Browse Articles

Δ8-THC—mediated PPARα activation mitigates murine autoimmune hepatitis by suppressing NLRP3 inflammasome Activity and oxidative stress 2259475

Abstract Introduction Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor highly expressed in liver and immune cells, plays a critical role in mediating anti-inflammatory and antioxidant responses. Aberrant activation of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome and excessive ROS (reactive oxygen species) production are key drivers of hepatic inflammation and tissue injury. The aim of present study was to test the hypothesis that Δ8-THC protects against autoimmune hepatitis (AIH) by activating PPARα to suppress inflammasome signaling and oxidative stress. Methods AIH was induced in C57BL/6 mice by i.v. concanavalin A (ConA, 12.5 mg/kg) and treated i.p. with vehicle or Δ8-THC (20mg/kg). RNA sequencing and Western blot were used to assess NLRP3 inflammasome activation and PPARα expression in hepatic immune cells, while ROS levels were measured using the CellROX assay. Network and functional enrichment analyses identified critical regulators of inflammatory pathways. Results We found that PPARα expression was markedly reduced in ConA-treated livers. Interestingly, Δ8-THC treatment significantly upregulated hepatic PPARα and suppressed inflammasome-related genes, including NLRP3, caspase-1, and IL-1β, compared to ConA+vehicle treated mice. Moreover, Δ8-THC protected mice from liver injury by reducing ROS accumulation in a dose-dependent manner. The protective effect of Δ8-THC-induced PPARα activation further relied on the suppression of inflammatory mediators including IL-13, IL-23α, IL-15rα, TNFRSF4, TNFRSF9, CXCR1/2, IL-36γ, IL-21, and IFNLR1 induced by ConA. This was further accompanied by downregulation of inflammation-associated hepatic transcripts such as TREM1, GPR84, IFITM6, OLFM4, FPR2, BST1, ADAM8, and S100A8/9. Conclusion Together, this study demonstrates that Δ8-THC activates PPARα signaling to inhibit NLRP3 inflammasome activation and ROS production, thereby attenuating liver inflammation and highlighting its potential therapeutic application. Funding Source NIH grants P20GM103641, P30GM154631, R01ES030144, and R01AI160896 Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Prior RSV Infection Enhances Alveolar Macrophage Function and Protects Against Secondary S. pneumoniae Infection 2254062

Abstract Introduction Respiratory syncytial virus (RSV) and Streptococcus pneumoniae (Spn) are leading causes of respiratory infections in children under the age of five. Nearly all infants are infected with RSV by age two, with 36% experiencing reinfection, while 65% of children are exposed to Spn. Despite this high prevalence, little is understood about the long-term impact a primary RSV infection impacts the susceptibility to subsequent bacterial exposure. Trained immunity, defined innate immunological memory driven by epigenetic modifications and metabolic reprogramming, can enhance the responsiveness of alveolar macrophages (AMs) to subsequent infections. Methods Mice are infected with RSV and monitored for weight loss and respiratory function over 10 days and then challenged with Spn and observed for 48 hours. Tissues are collected for CFU counts, ELISA, and flow cytometry. Pharmacological inhibitors are used to identify immune mechanisms driving RSV-mediated protection against Spn. Results Preliminary data reveals that AMs previously exposed to RSV are transcriptionally distinct from naïve AMs. Prior RSV infection induces protection against a subsequent challenge with Spn, demonstrated by enhanced recovery in weight loss and airway obstruction in mice previously infected with RSV compared to naïve mice, along with a 2-3-log reduction in bacterial burden in the lungs, nasal passages, and blood up to 30 days post-viral infection. Prior RSV infection results in heightened AM expression of CD80, CD86, MHC II, and LAMP-1, indicating enhanced function. Importantly, blocking IL-1β during RSV infection abrogates this protection, highlighting a critical role for IL-1 signaling. Conclusion Our results suggest that IL-1β production during RSV infection induces protection against Spn following viral clearance through non-specific trained immunity of AMs. This work highlights a novel mechanism of cross-protection in respiratory infection with potential implications for therapeutic strategies targeting innate immune memory. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

ST2 enforces a ‘repair-ready’ Treg phenotype that homes to and ameliorates neuroinflammation 2260164

Abstract Introduction Regulatory T cell (Treg) therapy faces clinical challenges related to a lack of persistence, stability, homing and scalability. Improvements often address singular issues and fail to engender ‘repair-ready’ cells. Methods We developed GNTI-823, an engineering strategy to generate Tregs (EngTreg) from human CD4 T cells that constitutively express FOXP3 for stability and scalability; contain a rapamycin-activated chemically induced IL-2 signaling complex (CISC) for persistence; and express the IL-33-responsive alarmin receptor ST2 for inflammatory-homing and in vivo functionality. Results ST2 expression successfully conferred a ‘Tissue’ Treg phenotype, characterized by high expression of inflammatory homing receptors, metabolic genes and tolerogenic factors absent from non-ST2 EngTregs or circulating Tregs. Indeed, in a model of ischemic stroke, ST2-EngTreg cells demonstrated preferential homing and improved sensorimotor, learning and memory outcomes. in vitro, ST2-EngTregs sequestered higher amounts per cell of inflammatory factors, IL-33, TNF and IL2 that limit macrophage/microglial and T cell activation. Lastly, ST2-EngTregs remained stable and persisted under prolonged inflammatory and IL-2 scarce conditions. Conclusion Thus, GNTI-823 EngTregs are designed to home, function and persist in neuroinflammatory sites, which show pre-clinical promise for the treatment of ischemic stroke and other neuroinflammatory and degenerative conditions. Funding Source NIH SBIR Topic Categories Translational and Interventional Immunology (TI)

Discovery of highly potent and selective VAV1 molecular glue degraders for the treatment of inflammatory disorders 2332299

Abstract Introduction VAV1 is a highly specific target for immune-mediated diseases. VAV1 functions as a guanine nucleotide exchange factor (GEF) in T- and B-cell receptor signaling and is essential for immune cell activation, proliferation, and inflammatory responses. Despite its therapeutic potential, VAV1 has historically been difficult to target with small molecules due to its multidomain architecture and dual roles as both a GEF and a scaffolding protein involved in GEF-independent signaling pathways. Here, we describe a novel protein degradation strategy using molecular glue degraders (MGDs) to overcome these challenges. Methods Endogenous Vav1 protein levels were detected in Jurkat cells by HiBiT assay. In human and mouse whole blood assays, cells were profiled for VAV1 levels in CD3+ T cells with flow cytometry. Label-free mass spectrometry with data-independent acquisition (DIA) proteomics were used to detect protein abundance levels in human PBMC treated with compounds. In vivo pharmacokinetics and efficacies of the compounds upon oral treatment were evaluated in ICR mice and inflammatory disease models including collagen-induced arthritis (CIA), experimental autoimmune encephalomyelitis (EAE) and naïve CD4+ T cell transfer model of inflammatory bowel disease (IBD). Results The compounds demonstrated robust VAV1 degradation in both cellular and whole blood assays. The half-maximal degradation concentration (DC50) ranged from sub-nanomolar to low nanomolar, with Dmax values exceeding 95%. Proteomics analysis of human PBMCs confirmed consistent and selective VAV1 degradation. Oral administration of the compounds in animal models resulted in dose-dependent VAV1 degradation and corresponding improvements in disease scores. Conclusion We have discovered potent and selective VAV1 molecular glue degraders with favorable in vivo pharmacokinetic and pharmacodynamic properties. Further investigations are needed to explore their potential in treating a range of inflammatory conditions, including neuroinflammation. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)

An In Situ H ₂ S‐Activated Plasmonic Nanozyme for Near‐Infrared II Photo‐Thermoelectric Catalytic Therapy

ABSTRACT Thermoelectric catalytic therapy represents an emerging therapeutic modality for diverse diseases such as cancer, but faces limitations in efficacy and safety due to low thermoelectric efficiency and systemic toxicity risks. Herein, we report an in situ H 2 S‐activated plasmonic nanozyme, Cu 2 O‐HTB@D, fabricated by co‐loading Cu 2 O nanoparticles and 4‐hydroxythiobenzamide (4‐HTB) into tetrasulfide‐rich dendritic mesoporous organosilica nanoparticles (DMONs) for near‐infrared II (NIR‐II) plasmonic thermoelectric (PTE) cancer catalytic therapy. Upon accumulation in the tumor microenvironment, the tetrasulfide‐rich DMON framework reacts with overexpressed glutathione (GSH), triggering structural disintegration and release of Cu 2 O and 4‐HTB. Subsequently, H 2 S generated from the reaction of DMONs and 4‐HTB with GSH induces in situ conversion of Cu 2 O into Cu 2‐x S. The resulting Cu 2‐x S exhibits strong NIR‐II plasmonic and PTE properties with peroxidase‐, catalase‐ and oxidase‐like multi‐enzymatic activities, enabling robust ∙OH and ˙O 2 ‾ generation amplified by plasmonic hyperthermia and PTE effects under 1064 nm laser irradiation. In vivo studies demonstrate exceptional tumor suppression in a triple‐negative breast cancer murine model with high targeting specificity and minimal systemic toxicity after intravenous administration of Cu 2 O‐HTB@D. This strategy highlights a clinically translatable approach for spatially controlled catalytic therapy via in situ generation of plasmonic nanozymes.

All-Oral Combination of Revumenib, Decitabine, and Venetoclax for Relapsed or Refractory AML (SAVE)

PURPOSE Revumenib is an oral inhibitor of menin-KMT2A, a key dependency in acute myeloid leukemia (AML) with KMT2A rearrangement ( KMT2Ar ), NPM1 mutation ( NPM1mt ), or NUP98 rearrangement ( NUP98r ). Preclinical studies suggest synergy with BCL2 inhibition. METHODS In this phase I-II study, we evaluated an all-oral regimen of revumenib, decitabine/cedazuridine, and venetoclax in patients 12 years and older with relapsed or refractory AML. Decitabine/cedazuridine was given on days 1-5, venetoclax on days 1-14, and revumenib twice daily on days 1-28. The primary objectives were to determine the recommended phase II dose (RP2D) and to assess efficacy according to the composite complete remission (CRc) rate. RESULTS Forty-two patients were enrolled (median age, 40 years; range, 12-82) including 40% with KMT2Ar, 38% with NPM1mt , and 21% with NUP98r. Patients had a median of two prior lines of therapy; 52% had prior venetoclax. The RP2D of revumenib was 160 mg twice daily with a strong CYP3A4 inhibitor. Grade ≥3 adverse events included febrile neutropenia (36%), lung infection (21%), and thrombocytopenia (21%). Differentiation syndrome occurred in 10% (5% grade 3) and resolved with glucocorticoids. The CRc rate was 71%, and the CR or complete remission with partial hematologic recovery (CR/CRh) rate was 60%, with measurable residual disease negativity by flow cytometry in 80% of these patients. The median duration of CR/CRh for all patients was 10.5 months, not reached in KMT2Ar , 10.7 months in NPM1mt , and 5.9 months in NUP98r . Emergent mutations in the menin-binding site occurred in 13%. CONCLUSION This combination was associated with high response rates and durable remissions, with an acceptable safety, in heavily pretreated patients with AML harboring alterations susceptible to menin inhibition.

Longitudinal dynamics of the maternal gut virome associate with metabolic features of preterm birth

RNF43 p.G659fs activates the PI3K/AKT-HLA-E axis to drive NK cell dysfunction in MSI-high colorectal cancer 2257795

Abstract Introduction The RNF43 p.G659fs (RNF43659mut) mutation is a recurrent alteration in ∼8% of colorectal cancers (CRCs), enriched in microsatellite instability-high (MSI-H) tumors. While this mutation activates the PI3K/AKT pathway independent of WNT signaling, its immunologic impact remains undefined. Given the central role of PI3K/AKT/mTOR signaling in immune evasion, we investigated how RNF43659mut influences natural killer (NK) cell function in MSI-H CRC. Methods Single-cell RNA sequencing and multiplex immunohistochemistry of MSI-H CRC tumors were integrated with in vitro coculture assays using RNF43659mut isogenic lines and MSI-H patient derived organoids (PDOs). NK cell phenotypes were assessed by bulk RNA sequencing and flow cytometry, while pharmacologic and siRNA-based inhibition probed PI3K/AKT pathway dependence. Spatial analyses mapped PI3K/AKT activation, HLA-E expression, and NK cell localization within patient tumors. Results RNF43659mut tumors exhibited increased NK cell infiltration but marked functional exhaustion, characterized by reduced CD56dim/CD56bright subsets, lower activation markers (CD16, NKG2D), and elevated inhibitory receptors (NKG2A, TIM3, KIR3DL1). Mechanistically, RNF43659mut driven PI3K/AKT activation upregulated HLA-E, leading to suppression of NK cytotoxicity. PI3K/AKT blockade using inhibitors or siRNA restored NK activity and enhanced tumor cell killing in cocultures. Spatial profiling revealed NKG2A+ NK cells juxtaposed to HLA-E+, PI3K/AKT-activated tumor cells, indicating a localized immunosuppressive niche. Conclusion RNF43659mut establishes an immune evasive microenvironment in MSI-H CRC through PI3K/AKT-dependent HLA-E induction and NK cell dysfunction. Targeting the PI3K/AKT-HLA-E/NKG2A axis represents a promising strategy to reverse immune suppression and improve immunotherapy response in MSI-H colorectal cancer. Funding Source NA Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

One-carbon metabolism reprograms macrophages under inflammatory environments to drive efferocytosis and resolution 2260124

Abstract Introduction Macrophages resolve inflammation to maintain tissue homeostasis by clearing apoptotic cells, a process known as efferocytosis. Immune—metabolic interactions are proposed to regulate macrophage functions; however, the role of one-carbon (1C) metabolism metabolites–serine, glycine, and methionine– in resolution remains unclear. Levels of 1C metabolites are reduced in diabetes, a condition that induces non-resolution after wound injury. Methods Mouse bone marrow derived macrophages (BMDMs) were cultured in physiological media supplemented with 1C metabolites. Efferocytosis using live cell imaging, lipid droplet (LD) accumulation, and gene/protein expression were analyzed. Diabetic (db/db) mice after dorsal skin biopsy were studied as a model of 1C deficiency and non-resolution. Results Supplementing BMDMs with 1C metabolites–serine and methionine–enhanced efferocytosis specifically in an inflammatory environment, which exhibited reduced efferocytosis compared to normal or anti-inflammatory environments. Enhanced efferocytosis by 1C was accompanied by decreased LD formation. Pharmacological manipulation identified that the amino acid—sensing mTORC1 and methylation through S-adenosylmethionine were required for 1C-induced lipid metabolism and efferocytosis. RNA-seq revealed that 1C induced-resolution reprogramming included LD dynamics, lipid metabolism, and efferocytosis as well as upregulated cell cycle genes and downregulated inflammatory response, highlighting a role in methylation-dependent gene regulation in macrophages. In vivo, wound macrophages in the inflammatory phase accumulated LD, which was inhibited by serine supplementation. Systemic but not topical serine supplementation promoted wound closure in db/db mice. Conclusion 1C metabolism promotes pro-resolution programming in macrophages in inflammatory environments through amino acid sensing and methylation-dependent gene regulation. Serine supplementation may induce such programming in wound macrophages to promote wound healing. Funding Source NIGMS, NIDDK Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

Rapid expansion and comprehensive profiling of lung tumor infiltrating lymphocytes using a highly scalable TCR sequencing method 2258388

Abstract Introduction Tumor infiltrating lymphocytes (TILs) have the ability to migrate into the tumor microenvironment (TME), recognize malignant cells, and achieve their clearance. Recent trials leveraging adoptive cell therapy (ACT) with ex-vivo expanded TILs in solid cancers have been successful in achieving disease remission. Their success relies heavily on persistence of tumor-specific TILs in circulation in patients after ACT administration. Two main challenges that have been slowing down the large-scale production of these therapies are the absence of fast and contamination-free TIL expansion protocols and the need for methods to assess the functional state and clonotype make-up of the TIL product prior to infusion. Methods Here we showcase newly developed methods to overcome these challenges and demonstrate their utility by generating a lung tumor TILs multimodal single cell dataset. Results Specifically, we demonstrate that the CliniMACS Prodigy Platform is able to quickly and reliably expand tumor infiltrating T cells in less than 2 weeks and perform single cell immune profiling sequencing in a subset of these cells to characterize their transcriptional state and dissect their T cell receptor (TCR) diversity. Using the gene expression data, we identify all expected T cell subsets using canonical cell type markers. Furthermore, we show we can detect paired TCR CDR3α/β sequences > 92% of the cells profiled. Using this information, we estimate the frequency of each CDR3 clonotype and identify hyperexpanded clonotypes that might be tumor reactive and are good candidates for further investigation. Conclusion Overall, we developed methods for the rapid expansion and deep profiling of TILs. We performed a proof of concept experiment that demonstrated their utility and identified expanded clonotypes that can be used to inform the design of future immunotherapies. We hope our methods will enable immunologists to create safer, faster and patient-specific treatments that achieve long-term tumor remission. Funding Source n/a Topic Categories Technological Innovations in Immunology (TECH)

Microbiome-Derived RNA as a Trigger for Heritable Innate Immunity 2252988

Abstract Introduction The microbiome shapes host immunity, yet the molecular signals by which specific bacteria modulate innate defenses remain poorly understood. In Caenorhabditis elegans, the Intracellular Pathogen Response (IPR) is a transcriptional program activated by obligate intracellular pathogens and shares features with mammalian type I interferon responses. We aimed to identify microbiome-derived triggers of the IPR and mechanisms of host protection. Methods We screened twelve native bacterial isolates using an IPR GFP reporter. Reporter activation in different tissues was observed by microscopy, and bacterial inactivation or RNA treatments were used to identify the molecular triggers. Transcriptomic profiling (RNA-seq, qRT-PCR) identified host genes induced by bacterial exposure. Pathogen burden was quantified by FISH, and developmental assays measured fitness effects. Results Stenotrophomonas indicatrix (JUb19) robustly activated the IPR in intestine, epidermis, neurons, and somatic gonad despite residing extracellularly, making it the first non-invasive bacterium known to trigger this pathway. Heat-killed bacteria failed to induce the IPR, whereas chemical or mechanical inactivation retained activity, implicating a heat-labile trigger. Bacterial RNA contributed to IPR activation, revealing microbiome RNA as a novel immune signal. Transcriptomic analyses showed induction of IPR genes, lysozymes, and metabolic regulators that enhance resistance to intracellular pathogens, with modest fitness costs. Remarkably, protection was inherited by naïve progeny that had never been exposed to JUb19. Conclusion Our findings identify a previously unrecognized extracellular mechanism by which microbiome-derived RNA activates epithelial immunity and provides intergenerational protection in C. elegans, linking commensal bacteria, RNA signaling, and heritable host defense. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

Site-Selective Proximity-Synthetic Editors Rewrite p53 Acetylation to Dynamically Control Treg Lineage Differentiation 2307367

Abstract Introduction Regulatory T cells arise when CD4+ T cells commit to a regulatory fate, a process essential for immune tolerance and graft acceptance but whose failure drives autoimmunity; conversely, reinforcing this program in tumors enables immune evasion. Despite this bidirectional role, no pharmacological strategy can directly control Treg lineage commitment. p53, the guardian of the genome, integrates metabolic and chromatin signals via post-translational modifications, yet its role in CD4+ T-cell fate remains poorly understood. Methods We combined in silico modeling with biochemical acetylation assays and functional immunology approaches. Lysine-selective p53 acetylation was examined using genetic and pharmacological tools. We engineered first-in-class Proximity-Synthetic Editors (PSEs), bifunctional small molecules linking a cell-penetrant p53-binding peptide to selective TIP60 or p300 activators. Treg differentiation and function were assessed in vitro and in vivo in cardiac allograft and experimental autoimmune encephalomyelitis models. Results We identify a binary p53 acetylation logic governing Treg lineage fate. TIP60-mediated acetylation of p53 at K120 is required for efficient Treg induction, whereas p300-driven C-terminal acetylation at K373—382 suppresses Treg differentiation. TIP60-directed PSEs enforce K120 acetylation, promoting Foxp3 expression and Treg differentiation, resulting in prolonged allograft survival and ameliorated EAE. Conversely, p300-directed PSEs inhibit Treg differentiation, accelerate graft rejection, and exacerbate EAE scores. Conclusion These findings define p53 acetylation as a decisive molecular code governing Treg lineage commitment and demonstrate that proximity-induced pharmacology enables direct, reversible, and site-selective control of intracellular fate decisions. By enabling bidirectional manipulation of immune tolerance with small molecules, this platform establishes a new paradigm for precision immunomodulation across autoimmunity and organ transplantation. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)

NRF2 inhibition of alveolar macrophage MHC II expression during Mycobacterium tuberculosis infection 2254024

Abstract Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major global health concern. Alveolar macrophages (AMs) are the initial host targets of Mtb. During Mtb infection, AMs up-regulate a NRF2 regulated cell-protective program, which is detrimental to host control and impedes AM activation, including MHC II expression. MHC II is critical for CD4+ T cell activation and host immunity during Mtb infection. We hypothesized that NRF2 regulates AM antigen presentation and their ability to present to T cells. Methods To investigate the importance of NRF2-mediated inhibition of MHC class II expression in AMs, we used an in vivo murine aerosol infection model and in vitro murine macrophage models, including primary AMs, ex vivo murine AMs (mexAMs) derived from WT, NRF2 KO (NRF2-/-), or NRF2 myeloid-conditional knock-out strains, and bone marrow-derived macrophages (BMDMs) as a model of recruited macrophages. Results We found that NRF2 inhibits MHC II, but not MHC I, specifically in AMs, following Mtb infection in vitro and in vivo. NRF2 dampens Ciita and H2-Ab1 gene expression in uninfected AMs, and MHC II inhibition by NRF2 is retained following innate stimuli and IFNγ exposure. Notably, NRF2 expression in Mtb-infected AMs eventually impedes their ability to activate ESAT6-specific CD4+ T cells. Conclusion Thus, although NRF2 expression enhances cell-protective functions, it has the unexpected consequence of limiting innate-adaptive crosstalk, which can impair CD4+ T cell activation and host immunity during Mtb infection. Targeting NRF2 signaling pathways in AMs represents a promising avenue for therapeutic interventions aimed at enhancing host immune defenses to limit bacterial growth. Funding Source R21AI163809 NIH/NIAID, 1R01AI77653-OIAI Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Impact of mRNA COVID-19 Vaccination on Immunometabolic Profiles in Patients with Lymphoid Malignancies 2260057

Abstract Introduction Metabolomics provides a comprehensive view of small molecules that reflect immune and physiological states. Understanding metabolic responses to vaccination reveals mechanisms of immune activation and variability. Patients with lymphoid malignancies (LM) often exhibit impaired vaccine responses, yet the metabolic basis remains unclear. This study uniquely investigates vaccine-induced metabolic remodeling in this immunocompromised population compared with healthy controls (HC). Methods A prospective cohort of 41 LM patients and 27 HC was analyzed. Plasma samples were collected before and after mRNA COVID-19 vaccination. Anti-Spike IgG levels were quantified using a single-molecule array (Simoa) assay, and untargeted metabolomics was performed using ultra-performance liquid chromatography mass spectrometry, identifying 1,492 metabolites. Multivariate clustering, pathway enrichment, and generalized additive mixed models assessed metabolic changes and responder-specific trajectories. Results Healthy controls showed a robust increase in anti-Spike antibody levels, while LM participants had lower and more heterogeneous responses. Distinct metabolic clustering was observed between LM and HC, and within LM between responders and non-responders. Enrichment analyses revealed remodeling of Amino Acid, Lipid and Energy pathways across vaccine doses. Responders showed activation of tryptophan, lysine, and fatty acid oxidation consistent with immunometabolic engagement, while non-responders showed dysregulation in acylcarnitine and lysophospholipid metabolism, suggesting altered lipid remodeling and mitochondrial function. Conclusion This study represents a unique metabolomic investigation of mRNA COVID-19 vaccination in patients with lymphoid malignancies, revealing immune activation in responders and metabolic dysregulation in non-responders. Findings highlight metabolomics as a precision tool for identifying vaccine responsiveness biomarkers and understanding immune regulation in immunocompromised hosts. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)

Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515

Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

Mitigating “Electrostrictive” Coupled‐Disruption and Crafting Endogenous Solid‐Liquid Interface Toward Mixed Phosphate Cathode for Sodium‐Ion Batteries

ABSTRACT Na 4 Fe 2 Mn(PO 4 ) 2 (P 2 O 7 ) has received widespread attention due to high energy density and less structural variations. However, its rate capability and cycling performance are far inferior to expectations. This study unveils underlying failure mechanisms for the performance degradation: “electrostrictive” coupled‐disruption driven by charge changes causes the Na + channels closure, while irregular cathode electrolyte interphase (CEI) growth hinders interface Na + diffusion and causes transition metal dissolution. Therefore, halogen elements (F, Cl, Br) are introduced into the material through defect‐engineering. The strong electronegativity of F and the spatial effects of Cl/Br effectively regulate the coordination environment to suppress the coupled‐disruption. Furthermore, the surface halogen elements spontaneously combine with Na + , ultimately forming uniform, surface organic‐rich and interior inorganic‐rich CEI layers. Based on this, the modified material shows high‐rate performance (55.0 mAh g −1 at 200 C) with ultra‐long cycle stability (98% after 20000 cycles at 50 C) and exhibits excellent electrochemical performance in full‐cell and all‐solid‐state battery applications.

Defining Cardiovascular Endpoints in Oncology Trials: Challenges and Opportunities: A Scientific Statement From the American Heart Association

The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision making, ultimately improving patient safety while supporting innovation in cancer therapeutics.

De novo L-(+)-tartaric acid biosynthesis in multi-modular engineered yeasts

Evaluating Film and Anime as Tools for Introducing Immunology to Students 2257917

Abstract Introduction Film and anime offer a unique way of relaying information to students. The goal of this study was to evaluate the use of media, specifically “Cells at Work!” (CAW), an animated series centered on immunology, and “Invasion of the Body Snatchers” (IBS), a movie used as an analogy for immunological concepts, as learning tools for immunology. Methods First-year medical students (classes of ‘27, ‘28, ‘29) at California Northstate University College of Medicine (CNUCOM) were recruited to participate. For CAW, students took a pre- and post-video quiz (Group 1) or only the post-video quiz (Group 2). For IBS, students watched the movie prior to seeing the analogies in lecture. After attending lecture, students took a subjective survey on the analogy’s effectiveness. After the summative examination, all study participants completed a subjective survey on their perception of these learning tools. Results For CAW, Group 1 (N = 53) had a pre-video average of 64.2% and post-video average of 75.5%, showing a significant increase (p-value = 0.00024). Compared to Group 1’s pre-video average, Group 2 (N = 49) had a significantly higher post-video average of 73.6% (p-value = 0.0024). The post-summative subjective survey (N = 79) revealed that 97.5% agreed that CAW would be helpful for introducing immunology to first-time learners. For IBS, the post-lecture subjective survey (N = 76) revealed that 84.2% agreed that they enjoyed and were engaged by the movie analogy. For the post-summative subjective survey (N = 61), 82% agreed that they felt more confident in their ability to learn immunology after learning the IBS analogy. Conclusion The results suggest that film and anime can be helpful tools for learning immunology, enhancing understanding and positively influencing student perceptions. This study highlights how media can be leveraged to provide a more entertaining approach to difficult subjects, supporting further exploration into less conventional educational methods. Funding Source (1) Seed grant from California Northstate University, College of Medicine; (2) Seed grant from California Northstate University, Institute for Teaching and Learning Excellence (ITLE) Topic Categories Immunology Education and Communication (EDU)

Tissue-directed maintenance of human B-cell memory after vaccination and infection 2260241

Abstract Introduction Vaccines differ in their efficacy and durability of protection. Clinical titer studies show that some, e.g. measles, confer lifelong immunity, while others wane within months or years. The memory B cells (MBCs) that sustain these responses reside mainly in lymphoid tissues, but it remains unclear whether these compartments maintain distinct subsets, how they contribute to vaccine immunity, and how they vary with age or antigen. Methods We profiled four ag-specific MBC populations, specific for childhood vaccines measles and tetanus and ubiquitous viruses SARS-CoV-2 and H1N1 influenza, across paired blood, spleen, lymph nodes, and bone marrow, by flow cytometry and paired single-cell RNA and B-cell receptor (BCR) sequencing. Results MBC isotype, subset, and phenotype differed markedly between tissue sites, specificity, and age. Lymph nodes were reservoirs for classical IgG+ memory with high expression of the residency marker CD69. In other sites, whereas measles retained a classical phenotype, tetanus MBCs were enriched for non-switched memory. Notably, SARS-CoV-2 and influenza responses were highly switched but, with age, uniquely accumulated hyporesponsive CD27- CD21- atypical memory in the blood, bone marrow, and spleen. RNA sequencing resolved three core MBC subsets enriched in distinct tissues: tissue-adapted classical MBCs in lymph nodes, marginal zone—like MBCs in spleen, and atypical MBCs in bone marrow. All three subsets were represented within ag-specific populations, but their relative proportions were shaped by both tissue and antigen. Clonal and phylogenetic analyses revealed that expanded ag-specific clones, including cells with identical BCRs, spanned multiple subsets, indicating that MBC identity is flexible but primarily shaped by local context rather than lineage. Conclusion This work uncovers functionally distinct tissue reservoirs of vaccine and infection-induced memory and the host and antigen factors that shape them, highlighting new opportunities for vaccine design. Funding Source NIH U19 AI128949, DARPA Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)