EphA2 specific chimeric antigen receptor engineered T cells for the treatment of prostate cancer.

Erythropoietin-producing hepatocyte receptor A2 (EphA2) is an attractive target for immunotherapy due to its high expression in a variety of solid tumors including prostate cancer. Among various types of immunotherapeutics, chimeric antigen receptor T (CAR-T) cell therapy has made promising progress in hematological and solid tumors. Here, we detected the expression of EphA2 in prostate cancer cells and developed a second-generation CAR targeting EphA2 with CD28 as a co-stimulatory receptor to explore its tumor suppressive potential for prostate cancer in vitro and in vivo. EphA2 was highly expressed on the surface of PC3 and DU145 cells. EphA2 CART cells effectively inhibited prostate cancer growth in an antigen-dependent manner in vitro and in vivo. In addition, tumor cells could stimulate the proliferation of CAR-T cells and the release of cytokine IFN-γ in vitro. These findings shed light on EphA2 as a potential target for prostate cancer, promising EphA2 specific CAR-T cells for the treatment of prostate cancer.

Self-Oxygenated Hydrogel Enhances Immune Cell Response and Infiltration Via Triggering Dual DNA Damage to Activate cGAS-STING and Inhibiting CAFs.

Immune checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of reactive oxygen species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H2O2 to O2, reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses.

Nordalbergin Synergizes with Novel ß-Lactam Antibiotics against MRSA Infection.

The synergetic strategy has created tremendous advantages in drug-resistance bacterial infection treatment, whereas challenges related to novel compound discovery and identifying drug-binding targets still remain. The mechanisms of antimicrobial resistance involving ß-lactamase catalysis and the degradation of ß-lactam antibiotics are being revealed, with relevant therapies promising to improve the efficacy of existing major classes of antibiotics in the foreseeable future. In this study, it is demonstrated that nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, efficiently potentiated the activities of ß-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) by suppressing ß-lactamase performance and improving the bacterial biofilm susceptibility to antibiotics. Nordalbergin was found to destabilize the cell membrane and promote its permeabilization. Moreover, nordalbergin efficiently improved the therapeutic efficacy of amoxicillin against MRSA pneumonia in mice, as supported by the lower bacterial load, attenuated pathological damage, and decreased inflammation level. These results demonstrate that nordalbergin might be a promising synergist of amoxicillin against MRSA infections. This study provided a new approach for developing potentiators for ß-lactam antibiotics against MRSA infections.

Ultrasensitive Hierarchical AuNRs@SiO2@Ag SERS Probes for Enrichment and Detection of Insulin and C-Peptide in Serum.

Introduction: Insulin and C-peptide played crucial roles as clinical indicators for diabetes and certain liver diseases. However, there has been limited research on the simultaneous detection of insulin and C-peptide in trace serum. It is necessary to develop a novel method with high sensitivity and specificity for detecting insulin and C-peptide simultaneously. Methods: A core-shell-satellites hierarchical structured nanocomposite was fabricated as SERS biosensor using a simple wet-chemical method, employing 4-MBA and DTNB for recognition and antibodies for specific capture. Gold nanorods (Au NRs) were modified with Raman reporter molecules and silver nanoparticles (Ag NPs), creating SERS tags with high sensitivity for detecting insulin and C-peptide. Antibody-modified commercial carboxylated magnetic bead@antibody served as the capture probes. Target materials were captured by probes and combined with SERS tags, forming a "sandwich" composite structure for subsequent detection. Results: Under optimized conditions, the nanocomposite fabricated could be used to detect simultaneously for insulin and C-peptide with the detection limit of 4.29 × 10-5 pM and 1.76 × 10-10 nM in serum. The insulin concentration (4.29 × 10-5-4.29 pM) showed a strong linear correlation with the SERS intensity at 1075 cm-1, with high recoveries (96.4-105.3%) and low RSD (0.8%-10.0%) in detecting human serum samples. Meanwhile, the C-peptide concentration (1.76 × 10-10-1.76 × 10-3 nM) also showed a specific linear correlation with the SERS intensity at 1333 cm-1, with recoveries 85.4%-105.0% and RSD 1.7%-10.8%. Conclusion: This breakthrough provided a novel, sensitive, convenient and stable approach for clinical diagnosis of diabetes and certain liver diseases. Overall, our findings presented a significant contribution to the field of biomedical research, opening up new possibilities for improved diagnosis and monitoring of diabetes and liver diseases.

The research advances in Kirsten rat sarcoma viral oncogene homolog (KRAS)-related cancer during 2013 to 2022: a scientometric analysis.

Introduction: Cancer represents a significant global public health concern. In recent years, the incidence of cancer has been on the rise worldwide due to various factors, including diet, environment, and an aging population. Simultaneously, advancements in tumor molecular biology and genomics have led to a shift from systemic chemotherapy focused on disease sites and morphopathology towards precise targeted therapy for driver gene mutations. Therefore, we propose a comprehensive review aimed at exploring the research hotspots and directions in the field of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers over the past decade, providing valuable insights for cancer treatment strategies. Specifically, we aim to present an intellectual landscape using data obtained from the Web of Science (WoS) regarding KRAS mutation. Methods: Bibliometrix, VOSviewer, CiteSpace, and HistCite were employed to conduct scientometric analyses on national publications, influential authors, highly cited articles, frequent keywords, etc. Results: A total of 16,609 publications met the screening criteria and exhibited a consistent annual growth trend overall. Among 102 countries/regions, the United States occupied the vast majority share of the published volume. The journal Oncotarget had the highest circulation among all scientific publications. Moreover, the most seminal articles in this field primarily focus on biology and targeted therapies, with overcoming drug resistance being identified as a future research direction. Conclusion: The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast.

Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm.

Cytokine storm (CS) is linked with macrophage dysfunction and acute lung injury (ALI), which can lead to patient mortality. Glycolysis is preferentially exploited by the pro-inflammatory macrophages, in which pyruvate kinase M2 (PKM2) is a critical enzyme. The mechanism underlying the link between CS and ALI involves cell death, with the recently discovered programmed cell death known as ferroptosis being involved. However, the relationship between the glycolysis and ferroptosis in the context of CS-related ALI remains unclear. CS-associated ALI induced by poly I:C (10 mg/kg, i.v) and LPS (5 mg/kg, i.p) (IC: LPS) exhibit significant ferroptosis. Ferrostatin-1 (ferroptosis inhibitor) treatment attenuated IC:LPS­induced mortality and lung injury. Moreover, Alveolar macrophage (AM) from IC:LPS model exhibited enhanced glycolysis and PKM2 translocation. The administration of ML-265(PKM2 monomer/dimer inhibitor) resulted in the formation of a highly active tetrameric PKM2, leading to improved survival and attenuation of ALI. Furthermore, ML-265 treatment decreased ferroptosis and restored the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infection, intracellular expression level of PKM2 were correlated with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation was noticed in CD14+ blood monocytes of lung infection patients with CS. In conclusion, PKM2 is a key regulatory node integrating metabolic reprograming with intra-nuclear function for the regulation of ferroptosis. Targeting PKM2 could be explored as a potential means in the future to prevent or alleviate hyper-inflammatory state or cytokines storm syndrome with aberrant ferroptotic cell death.

An Efficient Homologous Recombination-Based In Situ Protein-Labeling Method in Verticillium dahliae.

Accurate determination of protein localization, levels, or protein-protein interactions is pivotal for the study of their function, and in situ protein labeling via homologous recombination has emerged as a critical tool in many organisms. While this approach has been refined in various model fungi, the study of protein function in most plant pathogens has predominantly relied on ex situ or overexpression manipulations. To dissect the molecular mechanisms of development and infection for Verticillium dahliae, a formidable plant pathogen responsible for vascular wilt diseases, we have established a robust, homologous recombination-based in situ protein labeling strategy in this organism. Utilizing Agrobacterium tumefaciens-mediated transformation (ATMT), this methodology facilitates the precise tagging of specific proteins at their C-termini with epitopes, such as GFP and Flag, within the native context of V. dahliae. We demonstrate the efficacy of our approach through the in situ labeling of VdCf2 and VdDMM2, followed by subsequent confirmation via subcellular localization and protein-level analyses. Our findings confirm the applicability of homologous recombination for in situ protein labeling in V. dahliae and suggest its potential utility across a broad spectrum of filamentous fungi. This labeling method stands to significantly advance the field of functional genomics in plant pathogenic fungi, offering a versatile and powerful tool for the elucidation of protein function.

The effects of scar in psychological disorder: A bibliometric analysis from 2003 to 2022.

Scars are fibrous tissues that replace normal tissue during the wound healing process. Scarring can lead to low self-esteem, social impairment, depression, anxiety, and other psychiatric and psychological distress, necessitating a comprehensive understanding of the latest perspectives, topical research, and directions in scarring-mental health. This is a biblioshiny and VOSviewer based bibliometric analysis study. All data were obtained from the Web of Science, and a total of 664 articles from 2003 to 2022 met the criteria. The last 7 years have been a period of rapid growth in the field, with 2022 having the highest number of articles. The United States is the core country with the highest production and citation rate. The most cited literature was written in 2003 by Van Loey NE et al. Van Loey NE is the most prolific and influential author in this field. The top five popular keywords include "quality of life", "depression", "management", "anxiety", and "prevalence". The paper concludes that the current focus of scholars in the field is on the treatment of scars and that multidisciplinary treatment of such patients is worth exploring. These findings provide relevant researchers with the current state of research and possible future directions in this field.

Conductive and Eco-friendly Biomaterials-based Hydrogels for Noninvasive Epidermal Sensors: A Review.

As noninvasive wearable electronic devices, epidermal sensors enable continuous, real-time, and remote monitoring of various human physiological parameters. Conductive biomaterials-based hydrogels as sensor matrix materials have good biocompatibility, biodegradability, and efficient stimulus response capabilities and are widely applied in motion monitoring, healthcare, and human-machine interaction. However, biomass hydrogel-based epidermal sensing devices still need excellent mechanical properties, prolonged stability, multifunctionality, and extensive practicality. Therefore, this paper reviews the common biomass hydrogel materials for epidermal sensing (proteins, polysaccharides, polyphenols, etc.) and the various types of noninvasive sensing devices (strain/pressure sensors, temperature sensors, glucose sensors, electrocardiograms, etc.). Moreover, this review focuses on the strategies of scholars to enhance sensor properties, such as strength, conductivity, stability, adhesion, and self-healing ability. This work will guide the preparation and optimization of high-performance biomaterials-based hydrogel epidermal sensors.

GetPrimers: A generalized PCR-based genetic targeting primer designer enabling easy and standardized targeted gene modification across multiple systems.

Genetic targeting (e.g., gene knockout and tagging) based on polymerase chain reaction (PCR) is a simple yet powerful approach for studying gene functions. Although originally developed in classic budding and fission yeast models, the same principle applies to other eukaryotic systems with efficient homologous recombination. One-step PCR-based genetic targeting is conventionally used but the sizes of the homologous arms that it generates for recombination-mediated genetic targeting are usually limited. Alternatively, gene targeting can also be performed via fusion PCR, which can create homologous arms that are orders of magnitude larger, therefore substantially increasing the efficiency of recombination-mediated genetic targeting. Here, we present GetPrimers (https://www.evomicslab.org/app/getprimers/), a generalized computational framework and web tool to assist automatic targeting and verification primer design for both one-step PCR-based and fusion PCR-based genetic targeting experiments. Moreover, GetPrimers by design runs for any given genetic background of any species with full genome scalability. Therefore, GetPrimers is capable of empowering high-throughput functional genomic assays at multipopulation and multispecies levels. Comprehensive experimental validations have been performed for targeting and verification primers designed by GetPrimers across multiple organism systems and experimental setups. We anticipate GetPrimers to become a highly useful and popular tool to facilitate easy and standardized gene modification across multiple systems.

Relationship between Composite Dietary Antioxidant Index and Aging.

BACKGROUND: Numerous studies have demonstrated a close relationship between antioxidant-rich diets and comorbidities as well as mortality. However, the relationship between such diets and aging remains unclear. The purpose of this study was to investigate the association between the Composite Dietary Antioxidant Index (CDAI) and aging. METHODS: All participants were from the National Health and Nutrition Examination Survey (NHANES) 2001-2010. Phenotypic age was calculated using a formula and subtracted from the chronological age to determine the aging. When the phenotypic age exceeded the chronological age, it was considered as aging. A weighted logistic regression model was employed to explore the relationship between CDAI and aging. Restricted cubic splines (RCSs) were used to examine the potential nonlinear relationship between them. Subgroup analysis and joint analysis were conducted to explore the effect of modifiers in these relationships. RESULTS: A total of 19,212 participants (weighted: 165,285,442 individuals) were included in this study. The weighted logistic regression model showed a significant correlation between CDAI and the risk of aging (OR = 0.90, 95% CI: 0.84-0.96). RCS analysis revealed an L-shaped dose-response relationship between CDAI and the risk of aging. Subgroup analysis indicated that the association between CDAI and aging was more pronounced in middle-aged individuals and non-smokers. The joint analysis demonstrated that although smoking accelerated aging among participants, a high CDAI diet could still offset these damages. CONCLUSIONS: The association between high CDAI and reduced risk of aging is particularly significant in young and middle-aged individuals and non-smokers. Consuming foods rich in CDAI components may potentially lower the risk of aging.

Isorhamnetin as a novel inhibitor of pneumolysin against Streptococcus pneumoniae infection in vivo/in vitro.

The increasing incidence of Streptococcus pneumoniae (S. pneumoniae) infection severely threatened the global public heath, causing a significant fatality in immunocompromised hosts. Notably, pneumolysin (PLY) as a pore-forming cytolysin plays a crucial role in the pathogenesis of pneumococcal pneumonia and lung injury. In this study, a natural flavonoid isorhamnetin was identified as a PLY inhibition to suppress PLY-induced hemolysis by engaging the predicted residues and attenuate cytolysin PLY-mediated A549 cells injury. Underlying mechanisms revealed that PLY inhibitor isorhamnetin further contributed to decrease the formation of bacterial biofilms without affecting the expression of PLY. In vivo S. pneumoniae infection confirmed that the pathological injury of lung tissue evoked by S. pneumoniae was ameliorated by isorhamnetin treatment. Collectively, these results presented that isorhamnetin could inhibit the biological activity of PLY, thus reducing the pathogenicity of S. pneumoniae. In summary, our study laid a foundation for the feasible anti-virulence strategy targeting PLY, and provided a promising PLY inhibitor for the treatment of S. pneumoniae infection.

Trends in research of exosomes associated with breast cancer over the past decade: a scientometric analysis.

Introduction: Breast cancer remains a significant global health challenge, accounting for 2.3 million new cases in 2020 and ranking as the most prevalent cancer by incidence and the fourth in cancer-related mortality worldwide. In China, breast cancer also rapidly increases incidence and burden. The research of exosomes in breast cancer has attracted more and more attention and has a rapid development. Recognizing the pivotal role of exosomes in breast cancer research, we have undertaken a comprehensive scientometric analysis of pertinent scholarly articles published over the past decade to elucidate the current research landscape for researchers. Methods: In this study, we gathered all pertinent publications from the Web of Science. Biblioshiny (a web interface for Bibliometrix), VOSviewer software, and CiteSpace software were used to analyze the information on publications, including global trends, countries, institutions, journals, authors, keywords, and citations. Results: A total of 1,239 articles and 625 review articles were retrieved. The annual global publication output has an increased trend in recent decades overall. China contributed the most articles. The publications of the USA had the most total link strength. Nanjing Medical University had the most total link strength. The most relevant source was the International Journal of Molecular Sciences. Tang JH contributed the most articles and had the highest H-index, G-index, and total link strength. The most cited document was "Tumor exosome integrins determine organotropic metastasis", with 2730 citations. The basic themes included "exosomes", "expression", "cells", "identification", "biomarkers", and "serum". The keyword "membrane vesicle" had the strongest bursts. The keywords "target", "biology", "suppressor cell", "molecular mechanism", "tumor progression", "inhibitor", and "model" appeared as prominent focal points in current research and active areas of exploration. Conclusion: Over the past decade, exosome research in breast cancer has undergone a discernible evolution, shifting from broader investigations of exosome roles to focused exploration of specific pathways relevant to breast cancer. Notably, the emphasis has extended to the clinical application of exosomes as biomarkers and potential therapeutic agents in breast cancer treatment.

NIR-triggered thermosensitive polymer brush coating modified intraocular lens for smart prevention of posterior capsular opacification.

Posterior capsule opacification (PCO) is the most common complication after cataract surgery. Drug-eluting intraocular lens (IOLs) is a promising concept of PCO treatment in modern cataract surgery. However, the large dose of drugs in IOL leads to uncontrollable and unpredictable drug release, which inevitably brings risks of overtreatment and ocular toxicity. Herein, a low-power NIR-triggered thermosensitive IOL named IDG@P(NIPAM-co-AA)-IOL is proposed to improve security and prevent PCO by synergetic controlled drug therapy and simultaneous photo-therapy. Thermosensitive polymer brushes Poly(N-isopropylacrylamide-co-Acrylic acid) (P(NIPAM-co-AA)) is prepared on IOL via surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization. Then, Doxorubicin (DOX) and Indocyanine green (ICG) co-loaded Gelatin NPs (IDG NPs) are loaded in P(NIPAM-co-AA) by temperature control. The IDG NPs perform in suit photodynamic & photothermal therapy (PTT&PDT), and the produced heat also provides a trigger for controllable drug therapy with a cascade effect. Such functional IOL shows excellent synergistic drug-phototherapy effect and NIR-triggered drug release behavior. And there is no obvious PCO occurrence in IDG@P(NIPAM-co-AA) IOL under NIR irradiation compared with control group. This proposed IDG@P(NIPAM-co-AA)-IOL serves as a promising platform that combines phototherapy and drug-therapy to enhance the therapeutic potential and medication safety for future clinical application of PCO treatment.

Dendritic cell type 3 arises from Ly6C+ monocyte-dendritic cell progenitors.

Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32+CD172a+ DC3, distinct from DC2, arising from Ly6C+ monocyte-DC progenitors (MDPs) through Lyz2+Ly6C+CD11c- pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7+Ly6C+CD11c+ pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.

B7-H3 specific CAR-T cells exhibit potent activity against prostate cancer.

B7-H3 is an attractive target for immunotherapy because of its high expression across multiple solid tumors, including prostate cancer, and restricted expression in normal tissues. Among various types of tumor immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematological tumors. However, the potency of CAR-T cell therapy in solid tumors is still limited. Here, we examined the expression of B7-H3 in prostate cancer tissues and cells and developed a second-generation CAR that specifically targets B7-H3 and CD28 as costimulatory receptor to explore its tumoricidal potential against prostate cancer in vitro and in vivo. The high expression of B7-H3 was detected on both the surface of PC3, DU145 and LNCaP cells and prostate cancer tissues. B7-H3 CAR-T cells efficiently controlled the growth of prostate cancer in an antigen-dependent manner in vitro and in vivo. Moreover, tumor cells could induce the proliferation of CAR-T cells and the release of high levels of cytokines of IFN-γ and TNF-α in vitro. Results demonstrated that B7-H3 is a potential target for prostate cancer therapy that supports the clinical development of B7-H3 specific CAR-T cells for prostate cancer.

Two clusters of systemic lupus erythematosus patients with muscle involvement in a Chinese cohort.

OBJECTIVES: This study aimed to depict the clinical features, including myositis specific or associated antibody (MSA/MAA) profile of systemic lupus erythematosus (SLE) patients with muscle involvement in a Chinese cohort. METHODS: We retrospectively studied a cohort of 1696 SLE inpatients and screened for concurrent myositis features from January 2013 to June 2021. Propensity score matching was applied to enroll controls without myositis features from our cohort. Demographic, clinical and laboratory variables were collected. MSA/MAA panels containing 16 autoantibodies (TIF1-γ, MDA5, NXP2, Mi-2α/ß, SAE1, Jo-1, PL-7, PL-12, EJ, OJ, SRP, HMGCR, cN-1A, PM-Scl75/100, Ku and Ro52) were tested by line-blotting assay. Binary logistic regression and K-means clustering were applied. RESULTS: Forty-one of 1696 (2.42%) SLE patients in our SLE inpatient cohort showed features of myositis. Binary logistic regression revealed that new-onset SLE (odds ratio [OR] = 4.77, 95% CI = 1.10-20.57), interstitial lung disease (ILD) (OR = 10.07, 95% CI = 1.65-61.51), positive anti-U1RNP antibody (OR = 4.38, 95% CI = 1.08-17.75), and Raynaud's phenomenon (OR = 7.94, 95% CI = 1.41-44.69) were associated with muscle involvement. Except for anti-Ro52 (50%), anti-Ku antibody (38.2%) was the next frequently detected MSA/MAA in the panel, followed by anti-NXP2 antibody (11.8%). It was noteworthy that multiple MSA/MAAs (≥2, excluding anti-Ro52) coexisted in 9 patients. Patients with myositis features were clustered into 2 subgroups. Cluster 1 was characterized by anti-Ku or anti-Ro52 with high SLE Disease Activity Index, whereas cluster 2 presented with anti-U1RNP, Raynaud's phenomenon and pulmonary arterial hypertension resembling mixed connective tissue disease. CONCLUSION: In our Chinese SLE inpatient cohort, muscle involvement was infrequent. Nevertheless, distinct features in these SLE patients deserve further study.

Regenerative cerium oxide nanozymes alleviate oxidative stress for efficient dry eye disease treatment.

Dry eye disease (DED) is the most common eye disease in ophthalmic consultation except for refractive errors. Therefore, an exploration of valid and alternative therapeutic interventions is essential to feed the urgent medical need. It has been demonstrated that oxidative stress causes multiple adverse effects in the pathogenesis of DED, thence alleviating oxidative stress is an effective therapeutic strategy for the DED treatment. Herein, we developed a cerium oxide nanozyme combined with branched poly(ethylene imine)-graft-poly(ethylene glycol) (bPEI-g-PEG). Owing to its stable hydrophilic chains on the surface reducing the cytotoxicity and loads of amines groups that be combined with cerium ions through coordination bonds, the modified nanozymes (referred to as CNP@bPEI-g-PEG) are water soluble and highly biocompatible. Meanwhile, due to its excellent antioxidant activity, CNP@bPEI-g-PEG nanozymes can mimic the activity of superoxide dismutase and catalase to scavenge intracellular reactive oxygen species (ROS). Experimental studies firmly demonstrated that the modified nanozymes were auto-regenerative and more active in scavenging excessive ROS and alleviating oxidative stress by cerium-element valence state recycling, recovering the morphology of corneal, conjunctival epithelium and the number of goblet cells. The advanced combination may offer a superior therapeutic strategy to deal with oxidative stress for effective treatment of DED.

Highly Chemoselective Synthesis of Purino[3,2-c]oxazoles via the Asymmetric Dearomative [3+2] Cycloaddition of Purines with Donor-Acceptor Oxiranes.

A Ni(II)/bisoxazoline-catalyzed asymmetric dearomative [3+2] cycloaddition of substituted purines with donor-acceptor oxiranes was developed. This reaction, which proceeds via highly chemoselective C-C bond cleavage of the oxiranes, accesses chiral purino[3,2-c]oxazole compounds (≤99% ee after enrichment via crystallization). The electronic effects of the purine ring determine the reactivity of the substrate. The general applicability of this method was illustrated by gram-scale synthesis, the diverse transformations of the product, and the promising biological activities of selected derivatives.

Major infections in newly diagnosed systemic lupus erythematosus: an inception cohort study.

OBJECTIVE: To evaluate the risk of major infections and the relationship between major infections and mortality in patients with newly diagnosed SLE. METHODS: A newly diagnosed (<3 months) hospitalised Systemic Lupus Inception Cohort (hSLIC) in our centre during 1 January 2013 and 1 November 2020 was established. All patients were followed up for at least 1 year or until death. Patient baseline characteristics were collected. Major infection events were recorded during follow-up, which were defined as microbiological/clinical-based diagnosis treated with intravenous antimicrobials. The cohort was further divided into a training set and a testing set. Independent predictors of major infections were identified using multivariable logistic regression analysis. Kaplan-Meier survival analyses were conducted. RESULTS: Among the 494 patients enrolled in the hSLIC cohort, there were 69 documented episodes of major infections during the first year of follow-up in 67 (14%) patients. The major infection events predominantly occurred within the first 4 months since enrolment (94%, 65/69) and were associated with all-cause mortality. After adjustments for glucocorticoid and immunosuppressant exposure, a prediction model based on SLE Disease Activity Index >10, peripheral lymphocyte count <0.8×109/L and serum creatinine >104 µmol/L was established to identify patients at low risk (3%-5%) or high risk (37%-39%) of major infections within the first 4 months. CONCLUSIONS: Newly onset active SLE is susceptible to major infections, which is probably due to underlying profound immune disturbance. Identifying high-risk patients using an appropriate prediction tool might lead to better tailored management and better outcome.