The influence of modified Qing E Formula on the differential expression of serum exosomal miRNAs in postmenopausal osteoporosis patients.

Objective: Although guidelines support the efficacy of Modified Qing' E Formula (MQEF) in treating postmenopausal osteoporosis (PMOP), its underlying mechanisms remain incompletely understood. This retrospective investigation aims to elucidate MQEF's impact on serum exosomal miRNA expression in postmenopausal osteoporosis patients and to explore potential therapeutic mechanisms. Methods: Following ethical approval and registration, postmenopausal osteoporosis patients aged 50-85 years, meeting the diagnostic criteria were randomly selected and received MQEF decoction supplementary therapy. Serum samples were collected pre- and post-treatment, followed by isolation and sequencing of exosomal miRNAs. Differential miRNAs in serum exosomes were identified, and bioinformatics analysis was conducted to discern the principal exosomal miRNAs involved in MQEF's effects on PMOP and the associated signaling pathways. Results: Eighteen clinical blood samples were collected. A total of 282,185 target genes were detected across the three groups. 306 miRNAs exhibited altered expression in serum exosomes of PMOP patients, while MQEF intervention resulted in changes in 328 miRNAs. GO enrichment analysis revealed the immune and endocrine systems was pertained. KEGG enrichment analysis indicated associations between PMOP occurrence and MQEF treatment with cytokine interactions, oxidative phosphorylation, and the renin-angiotensin system. Intersectional analysis identified 17 miRNAs, including 2 consistent trends. miR-3188 as a potentially pivotal miRNA implicated in both PMOP occurrence and MQEF treatment. Conclusion: This study constitutes the first randomized, retrospective clinical exploration confirming that MQEF demonstrates regulatory influence over exosomal miRNA expression in PMOP patients' serum, its impact likely involves modulation of the immune and endocrine systems, as well as the renin-angiotensin system.

Engineered nanoparticles for precise targeted drug delivery and enhanced therapeutic efficacy in cancer immunotherapy.

The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system. However, the challenge of practical and precise targeting of malignant cells persists. To address this, engineered nanoparticles (NPs) have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions, owing to their small size, low immunogenicity, and ease of surface modification. This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy, encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness. Moreover, it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities. Finally, the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy, which could shape the path for future advancements in this promising field.

Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration.

BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

PACAP ameliorates obesity-induced insulin resistance through FAIM/Rictor/AKT axis.

Obesity and obesity-related insulin resistance have been a research hotspot. Pituitary adenylate cyclase activating polypeptide (PACAP) has emerged as playing a significant role in energy metabolism, holding promising potential for attenuating insulin resistance. However, the precise mechanism is not fully understood. Palmitic acid and a high-fat diet (HFD) were used to establish insulin resistance model in Alpha mouse liver 12 cell line and C57BL/6 mice, respectively. Subsequently, we assessed the effects of PACAP both in vivo and in vitro. Lentivirus vectors were used to explore the signaling pathway through which PACAP may ameliorate insulin resistance. PACAP was found to selectively bind to the PACAP type I receptor receptor and ameliorate insulin resistance, which was characterized by increased glycogen synthesis and the suppression of gluconeogenesis in the insulin-resistant cell model and HFD-fed mice. These effects were linked to the activation of the Fas apoptotic inhibitory molecule/rapamycin-insensitive companion of mammalian target of rapamycin/RAC-alpha serine/threonine-protein kinase (FAIM/Rictor/AKT) axis. Furthermore, PACAP ameliorated insulin resistance by increasing solute carrier family 2, facilitated glucose transporter members 2/4 and inhibiting gluconeogenesis-related proteins glucose 6-phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 2 expression. Meanwhile, the phosphorylation of hepatic AKT/glycogen synthase kinase 3ß was promoted both in vivo and in vitro by PACAP. Additionally, PACAP treatment decreased body weight, food intake and blood glucose levels in obese mice. Our study shows that PACAP ameliorated insulin resistance through the FAIM/Rictor/AKT axis, presenting it as a promising drug candidate for the treatment of obesity-related insulin resistance.

Associations between teacher-parent relationships and preschool children's social behavior problems-the chain mediating roles of work-family conflict and parenting self-efficacy.

In the Chinese cultural context, the collaborative interaction characteristics among three key entities - families, kindergartens, and communities - and the mechanisms of their correlation with preschool children's social behavior problems have not been fully understood yet. Based on ecological systems Theory and social support theory, this study aimed to examine the correlation between parent-teacher relationships and preschool children's social behavior problems in Chinese kindergartens, as well as the mediating role of parents' work-family conflict and parenting self-efficacy. Structural equation modeling was used to test the research hypotheses based on a questionnaire survey of 1,784 parents of preschool children. The main findings of this study are as follows: (1) Parents' perceived positive parent-teacher relationships are negatively correlated with preschool children's social problems. (2) Parents' work-family conflict and parenting self-efficacy mediate the relationship between parent-teacher relationships and preschool children's social behavior problems; (3) Parents' work-family conflict and parenting self-efficacy play a chain mediating role in the influence of the parent-teacher relationship on preschool children's social behavior problems. Taken together, the results collectively further elucidate the correlation between parent-teacher relationships and preschool children's social behavior problems, while also discussing other relevant factors pertaining to children's social behavior problems. Theoretically, this study expands the understanding of how external environmental resources interact with home and family education. Practically, this research indicates that governments, early childhood education institutions, and workplaces need to strengthen their support for family education of preschool children. The findings contribute to promoting a multi-faceted co-operation aimed at enhancing the quality of early childhood education and fostering the social adaptability and holistic development of preschool children.

Comparative genomics of Tn6411 transposons carrying the blaIMP-1 gene in Pseudomonas aeruginosa.

We aimed to determine the molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa strains 18081308 and 18083286, which were isolated from the urine and the sputum of two Chinese patients, respectively. Additionally, we conducted a comparative analysis between Tn6411 carrying blaIMP-1 in strain 18083286 and transposons from the same family available in GenBank. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired drug resistance genes of these strains were identified. The carbapenem-resistant P. aeruginosa strains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same resistance genes (aacC2, tmrB, and blaIMP-1). Tn6411, a Tn7-like transposon carrying blaIMP-1, was found in strain 18083286 by single molecule real time (SMRT) sequencing. We also identified the presence of this transposon sequence in other chromosomes of P. aeruginosa and plasmids carried by Acinetobacter spp. in GenBank, indicating the necessity for heightening attention to the potential transferability of this transposon.

First-line serplulimab in metastatic colorectal cancer: Phase 2 results of a randomized, double-blind, phase 2/3 trial.

BACKGROUND: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING: This work was funded by Shanghai Henlius Biotech, Inc.

An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFß Signaling.

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFß/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

Causal association of circulating cytokines with sarcopenia-related traits: A Mendelian randomization study.

BACKGROUND: Observational studies have reported that circulating cytokines are associated with sarcopenia. However, the causal relationship between circulating cytokines and sarcopenia has not been elucidated. OBJECTIVES: This study aimed to investigate the causal relationship between circulating cytokines and sarcopenia with genetic data using Mendelian randomization (MR). METHODS: Two-sample bidirectional MR analysis was performed to investigate the causal relationship in individuals of European ancestry. The publicly available genome-wide association study statistics were used to select the key eligible single nucleotide polymorphisms significantly associated with circulating cytokines. Multiple MR analysis approaches, including inverse variance weighted (IVW), MR-Egger, weighted median method (WMM), and MR-Pleiotropy residual Sum and Outlier (MR-PRESSO) methods, were used for the analysis. Sarcopenia-related traits were appendicular lean mass (ALM) and grip strength. RESULTS: This study demonstrated the causal effect of genetically predicted circulating interleukin interleukin-16 (IL16) levels on both ALM [odds ratio (OR) = 0.990, 95% confidence interval (CI): 0.980-1.000, P = 0.049] and grip strength (OR = 0.971, 95% CI: 0.948-0.995, P = 0.020]. Additionally, C-X-C motif chemokine ligand 10 (CXCL10), interleukin-1beta (IL1B), and hepatocyte growth factor (HGF) were correlated with ALM, while vascular endothelial growth factor (VEGF), interleukin-12 (IL12), and interleukin-15 (IL15) were correlated with grip strength. The results of MR-Egger, weighted median, weighted mode, and simple mode methods were consistent with the IVW estimates. Sensitivity analysis revealed that horizontal pleiotropy did not bias the causal estimates. CONCLUSION: These findings indicate that inflammatory cytokines exert a significant causal effect on sarcopenia and provide promising leads for the development of novel therapeutic targets for the disease. By evaluating the role of circulating cytokines in the pathologic condition via a genetic epidemiological approach, our study made contributions to a further investigation of underlying mechanisms of sarcopenia.

Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats.

Sinapic acid (SA) is renowned for its many pharmacological activities as a polyphenolic compound. The cause of polycystic ovary syndrome (PCOS), a commonly encountered array of metabolic and hormonal abnormalities in females, has yet to be determined. The present experiment was performed to evaluate the antifibrotic properties of SA in rats with letrozole-induced PCOS-related ovarian fibrosis. SA treatment successfully mitigated the changes induced by letrozole in body weight (BW) (p < .01) and relative ovary weight (p < .05). Histological observation revealed that SA reduced the number of atretic and cystic follicles (AFs) and (CFs) (p < .01), as well as ovarian fibrosis, in PCOS rats. Additionally, SA treatment impacted the serum levels of sex hormones in PCOS rats. Luteinizing hormone (LH) and testosterone (T) levels were decreased (p < .01, p < .05), and follicle-stimulating hormone (FSH) levels were increased (p < .05). SA administration also decreased triglyceride (TG) (p < .01) and total cholesterol (TC) levels (p < .05) and increased high-density lipoprotein cholesterol (HDL-C) levels (p < .01), thereby alleviating letrozole-induced metabolic dysfunction in PCOS rats. Furthermore, SA treatment targeted insulin resistance (IR) and increased the messenger RNA (mRNA) levels of antioxidant enzymes in the ovaries of PCOS rats. Finally, SA treatment enhanced the activity of peroxisome proliferator-activated receptor-γ (PPAR-γ), reduced the activation of transforming growth factor-ß1 (TGF-ß1)/Smads, and decreased collagen I, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF) levels in the ovaries of PCOS rats. These observations suggest that SA significantly ameliorates metabolic dysfunction and oxidative stress and ultimately reduces ovarian fibrosis in rats with letrozole-induced PCOS.

Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.

Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, a novel oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.

Vertically Integrated Monolithic Neuromorphic Nanowire Device for Physiological Information Processing.

This study demonstrates the conceptual design and fabrication of a vertically integrated monolithic (VIM) neuromorphic device. The device comprises an n-type SnO2 nanowire bottom channel connected by a shared gate to a p-type P3HT nanowire top channel. This architecture establishes two distinct neural pathways with different response behaviors. The device generates excitatory and inhibitory postsynaptic currents, mimicking the corelease mechanism of bilingual synapses. To enhance the signal processing efficiency, we employed a bipolar spike encoding strategy to convert fluctuating sensory signals to spike trains containing positive and negative pulses. Utilizing the neuromorphic platform for synaptic processing, physiological signals featuring bidirectional fluctuations, including electrocardiogram and breathing signals, can be classified with an accuracy of over 90%. The VIM device holds considerable promise as a solution for developing highly integrated neuromorphic hardware for healthcare and edge intelligence applications.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

One-step biofabrication of liquid core-GelMa shell microbeads for in situ hollow cell ball self-assembly.

There are many instances of hollow-structure morphogenesis in the development of tissues. Thus, the fabrication of hollow structures in a simple, high-throughput and homogeneous manner with proper natural biomaterial combination is valuable for developmental studies and tissue engineering, while it is a significant challenge in biofabrication field. We present a novel method for the fabrication of a hollow cell module using a coaxial co-flow capillary microfluidic device. Sacrificial gelatin laden with cells in the inner layer and GelMa in the outer layer are used via a coaxial co-flow capillary microfluidic device to produce homogenous micro-beads. The overall and core sizes of core-shell microbeads were well controlled. When using human vein vascular endothelial cells to demonstrate how cells line the inner surface of core-shell beads, as the core liquifies, a hollow cell ball with asymmetric features is fabricated. After release from the GelMa shell, individual cell balls are obtained and deformed cell balls can self-recover. This platform paves way for complex hollow tissue modeling in vitro, and further modulation of matrix stiffness, curvature and biochemical composition to mimic in vivo microenvironments.

Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy.

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8+ T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8+ T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8+ T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8+ T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8+ T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8+ T cell infiltration and improve ICI efficacy.

Sinapic Acid Attenuates Chronic DSS-Induced Intestinal Fibrosis in C57BL/6J Mice by Modulating NLRP3 Inflammasome Activation and the Autophagy Pathway.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that results from repeated inflammation and serious complications. Sinapic acid (SA) is a hydroxycinnamic acid present in a variety of plants that has antioxidant, anti-inflammatory, anticancer, and other protective effects. This study investigated the antifibrotic effect of SA on chronic colitis induced by dextran sulfate sodium salt (DSS) in mice. We observed that SA could significantly reduce clinical symptoms (such as improved body weight loss, increased colon length, and decreased disease activity index score) and pathological changes in mice with chronic colitis. SA supplementation has been demonstrated to repair intestinal mucosal barrier function and maintain epithelial homeostasis by inhibiting activation of the NLRP3 inflammasome and decreasing the expression of IL-6, TNF-α, IL-17A, IL-18, and IL-1ß. Furthermore, SA could induce the expression of antioxidant enzymes (Cat, Sod1, Sod2, Mgst1) by activating the Nrf2/keap1 pathway, thus improving antioxidant capacity. Additionally, SA could increase the protein expression of downstream LC3-II/LC3-I and Beclin1 and induce autophagy by regulating the AMPK-Akt/mTOR signaling pathway, thereby reducing the production of intestinal fibrosis-associated proteins Collagen-I and α-SMA. These findings suggest that SA can enhance intestinal antioxidant enzymes, reduce oxidative stress, expedite intestinal epithelial repair, and promote autophagy, thereby ameliorating DSS-induced colitis and intestinal fibrosis.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Synergistic Effects of In-Situ Exsolved Ni-Ru Bimetallic Catalyst on High-Performance and Durable Direct-Methane Solid Oxide Fuel Cells.

Direct-methane solid oxide fuel cells (CH4-SOFCs) have gained significant attention as methane, the primary component of natural gas (NG), is cheap and widely available and the natural gas infrastructures are relatively mature. However, at intermediate temperatures (e.g., 600-650 °C), current CH4-SOFCs suffer from low performance and poor durability under a low steam-to-carbon ratio (S/C ratio), which is ascribed to the Ni-based anode that is of low catalytic activity and prone to coking. Herein, with the guidance of density functional theory (DFT) studies, a highly active and coking tolerant steam methane reforming (SMR) catalyst, Sm-doped CeO2-supported Ni-Ru (SCNR), was developed. The synergy between Ni and Ru lowers the activation energy of the first C-H bond activation and promotes CHx decomposition. Additionally, Sm doping increases the oxygen vacancy concentration in CeO2, facilitating H2O adsorption and dissociation. The SCNR can therefore simultaneously activate both CH4 and H2O molecules while oxidizing the CH* and improving coking tolerance. We then applied SCNR as the CH4-SOFC anode catalytic reforming layer. A peak power density of 733 mW cm-2 was achieved at 650 °C, representing a 55% improvement compared to that of pristine CH4-SOFCs (473 mW cm-2). Moreover, long-term durability testing, with >2000 h continuous operation, was performed under almost dry methane (5% H2O). These results highlight that CH4-SOFCs with a SCNR catalytic layer can convert NG to electricity with high efficiency and resilience.

Copper Modulated Lead-Free Cs4 MnSb2 Cl12 Double Perovskite Microcrystals for Photocatalytic Reduction of CO2.

In order to deal with the global energy crisis and environmental problems, reducing carbon dioxide through artificial photosynthesis has become a hot topic. Lead halide perovskite is attracted people's attention because of its excellent photoelectric properties, but the toxicity and long-term instability prompt people to search for new photocatalysts. Herein, a series of <111> inorganic double perovskites Cs4 Mn1-x Cux Sb2 Cl12 microcrystals (x = 0, 0.1, 0.2, 0.3, 0.4, and 0.5) are synthesized and characterized. Among them, Cs4 Mn0.7 Cu0.3 Sb2 Cl12 microcrystals have the best photocatalytic performance, and the yields of CO and CH4 are 503.86 and 68.35 µmol g-1 , respectively, after 3 h irradiation, which are the highest among pure phase perovskites reported so far. In addition, in situ Fourier transform infrared (FT-IR) spectroscopy and electron spin resonance (ESR) spectroscopy are used to explore the mechanism of the photocatalytic reaction. The results highlight the potential of this class of materials for photocatalytic reduction reactions.