Search Results (114)

Nephrolithiasis, predominantly driven by calcium oxalate (CaOx) crystal deposition, poses a significant global health burden due to its high prevalence and recurrence rates and limited preventive/therapeutic options. Recent research has underscored a pivotal role for macrophage polarization in nephrolithiasis pathogenesis. Pro-inflammatory phenotype macrophages exacerbate crystal-induced injury and foster stone formation by amplifying crystal adhesion via an NF-κB–IL-1β positive-feedback axis that sustains ROS generation and NLRP3 inflammasome activation, whereas anti-inflammatory phenotype macrophages facilitate crystal clearance and tissue repair. We have summarized the research on treating nephrolithiasis and related renal injury by targeting macrophage polarization in recent years, including therapeutic approaches through pharmacological methods, epigenetic regulation, and advanced biomaterials. At the same time, we have critically evaluated the novel therapeutic strategies for macrophage reprogramming and explored the future development directions of targeting macrophage reprogramming for nephrolithiasis treatment, such as using single-cell/spatial omics to reveal the heterogeneity of macrophages in the stone microenvironment, chimeric antigen receptor macrophages (CAR-Ms) as a potential therapy for specific crystal phagocytosis in certain areas, and multi-omics integration to address inter-patient immune differences. This review highlights that macrophage reprogramming is a transformative frontier in nephrolithiasis management and underscores the need for further research to translate these molecular insights into effective clinical applications. Full article

Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates. Full article

Background/Objectives: The physiological activation of cytotoxic CD8^pos T cells (CTLs) relies on the engagement of the TCR/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARG^TPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARG^TPR makes them recognizable for pre-existing anti-CMV_pp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARG^TPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARG^TPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARG^TPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways. Full article

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising platform for off-the-shelf immunotherapy due to their safety advantages over CAR-T cells, including lower risk of graft-versus-host disease, cytokine release syndrome, and neurotoxicity. However, their persistence and efficacy are limited by immunological challenges such as host T-cell-mediated rejection, NK cell fratricide, and macrophage-mediated clearance. This review summarizes gene editing strategies to overcome these barriers, including β2-microglobulin (B2M) knockout and HLA-E overexpression to evade T and NK cell attacks, CD47 overexpression to inhibit phagocytosis, and TIGIT deletion to enhance cytotoxicity. In addition, we discuss functional enhancements such as IL-15 pathway activation, KIR modulation, and transcriptional reprogramming (e.g., FOXO1 knockout) to improve persistence and antitumor activity. We also highlight the role of induced pluripotent stem cell (iPSC)-derived NK platforms, enabling standardized, scalable, and multiplex gene-edited products. Finally, we explore artificial intelligence (AI) applications in immunogenomic profiling and predictive editing to tailor NK cell therapies to patient-specific HLA/KIR/SIRPα contexts. By integrating immune evasion, functional reinforcement, and computational design, we propose a unified roadmap for next-generation CAR-NK development, supporting durable and broadly applicable cell-based therapies. Full article

Cysteine-rich protein 61 (CYR61) is a matricellular protein in the CCN family that is involved in cellular adhesion, migration, proliferation, and angiogenesis. CYR61 interacts with integrins α6β1, αvβ3, αvβ5, and αIIbβ3 to modulate tumor progression and metastasis while modifying the tumor microenvironment. CYR61 exhibits context-dependent roles in cancer, acting as both a tumor promoter and suppressor. Increased CYR61 expression is linked to extracellular matrix remodeling, immune modulation, and integrin-mediated signaling, making it a potential prognostic biomarker and therapeutic target. Emerging research highlights the utility of CYR61 in liquid biopsies for cancer detection and monitoring. Integrin-targeted therapies, including CYR61-blocking antibodies and CAR-T approaches, offer novel treatment strategies. However, therapy-induced toxicity and resistance remain challenges with these strategies. The further elucidation of the molecular mechanisms of CYR61 may enhance targeted therapeutic interventions and improve patient outcomes. Full article

Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer. Full article

Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches—such as perivascular or hypoxic microenvironments—that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients. Full article

Previously, we reported on the peptide–HLA-I fusion protein EpCAM-ReTARG^TPR, which allows us to redirect the cytotoxic activity of pre-existing anti-CMV CD8^pos T cell immunity to selectively eliminate EpCAM^pos cancer cells. EpCAM-ReTARG^TPR consists of the CMV pp65-derived peptide TPRVTGGGAM (TPR) fused in tandem with a soluble HLA-B*07:02/β2-microglobulin (β2M) molecule and an EpCAM-directed Fab antibody fragment. To further enhance its anticancer activity, we equipped EpCAM-ReTARG^TPR with the immune-potentiating cytokine muteins IL2^(H16A,F42A) and IFNα^R149A, respectively. Both cytokines are engineered to have attenuated affinity for their respective cytokine receptors. Compared to EpCAM-ReTARG^TPR, in vitro treatment of EpCAM^pos carcinoma cell lines with EpCAM-ReTARG^TPRvIL2 for 24 h increased the cytotoxic activity of PBMCs containing low levels of TPR-specific CD8^pos T cells by ~15%, whereas EpCAM-ReTARG^TPRIFNα^R149A induced an increase of ~50%. Moreover, treatment for 120 h with EpCAM-ReTARG^TPRIFNα^R149A inhibited the proliferative capacity of the cancer cell lines OvCAR3 and PC3M by ~91% without compromising the viability of the TPR-specific CD8^pos T cells and increased their capacity for IFNγ secretion. Importantly, EpCAM-ReTARG^TPRIFNα^R149A potently induced the elimination of primary EpCAM^pos refractory carcinoma cells from a Merkel cell carcinoma (MCC) patient. Taken together, the armoring of the carcinoma-directed peptide–HLA-I fusion protein EpCAM-ReTARG^TPR with IFNα^R149A potently enhanced the efficacy of pre-existing anti-CMV CD8^pos T cell immunity to selectively eliminate EpCAM^pos cancer cells. Full article

After eight generations of laboratory selection with β-cypermethrin, a P. okadai strain was cultivated that displayed a 10.04-fold increase in resistance (RS) relative to the susceptible strain (SS), with an estimation of heritability (h²) of 0.34. Compared with the SS, the developmental duration of the eggs was significantly prolonged (p < 0.05); however, the pupal stage duration was shorter, with no statistically significant difference. Moreover, the levels of GSTs, CarEs, and CYP450 activity were notably higher in the RS than in the SS. In addition, the level of CarE and CYP450 activity in the RS was significantly higher in the midgut (MG), fat body (FB), and Malpighian tubules (MTs) compared to the SS; however, the GSTs showed no statistically significant difference in the MTs. These results suggest that P. okadai‘s resistance to β-cypermethrin could be selected rapidly and the decreases in the intrinsic rate of increase (r) observed in the RS are likely due to mutations in the detoxification enzyme genes under the strong selection pressure exerted by β-cypermethrin. The increased activity of GSTs, CarEs, and CYP450 was associated with β-cypermethrin resistance in the RS of P. okadai. The data reported herein provide a foundation for future studies on the mechanisms responsible for β-cypermethrin resistance in P. okadai. Full article

Immunotherapy has shown limited efficacy in prostate cancer, largely due to low tumor immunogenicity, sparse tumor-infiltrating lymphocytes, and a suppressive microenvironment. Recent therapeutic strategies aim to boost immune responses and counteract immunosuppressive factors through interventions such as immune checkpoint inhibitors, immunogenic cell death-inducing therapies, and the targeted blockade of pathways like that of transforming growth factor-β. Vaccine-based approaches, potent immune adjuvants, and engineered chimeric antigen receptor (CAR) T cells are also being investigated to overcome local immune inhibitory signals. Advancements in imaging, multi-omic profiling, and liquid biopsies offer promising avenues for real-time monitoring, better patient selection, and precision treatment. This review provides an overview of the key immunosuppressive features of prostate cancer, current immunotherapeutic modalities, and emerging strategies to transform “cold” tumors into more responsive “hot” targets. By integrating these approaches, we may achieve more durable clinical benefits for patients with advanced or metastatic prostate cancer. Full article

Residential carbon emissions (RCEs) have become a major contributor to China’s overall carbon emission growth. A comprehensive analysis of the evolution characteristics of regional disparities in RCEs at the urban level, along with a thorough examination of the driving factors behind RCEs and the convergence, is crucial for achieving carbon reduction goals within regions. This study calculates the RCEs of 270 cities in China from 2011 to 2019 based on multiregional input–output tables and explores the regional differences and spatiotemporal evolution characteristics of RCEs using the Dagum Gini coefficient decomposition method and kernel density estimation. On this basis, we examine the driving factors of RCEs using an extended Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) econometric model and further analyze the convergence of RCEs by introducing a β-convergence model. The results are as follows: (1) The regional disparity of RCEs in China generally shows a wave-like declining trend, with the primary source of this disparity being the differences between city tiers. (2) Kernel density estimation shows that the greater the urban rank, the larger the regional disparity; the RCE distribution in third- and lower-tier cities is more concentrated. (3) Population density, population aging, and education level significantly exert a negative influence on RCEs, whereas economic development level, number of researchers, and number of private cars are positively correlated with RCEs. (4) Each urban agglomeration’s RCEs exhibits significant β-convergence, but the driving factors of RCEs and their convergence differ significantly across the urban agglomerations. This study provides targeted policy recommendations for China to achieve its emission reduction goals effectively. Each city cluster should tailor its approach to strengthen regional collaborative governance, optimize urban layouts, and promote low-carbon lifestyles in order to facilitate the convergence of RCEs and low-carbon transformation. Full article

One of the new areas that requires extensive study of the structure and properties of welded joints is the heat-affected zone (HAZ). This issue is particularly important for new constructions made of aluminium alloys intended for battery housing for powering electric car engines. Modern welding methods, such as EBW and FSW, meet the requirements related to the high precision of the process and the quality of the welded joint itself. This article presents the results of an analysis of the structure and strengthening of the HAZ of chemically modified AlMgSi(Cu) alloys via EBW and FSW. Microstructural observation was performed via SEM for each welded joint to determine the morphology of the precipitates. In the HAZ, β-Mg₂Si, Q-Al,MgCu,Si and α-Al,Fe,Si (Mn,Cu) phases with larger sizes and rounded shapes were visible than they were directly in the weld made via the EBW method. The joints produced by the FSW method were characterised by a wide weld area and an irregular weld line. Analysis of the crystallographic orientation via EBSD and grain orientation spread (GOS) revealed differences in the shape of the grains and the degree of recrystallisation in the weld area between the FSW and EBW methods. The distributions of HB (FSW) hardness and HV (EBW) microhardness measurements revealed a slight decrease in hardening in the HAZ. In joints welded by both methods, the hardness of the welds for alloys with increased copper and chromium contents increased by approximately 5%. Full article

Oral cancer, a subtype of head and neck cancer, poses significant global health challenges owing to its late diagnosis and high metastatic potential. The epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein, has emerged as a critical player in cancer biology, particularly in oral cancer stem cells (CSCs). This review highlights the multifaceted roles of EPCAM in regulating oral cancer metastasis, tumorigenicity, and resistance to therapy. EpCAM influences key pathways, including Wnt/β-catenin and EGFR, modulating CSC self-renewal, epithelial-to-mesenchymal transition (EMT), and immune evasion. Moreover, EpCAM has been implicated in metabolic reprogramming, epigenetic regulation, and crosstalk with other signaling pathways. Advances in EpCAM-targeting strategies, such as monoclonal antibodies, chimeric antigen receptor (CAR) T/NK cell therapies, and aptamer-based systems hold promise for personalized cancer therapies. However, challenges remain in understanding the precise mechanism of EpCAM in CSC biology and its translation into clinical applications. This review highlights the need for further investigation into the role of EPCAM in oral CSCs and its potential as a therapeutic target to improve patient outcomes. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions. Full article

Backgrounds/Objectives: Following previous findings on high-salt (HS)-intake-related increase of oxidative stress, this study explored whether carnosine (CAR; β-alanyl-L-histidine), a reactive oxygen species (ROS) scavenger, enhanced antioxidative defence and vascular function following HS, potentially via the NRF2 or HIF-1α signalling pathway. Methods: Sprague Dawley rats (64, 8–10 weeks old, both sexes) were divided into four groups (n = 6/group): CTRL (0.4% NaCl), HS (4% NaCl for 7 days), CTRL + CAR (0.4% NaCl and 150 mg/kg/day oral CAR supplementation), and HS + CAR (4% NaCl and CAR). Acetylcholine-induced relaxation (AChIR) and hypoxia-induced relaxation (HIR) were evaluated in norepinephrine-precontracted (NE, 10⁻⁷ M) aortic rings. HIR was also tested with NRF2 (ML-385, 5 × 10⁻⁶ M) and HIF-1α (LW6, 10⁻⁴ M) inhibitors. Gene expression of superoxide dismutases 1, 2, and 3 (SOD1, 2 and 3), glutathione peroxidases (GPx1 and 4), catalase (CAT), NRF2, and NAD(P)H dehydrogenase (quinone 1) (NQO1) in aortic tissue was measured by RT-qPCR. Ferric reducing antioxidant power (FRAP) and advanced oxidation protein products (AOPPs) assays were performed on serum samples. All experimental procedures conformed to the European Guidelines (directive 86/609) and were approved by the local and national Ethical Committees (#2158-61-46-23-36, EP355/2022). Results: HS impaired AChIR and HIR, both preserved by CAR. NRF2 and HIF-1α inhibitors suppressed HIR in the HS and HS + CAR groups. CAR significantly increased SOD1 and 2, NRF2, and NQO1 expression and SOD activity compared to the CTRL and HS groups. GPx1 and GPx4 were upregulated in HS + CAR compared to HS. CAR prevented an increase in AOPPs, which were elevated in HS, while FRAP was highest in HS + CAR. Conclusions: Carnosine enhances antioxidative defence by upregulating antioxidant enzymes and activities and preserves vascular relaxation, likely via NRF2 signalling. Full article