Mechanism of immune activation mediated by genomic instability and its implication in radiotherapy combined with immune checkpoint inhibitors.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

Self-assembled nanoparticles of costunolide and glycyrrhizic acid for enhanced ulcerative colitis treatment.

Ulcerative colitis (UC) is a persistent inflammatory condition that specifically targets the colon and rectum. Existing therapies fail to adequately address the clinical requirements of people suffering from this ailment. Despite the acknowledged potential of nanomedicines in the field of anti-inflammatory treatment, their widespread use in clinical settings is impeded by their expensive nature and the uncertainty surrounding their safety profiles. This study illustrates that two naturally occurring phytochemicals, Costunolide (COS) and Glycyrrhizic acid (GA), form carrier-free, multifunctional spherical nanoparticles (NPs) through noncovalent interactions, such as π-π stacking and hydrogen bonding. The COS-GA NPs displayed a synergistic anti-inflammatory effect, providing much more evidently improved therapeutic benefits for dextran sodium sulfate (DSS)-induced UC mice due to more effective reduction in inflammation and oxidative stress than did equal dosages of COS or GA used alone. In addition, COS-GA NPs have biocompatibility and biosafety properties unique to them. This study will serve as affirmation of the potential of COS-GA NPs as innovative natural anti-inflammatory and antioxidant activities and also such agents as drug discovery in UC, leading possibly to better outcomes in people living with this disabling condition.

Association of CD8+TILs co-expressing granzyme A and interferon-γ with colon cancer cells in the tumor microenvironment.

CD8+T cells secreting granzyme A (GZMA) can induce pyroptosis in tumor cells by effectively cleaving gasdermin B (GSDMB), which is stimulated by interferon-γ (IFN-γ). However, the interaction between GZMA-expressing CD8+T cells and GSDMB-expressing tumor cells in colon cancer remains poorly understood. Our research employed multi-color immunohistochemistry (mIHC) staining and integrated clinical data to explore the spatial distribution and clinical relevance of GZMA- and IFN-γ-expressing CD8+ tumor-infiltrating lymphocytes (TILs), as well as GSDMB-expressing CK+ cells, within the tumor microenvironment (TME) of human colon cancer samples. Additionally, we utilizing single-cell RNA sequencing (scRNA-seq) data to examine the functional dynamics and interactions among these cell populations. scRNA-seq analysis of colorectal cancer (CRC) tissues revealed that CD8+TILs co-expressed GZMA and IFN-γ, but not other cell types. Our mIHC staining results indicated that a significant reduction in the infiltration of GZMA+IFN-γ+CD8+TILs in colon cancer patients (P < 0.01). Functional analysis results indicated that GZMA+IFN-γ+CD8+TILs demonstrated enhanced activation and effector functions compared to other CD8+TIL subsets. Furthermore, GSDMB-expressing CK+ cells exhibited augmented immunogenicity. Correlation analysis highlighted a positive association between GSDMB+CK+ cells and GZMA+IFN-γ+CD8+TILs (r = 0.221, P = 0.033). Analysis of cell-cell interactions further showed that these interactions were mediated by IFN-γ and transforming growth factor-ß (TGF-ß), the co-stimulatory molecule ICOS, and immune checkpoint molecules TIGIT and TIM-3. These findings suggested that GZMA+IFN-γ+CD8+TILs modulating GSDMB-expressing tumor cells, significantly impacted the immune microenvironment and patients' prognosis in colon cancer. By elucidating these mechanisms, our present study aims to provide novel insights for the advancement of immunotherapeutic strategies in colon cancer.

[Regulatory effect of Tingli Dazao Xiefei Decoction on asthmatic rats by urine metabolomics].

Urine metabolomics based on ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS) was utilized to investigate the metabolic regulation mechanism of Tingli Dazao Xiefei Decoction(TLDZ) in rats with allergic asthma. SD male rats were divided into a normal group, a model group, a dexamethasone group, and a TLDZ group. The allergic asthma model was established by intraperitoneal injection of ovalbumin(OVA) to induce allergy, combined with atomization excitation. Urine metabolites from all rats were collected by UHPLC-Q-TOF-MS. The metabolic profiles of rats in each group were built by principal component analysis(PCA). Besides, the differential metabolites between the model group and the TLDZ group were selected by orthogonal partial least squares discriminant analysis(OPLS-DA), t-test(P<0.05), and variable importance in the projection(VIP) values of more than 3. The differential metabolites were identified through HMDB, METLIN, and other online databa-ses. Heat maps and clustering analysis for relative quantitative information of biomarkers in each group were drawn by MeV 4.8.0 software. Finally, MetaboAnalyst, MBRole, and KEGG databases were used to enrich related metabolic pathways and construct metabolic networks. The result demonstrated that TLDZ could effectively regulate the disordered urine metabolic profiles of asthmatic rats. Combined with multivariate statistical analysis and online databases, a total of 45 differential metabolites with significant changes(P<0.05) between the model group and the TLDZ group were screened out. Metabolic pathways including histidine metabolism, tryptophan metabolism, and arginine and proline metabolism were enriched. TLDZ could improve asthma by regulating related metabolic pathways and interfering with pathological processes such as immune homeostasis airway inflammation. The study investigates the molecular mechanism of anti-asthma of TLDZ from the perspective of urine metabolomics, and combined with previous pharmacological studies, it provides a scientific basis for the clinical development and application of TLDZ in the treatment of asthma.

[Exploration of cancer biological characteristics in people with different five movements and six climates constitution based on pan-cancer Bulk RNA-Seq].

According to the theory of five movements and six climates, the innate constitution plays a crucial role in determining the underlyingpa thological mechanisms of diseases later in life. Previous studies have demonstrated a close association between the constitution, as defined by the theory of five movements and six climates, and the development of various types of tumors. Furt hermore,the tumorsubtype determined by the constitution has prognostic implications. This highlights the potential of utilizing the fivemovements and six climates theory to guide the implementation of precision medicine strategies in thefield of oncology. However, no resear ch has yet been conducted to investigate the use of this theory in guiding the development of tumor molecular classification and precisi onmedicine strategies. The objective of this research is to uncover the biological characteristics of each constitution within a pancanc ercohort and identify potential anti-tumor drugs that are applicable to patients with different constitutional types. By doing so, we aimto c ontribute to the establishment of a precision medicine strategy for tumors derived from the original concepts of traditional Chi nesemedicine(TCM). In this study, we obtainedpan-cancer Bulk RNA-Seq data from UCSC Xena, GWAS cohort data from the UKBiobank, and cis-eQTLs data from eQ TLGen and GTEx V8. We employed machine learning methods to screen for hub genes associated with each constitution. Subsequently, we utilized informatics tools to explore the biological characteristics of each constitut iondefined by the theory of five movements and six bioclimates. Further, potential anti-tumor drugs suitable for patients with differen tconstitutional types were identified through mendelian randomization, molecular docking, and drug-like prediction techniques. Withinthe pan-cancer cohort, significant differences were observed among different constitutions in terms of progression-free interval, biological f unctions, immune cell abundance, tumor drug sensitivity, and immunotherapy response. These findings suggest that the five movements and six climates theory can guide tumor molecular classification and the development of precision medicine strategies. Moreover,the biological characteristics inherent to each constitution partially shed light on the scientific implications of Chinese medicinetheories, offering a fresh perspective towards clinical cancer treatment. Through molecular docking and drug-like prediction, several po tential anti-tumor drugs such as 17-beta-estradiol, serotonin, trans-resveratrol, and linoleic acid were identified. Overall, the util izationof multi-omics approaches pro vides a powerful tool to unravel the scientific foundations of TCM theories. The elucidation of themu lti-omics features associated witheach constitution in tumors serves as the basis for applying the five movements and six climates theoryto tumor molecular classification and the development of precision medicine strategies.

Illness uncertainty and dysphagia in Chinese oral cancer patients: the mediation effect of catastrophic cognition.

PURPOSE: Dysphagia, a serious symptom of oral cancer, is also the most common. Further, patients who are more uncertain regarding their illness tend to catastrophize, which may affect their rehabilitation and long-term survival rate. Considering this relationship, this study aimed to investigate the occurrence of dysphagia in Chinese patients with oral cancer and explore the correlation between catastrophic cognition, illness uncertainty, and dysphagia. METHODS: Applying a cross-sectional design, convenience sampling was used to recruit 180 patients with oral cancer. Advanced statistical methods were employed to analyze the mediating effects of catastrophic cognition on illness uncertainty and dysphagia. RESULTS: Chinese patients with oral cancer had a mean dysphagia score of 52.88 ± 10.95. Catastrophic cognition and illness uncertainty in patients with oral cancer were significantly positively correlated (r = 0.447, P < 0.001). There was a significant negative correlation between dysphagia score and catastrophic cognition (r = -0.385, P < 0.001), and between dysphagia and illness uncertainty (r = -0.522, P < 0.001). Bootstrapping results indicated that the mediating effect of catastrophic cognition between illness uncertainty and dysphagia was -0.07 (95% CI: [-0.15, -0.03]) and significant, and the mediation effect accounted for 15.6% of the total effect. CONCLUSIONS: Chinese patients with oral cancer have poor swallowing function. Results suggest that catastrophic cognition partially mediated the relationship between illness uncertainty and dysphagia in patients with oral cancer. Medical staff can improve patients' swallowing function by reducing the level of catastrophic cognition via decreasing the level of illness uncertainty.

The independent and combined effects of physical activity and depressive symptoms on frailty in community-dwelling older adults: A cross-sectional study.

AIMS: To investigate the independent and combined effects of physical activity (PA) and depressive symptoms on the risk of frailty in community-dwelling older adults. BACKGROUND: Older adults face a high risk of frailty which is commonly used to predict adverse health outcomes in older patients. Engaging in PA and without depressive symptoms are crucial factors to prevent frailty. It is essential to investigate the independent and combined effects of these two variables on the risk of frailty. METHODS: We included 3392 community-dwelling older adults. The FRAIL Scale was used to assess older adults' frail status (robust, prefrail and frail). Multiple logistic regression was utilized to examine the independent and combined effects of PA and depressive symptoms on the risk of prefrailty and frailty. The combined effects were visualized by marginal plots. RESULTS: The prevalence of prefrailty and frailty in older adults were 42.16% and 10.58%. Compared with the group of "Light physical activity and With depressive symptoms", "Vigorous physical activity and Without depressive symptoms" had the lowest risk of prefrailty and frailty. CONCLUSIONS: Older adults who do not engage in PA or have depressive symptoms increased the risk of frailty, but older adults with depressive symptoms could lower the risk of frailty through PA. RELEVANCE TO CLINICAL PRACTICE: It is effective to reduce the risk of frailty by directing older adults to do moderate physical activity, although they have depressive symptoms. The focus should also be on older adults with depressive symptoms, who have at least more than twice and fourfold risk of prefrailty and frailty compared to those without. IMPACT: This study offers insights for future interventions aimed at preventing frailty in older adults. REPORTING METHOD: This study adhered to the STROBE checklist. PATIENT OR PUBLIC CONTRIBUTIONS: Older adults participated in this study and completed questionnaires.

ScHGSC-IGDC: Identifying genes with differential correlations of high-grade serous ovarian cancer based on single-cell RNA sequencing analysis.

Due to the high heterogeneity of ovarian cancer (OC), it occupies the main cause of cancer-related death among women. As the most aggressive and frequent subtype of OC, high-grade serous cancer (HGSC) represents around 70 % of all patients. With the booming progress of single-cell RNA sequencing (scRNA-seq), unique and subtle changes among different cell states have been identified including novel risk genes and pathways. Here, our present study aims to identify differentially correlated core genes between normal and tumor status through HGSC scRNA-seq data analysis. R package high-dimension Weighted Gene Co-expression Network Analysis (hdWGCNA) was implemented for building gene interaction networks based on HGSC scRNA-seq data. DiffCorr was integrated for identifying differentially correlated genes between tumor and their adjacent normal counterparts. Software Cytoscape was implemented for constructing and visualizing biological networks. Real-time qPCR (RT-qPCR) was utilized to confirm expression pattern of new genes. We introduced ScHGSC-IGDC (Identifying Genes with Differential Correlations of HGSC based on scRNA-seq analysis), an in silico framework for identifying core genes in the development of HGSC. We detected thirty-four modules in the network. Scores of new genes with opposite correlations with others such as NDUFS5, TMSB4X, SERPINE2 and ITPR2 were identified. Further survival and literature validation emphasized their great values in the HGSC management. Meanwhile, RT-qPCR verified expression pattern of NDUFS5, TMSB4X, SERPINE2 and ITPR2 in human OC cell lines and tissues. Our research offered novel perspectives on the gene modulatory mechanisms from single cell resolution, guiding network based algorithms in cancer etiology field.

Targeted delivery of FAK siRNA by engineered exosomes to reverse cetuximab resistance via activating paraptosis in colon cancer.

BACKGROUND: Cetuximab is extensively used in the treatment of metastatic colorectal cancer (mCRC). However, resistance poses a significant challenge to successful therapy. Recently, paraptosis, a non-classical programmed cell death, has garnered increased attention for its potential application value in antitumor treatments. We aimed to identify the essential pathways and signaling molecules involved in paraptosis inhibition and select them as therapeutic targets in cetuximab resistance. Additionally, engineered exosome technology is used as a drug delivery system with both targeted and effector properties. RESULTS: By comparing the differential expression of paraptosis-related genes between drug-resistant colon cancer cells and sensitive cells, it was observed that the paraptosis level induced by cetuximab was significantly downregulated in drug-resistant cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified the focal adhesion kinase (FAK) signaling pathway as a key pathway involved in the suppression of paraptosis. The biological function of FAK in cetuximab-resistant cells was investigated through cell morphology observation, CCK-8 assay, colony formation assay, RT-qPCR, Western Blot, and loss-of-function experiments. The results showed that the FAK signaling pathway was significantly upregulated in cetuximab-resistant colon cancer cells, and siRNA interference targeting FAK could notably inhibit cell proliferation while upregulating the paraptosis level. Based on this, engineered colon cancer cells targeted and FAK siRNA loaded exosomes (CT-Exo-siFAK1) were constructed. In vitro experiments, CT-Exo-siFAK1 could effectively activate paraptosis and inhibit the proliferation of drug-resistant colon cancer cells. In vivo experiments also confirmed that CT-Exo-siFAK1 significantly suppressed tumor growth and metastasis while upregulating the paraptosis level. CONCLUSION: This study suggests that FAK signaling pathway-mediated inhibition of paraptosis levels is crucial in the sensitivity of cetuximab targeted therapy in colon cancer, and the use of engineered exosomes to deliver FAK siRNA may be an effective strategy to reverse cetuximab resistance.

A new flavonostilbene glycoside and four new stilbene derivatives from the roots of Polygonum multiflorum.

One new flavonostilbene glycoside, polygonflavanol C (1), two new dimeric stilbene glycosides, multiflorumiside M and multiflorumiside N (2-3), one new diphenyl ethanol glycoside, (R)-2,3,5,4'-tetrahydroxy-diphenylethanol 2-O-ß-D-glucopyranoside (4), and one new deoxybenzoin glycoside, 2,4,3',5'-tetrahydroxy-6-methyl-deoxybenzoin 2-O-ß-D-glucopyranoside (5), together with six known ones (6-11), were isolated from the roots of Polygonum multiflorum. Their structures were elucidated by the comprehensive spectroscopic analyses. In addition, compounds 1 and 7 showed significantly in vitro anti-inflammatory activity.

GeTeSEPdb: A comprehensive database and online tool for the identification and analysis of gene profiles with temporal-specific expression patterns.

Gene expression is dynamic and varies at different stages of processes. The identification of gene profiles with temporal-specific expression patterns can provide valuable insights into ongoing biological processes, such as the cell cycle, cell development, circadian rhythms, or responses to external stimuli such as drug treatments or viral infections. However, currently, no database defines, identifies or archives gene profiles with temporal-specific expression patterns. Here, using a high-throughput regression analysis approach, eight linear and nonlinear parametric models were fitted to gene expression profiles from time-series experiments to identify eight types of gene profiles with temporal-specific expression patterns. We curated 2684 time-series transcriptome datasets and identified 2644,370 gene profiles exhibiting temporal-specific expression patterns. The results were stored in the database GeTeSEPdb (gene profiles with temporal-specific expression patterns database, http://www.inbirg.com/GeTeSEPdb/). Moreover, we implemented an online tool to identify gene profiles with temporal-specific expression patterns from user-submitted data. In summary, GeTeSEPdb is a comprehensive web service that can be used to identify and analyse gene profiles with temporal-specific expression patterns. This approach facilitates the exploration of transcriptional changes and temporal patterns of responses. We firmly believe that GeTeSEPdb will become a valuable resource for biologists and bioinformaticians.

Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.

In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

GRA47 is important for the morphology and permeability of the parasitophorous vacuole in Toxoplasma gondii.

Establishing an intact intracellular parasitophorous vacuole (PV) that enables efficient nutrient uptake and protein trafficking is essential for the survival and proliferation of Toxoplasma gondii. Although the PV membrane (PVM)-localized dense granule protein 17 (GRA17) and GRA23 mediate the permeability of the PVM to small molecules, including nutrient uptake and excretion of metabolic by-products, the molecular mechanism by which T. gondii acquires nutrients remains unclear. In this study, we showed that the secreted protein GRA47 contributed to normal PV morphology, PVM permeability to small molecules, growth, and virulence in T. gondii. Co-immunoprecipitation analysis demonstrated potential interaction of GRA47 with GRA72, and the loss of GRA72 affected PV morphology, parasite growth and infectivity. To investigate the biological relationship among GRA47, GRA72, GRA17 and GRA23, attempts were made to construct strains with double gene deletion and overexpressing strains. Only Δgra23Δgra72 was successfully constructed. This strain exhibited a significant increase in the proportion of aberrant PVs compared with the Δgra23 strain. Overexpressing one of the three related GRAs partially rescued PVs with aberrant morphology in Δgra47, Δgra72 and Δgra17, while the expression of the Plasmodium falciparum PVM protein PfExp2, an ortholog of GRA17 and GRA23, fully rescued the PV morphological defect in all three Δgra strains. These results suggest that these GRA proteins may not be functionally redundant but rather work in different ways to regulate nutrient acquisition. These findings highlight the versatility of the nutrient uptake mechanisms in T. gondii, which may contribute to the parasite's remarkable ability to grow in different cellular niches in a very broad range of hosts.

The combined use of B vitamins and probiotics promotes B vitamin absorption and increases Akkermansia abundance.

B vitamins and probiotics are commonly used dietary supplements with well-documented health benefits. However, their potential interactions remain poorly understood. This study aims to explore the effects and underlying mechanisms of the combined use of B vitamins and probiotics by liquid chromatography-triple quadrupole mass spectrometry analysis, pharmacokinetic modeling, and 16S rRNA gene sequencing. By intragastric administration of seven B vitamins and three Lactobacillus strains to healthy rats (n = 8 per group), we found that probiotics significantly promoted the absorption (by approximately 14.5% to 71.2%) of vitamins B1, B3, B5, and B12. By conducting in vitro experiments (n = 3 per group) and a pseudo-germ-free rat model-based pharmacokinetic study (n = 6 per group), we confirmed that probiotics primarily enhanced the B vitamin absorption through gut microbiota-mediated mechanisms, rather than by directly producing B vitamins. Furthermore, we evaluated the effects of B vitamins and probiotics on the colon and gut microbiota by treating the pseudo-germ-free rats with blank solution, B vitamins, probiotics, and B vitamins + probiotics (n = 5 per group), respectively. Histopathological examination showed that the combination of B vitamins and probiotics synergistically alleviated the rat colon damage. High-throughput genetic sequencing also revealed the synergistic effect of B vitamins and probiotics in modulating the gut microbiota, particularly increasing the abundance of Verrucomicrobia and Akkermansia. In summary, the combined administration of B vitamins and probiotics may have a higher efficacy than using them alone.

Association between driving pressure-guided ventilation and postoperative pulmonary complications in surgical patients: a meta-analysis with trial sequential analysis.

BACKGROUND: Prior studies have reported inconsistent results regarding the association between driving pressure-guided ventilation and postoperative pulmonary complications (PPCs). We aimed to investigate whether driving pressure-guided ventilation is associated with a lower risk of PPCs. METHODS: We systematically searched electronic databases for RCTs comparing driving pressure-guided ventilation with conventional protective ventilation in adult surgical patients. The primary outcome was a composite of PPCs. Secondary outcomes were pneumonia, atelectasis, and acute respiratory distress syndrome (ARDS). Meta-analysis and subgroup analysis were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CI). Trial sequential analysis (TSA) was used to assess the conclusiveness of evidence. RESULTS: Thirteen RCTs with 3401 subjects were included. Driving pressure-guided ventilation was associated with a lower risk of PPCs (RR 0.70, 95% CI 0.56-0.87, P=0.001), as indicated by TSA. Subgroup analysis (P for interaction=0.04) found that the association was observed in non-cardiothoracic surgery (nine RCTs, 1038 subjects, RR 0.61, 95% CI 0.48-0.77, P< 0.0001), with TSA suggesting sufficient evidence and conclusive result; however, it did not reach significance in cardiothoracic surgery (four RCTs, 2363 subjects, RR 0.86, 95% CI 0.67-1.10, P=0.23), with TSA indicating insufficient evidence and inconclusive result. Similarly, a lower risk of pneumonia was found in non-cardiothoracic surgery but not in cardiothoracic surgery (P for interaction=0.046). No significant differences were found in atelectasis and ARDS between the two ventilation strategies. CONCLUSIONS: Driving pressure-guided ventilation was associated with a lower risk of postoperative pulmonary complications in non-cardiothoracic surgery but not in cardiothoracic surgery. SYSTEMATIC REVIEW PROTOCOL: INPLASY 202410068.

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.

Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

Bio-based melamine formaldehyde resins for flame-retardant polyurethane foams.

The polyurethane (PU) foams can be functionally tailored by modifying the formulation with different additives. One such additive is melamine (MA) formaldehyde resin for improving their flame-retardant properties. In this work, the glycerol-modified (GMF), sodium alginate (SGMF)- and lignosulfonate-modified melamine formaldehyde (LGMF) were prepared and used as flame retardants reacting with isocyanate to prepare the corresponding rigid polyurethane foams (GMF-PU, SGMF-PU and LGMF-PU). The thermomechanical properties and flame-retardant properties of the foams were characterized. The results showed that the specific compression strength of GMF-PU, SGMF-PU and LGMF-PU increased substantially compared to the foams from physical addition of MA, sodium alginate and lignosulfonate, all of which were greater than that of the foam without any flame retardant (PPU). Meanwhile, the cell wall of the foam pores became thicker and the closed pore ratio increased. The sodium alginate and lignosulfonate played a key role in enhancing foam thermal stability. The limiting oxygen index values and cone calorimetry results indicated the flame-retardant efficiency of GMF-PU, SGMF-PU and LGMF-PU was significantly enhanced relative to PPU. Meanwhile, the heat and smoke release results indicated sodium alginate and lignosulfonate could reduce the amount of smoke generation to different degrees during the combustion of the foam.