搜索结果：Human immunology

Botanical supplements have been used for the prevention and treatment of human diseases since ancient times and remain important, widely consumed therapeutics. While they display promising efficacy across a broad spectrum of biological activities, poor oral bioavailability often limits their utility. Upon ingestion, these compounds may remain in the gastrointestinal tract prior to absorption, during which time they interact with gut microbiota. These interactions can significantly alter their bioavailability since microbial enzymes, known for their wide substrate specificity, are capable of readily transforming xenobiotics, often changing their biological activity as well as their bioavailability. Herein, we summarize the chemistry of microbial biotransformations of botanical supplements, highlighting key enzymatic transformations. The reciprocal interactions between four widely used botanical supplements and the human gut microbiome are outlined including green tea, açai, red wine, and mangosteen. Their microbial metabolism and modulation of human gut microbiota is discussed, highlighting the various enzymes and metabolites reported from relevant literature. Although the direct effect of microbiome bioconversion of botanical supplements is largely unexplored due to the complexity of both systems, this review provides a framework for research to determine the bidirectional effects of botanicals and gut microbiota on human health.

Human TAPBPR is known to function as a Major Histocompatibility Complex class I (MHC-I) peptide exchange catalyst that shapes the peptide repertoire presented to immune cells. However, investigations characterizing TAPBPR from other species are limited. Here, we characterize mouse TAPBPR, exploring its association partners in mouse cell lines and comparing its function to human TAPBPR. We find that mouse TAPBPR binds MHC-I and calnexin, with a notably sustained interaction with H2-Db compared to H2-Kb. We reveal that mouse TAPBPR restricts the peptide repertoire presented on H2-Db and H2-Kb on MC-38 cells. Intriguingly, mouse TAPBPR presence promotes the selection of peptides with a C-terminal methionine on H2-Kb. We reveal that in the presence of high-affinity peptides, mouse TAPBPR can promote loading of both H2-Db and H2-Kb. Furthermore, mouse TAPBPR efficiently loaded a peptide with a C-terminal methionine onto H2-Kb. Together, our findings suggest that mouse TAPBPR plays an important role in shaping the MHC-I immunopeptidome by functioning as a peptide editor, similar to its human counterpart.

RNA viruses evolve rapidly, enabling them to evade host immunity and antiviral therapies and complicating durable diagnostics strategies. There is a pressing need for approaches that provide broad-spectrum viral suppression and detection. We designed four Cas13d crRNAs targeting a conserved 26-nucleotide sequence in coronavirus (CoV) nsp12. Their antiviral efficacy was evaluated in vitro against the target sequences of all seven human CoVs, showing potent activity across the tested samples. The same crRNAs were adapted for a Cas13d-based specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) assay to detect multiple human CoVs, demonstrating high sensitivity, with the ability to detect as few as a single copy of SARS-CoV-2 RNA, while showing no detectable signal for other seasonal respiratory viruses, such as influenza. This dual-function approach underlines the versatility and potential of CRISPR technologies in both managing and detecting viral infections. Additionally, bioinformatic analysis revealed that the crRNA targets are highly conserved across animal coronaviruses, suggesting that targeting of this sequence could facilitate the rapid development of treatment options and diagnostics during a new pandemic of an emerging coronavirus. This could significantly aid in pandemic preparedness and response efforts.

Bacillus cereus is responsible for a wide range of intestinal and extraintestinal infections in humans. Its pathogenicity relies on multiple factors, including extracellular toxins, direct interaction with host tissues, and adaptive mechanisms that promote host colonization. B. cereus group bacteria are also insect pathogens (e.g., Bacillus thuringiensis), suggesting that certain virulence mechanisms may be conserved between mammals and insects. In this study, we used Galleria mellonella as an infection model to assess the pathogenicity of two B. cereus strains (i.e., T1 and B10502), which were previously isolated from food poisoning outbreaks and that differ in their virulence toward human enterocyte cell cultures. We combined genomic analysis with larval infection assays to examine survival, bacterial persistence, immune activation, and spore formation. Whole-genome phylogenetic analysis revealed that the two strains belong to distinct branches of the B. cereus sensu lato species. Both strains induced dose-dependent mortality following oral gavage, with strain T1 showing a better persistence than strain B10502 in both living and dead larvae, with heat-resistant spores detectable up to 144 h post-infection, unlike strain B10502. Infection with strain B10502 elicited higher phenoloxidase activity and greater melanization than with strain T1. Both strains similarly reduced hemocyte viability. Genomic comparisons revealed that both strains share a core set of virulence factors, including the non-hemolytic enterotoxin (Nhe) complex, various hemolysins, and phospholipases, while exhibiting significant differences in genes, such as hblABCD complex, mpbE, clpC, clpP, and ilsA. These findings demonstrate that G. mellonella is a useful infection model to discriminate B. cereus strains with different virulence biological activities on larval colonization and innate immune markers, providing new insights into the mechanisms underlying the pathogenicity of foodborne B. cereus strains.

Regulatory T cells (Tregs) play a central role in maintaining immune tolerance and supporting maternal-fetal homeostasis throughout human pregnancy. Clinical and experimental evidence demonstrates that dysregulation of peripheral and decidual Tregs manifested as quantitative deficits, impaired suppressive function or lineage instability increased the risk of various pathological pregnancies, such as recurrent implantation failure (RIF), recurrent spontaneous abortion (RSA), pre-eclampsia (PE) and preterm birth (PTB). Recently, novel therapeutic strategies targeting Tregs have emerged in oncology, transplantation, and autoimmune diseases. However, their application in pathological pregnancy remains in its infancy. This review outlines the spatiotemporal dynamics of peripheral and decidual Tregs throughout gestation, elucidating their roles in maintaining maternal-fetal homeostasis and their dysregulation in pathological pregnancies. We also critically evaluated the therapeutic strategies targeting Tregs and Tregs-associated signaling pathways, including hormonal support, traditional intravenous immunoglobulin, as well as emerging interventions such as immunometabolic reprogramming and engineered cellular therapies like chimeric antigen receptor Tregs. This review may provide insights for understanding the roles of Tregs in physiological and pathological pregnancy, as well as provide new idea in the immunotherapy of pathological pregnancy.

Beyond established risk factors such as genetics and hormones, the human microbiome has emerged as a pivotal player in breast cancer pathogenesis. This review delineates the technological evolution in breast microbiome research, spanning traditional culture methods to high-throughput sequencing and cutting-edge spatial omics. We elucidate the role of the gut-breast axis in modulating breast cancer development through its influence on estrogen metabolism, immune responses, and microbial metabolites. Furthermore, we analyze the distinctive compositional features of the intratumoral microbiota and their dual, context-dependent roles in promoting invasion, inducing immunosuppression, and driving metabolic reprogramming within the tumor microenvironment. Novel microbiome-based therapeutic strategies, including targeted microbiota depletion, engineered microbial therapeutics, and dietary interventions, are summarized. Finally, we discuss the translational potential of microbiome research in refining breast cancer risk prediction, evaluating treatment responses, and advancing personalized prevention and treatment strategies, ultimately contributing to improved patient outcomes.

Lipid phosphate phosphatases (LPPs) dephosphorylate lipid phosphates to regulate signaling and metabolism. Among the three mammalian isoforms, LPP1, LPP2, and LPP3, LPP2 has been strongly associated with cancer, making it a potential therapeutic target. However, the molecular mechanisms underlying its structural organization, substrate recognition, and catalysis remain elusive. Here, we report the cryo-EM structure of human LPP2 (hLPP2). hLPP2 assembles as a homo-tetramer, with phosphatidylcholine bound in the substrate pocket. The tetrameric arrangement provides a structural basis for LPP oligomerization. The wide, open-ended substrate pocket explains the enzyme's broad substrate specificity. Structural comparison with PAP2 family members, including hG6PC1 and ecPgpB, suggests a conserved catalytic mechanism and highlights the regulatory role of residue E159 in stabilizing the catalytic center and phosphate release. Collectively, these findings advance our understanding of the structural basis and enzymatic mechanism of LPPs and may provide insights for the development of novel cancer therapies.

Human respiratory syncytial virus (RSV) is one of the main viral agents associated with the development of acute respiratory infections (ARIs), particularly during infancy and early childhood. RSV vaccine have recently been approved, however, are currently limited to older adults and pregnant women, with no approval for young children. In the absence of broadly effective and accessible preventive or therapeutic options for this vulnerable population, understanding the biology of RSV represents a critical alternative strategy. While several viral proteins have been reported to regulate the expression of interferon-stimulated genes (ISGs) to evade the host antiviral immune response, recent studies have shown that some viruses can also recruit host cellular proteins to facilitate their replication or modulate antiviral pathways. In this context, the nucleolus, and its resident proteins, such as fibrillarin (FBL), have been suggested to play a role in the regulation of inflammatory responses and in the activation of genes involved in early antiviral defense mechanisms. To analyze FBL expression under viral infection conditions, immunofluorescence assays (IFA) and Western blot (WB) analyses were performed. The effects of FBL depletion were evaluated using WB, IFA, RT-qPCR, and lytic plaque assays. Three experimental conditions were established: uninfected A549 cells (mock), RSV-infected cells, and RSV-infected cells with FBL knockdown. To determine the relationship between FBL and interferon-stimulated gene (ISG) expression, RT-qPCR assays were performed to quantify the expression levels of selected ISGs, including OAS1, OAS2, IFIT3, PKR, and RIG-I. Additionally, FBL-knockdown cells were transfected with a GFP-FBL construct to restore FBL expression, and the recovery of RSV infection was evaluated by IFA, RT-qPCR, and plaque-forming unit (PFU) assays. Moreover, the downregulation of ISG expression in cells with restored GFP-FBL was assessed by RT-qPCR. Finally, p53 knockdown assays were performed to evaluate changes in FBL expression and the reduction of RSV infection, as determined by WB. RSV infection was found to induce FBL expression at early stages of infection in A549 cells. Additionally, our data suggest that FBL suppresses the expression of interferon-stimulated genes (ISGs). Conversely, silencing of FBL significantly reduced RSV infection. Importantly, this reduction in viral replication was associated with increased ISG expression in FBL-deficient A549 cells upon RSV infection. Furthermore, exogenous expression of FBL in FBL-knockdown cells restored RSV infection and led to a concomitant reduction in ISG expression following the recovery of FBL protein levels. Finally, p53-knockdown cells reduced viral protein M2-1 levels without affecting FBL expression, pointing to the involvement of other regulatory mechanism controlling FBL during RSV infection. Our data show that RSV infection promotes the expression of the FBL protein, creating an environment devoid of early antiviral response mediators such as ISGS.

Gut microbiota and bile acids have been reported to affect sepsis progression, but the underlying mechanisms remain largely unknown. Here we investigated gut microbiota-bile acid interplay in two paediatric sepsis cohorts. Integration of bile acid-targeted metabolomics with gut metagenome data from paediatric sepsis patients identified deoxycholic acid 3-sulfate (DCA-3S) as significantly associated with paediatric sepsis progression. In vitro and in vivo experiments identified Enterococcus raffinosus as the primary producer of DCA-3S, contributing at least 80% of its total production, challenging the conventional notion of hepato-centric bile acid sulfation pathways. Intervention experiments in mouse and intestinal organoid models revealed that DCA-3S administration effectively alleviated sepsis by improving intestinal barrier function and attenuating inflammatory response. Collectively, our findings highlight a previously unrecognized microbial contribution to bile acid sulfation and position DCA-3S as a promising diagnostic and therapeutic biomarker for paediatric sepsis.

Acute Lymphoblastic Leukemia (ALL) remains the most prevalent childhood malignancy. While chemotherapy has improved survival rates, multidrug resistance (MDR) mediated by P-glycoprotein (P-gp/ABCB1) overexpression persists as a major cause of treatment failure and relapse. Natural Killer (NK) cells are pivotal for anti-leukemic surveillance but are often compromised during treatment due to their susceptibility to chemotherapy, a vulnerability intrinsically linked to their own expression of P-gp. Strategies to transiently enhance NK cell chemoresistance could therefore preserve immune function and improve therapeutic outcomes. We hypothesized that stimulating Toll-Like Receptor 2 (TLR2) on NK cells could modulate P-gp expression or activity, enhancing their resilience to cytotoxic drugs. In this study, we first characterized NK cells from pediatric ALL patients, confirming the constitutive expression of both the therapeutic target (TLR2) and the drug efflux pump (P-gp) across all major subpopulations. Using a healthy donor model, we then dissected the functional consequences of specific TLR2 heterodimer engagement. While agonists for both TLR2/1 (PCSK) and TLR2/6 (LTA, MALP-2) induced functional activation, their effects on P-gp were divergent. In a PBMC context, stimulation with the TLR2/1 agonist PCSK significantly enhanced the efflux of the chemotherapeutic agent Methotrexate (MTX), but not Rhodamine 123. This functional enhancement occurred without increasing P-gp surface expression, suggesting a modulation of transporter kinetics. Crucially, mechanistic assays in purified NK cells revealed that this MTX efflux enhancement relies on the cellular microenvironment, whereas direct high-dose TLR2/1 stimulation paradoxically led to P-gp loss. Furthermore, we demonstrated that the immunomodulatory effects of PCSK extend beyond chemoresistance to directly potentiate anti-leukemic effector functions; PCSK stimulation significantly enhanced NK cell cytotoxicity against RS4;11 leukemic blasts without compromising effector viability. These findings identify a novel immunomodulatory axis where TLR2 signaling differentially regulates P-gp function and effector capacity in NK cells depending on the specific heterodimer engaged and the cellular context. We propose that controlled TLR2/1 stimulation represents a potential dual-benefit strategy to protect NK cells from chemotherapy-induced suppression while boosting their anti-leukemic activity in ALL.

Interleukin-15 (IL-15) is expressed in various cancers, including melanoma, where it exists in distinct membrane-associated isoforms. Primary melanoma cells predominantly express the non-cleavable transmembrane form (tmbIL-15), while metastatic cells also express a cleavable membrane-bound form (mbIL-15) complexed with IL-15Rα. As tmbIL-15 is capable of reverse signaling upon IL-15Rα engagement, we investigated how this signaling axis modulates melanoma cell behavior across tumor stages. Transcriptomic analysis of melanoma patients revealed that high IL-15 expression correlates with immune activation, inflammation and epithelial-to-mesenchymal transition (EMT), along with coordinated upregulation of IL-15 receptor subunits. Proteomic profiling of melanoma cell lines stimulated with soluble IL-15Rα (sIL-15Rα) uncovered distinct, stage-specific responses. Although several proteins were commonly deregulated across cell lines, most showed opposite regulation in primary versus metastatic models, indicating that tmbIL-15 reverse signaling triggers context-dependent programs influenced by tumor progression. A stringent cross-comparison identified five proteins (PSAP, MARCKS, eEF1A1, DDX39B, and RACK1) as consistently and differentially regulated across tumor stages. Further comparison with published NK cell co-culture and EMT cytokine stimulation datasets revealed a subset of shared effectors, notably PSAP, TPM3 isoform 2 and MARCKS, suggesting that IL-15Rα-induced tmbIL-15 signaling is part of the immune editing phenomenon eliciting pro-tumoral activities complementary to the EMT process. Among these, PSAP emerged as the most robustly and consistently modulated effector, upregulated in primary melanoma cells and downregulated in metastatic ones upon sIL-15Rα stimulation. Its expression correlated positively with CD8+ T cell infiltration and negatively with NK cell infiltration, with distinct transcriptomic programs associated with high PSAP expression in primary versus metastatic settings. Altogether, these findings identify PSAP as a stage-specific mediator of tmbIL-15 reverse signaling in melanoma, integrating immune and EMT-related cues with potential implications for tumor progression and microenvironmental remodeling.

Endothelial cells (ECs) orchestrate vascular homeostasis and resilience but can undergo reprogramming into a mesenchymal-like phenotype through an endothelial-to-mesenchymal transition (EndMT). Crucially, EndMT is a linchpin underlying several cardiometabolic diseases, but is almost universally studied as an endpoint. The transcription factor ERG (ETS-related gene) is critical to the maintenance of EC identity and function, yet the dynamic transcriptional and functional consequences of ERG loss on EndMT programs, and whether this can be reversed, has not been explored. We modeled both acute and chronic ERG loss in human aortic ECs using siRNA knockdown and CRISPR/Cas9-mediated ERG deletion. We profiled temporal changes in chromatin accessibility (ATAC-seq), transcriptomic responses (RNA-seq), and endothelial phenotypes, including migration and barrier integrity. The temporal kinetics of ERG loss and restoration was assessed by comparing stable ERG knockout to transient ERG knockdown and recovery over time. The implications to human disease were deciphered by examining ERG gene regulatory networks in human atherosclerosis and linkage with genetic variation associated with human cardiovascular disease. Analysis of gene regulatory networks revealed profound and dynamic rewiring of endothelial and mesenchymal transcriptional programs upon loss of ERG. While endothelial identity was rapidly lost by 24 h of ERG knockdown, acquisition of mesenchymal identity, barrier dysfunction, and enhanced cell migration required 72 h to manifest. Loss of ERG was accompanied by a rapid reduction in accessibility of ETS motifs and an extensive gain in open chromatin containing AP1 motifs. Disease-relevant endothelial dysfunction programs were associated with dynamically reorganized transcriptional networks. Importantly, restoration of ERG expression reversed EndMT gene regulatory networks and phenotypes. Overall, this study highlights the ETS factor, ERG, as an essential transcriptional safeguard of endothelial identity and function, and demonstrates that ERG loss initiates a progressive, yet reversible, EndMT program with EC identity loss preceding a gain of mesenchymal gene regulatory networks and phenotypes. This study establishes loss of ERG as an early initiating event in EndMT and suggests that ERG-targeted therapies may hold promise for promoting endothelial resilience.

Animal models are crucial for mechanistic studies and therapeutic development of human diseases. At present, the etiology of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic disease of the urinary bladder, remains undefined. Therefore, numerous theories of pathogenesis have been proposed, and various animal models have been developed based on these theories. This enigmatic human disease can be categorized into two subtypes: Hunner-type IC (HIC) and bladder pain syndrome (BPS). These two subtypes of IC/BPS have different pathological mechanisms, but their clinical symptoms overlap. Recent evidence indicates that HIC is an immune-mediated inflammatory disease of the urinary bladder, while BPS is a minimally inflamed bladder condition comprising various clinical phenotypes. Furthermore, increasing evidence suggests that autoimmunity may play a significant role in IC/BPS, particularly in HIC. Today, the rodent models of experimental autoimmune cystitis (EAC) are being used in HIC research. This article provides an overview of immune-mediated inflammation and autoimmunity in IC/BPS, as well as EAC models that can be used for HIC research, with a focus on the URO-OVA model, a novel transgenic EAC model that effectively mimics HIC. The URO-OVA model develops chronic bladder inflammation, pelvic/bladder pain, and voiding dysfunction seen in human HIC patients. It responds to treatment with dimethyl sulfoxide (DMSO) and specific inhibitors, such as Toll-like receptor (TLR)4, mitogen-activated protein (MAP) kinase, and interferon (IFN)-γ inhibitors. The URO-OVA model is stable and reproducible, providing a unique EAC model for HIC research that incorporates immune/autoimmune components in its pathophysiology.

Visual impairment affects over 2.2 billion people worldwide and the major causes include age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. For research in these areas, although animal models offer a more physiologically complex system than in vitro approaches, their use raises ethical considerations, and species-specific differences such as variations in protein sequences and signaling pathways. This can limit the direct translatability of the outcomes. Traditional 2-D cell cultures, in contrast, lack the multicellular organization and dynamic microenvironment necessary to replicate human retinal complexity. Retinal organoids (ROs), three-dimensional tissue constructs derived from pluripotent stem cells, have emerged as a promising model due to their human origin and complex cellular interactions that cannot be achieved in conventional 2-D/3-D co-culture models. In this review, we provide a brief overview of the evolution from 2-D to 3-D retinal models, highlight the structural and functional features of ROs including the presence of layered retinal architecture, photoreceptor outer segment formation, and light-responsive electrophysiological activity and summarize their applications in disease modeling, drug discovery, and gene and cell therapy. ROs represent a significant advancement over traditional models by enabling the recapitulation of human-specific retinal development, facilitating the study of patient-derived disease phenotypes, and providing a platform for personalized therapeutic screening. Their development has deepened understanding of pathological mechanisms in conditions such as retinitis pigmentosa and AMD, while enabling preclinical testing of targeted interventions like CRISPR-based gene editing and photoreceptor cell replacement. Nonetheless, challenges remain in fully replicating retinal vascularization, long-term functional maturation, and synaptic connectivity, underscoring the need for continued refinement and integration with complementary model systems.

Pancreatic islets of Langerhans are central to the pathogenesis of all major forms of diabetes. The ability to study human islets ex vivo has advanced our understanding of diabetes and aided in the development of novel therapeutics. However, for decades, very few laboratories had access to this critical resource and experiments on human islets were typically underpowered. More recently, multiple consortia around the world have started to enable islet biology at scale, enriching our understanding of the intra-individual variability of islet function and disease mechanisms. This article reviews and compares existing large-scale human islet tissue and data resources, offering suggestions for their improvement and for developing new resources.

Pre-existing pathogen-specific antibodies shape vaccine outcomes, yet their impact on local reactogenicity and qualitative features of the immune response are not fully defined. In this prospective human cohort receiving seasonal influenza vaccination, high baseline hemagglutinin-specific IgG1 levels were associated with more pronounced local thermal responses at the vaccinated arm and greater vaccine-induced antibody levels. These IgG antibodies formed immune complexes with hemagglutinin, activated complement and enhanced Fc-receptor-dependent monocyte activation and phagocytosis in vitro, connecting pre-existing immunity to innate activation and local reactogenicity. Despite higher antibody levels and early plasmablast responses in subjects with strong thermal reactogenicity after vaccination, we observed lower avidity and hemagglutinin-inhibition capacity, suggesting extrafollicular responses. T cell responses were unaltered. These findings support a model in which pre-existing hemagglutinin-specific IgG may contribute to local thermal reactogenicity and qualitative features of the vaccine response through immune complex-mediated pathways, providing a framework for how prior immunity may shape human vaccine responsiveness.

Prenylated hydroxychalcones (xanthohumols) are hop-derived flavonoids with promising anticancer activity; however, their membrane interactions and structure-activity relationships remain incompletely understood. Here, xanthohumol C (XHC) and its semi-synthetic derivatives, 1″,2″-dihydroxanthohumol C (DHXHC) and 1″,2″-dihydroxanthohumol K (DHXHK), were evaluated for cytotoxic, pro-apoptotic, and membrane-modulating effects in comparison with xanthohumol (XH). In vitro antiproliferative activity against eleven human and one murine cancer cell lines yielded IC50 values in the micromolar range, with XHC showing the highest activity toward epidermoid carcinoma, urinary bladder carcinoma, and glioblastoma cells. Apoptosis induction was confirmed in MCC-13 Merkel carcinoma cells. Hemolytic activity toward human erythrocytes was concentration-dependent in the range of 10-100 μM, with XHC classified as toxic at 100 μM, while DHXHC and DHXHK were only slightly toxic. Membrane interactions were studied using fluorescence spectroscopy in cancer cell-mimicking lipid membranes. At low micromolar concentrations (0.5-5 μM), XHC and DHXHC increased DPH anisotropy, indicating membrane stiffening, while Laurdan generalized polarization decreased, consistent with enhanced interfacial hydration. In contrast, DHXHK showed negligible membrane effects. These results suggest that differences in molecular structure, including planarity, may contribute to the observed variation in membrane interactions and cytotoxic effects among xanthohumol derivatives.

The heterogeneity of cancer renders its response to immunotherapy elusive, warranting the identification of robust biomarkers for evaluation. As a form of recently defined regulated cell death (RCD), cuproptosis is driven by copper-dependent proteotoxic stress in mitochondria tricarboxylic acid cycle (TCA cycle), exerting a sophisticated role in antitumor immunity, yet remains poorly understood. Here, we established a cuproptosis score to characterize the immune landscape across 23 human cancers and established the correlation of cuproptosis score with patient immunotherapy outcomes through multi-omics analysis. Bulk and single-cell transcriptomic analysis revealed that with cuproptosis-low patients tend to have improved immunotherapy outcomes compared to those with high cuproptosis scores, with increased immune infiltration and function, as well as abundant cytokines, checkpoints and major histocompatibility complex (MHC) molecules expression. Spatial transcriptomic analysis indicated that immune cells exhibited higher cuproptosis scores than tumor cells, hinting that immune cells are vulnerable to cuproptosis. Further metabolomic and transcriptomic analysis of underlying intrinsic features revealed that cuproptosis-low tumors exhibited a metabolic and signaling pathway profile enrichment favoring antitumor immunity and potent immunogenicity. Overall, our multi-omics analysis suggests cuproptosis score as a robust biomarker for immunotherapy benefit in multiple cancers, reveals cuproptosis-related extrinsic and intrinsic immune landscapes, and provides a broad framework for understanding the relevance of cuproptosis to cancer immunology and clinical benefits of immunotherapy.

International changes in the focus of medical school education have led to a decrease in the time allocated to anatomy education, with human specimen dissection particularly affected. This study evaluates whether a dissection-based course facilitates the retention of three-dimensional (3-D) anatomical relationships in senior medical students who previously completed anatomy training without dissection. Fifteen year 4 or 5 medical students, who had completed preclinical anatomy instruction and 1 or 2&#x2009;years of clinical training, were competitively selected to undertake a Clinical Anatomy Intercalation programme that included a 16-week full body human specimen dissection course. Participants completed four assessments administered before, midway through, at the end, and 1&#x2009;month after the dissection course. Each assessment had 24 questions based on six prosection images representing major body regions. Half of the questions assessed anatomical identification, while the reminder evaluated 3-D understanding of anatomy. A post-course Likert scale questionnaire captured participants' perceptions of dissection as a learning tool. Overall test scores improved across the first three assessments, with questions relating to 3-D anatomical understanding showing a statistical improvement with each sequential in-course test. No statistically significant difference was observed between end of course and one-month post-course tests, indicating knowledge retention. Performance was significantly lower in head and neck anatomy compared to thoracic, abdominal, and pelvic regions (p&#x2009;<&#x2009;0.001). Likert scale questionnaire responses indicated strong participant support for dissection as an education tool. This study demonstrates that a dissection-based anatomy course significantly enhances 3D anatomical knowledge gain and supports retention, which senior medical students can apply in clinical practice. Participants highly valued the experience, suggesting that dissection is still a vital component of medical education.