture. The cathode potential, controlled pH and initial substrate dosage were optimized at -1.0 V (vs Ag/AgCl), 7.0 and 30 g/L, respectively. Under the optimal conditions, 12.50 g/L butyrate with yield of 0.51 g/g-rice straw were obtained in batch-operated CEF system. In fed-batch mode, butyrate production significantly increased to 19.66 g/L with the yield of 0.33 g/g-rice straw, but 45.99% butyrate selectivity still needs to be improved in future. Enriched butyrate producing bacteria (Clostridium cluster XIVa and IV) with proportion of 58.75% on the 21st day of the fed-batch fermentation, contributed to the high-level butyrate production. The study provides a promising approach for efficient butyrate production from lignocellulosic biomass.

The flexible linker and CotG were more effective for the spore surface display of keratinase KERQ7.

Feather, horn, hoof, and other keratin waste are protein-rich but limited by natural keratinase synthesis, activity, pH, and temperature stability. It is challenging to realize its large-scale application in industries. Bacillus subtilis spores are a safe, efficient, and highly resistant immobilized carrier, which can improve target proteins' resistance. In this research, KERQ7, the keratinase gene of Bacillus tequilensis strain Q7, was fused to the Bacillus subtilis genes coding for the coat proteins CotG and CotB, respectively, and displayed on the surface of B. subtilis spores. Compared with the free KERQ7, the immobilized KERQ7 showed a greater pH tolerance and heat resistance on the spore surface. The activity of CotG-KERQ7 is 1.25 times that of CotB-KERQ7, and CotG-KERQ7 is more stable. When the flexible linker peptide L3 was used to connect CotG and KERQ7, the activity was increased to 131.2 ± 3.4%, and the residual enzyme activity was still 62.5 ± 2.2% after being kept at 60 ℃ for 4 h. These findings indicate that the flexible linker and CotG were more effective for the spore surface display of keratinase to improve stress resistance and promote its wide application in feed, tanning, washing, and other industries.

Coupling Chlorin-Based Photosensitizers and Histone Deacetylase Inhibitors for Photodynamic Chemotherapy.

Photodynamic therapy combined with chemotherapy is a promising strategy to improve the antitumor efficacy. On the basis of coupling the chlorin-based photosensitizer pyropheophorbide a (Pyro) and histone deacetylase inhibitors (HDACis) to fabricate dual-mode antitumor molecules, a series of dual-mode antitumor prodrug molecules were synthesized and assessed for antitumor activity in vitro and in vivo. The data demonstrated that compound 4, with the most favorable phototoxicity and dark toxicity, could significantly inhibit the cell migration and upregulate the expression of acetyl-H3 protein, functioning as a photosensitizer and HDACi, respectively. Furthermore, compared with talaporfin, Pyro, and SAHA, compound 4 demonstrated the best inhibitory effect on tumor growth and metastasis in tumor-bearing mice; therefore, represented by compound 4, this pharmacophore coupling strategy is much more promising and effective than the pharmacophore fusion strategy for fabricating photodynamic and chemotherapeutical dual-mode molecules.

Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity. RESULTS: 17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain. CONCLUSIONS: For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.

Discovery of 2-vinyl-10H-phenothiazine derivatives as a class of ferroptosis inhibitors with minimal human Ether-a-go-go related gene (hERG) activity for the treatment of DOX-induced cardiomyopathy.

Ferroptosis was an iron-dependent, nonapoptotic form of regulated cell death. In our previous study, we discovered a potent ferroptosis inhibitor with phenothiazine scaffold (1), but subsequent investigation showed that this compound had potent hERG binding affinity. Herein, we report the discovery of a series of 2-vinyl-10H-phenothiazine derivatives as new class of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the identification of compound 7j, which exhibited significantly reduced hERG inhibition (IC50 > 30 µM) while maintaining high ferroptosis inhibitory activity (EC50 = 0.001 µM on the erastin-induced HT1080 cell ferroptosis model). Further studies confirmed 7j acted as a ROS scavenger and could relieve DOX-induced cardiomyopathy. 7j also displayed favorable pharmacokinetic properties and exhibited no obvious toxicity in vivo and vitro. Overall, this study provides a promising lead compound for drug discovery targeting ferroptosis.