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Objectives: To identify the failure patterns and prognostic factors of nonmetastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era., Methods: Data on 847 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2012 and 2016 were retrospectively reviewed. Survival outcome, failure patterns and prognosis factors were analyzed., Results: The 5-year local relapse-free survival, nodal relapse-free survival, distant metastasis-free survival, disease-free survival, and overall survival rates were 94.3%, 95.3%, 84.8%, 76.5% and 85.7%, respectively. The major local recurrence sites were the nasopharynx (91.5%, 43/47) and skull base (68.1%, 32/47); 39 patients had in-field failures, four had marginal failures, and four had out-field failures. Level IIb (62.2%, 23/37) was the most frequent regional recurrence site, followed by IIa (35.1%, 13/37) and retropharyngeal region (32.4%, 12/37); 35 cases had in-field failure alone, one had out-field failure alone, and one had both in- and out-field failure. TNM stage was the most significant factor for prognosis prediction. 402 (47.5%) patients had acute adverse events of grade 3 or 4; leukopenia (31.5%) and mucositis (26.7%) was the most common hematological and non-hematological event, respectively. Late complications were slight or moderate damages; xerostomia (647/847, 76.4%) and hearing impairment (422/847, 49.8%) remained the most troublesome., Conclusion: NPC patients treated with IMRT obtained satisfactory survival outcomes. The key failure pattern was distant metastasis. The main pattern of local-regional failure was in-field failure. Screening high risk patients with distant metastases and optimizing radiotherapy targets should be studied., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Several recent studies have confirmed that intratumoural microorganisms can affect the occurrence and development of hepatocellular carcinoma (HCC); however, their role in tumor progression remains unclear. Hence, there is a need for further research on the role of intratumoural microorganisms in HCC., Aim: To investigate the changes in intratumoural microorganisms in HCC and the effect of Propionibacterium on HCC progression., Methods: HCC and normal liver tissue specimens were subjected to fluorescence in situ hybridization (FISH). After performing 16S rRNA sequencing on HCC and peritumoral tissues to analyze the differences between the two groups. Propionibacterium was cocultured with HCC cells in vitro . Changes in cell proliferation and migration capacity were evaluated. The expression of NF-κB pathway related proteins in tumor cells was compared. The orthotopic liver implantation model and the subcutaneous xenograft model were constructed. liver tissues and subcutaneous tumors were collected 2 weeks later., Results: FISH demonstrated the presence of microorganisms in HCC and normal liver tissues. 16S rRNA sequencing revealed an abundance of Lysobacter , Lachnospiraceae , Pseudomonas , and Lactobacillus in HCC tissues. The distribution and abundance of Propionibacterium showed differences between HCC and peritumoral tissues ( P < 0.05). In vitro studies demonstrated that Propionibacterium and its metabolite propionic acid (PA) inhibited the proliferation and migration of HCC cells ( P < 0.05). The expression of the proteins in NF-κB signaling pathway also decreased in HCC cells ( P < 0.05)., Conclusion: Microorganisms in HCC and normal liver tissues displayed significant disparities. The PA-producing bacterium Propionibacterium in HCC exerts an effect on the NF-κB pathway, thereby affecting the biological behavior of HCC., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Germline pathogenic mutation of the BRCA gene increases the prevalence of breast cancer. Reports on the benign variants of BRCA genes are limited. However, the definition of these variants might be altered with the accumulation of clinical evidence. Therefore, in the present study, we focused on benign single nucleotide polymorphisms (SNPs) of BRCA genes. Linkage disequilibrium was calculated from whole genome sequencing of the BRCA genes obtained from 500 healthy controls and 49 breast cancer patients. Sanger sequencing was used to confirm the mutation. The linkage disequilibrium was noted for seven and three SNPs in the BRCA1 and BRCA2 genes, respectively. Breast cancer with BRCA1/2 linkage disequilibrium was not correlated with a personal history of benign diseases or family history of cancer. Nevertheless, breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor-infiltrating lymphocytes and positive extensive intraductal components. The patients with BRCA1 linkage disequilibrium tended to have worse disease-specific survival. Cancers with BRCA2 linkage disequilibrium are associated with a lower ratio of grade III cancer. Moreover, patients with BRCA2 linkage disequilibrium tended to have better overall survival. In conclusion, linkage disequilibrium from benign SNPs of the BRCA genes potentially affects cancer characteristics., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This study investigates the formation of atmospheric molecular clusters containing ammonia (NH 3 , A), methylamine (CH 3 NH 2 , MA), or dimethylamine (CH 3 NHCH 3 , DMA) with nitric acid (HNO 3 , NA) using quantum mechanics. The Atmospheric Cluster Dynamic Code (ACDC) was employed to simulate the total evaporation rate, formation rate, and growth pathways of three types of clusters under dry and hydrated conditions. This study evaluates the enhancing potential of A/MA/DMA for NA-based new particle formation (NPF) at parts per trillion (ppt) levels. The results indicate that A/MA/DMA can enhance NA-based NPF at high nitric acid concentrations and low temperatures in the atmosphere. The enhancing potential of MA is weaker than that of DMA but stronger than that of A. Cluster growth predominantly follows the lowest free energy pathways on the acid-base grid, with the formation of initial acid-base dimers (NA)(A), (NA)(MA), and (NA)(DMA) being crucial. Hydration influences the evaporation rate and formation rate of clusters, especially for initial clusters. When the humidity is at 100%, the formation rate for NA-A, NA-MA, and NA-DMA clusters can increase by approximately 10 9 , 10 7 , and 10 4 -fold compared to the corresponding unhydrated clusters, respectively. These results highlight the significance of nitric acid nucleation in NPF events in low-temperature, high-humidity atmospheres, particularly in regions like China with significant automobile exhaust pollution.

Multicomponent radical tandem reactions have emerged as a crucial technique for synthesizing complex molecules in organic chemistry. In this study, we report a palladium-catalyzed four-component difluoroalkylative carbonylation of enynes and ethyl difluoroiodoacetate. This transformation proceeds through a multistep sequential reaction that introduces reactive difluoro and carbonyl groups while constructing the benzofuran skeleton. Moreover, a variety of valuable 2,3-disubstituted benzofuran derivatives were obtained in respectable yields with excellent functional group compatibility.

The Narasaka-Heck reaction is one of the most straightforward methods for constructing pyrroline derivatives. Herein, we report a novel nickel-catalyzed three-component carbonylation reaction, which cleverly realizes the continuous construction of C(sp 3 )-N bonds and C(sp 3 )-C(sp 2 ) bonds and effectively promotes the synthesis of acyl-substituted pyrroline derivatives. Furthermore, this strategy not only expands the conversion pathway of γ,δ-unsaturated oxime esters but also provides a new method for the synthesis of nitrogen-containing heterocyclic compounds.

Background: Platelet contains growth factors that enhance tissue repair mechanisms, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF-AA and -AB), and transforming growth factor (TGF)-β. Autologous platelet-rich plasma (PRP) has been shown to significantly improve the treatment of tendon injuries compared with hyaluronic acid and placebo. The topic of agreement between platelet concentrations and growth factors has been covered in some previous studies, but growth factor levels did not correlate well with platelet concentrations., Method: In this study, autologous PRP was prepared by concentrating platelets through a J6-MI centrifuge. The automatic hematology analyzer Sysmex XN-20 was used to analyze the platelet concentration in PRP, and the PRP growth factors were determined by ELISA, including PDGF, transforming growth factor- β1 (TGF-β1), and EGF. Statistical analysis was conducted on data from 107 patients who received autologous PRP using Pearson correlation analysis., Results: Pearson correlation analysis revealed PDGF, TGF, and EGF had a strong positive correlation with the platelet concentration of the final PRP product (r = 0.697, p < 0.0001; r = 0.488, p < 0.0001; r = 0.572, p < 0.0001, respectively) CONCLUSIONS: There was a strong positive correlation between the concentration of platelets in the final PRP product and the levels of PDGF-AB, TGF-β, and EGF. These results suggested straightforward and cost-effective growth factor tests can provide valuable information about platelet content in PRP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background : Hematopoietic stem cell transplantation (HSCT) is one of the mainstream treatments for patients with hematologic malignancies. The matching status of human leukocyte antigen (HLA) between the donor and recipient is highly related to the outcomes of HSCT. Haploidentical HSCT (haplo-HSCT) has emerged as a type of HSCT for patients who cannot find a fully HLA-matched donor. In this study, we investigated whether the single nucleotide polymorphisms (SNPs) of the HLA-related genes and the genes encoding co-stimulatory molecules located on the non-HLA region are related to the outcomes of haplo-HSCT. Methods : The genomic DNAs of 24 patients and their respective donors were isolated from the peripheral blood obtained before performing haplo-HSCT. A total of 75 SNPs of the HLA-related genes (HCP5, NOTCH4, HLA-DOA, LTA, HSPA1L, BAG6, RING1, TRIM27, and HLA-DOB) and the genes located in the non-HLA genes involved in co-stimulatory signaling (CTLA4, TNFSF4, CD28, and PDCD1) were selected to explore their relationship with the outcomes after haplo-HSCT, including graft-versus-host disease, survival status, and relapse. Results : Our data revealed that specific donor or patient SNPs, including rs79327197 of the HLA-DOA gene, rs107822 and rs213210 of the RING1 gene, rs2523676 of the HCP5 gene, rs5742909 of the CTLA4 gene, rs5839828 and rs36084323 of the PDCD1 gene, and rs1234314 of the TNFSF4 gene, were significantly related to the development of adverse outcomes post-haplo-HSCT. Conclusions : These SNPs may play important roles in post-transplant immune response that can be considered during the selection of suitable donors.

We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method proceeded by inserting a polythiourea into the C═S π-bond, intramolecular ring proton migration, and ring opening. Salient features of this strategy are mild reaction conditions, a novel product structure, excellent stereochemistry, and a good functional group tolerance. Furthermore, a series of density functional theory calculations were performed to gain insights into the transfer mechanism.

An efficient [3 + 2] cycloaddition reaction between in situ generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are demonstrated to be a new class of reaction partner for vinylsulfonium salts to conduct the [3 + 2] cycloaddition reaction. The process provides a concise and efficient method for the construction of pyrazole derivatives under mild reaction conditions with broad substrate scope, good product yields, and high regioselectivity.

The role of stressors, insect bites, and infections on disease relapse of ANCA vasculitis has yet to be entirely explored, with limited retrospective studies focused on disease onset from small participant cohorts. Our study analyzes longitudinal survey data from 2011-2022 to evaluate this perspective from a large ANCA vasculitis cohort. We collected surveys every three to six months to obtain information on self-reported psychological stressors and significant life events, insect bites, and infections throughout clinical disease. We defined cohorts as those who relapsed (Relapse Cohort) and controls as those who did not relapse (Remission Cohort) during the study period. Survey responses were retrospectively reviewed during a 15-month timeframe prior to relapse or during 15 months of remission and categorized by type of stress event, insect bite, and infections at every available 3-month interval. There were no significant differences in stress and insect bites between the relapse and remission cohorts. Patients who relapsed reported more frequent upper respiratory infections and other infections, such as those affecting the skin and eyes, but there were no significant differences in the incidence of pulmonary or urinary infections compared to the remission cohort. There was a significant difference in reported upper respiratory infections 9 to 15 months prior to the relapse date, indicating a remote history of infections as a potentially significant physical stressor that may contribute to disease relapse. More frequent patient-reported infections, specifically upper respiratory infections, may contribute to patient vulnerability to relapse. Counseling and close monitoring of patients after infectious symptoms could aid in earlier detection of disease flares. Future studies are essential to further understand the importance of distal risk factors and how they impact relapse., Competing Interests: VKD reports the following—consultancy: Amgen, Bayer, Forma Therapeutics, Merck, Novartis, and Travere; honoraria: UpToDate; and research funding. SLH reports honoraria from National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant reviewer and serving as a Veterans Affairs and American Society of Nephrology grant reviewer. RJF reports honoraria from other universities for presentations. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Collie, Chen, Hu, Blazek, Derebail, Wu, Jain, Orzechowski, Poulton, Henderson, Falk and Hogan.)

The interactions of the micro-mechanism of hydroxymethanesulfonic acid (HMSA) with the typical small organic molecule in atmospheric (X = methanol, formaldehyde, formic acid, methyl formate, dimethyl ether, acetone) has been investigated by density functional theory (DFT), quantum theory of atoms in molecules (QTAIM), Generalized Kohn-Sham Enery Decomposition Analysis (GKS-EDA) and the atmospheric clusters dynamic code (ACDC). The results of DFT show that the stable six- to eight-membered ring structures are easily formed in HMSA-X clusters. According to the topological analysis results of the AIM theory and the IRI method, a strong hydrogen bonding interaction is present in the complex. GKS-EDA results show that electrostatic energy is the main contributor to the interaction energy as it accounts for 51 %-55 % of the total attraction energy. The evaporation rates of HMSA-HMSA and HMSA-HCOOH clusters were much lower than those of the other HMSA complexes. In addition, the Gibbs energy of formation (ΔG) of HMSA-X dimers is investigated under atmosphere temperature T = 217-298 K and p = 0.19-1.0 atm, the ΔG decreased with decreasing of the atmosphere temperature and increased with the decrease of atmospheric pressure, indicating that the low temperature and high pressure may significantly facilitate to the formation of dimers., Competing Interests: Declaration of competing interest First of all, thank you very much for your busy schedule to view the submitted manuscripts. I confirm that this manuscript has not been submitted to some other journal. There are no financial conflicts to declare, I guarantee that the above statement is true, and I shall bear corresponding responsibilities arising from any violation of the statement therefrom. All data is provided in full in the results section of this paper. I guarantee that the above statement is true, and I shall bear corresponding responsibilities arising from any violation of the statement therefrom., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A novel three-component cyclization carbonylation reaction of iodoarene-tethered propargyl ethers with amine and CO is reported. This palladium-catalyzed cascade reaction undergoes a sequence of oxidative addition, unsaturated bond migration, carbonyl insertion, and nucleophilic attack to deliver the benzofuran skeleton. Both aromatic amines and aliphatic amines could proceed smoothly in this transformation under one atm of CO.

This study investigated the effects of modified Fangji Huangqi Decoction on the expression of proteins related to epithelial-mesenchymal transition(EMT) in a mouse model of unilateral ureteral obstruction( UUO) and in a rat renal tubular epithelial cell(NRK-52E) model of fibrosis induced by transforming growth factor β1(TGF-β1). It aims to decipher the molecular mechanism by which modified Fangji Huangqi Decoction alleviates renal interstitial fibrosis. C57/BL mice were subjected to UUO.After the surgery, the mice were treated with 0. 5-fold and 2-fold concentrations of modified Fangji Huangqi Decoction and fosinopril sodium(positive control) for 7 days. The interstitial collagen deposition in the kidney was assessed by Masson staining. Western blot and RT-qPCR were employed to determine the expression levels of TGF-β1, phosphorylated Smad2/3(p-Smad2/3), Smad2/3, Snail,epithelial cadherin(E-cadherin), alpha smooth muscle actin(α-SMA), and vimentin. The NRK-52E cell model induced by TGF-β1was treated with the serum samples collected from SD rats treated with different concentrations of modified Fangji Huangqi Decoction.The CCK-8 assay was employed to examine the effects of the serum samples on NRK-52E cell proliferation. The cell morphology in different groups was observed under a microscope. Furthermore, the modeled cells were treated with the serum containing 1-fold decoction. Western blot and RT-qPCR were then employed to measure the expression levels of p-Smad2/3, Smad2/3, Snail,E-cadherin, α-SMA, and vimentin in the cells. Under the same conditions, sh RNA was used to silence the Snail gene, and measurements were repeated before and after treatment with the serum containing 1-fold decoction. The results indicated that modified Fangji Huangqi Decoction alleviated the fibrotic injury in the mouse model of UUO and the fibrosis in the NRK-52E cell model. The treatment with the decoction down-regulated the protein and m RNA levels of EMT-related indicators including p-Smad2/3, α-SMA,Snail, and vimentin, while it up-regulated the expression of E-cadherin. After sh RNA silencing of the Snail gene, the protein and m RNA levels of E-cadherin, α-SMA, and vimentin showed no significant differences before and after treatment with the serum containing the decoction. The results suggest that modified Fangji Huangqi Decoction may alleviate renal interstitial fibrosis by inhibiting the TGF-β1/Smad/Snail signaling pathway and regulating the EMT process.

Background: Xanthomonas oryzae pv. oryzae (Xoo) is often considered one of the most destructive bacterial pathogens causing bacterial leaf blight (BLB), resulting in significant yield and cost losses in rice. In this study, a series of novel derivatives containing the isopropanolamine moiety linked to various substituted phenols and piperazines were designed, synthesized and screened., Results: Antibacterial activity results showed that most compounds had good inhibitory effects on Xoo, among which compound W2 (EC 50  = 2.74 μg mL -1 ) exhibited the most excellent inhibitory activity, and W2 also had a certain curative effect (35.89%) on rice compared to thiodiazole copper (TC) (21.57%). Scanning electron microscopy (SEM) results indicated that compound W2 could cause rupture of the Xoo cell membrane. Subsequently, proteomics and quantitative real-time polymerase chain reaction revealed that compound W2 affected the physiological processes of Xoo and may exert antibacterial activity by targeting the two-component system pathway. Interestingly, W2 upregulated Xoo's methyltransferase to impact on its pathogenicity., Conclusion: The present study offers a promising phenolic-piperazine-sopropanolamine compound as an innovative antibacterial strategy by specifically targeting the two-component system pathway and inducing upregulation of methyltransferase to effectively impact Xoo's pathogenicity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg -1 ·d -1 , ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

O -Acylhydroxylamine has been widely employed as an electrophilic amination reagent in transition-metal-catalyzed C-N coupling reactions, but its use as an electrophilic oxygen source has not been disclosed. Here, we report a Pd-catalyzed 1,2-oxyarylation of alkenes with O -acylhydroxylamines as an oxidant and an oxygen source for the first time. With simple amide as the monodentate directing group, this method features a broad substrate scope, good functional group tolerance, and mild conditions.

We introduce switchable chemoselectivity strategies based on the hydrazone phosphaketene intermediate to synthesize three classes of 1,2,4-diazaphosphol derivatives. First, the five-membered heterocyclic P and O anion intermediates acted as nucleophilic agents in the selective construction of C-P and C-O bonds. Second, the phosphinidene served as a phosphorus synthon, allowing for the formation of C-P and C-N bonds. Finally, a stepwise mechanism, supported by DFT calculations, was invoked to explain the reaction selectivity.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells., Competing Interests: Declaration of interests The authors disclose no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: This study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC)., Patients and Methods: This multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M-NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety., Results: A total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8-25.2) months. ORR was 26.1 % (95 %CI:10.2-48.4). The ORR were 44.4 % (95 %CI: 13.7-78.8) and 14.3 % (95 %CI:1.8-42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2-73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9-45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84-9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5-91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs., Conclusion: Cadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background and Aims: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF., Approach and Results: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF., Conclusions: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF., (Copyright © 2024 American Association for the Study of Liver Diseases.)

In recent years, the automatic machine for microbial identification and antibiotic susceptibility tests has been introduced into the microbiology laboratory of our hospital, but there are still many steps that need manual operation. The purpose of this study was to establish an auto-verification system for bacterial naming to improve the turnaround time (TAT) and reduce the burden on clinical laboratory technologists. After the basic interpretation of the gram staining results of microorganisms, the appearance of strain growth, etc., the 9 rules were formulated by the laboratory technologists specialized in microbiology for auto-verification of bacterial naming. The results showed that among 70,044 reports, the average pass rate of auto-verification was 68.2%, and the reason for the failure of auto-verification was further evaluated. It was found that the main causes reason the inconsistency between identification results and strain appearance rationality, the normal flora in the respiratory tract and urine that was identified, the identification limitation of the mass spectrometer, and so on. The average TAT for the preliminary report of bacterial naming was 35.2 h before, which was reduced to 31.9 h after auto-verification. In summary, after auto-verification, the laboratory could replace nearly 2/3 of manual verification and issuance of reports, reducing the daily workload of medical laboratory technologists by about 2 h. Moreover, the TAT on the preliminary identification report was reduced by 3.3 h on average, which could provide treatment evidence for clinicians in advance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ou, Chang, Chen, Chuang, Tsao, Wu, Kuo, You and Huang.)

Background: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors., Aim: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients., Methods: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA)., Results: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit., Conclusion: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Plant bacterial infections and plant viruses seriously affect the yield and quality of crops. Based on the various activities of tryptanthrin, a series of tryptanthrin analogues bearing F and piperazine moieties were designed, synthesized, and evaluated for their biological activities against three plant bacteria and tobacco mosaic virus (TMV)., Results: Bioassay results indicated that compounds 6a-6l displayed excellent antibacterial activities in vitro and 6a-6c and 6g exhibited better antiviral activities against TMV than commercial ribavirin. In particular, 6b showed the most effect on Xanthomonas oryzae pv. oryzae (Xoo) with a half-maximal effective concentration (EC 50 ) of 1.26 μg mL -1 , compared with the commercial pesticide bismerthiazol (BT; EC 50  = 34.3 μg mL -1 ) and thiodiazole copper (TC; EC 50  = 73.3 μg mL -1 ). Meanwhile, 6a also had the best antiviral activity at 500 μg mL -1 for curative, protection, and inactivation purposes, compared with ribavirin in vivo., Conclusion: Compound 6b could cause changes in bacterial morphology, induce the accumulation of reactive oxygen species, promote apoptosis of bacterial cells, inhibit the formation of biofilm, and block the growth of Xoo cells. Proteomic analysis revealed major differences in the bacterial secretory system pathways T2SS and T6SS, which inhibited membrane transport. Molecular docking revealed that 6a and 6g could interact with TMV coat protein preventing virus assembly. These results suggest that tryptanthrin analogues bearing F and piperazine moieties could be promising candidate agents for antibacterial and antiviral use in agricultural production. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Introduction: Autoimmune diseases result from the loss of immune tolerance, and they exhibit complex pathogenic mechanisms that remain challenging to effectively treat. It has been reported that the altered expression levels of co-stimulatory/inhibitory molecules will affect the level of T/B cell activation and lead to the loss of immune tolerance., Methods: In this study, we evaluated the gene polymorphisms of the ligand genes corresponding co-stimulatory system that were expressed on antigen-presenting cells (CD80, CD86, ICOSLG, and PDL1) from 60 systemic lupus erythematosus (SLE) patients and 60 healthy controls., Results: The results showed that rs16829984 and rs57271503 of the CD80 gene and rs4143815 of the PDL1 gene were associated with SLE, in which the G-allele of rs16829984 (p=0.022), the A-allele of rs57271503 (p=0.029), and the GG and GC genotype of rs4143815 (p=0.039) may be risk polymorphisms for SLE., Discussion: These SNPs are in the promoter and 3'UTR of the genes, so they may affect the transcription and translation activity of the genes, thereby regulating immune function and contributing to the development of SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Lin, Hsu and Yu.)

Rare-earth-doped silica-based composite glasses (Re-SCGs) are widely used as high-quality laser gain media in defense, aerospace, energy, power, and medical applications. The variable regional chemical environments of Re-SCGs can induce new photoluminescence properties of rare-earth ions but can cause the selective aggregation of rare-earth ions, limiting the application of Re-SCGs in the field of high-power lasers. Here, topological engineering is proposed to adjust the degree of cross-linking of phase-separation network chains in Re-SCGs. A combination of experimental and theoretical characterization techniques suggested that the selective aggregation of rare-earth ions originates from the formation of phase-separated structures in glasses. The decomposition of nanoscale phase separation structures to the sub-nanometer scale, enabled by incorporating Al 3+ ions, not only maintains the high luminescence efficiency of rare earth ions but also increases light transmittance and reduces light scattering. Furthermore, our investigation encompassed the exploration of the inhibitory mechanism of Al 3+ ions on phase-separation structures, as well as their influence on the spectral characteristics of Re-SCGs. This work provides a new design concept for composite glass materials doped with rare-earth ions and could broaden their application in the field of high-power lasers.

In the past decade, recombinant adeno-associated virus (rAAV) has gained increased attention as a prominent gene therapy technology to treat monogenetic diseases. One of the challenges in rAAV production is the enrichment of full rAAV particles containing the gene of interest (GOI) payload. By adjusting the mobile phase properties of anion-exchange chromatography (AEX), it was demonstrated that empty and full separation of rAAV was improved in monolith based preparative AEX chromatography. When compared to the baseline method using NaCl, the use of tetraethylammonium acetate (TEA-Ac) in the AEX mobile phase resulted in enhanced resolution from 0.75 to 1.23 between "Empty" and "Full" peaks by salt linear gradient elution, as well as increased the percentage of full rAAV particles from 20% to 36% and genome recovery from 59% to 62%. Furthermore, a dual wash plus step elution AEX method was developed. Wherein, the first wash step harnesses TEA-Ac to separate empty and full capsids, which is followed by a second wash step that ensures no TEA-Ac salt is carried over into AEX eluate. The resulting optimized AEX purification method has the potential to be adapted for manufacturing and purification processes involving various rAAV production platforms that experience empty and full rAAV separation challenges., (© 2023 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.)

Recombinant adeno-associated virus (rAAV) empty and full capsid separation has been a topic of interest in the rAAV gene therapy community for many years and the anion exchange chromatography (AEX) step has undergone various process optimizations to improve rAAV empty capsid separation, including AEX stationary phase, mobile phase, and process parameters. Here, we present a new AEX method that employs both weak partitioning chromatography (WPC) and multi-column chromatography (MCC) to achieve improved full rAAV percentage in the AEX pool. The WPC technology allows empty rAAV to be displaced by full rAAV during loading, while the MCC technology enables parallel column processing which further increases AEX step productivity. Our results show that, compared to baseline AEX batch chromatography, the AEX-WPC-MCC method demonstrated improvements in both AEX pool full rAAV percentage (∼ 20% increase) and rAAV genome recovery (∼ 20% increase). As a result, the productivity (full capsid generated per liter of AEX column per hour of processing time) of the AEX step increased by ∼34-fold from the baseline AEX batch run to the AEX-WPC-MCC run. It is foreseeable that this AEX-WPC-MCC method could find applications in large-scale rAAV manufacturing processes to improve AEX yield and reduce the cost of goods of rAAV manufacturing., (© 2023 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.)

Digital pathology allows computerized analysis of tumor ecosystem using whole slide images (WSIs). Here, we present single-cell morphological and topological profiling (sc-MTOP) to characterize tumor ecosystem by extracting the features of nuclear morphology and intercellular spatial relationship for individual cells. We construct a single-cell atlas comprising 410 million cells from 637 breast cancer WSIs and dissect the phenotypic diversity within tumor, inflammatory and stroma cells respectively. Spatially-resolved analysis identifies recurrent micro-ecological modules representing locoregional multicellular structures and reveals four breast cancer ecotypes correlating with distinct molecular features and patient prognosis. Further analysis with multiomics data uncovers clinically relevant ecosystem features. High abundance of locally-aggregated inflammatory cells indicates immune-activated tumor microenvironment and favorable immunotherapy response in triple-negative breast cancers. Morphological intratumor heterogeneity of tumor nuclei correlates with cell cycle pathway activation and CDK inhibitors responsiveness in hormone receptor-positive cases. sc-MTOP enables using WSIs to characterize tumor ecosystems at the single-cell level., (© 2023. Springer Nature Limited.)

Di- and multinuclear hafnium complexes bridged by ligands have been rarely reported. In this article, a novel 3,5-disubstituted pyrazolate-bridged ligand LH 5 with two [N 2 N] 2- -type chelating side arms was designed and synthesized, which supported a series of dinuclear hafnium complexes. Dinuclear hafnium azides [LHf 2 (μ-1,1-N 3 ) 2 (N 3 ) 2 ][Na(THF) 4 ] 3 and [LHf 2 (μ-1,1-N 3 ) 2 (N 3 ) 2 ][Na(2,2,2-Kryptofix)] 4 were further synthesized and structurally characterized, featuring two sets of terminal and bridging azido ligands like jellyfishes. The reactivity of 3 under reduction conditions was conducted, leading to a formation of a tetranuclear hafnium imido complex [L 1 Hf 2 (μ 1 -NH)(N 3 ){μ 2 -K}] 2 5. DFT calculations revealed that the mixed imido azide 5 was generated via an intramolecular C-H insertion from a putative dinuclear Hf IV -nitridyl intermediate., (© 2023 Wiley-VCH GmbH.)

The screening procedure for antibodies is considered the most tedious among the three pretransfusion operations, i.e., ABO and Rhesus (Rh) typing, irregular antibody screening/identification, and crossmatching tests. The commonly used screening method for irregular antibodies in clinics at present is a manual polybrene test (MP). The MP test involves numerous reagent replacement and centrifuge procedures, and the sample volume is expected to be relatively less. Herein, screening red blood cells (RBCs) and serum irregular antibodies are encapsulated in microdroplets with a diameter of ~300 μm for a hemagglutination reaction. Owing to the advantage of spatial limitation in microdroplets, screening RBCs and irregular antibodies can be directly agglutinated, thereby eliminating the need for centrifugation and the addition of reagents to promote agglutination, as required by the MP method. Furthermore, the results for a large number of repeated tests can be concurrently obtained, further simplifying the steps of irregular antibody screening and increasing accuracy. Eight irregular antibodies are screened using the proposed platform, and the results are consistent with the MP method. Moreover, the volume of blood samples and antibodies can be reduced to 10 μL and 5 μL, respectively, which is ten times less than that using the MP method.

In clinical practice, it is found that autoimmune thyroid disease often additionally occurs with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In addition, several studies showed that eye-specific autoimmune diseases may have a strong relationship with systemic autoimmune diseases. We focused on Graves' disease (GD) with ocular conditions, also known as Graves' ophthalmopathy (GO), trying to find out the potential genetic background related to GO, RA, and SLE. There were 40 GO cases and 40 healthy controls enrolled in this study. The association between single-nucleotide polymorphisms (SNPs) of the co-stimulatory molecule genes and GO was analyzed using a chi-square test. It showed that rs11571315, rs733618, rs4553808, rs11571316, rs16840252, and rs11571319 of CTLA4 , rs3181098 of CD28 , rs36084323 and rs10204525 of PDCD1 , and rs11889352 and rs4675379 of ICOS were significantly associated with GO based on genotype analysis and/or allele analysis ( p < 0.05). After summarizing the GO data and the previously published SLE and RA data, it was found that rs11571315, rs733618, rs4553808, rs16840252, rs11571319, and rs36084323 were shared in these three diseases. Furthermore, the bio-function was confirmed by dual-luciferase reporter assay. It was shown that rs733618 T > C and rs4553808 A > G significantly decreased the transcriptional activity (both p < 0.001). This study is the first to confirm that these three diseases share genetically predisposing factors, and our results support the proposal that rs733618 T > C and rs4553808 A > G have bio-functional effects on the transcriptional activity of the CTLA4 gene.

Background: The second-and third-generation drug-eluting stents (DESs) in-stent restenosis (ISR) genetic risk score (GRS) model has been previously validated. However, the model has not been validated in geriatric patients. Therefore, we conducted this study to test the feasibility of the DES-ISR GRS model in geriatric patients with coronary artery disease (CAD) in Taiwan., Methods: We conducted a retrospective, single-center cohort study and included geriatric patients (age ≥ 65 years) with CAD and second-or third-generation DES(s) deployment. Patients undergoing maintenance dialysis were excluded. ISR was defined as ≥ 50% luminal narrowing on the follow-up coronary arteriography. The DES-ISR GRS model included five selected exonic single-nucleotide polymorphisms (SNPs): CAMLG, GALNT2, C11orf84, THOC5, and SAMD11. The GRS was defined as the sum of the five selected SNPs for the risk allele., Results: We enrolled 298 geriatric patients from January 2010 and December 2019 in this study. After propensity score matching, there were 192 geriatric patients with CAD in the final analysis, of which 32 patients had ISR. Patients were divided into two groups based on their GRS values: low (0-2) and high (≥ 3) GRS. A high GRS was significantly associated with DES-ISR in geriatric patients., Conclusion: Those geriatric patients with a high GRS had significantly higher second-or third-generation DES ISR rates. The five SNP-derived DES-ISR GRS model could provide genetic information for interventional cardiologists to treat geriatric patients with CAD., Trial Registration: The primary study protocol was registered with clinicaltrials.org. with registration number: NCT03877614; on March 15, 2019. ( http://clinicaltrials.gov/ct2/show/NCT03877614 )., (© 2023. The Author(s).)

The purpose of this study was to investigate the effect of notoginsenoside R&#95;1(NGR&#95;1) on alleviating kidney injury by regulating renal oxidative stress and the Nrf2/HO-1 signaling pathway in mice with IgA nephropathy(IgAN) and its mechanism. The mouse model of IgAN was established using a variety of techniques, including continuous bovine serum albumin(BSA) gavage, subcutaneous injections of carbon tetrachloride(CCl&#95;4) castor oil, and tail vein injections of lipopolysaccharide(LPS). After successful modeling, mice with IgAN were randomly separated into a model group, low, medium, and high-dose NGR&#95;1 groups, and a losartan group, and C57BL6 mice were utilized as normal controls. The model and normal groups were given phosphate buffered saline(PBS) by gavage, the NGR&#95;1 groups were given varying dosages of NGR&#95;1 by gavage, and the losartan group was given losartan by gavage for 4 weeks. The 24-hour urine of mice was collected after the last administration, and serum and kidney tissues of mice were taken at the end of the animal experiment. Then urine red blood cell count(URBCC), 24-hour urine protein(24 h protein), serum creatinine(Scr), and blood urea nitrogen(BUN) levels were measured. The enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of galactose-deficient IgA1(Gd-IgA1), kidney injury molecule 1(Kim-1), and neutropil gelatinase-associated lipocalin(NGAL) in the mouse serum. The assay kits were used to detect the levels of malondialdehyde(MDA) and superoxide dismutase(SOD), and immunofluorescence(IF) was used to detect the expression level of glutathione peroxidase 4(GPX4) in the mesangial region. Western blot was used to detect the protein expression of nuclear transcription factor E2 related factor 2(Nrf2)/heme oxygenase 1(HO-1) signaling pathway in the renal tissue. Hematoxylin-eosin(HE) staining was used to observe pathological alterations in the glomerulus of mice. The results revealed that, as compared with the model group, the serum Gd-IgA1 level, URBCC, 24 h protein level, renal damage markers(Kim-1 and NGAL) in the high-dose NGR&#95;1 group decreased obviously and renal function indicators(BUN, Scr) improved significantly. The activity of SOD activity and expression level of GPX4 increased significantly in the high-dose NGR&#95;1 group, whereas the expression level of MDA reduced and protein expression levels of Nrf2 and HO-1 increased. Simultaneously, HE staining of the renal tissue indicated that glomerular damage was greatly decreased in the high-dose NGR&#95;1 group. In conclusion, this study has clarified that NGR&#95;1 may alleviate the kidney injury of mice with IgAN by activating the Nrf2/HO-1 signaling pathway, improving antioxidant capacity, and reducing the level of renal oxidative stress.

Background: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma., Methods: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m 2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m 2 intravenously on days 1 and 8) and cisplatin (80 mg/m 2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m 2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m 2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up., Findings: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths., Interpretation: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio., Funding: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The human leukocyte antigen (HLA) has been linked to the majority of autoimmune diseases (ADs). However, non-HLA genes may be risk factors for ADs. A number of genes encoding proteins involved in regulating T-cell and B-cell function have been identified as rheumatoid arthritis (RA) susceptibility genes., Methods: In this study, we investigated the association between RA and single-nucleotide polymorphisms (SNPs) of co-stimulatory or co-inhibitory molecules in 124 RA cases and 100 healthy controls without immune-related diseases [including tumor necrosis factor superfamily member 4 (TNFSF4), CD28, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and programmed cell death protein 1 (PDCD1)]., Results: The results showed that there were 13 SNPs associated with RA, including rs181758110 of TNFSF4 (CC vs. CT, p = 0.038); rs3181096 of CD28 (TT vs. CC + CT, p = 0.035; CC vs. TT, p = 0.047); rs11571315 (TT vs. CT, p = 0.045), rs733618 (CC vs. TT + CT, p = 0.043), rs4553808 (AA vs. AG vs. GG, p = 0.035), rs11571316 (GG vs. AG vs. AA, p = 0.048; GG vs. AG + AA, p = 0.026; GG vs. AG, p = 0.014), rs16840252 (CC vs. CT vs. TT, p = 0.007; CC vs. CT, p = 0.011), rs5742909 (CC vs. CT vs. TT, p = 0.040), and rs11571319 of CTLA4 (GG vs. AG vs. AA, p < 0.001; GG vs. AG + AA, p = 0.048; AA vs. GG + AG, p = 0.001; GG vs. AA, p = 0.008; GG vs. AG, p ≤ 0.001); and rs10204525 (TT vs. CT + CC, p = 0.024; TT vs. CT, p = 0.021), rs2227982 (AA vs. GG, p = 0.047), rs36084323 (TT vs. CT vs. CC, p = 0.022; TT vs. CT + CC, p = 0.013; CC vs. TT + CT, p = 0.048; TT vs. CC, p = 0.008), and rs5839828 of PDCD1 (DEL vs. DEL/G vs. GG, p = 0.014; DEL vs. DEL/G + GG, p = 0.014; GG vs. DEL + DEL/G, p = 0.025; DEL vs. GG, p = 0.007)., Discussion: Consequently, these SNPs may play an important role in immune regulation, and further research into the role of these SNPs of immune regulatory genes in the pathogenesis of RA is required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Wen, Lin, Hsu and Yu.)

Rationale & Objective: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response., Study Design: Prospective, multicenter, observational study., Study Participants: CureGN participants with proven MCD on biopsy., Exposure: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period., Outcome: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure., Analytical Approach: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission., Results: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002)., Limitations: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy., Conclusions: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response., Plain-Language Summary: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We report a highly regioselective three-component coupling reaction of styrene, CO gas, and an amine compound to synthesize multisubstituted α,β-unsaturated amides, which involves a palladium-catalyzed sequential 1,4-palladium migration, C(sp 2 )-H activation, carbonylation, and amination. Salient features of this strategy include the use of 1 atm of CO, excellent stereochemistry, and good functional group tolerance. Further, a series of control experiments and density functional theory calculations were performed to afford some insights for the transfer mechanism.

A growing number of studies showed that single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA)-related genes were associated with the outcome of hematopoietic stem cell transplantation (HSCT). Thus, other SNPs located nearby the classical HLA genes must be considered in HSCT. We evaluated the clinical feasibility of MassARRAY by comparing to Sanger sequencing. The PCR amplicons with each one of the 17 loci that were related to the outcomes of HSCT published by our previous study were transferred onto a SpectroCHIP Array for genotyping by mass spectrometry. The sensitivity of MassARRAY was 97.9% (614/627) and the specificity was 100% (1281/1281), where the positive predictive value (PPV) was 100% (614/614) and the negative predictive value (NPV) was 99.0% (1281/1294). MassARRAY is high-throughput, which can accurately analyze multiple SNPs at the same time. Based on these properties, we proposed that it could be an efficient method to match the genotype between the graft and the recipient before transplantation., (© 2023. The Author(s).)

A novel and efficient method for the catalytic installation of a carbonyl group via remote radical coupling is disclosed. The nickel-catalyzed reaction proceeds to undergo a sequential single-electron transfer, 1,5-hydrogen atom transfer, and carbonyl insertion, thus providing the α-substituted ketone. Further, this reaction could be carried out smoothly under normal pressure and redox-neutral conditions, and demonstrated functional-group compatibility and excellent site-selectivity.

A series of 1,4-naphthoquinone derivatives containing were synthesized as anti-cancer agents and the crystal structure of compound 5a was confirmed by X-ray diffraction. In addition, the inhibitory activities against four cancer cell lines (HepG2, A549, K562, and PC-3) were tested, respectively, and compound 5i showed significant cytotoxicity on the A549 cell line with the IC 50 of 6.15 μM. Surprisingly, in the following preliminary biological experiments, we found that compound 5i induced autophagy by promoting the recycling of EGFR and signal transduction in the A549 cell, resulting in the activation of the EGFR signal pathway. The potential binding pattern between compound 5i and EGFR tyrosine kinase (PDB ID: 1M17) was also identified by molecular docking. Our research paves the way for further studies and the development of novel and powerful anti-cancer drugs.