VLA1553 is a live-attenuated chikungunya virus vaccine approved for active immunization, in the EU, Brazil, Canada and the UK, as a prophylactic measure for individuals travelling to or living in areas where the chikungunya virus is circulating. Due to the unpredictable epidemic occurrence of chikungunya, a 50% micro-plaque reduction neutralization test titre (μPRNT50) of ≥150, was previously accepted by regulators as an immunological surrogate endpoint that is reasonably likely to predict clinical benefit. At this point in time, this phase 3b open-label, single-arm long-term focuses on antibody persistence in a subset (N = 363) of VLA1553 vaccinees from a pivotal phase 3 trial (Schneider et al., 2023) where 4115 adult participants received VLA1553 or placebo. At Year 4, 254 participants remained in follow-up with slightly more females than males. The population is predominantly White with no Hispanic or Latino background. The seroresponse rate was 94.5% (240/254, 95% CI 90.9% to 97.0%). The Day 29 GMT for the long-term follow-up cohort was 3542, and remained high with 1056 at Year 1, 785 at Year 2, 737 at Year 3 and 589 at Year 4, considerably exceeding the seroresponse threshold of 150. In adults aged ≥65 years, antibody persistence was similar to younger adults throughout the follow-up. Single dose vaccination with our live-attenuated chikungunya virus vaccine VLA1553 resulted in persistent neutralizing antibody titers well above the defined seroresponse threshold for at least 4 years.
A significant advancement has been made in recent years in understanding subcutaneous (SC) absorption of biologics. Still, the accurate prediction of human SC absorption of antibody-based therapeutics remains an unmet need. A review article published in 2014 (Kagan. Pharmacokinetic Modeling of the Subcutaneous Absorption of Therapeutic Proteins. Drug Metabolism and Disposition 11: 1890-1905) - summarized and categorized published pharmacokinetic (PK) models for describing SC absorption of biologics. This review provides a contemporary update and extension of the previous review based on the considerable progress in the field over the last decade with the main focus on antibody-based therapeutics. Narrative analysis of approaches utilized in clinical population PK models for describing absorption of SC products approved by the FDA was performed. Moreover, we summarized advancement in development of physiologically-based pharmacokinetic models for SC absorption (SC-PBPK), hyaluronidase-facilitated SC delivery, physics-based models of SC injection site and lymphatics, and other mechanistic models. Lastly, other quantitative approaches aimed at predicting SC absorption in humans based on in-silico, in-vitro, and in-vivo preclinical and clinical data were described. The manuscript provides a valuable tool for all professionals engaged in the development, advancement, and clinical translation of biologics, including antibody-based therapeutics.
Pregnancy in patients with primary or secondary antibody deficiencies presents unique clinical challenges shaped by impaired humoral immunity, increased susceptibility to infection, and decreased maternal-fetal placental IgG transfer. Immunologic shifts across gestation, limited B-cell reconstitution after anti-CD20 therapy, and alterations in IgG metabolism further complicate maternal and neonatal outcomes. While earlier diagnosis, advances in immunoglobulin replacement therapy (IgRT), antimicrobial prophylaxis, and management of infectious/noninfectious complications have enabled many affected patients to reach adulthood and achieve successful pregnancies, the data suggest persistently elevated risks of fetal loss, preterm birth, and neonatal hypogammaglobulinemia, particularly in patients with prior severe infection, those not yet diagnosed with antibody deficiencies, and those not receiving adequate prophylaxis. This review synthesizes current evidence on immunologic adaptation in pregnancy, infection-related and autoimmune complications, medication safety, including IgRT optimization, antimicrobial prophylaxis, and management of immunomodulatory agents. We outline practical strategies for immunologic, obstetric, and neonatal care. Safe and effective management requires individualized planning, careful IgRT dose adjustment, avoidance of teratogenic therapies, and coordinated multidisciplinary care, involving maternal-fetal medicine, immunology, and neonatology. Significant knowledge gaps persist, particularly regarding secondary antibody deficiency, neonatal immune recovery after anti-CD20 exposure, and optimal IgRT dosing across diverse inborn errors of immunity. Prospective registries, harmonized outcome definitions, and consensus-driven guidelines will be essential to improving reproductive care and long-term outcomes for mothers and infants affected by antibody deficiency.
A traumatic spinal cord injury (SCI) is caused by an acute insult to the spinal cord that inflicts severe damage to the nerve tissue and leads to impaired motor, sensory, and autonomic functions. After the initial injury, a secondary injury phase occurs, which is characterized by an excessive inflammatory response mediated by resident and infiltrating peripheral immune cells that accumulate within the spinal cord lesion. Increasing evidence supports the involvement of B cells in this secondary injury phase post-SCI. Elevated B cell numbers have been reported following experimental SCI, both within and outside of the spinal cord, as well as in human post-mortem spinal cord tissue. In the injured spinal cord, B cells have been detected at different stages of maturation and have been shown to form ectopic follicle-like structures, indicating their functional relevance post-SCI. Furthermore, enhanced B cell differentiation into antibody-secreting cells has been observed, accompanied by increased (auto)antibody levels against various central nervous system proteins. Importantly, B cell depletion and knockout mouse studies have indicated that B cells could modulate other immune cells and contribute to impaired functional recovery after traumatic SCI, highlighting the potential of targeting B cell responses in the development of more specific and personalized therapeutic strategies for SCI patients. Hence, this review provides a comprehensive overview of recent advances in understanding the role of B cells in traumatic SCI, integrating findings from both animal and human studies.
The analytical accuracy of immunoassays heavily depends on antibody-antigen recognition, but the random immobilization of antibodies on the sensing platform severely hinders recognition. This article introduces a recognition-detection split electrochemiluminescence (ECL) immunosensor with a cobalt-based metal-phenol network as a site-oriented immobilization platform. Cobalt ions enriched on gold-nanoparticle-modified magnetic beads play a significant role in anchoring the structural domains of the histidine-rich portion of the fragment crystallizable region in the antibody. Hence, the precise immobilization of the antibody and highly effective targeting of the antigen are achieved. In addition, luminescent metal-organic framework nanoreactors based on intra-reticular charge transfer mechanism are synthesized. The "two-in-one" nanoreactors integrating luminophores and co-reactants exhibit better intrinsic ECL efficiency and extrinsic ECL intensity than the luminophore alone. Magnetic-separation-based sandwich-type identification overcomes errors associated with solid-state heterogeneous incubation. The developed biosensor achieves a limit of detection of 0.3 pg/mL (S/N = 3) for heart-type fatty acid binding proteins in the detection range from 0.5 pg/mL to 100 ng/mL. The proposed "two-in-one" approach can guide the development of efficient ECL emitters, and identification based on the metal-phenol network provides an efficient route for sensing applications.
Predicting antibody and NANOBODY® VHH-antigen complexes remains a critical challenge for state-of-the-art structure prediction models, limiting their impact in therapeutic discovery pipelines. We introduce SNAC-DB, an ML-ready database and curation pipeline enriched with structural biology expertise, designed to accelerate model accuracy and generalization by providing 31-37% expanded structural diversity over existing resources like SAbDab through comprehensive re-curation that extracts maximum value from available experimental structures. SNAC-DB expands coverage by capturing often-overlooked complexes and accurately identifying complete multi-chain epitopes through improved biological-assembly based logic. Built for ML practitioners, SNAC-DB provides standardized formats with multi-threshold structure-based clustering to enable principled sample weighting during training. Using a rigorous benchmark of public PDB entries deposited post-May 2024 plus confidential therapeutic structures, we evaluate seven leading models (Protenix-v1, OpenFold-3p2, RosettaFold-3, Boltz-2, Boltz-1x, Chai-1, and AlphaFold2.3-multimer) with evaluation methodology tailored to antibody/NANOBODY® VHH-antigen complexes to ensure correct handling of multi-chain epitopes, revealing systematic performance gaps: success rates rarely exceed 25%, confidence-based ranking fails to identify best predictions even when accurate structures exist in ensembles, and all models consistently struggle with therapeutically relevant NANOBODY® VHHs. Systematic evaluation of sampling strategies demonstrates that while generating 1000 samples per target substantially increases the likelihood of producing accurate structures (oracle selection improves from 11.9% to 50.5%), confidence-based ranking remains nearly flat (between 10.9% and 14.9%), revealing that improved ranking mechanisms represent a more tractable path to performance gains. Finally, fine-tuning GeoDock on SNAC-DB yields higher success rates than training on SAbDab (11.0% vs. 7.1% for antibodies; 7.0% vs. 4.0% for NANOBODY® VHHs), suggesting that SNAC-DB's expanded structural diversity translates to improved model generalization.
Central demyelinating disorders, notably myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), exhibit diverse clinical and radiological manifestations, thereby complicating accurate diagnosis. We present the case of a 78-year-old female patient who developed progressively worsening bilateral lower limb numbness and weakness, accompanied by fecal incontinence over a two-month period. Spinal MRI identified a longitudinally extensive lesion within the spinal cord, and serological analysis revealed MOG antibodies at a titer of 1:100. The patient experienced partial clinical improvement following glucocorticoid treatment, with no further neurological decline. Nevertheless, subsequent spinal magnetic resonance angiography uncovered a spinal arteriovenous malformation. This case underscores the potential diagnostic overlap between demyelinating and vascular myelopathies and highlights that partial responsiveness to steroids and the presence of specific antibodies do not preclude concurrent vascular pathology. Therefore, comprehensive diagnostic assessment, including vascular imaging, is warranted in patients exhibiting atypical or progressive myelopathy despite evidence suggestive of immune-mediated disease. These observations emphasize the clinical heterogeneity inherent to central demyelinating disorders and contribute valuable insights into the neuroimmunological and diagnostic challenges associated with such conditions.
Antiglomerular basement membrane (anti-GBM) disease and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are uncommon causes of rapidly progressive glomerulonephritis. Their coexistence, termed double-positive disease, is rare and associated with severe renal and pulmonary manifestations. A 27-year-old male came with complaints of inflammatory polyarthralgia followed by progressive dyspnea and hemoptysis. Investigations revealed azotemia, active urinary sediment with proteinuria, bilateral pulmonary infiltrates, and dual seropositivity for anti-GBM antibodies and proteinase-3-ANCA. A diagnosis of double-positive vasculitis with pulmonary-renal syndrome was made. The treatment of the patient started with intravenous methylprednisolone, therapeutic plasma exchange, and intravenous cyclophosphamide, followed by oral glucocorticoids. Renal function improved significantly, with serum creatinine decreasing from 2.44 mg/dL at presentation to 1.42 mg/dL at discharge. The patient remained clinically stable during follow-up. Double-positive anti-GBM and ANCA disease represents a distinct clinical entity with overlapping features of both conditions. Early recognition and aggressive immunosuppressive therapy can result in favorable renal outcomes. RésuméLa maladie des anticorps anti-membrane basale glomérulaire (anti-MBG) et les vascularites associées aux anticorps anti-cytoplasme des neutrophiles (ANCA) constituent des causes peu fréquentes de glomérulonéphrite rapidement progressive. Leur coexistence, qualifiée de « maladie à double positivité », est rare et s’accompagne de manifestations rénales et pulmonaires sévères. Un patient âgé de 27 ans s’est présenté pour des plaintes de polyarthralgies inflammatoires, suivies d’une dyspnée progressive et d’une hémoptysie. Les examens complémentaires ont révélé une azotémie, un sédiment urinaire actif avec protéinurie, des infiltrats pulmonaires bilatéraux et une double séropositivité pour les anticorps anti-MBG et les ANCA anti-protéinase 3. Le diagnostic de vascularite à double positivité, associée à un syndrome pneumorénal, a été posé. Le traitement du patient a débuté par l’administration intraveineuse de méthylprednisolone, des échanges plasmatiques thérapeutiques et de la cyclophosphamide par voie intraveineuse, suivis par des glucocorticoïdes par voie orale. La fonction rénale s’est nettement améliorée, la créatininémie passant de 2,44 mg/dL lors de la présentation initiale à 1,42 mg/dL au moment de la sortie. Le patient est demeuré cliniquement stable au cours du suivi. La maladie à double positivité anti-MBG et ANCA constitue une entité clinique distincte, présentant des caractéristiques communes aux deux affections. Un diagnostic précoce et une thérapie immunosuppressive intensive peuvent permettre d’obtenir un pronostic rénal favorable.
暂无摘要（点击查看详情）
暂无摘要（点击查看详情）
In the 2023-24 influenza season, adults born in the 1957-1985 birth cohort had the lowest vaccine effectiveness (VE) against A(H1N1)pdm09 viruses than other age groups, including those in the 1986-2005 birth cohort. Here, we investigated A(H1N1)pdm09 antibody levels in sera collected from influenza cases and controls to explain the birth cohort effect of the low VE. Acute sera within 7 days and convalescent sera at 28 days post-symptom onset were collected from adult patients (18-66 years, 1986-2005 and 1957-1985 birth cohorts) enrolled in the US Influenza VE Network study during the 2023-2024 season. Hemagglutination inhibiting (HI) antibodies and binding antibodies in sera were assessed against representative A(H1N1) viruses and hemagglutinin antigens. A(H1N1)pdm09-infected cases in the 1957-1985 birth cohort had significantly lower HI antibodies in the acute sera against circulating A(H1N1)pdm09 viruses in 2023-24 season than those born in 1986-2005. Over 60% of the cases in the 1957-1985 birth cohort had HI antibodies ≤10 to the circulating A(H1N1)pdm09 viruses. Nonetheless, vaccinated cases in the same 1957-1985 birth cohort were able to mount robust antibody responses to A(H1N1)pdm09 virus infection, suggesting low vaccine immunogenicity. Antibody landscape analysis by both HI and binding antibodies revealed that these patients born in 1957-1985 with the lowest VE were likely primed with USSR/77-like A(H1N1) viruses. HI antibody levels in the acute sera around the time of encountering influenza viruses were associated with protection against influenza A(H1N1)pdm09 infection. Improving immunogenicity of the vaccines could help improve VE and overcome the birth cohort effects.
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants. Two effective preventive strategies exist: maternal RSV Prefusion F vaccination during pregnancy and child immunisation with monoclonal antibodies. To assess pregnant individuals' acceptance of, and preferences between, maternal RSV vaccination and infant monoclonal antibodies across diverse global settings after receiving standardized information on RSV risks and expected protective benefits. Cross-sectional study conducted between March 2024 and March 2025 among pregnant individuals recruited by convenience sampling in partner centres across eight countries (Brazil, Canada, Colombia, Spain, France, Italy, Luxembourg, and Switzerland). The primary outcome was acceptance of RSV vaccination during pregnancy, and the secondary outcome was preference between maternal RSV vaccination and infant Nirsevimab; associated factors were assessed using multivariable logistic regression, with country group included as a design-related adjustment variable. Among 887 participants, 675 (76.1%) reported accepting RSV vaccination during pregnancy: 96 (10.8%) were already vaccinated and 579 (65.3%) would have liked to receive it when available. Acceptance of the RSV vaccine during pregnancy differed across main study sites, ranging from 70.4% in Switzerland to 79.1% in Colombia. Factors independently associated with willingness to be vaccinated included having a child previously hospitalised in neonatal intensive care unit, uptake of other recommended vaccines during pregnancy, and perceiving a positive influence from health authorities. Most of participants (69.8%, 619/887) preferred maternal RSV vaccination over child immunisation with monoclonal antibody administration (14.5%, 129/887). Factors independently associated with vaccination preference included: having received other recommended vaccines during pregnancy, whereas history of pre-eclampsia or perception of foetal or obstetrical risk associated with this vaccine favoured preference for the monoclonal antibody. Additional motivations for preferring maternal RSV vaccination included: avoiding an extra injection for the newborn, perceived greater efficacy, and a preference for endogenous antibody-mediated protection. This multinational study demonstrates high acceptance of maternal RSV vaccination and a predominant preference for this strategy over infant immunisation. These findings highlight the importance of tailored communication addressing pregnant individuals' concerns about safety and efficacy, alongside policies that align with parental vaccination preferences to facilitate effective implementation.
This study sought to evaluate the clinical implications of thrombocytopenia in pediatric patients diagnosed with systemic lupus erythematosus (SLE) and to explore its relationship with various disease features. Furthermore, the research aimed to identify risk factors that affect the occurrence of SLE-associated thrombocytopenia. A single-center retrospective study was conducted involving 236 pediatric patients diagnosed with SLE at Children's Hospital of Fudan University from January 2020 and December 2025. Clinical information and laboratory parameters, such as complement levels, autoantibody profiles, and platelet counts, were systematically collected. Participants were divided into two groups and those without, based on their platelet counts at the time they were diagnosed with SLE. The presence of thrombocytopenia was determined at diagnosis, and further subgroup analyses were carried out based on the severity of the condition. All statistical analyses, such as logistic regression and one-way ANOVA, were conducted using SPSS version 26.0. Thrombocytopenia was observed in 19.5% (46 out of 236) of the patients. In comparison to the cohort without thrombocytopenia, the thrombocytopenia group demonstrated significantly increased incidences of leukopenia, leukocyte reduction, and positivity for antiphospholipid antibody IgM, anti-β2-glycoprotein-1 antibody, and lupus anticoagulant (P < 0.05). Furthermore, severe thrombocytopenia (defined as a platelet count below 50 × 10⁹/L) was correlated with a markedly higher prevalence of lupus anticoagulant positivity relative to the mild-to-moderate thrombocytopenia subgroup. Logistic regression analysis revealed that leukopenia, elevated erythrocyte sedimentation rate (ESR), positivity for Anti-β2 glycoprotein 1 antibodies, high lupus anticoagulant, and neuropsychiatric manifestations were significantly associated with the presence of thrombocytopenia. Thrombocytopenia frequently occurs in pediatric patients with SLE and demonstrates a significant correlation with leukopenia, the presence of antiphospholipid antibodies, and involvement of major organs. Additionally, further multicenter prospective investigations are necessary to clarify the contribution of platelets to the pathogenesis of SLE. In clinical practice, when thrombocytopenia is identified in pediatric SLE patients, thorough evaluation for antiphospholipid antibodies and neuropsychiatric systemic lupus erythematosus (NPSLE) is warranted.
Dengue virus (DENV) continues to pose a major global health challenge, with widespread distribution, frequent outbreaks, and four antigenically distinct serotypes complicating efforts for effective prevention and treatment. Despite decades of research, no universally protective vaccine or widely approved therapeutic exists, and the risk of antibody-dependent enhancement further complicates intervention strategies. This review provides an integrated perspective on dengue prevention and treatment, positioning vaccines, monoclonal antibodies, antiviral drugs, and host-directed therapies along the continuum of infection. It synthesizes recent advances in dengue prophylaxis and therapy, highlighting key innovations in vaccines, monoclonal antibodies, and antiviral compounds. Live-attenuated and chimeric tetravalent vaccines have progressed from early development to advanced clinical trials, demonstrating promising immunogenicity, safety, and potential for simplified dosing regimens. Concurrently, engineered monoclonal antibodies targeting conserved viral epitopes have improved neutralization breadth and reduced enhancement risk, while combination strategies may further limit viral escape. Antiviral development has explored both direct-acting and host-directed mechanisms, revealing potent candidates in preclinical models, although clinical translation remains challenging. Together, these advances illustrate a multifaceted approach to dengue control, integrating vaccine optimization, rational antibody design, and targeted therapeutics. By contextualizing recent progress and remaining challenges, this review underscores the urgent need for coordinated efforts to develop safe, effective, and broadly deployable interventions, ultimately supporting global efforts to reduce the burden of dengue.Trial registration: ClinicalTrials.gov identifier: NCT04722627..Trial registration: ClinicalTrials.gov identifier: NCT05201794..Trial registration: ClinicalTrials.gov identifier: NCT06006559..Trial registration: ClinicalTrials.gov identifier: nct05710224..Trial registration: ClinicalTrials.gov identifier: NCT04273217..Trial registration: ClinicalTrials.gov identifier: NCT06799741..Trial registration: Clinical Trials Registry India identifier: CTRI/2021/07/035290..
Despite the reduced clinical severity of Omicron SARS-CoV-2 variants compared to earlier lineages, kidney transplant recipients (KTR) continue to experience higher SARS-CoV-2 mortality rates than the general population. Seroconversion rates following SARS-CoV-2 mRNA vaccination remain lower in KTR after three vaccine injections. We evaluated anti-SARS-CoV-2 neutralizing antibody activity and cellular responses, as well as whole blood gene expression profiles after XBB.1.5 mRNA vaccination boost in a cohort of KTR. We demonstrated that XBB.1.5 mRNA boosting increased both the magnitude and frequency of neutralizing antibody responses against different SARS-CoV-2 variants and found that the neutralizing activity against Wuhan strain or XBB.1.5 subvariant was driven by different anti-Spike binding IgG subclasses. We also demonstrated that Spike-specific CD4⁺ T-cell responses were significantly boosted against Wuhan strain and XBB.1.5 subvariant one month following XBB.1.5 mRNA vaccination. Lastly, we showed that XBB.1.5 boost induced overexpression of genes associated with type I IFN and innate immune responses at day 1, but also activated T and NK-cells at day 3 that persist at day 7 post-vaccination. Globally, increasing the number of vaccine injections using updated XBB.1.5 mRNA vaccine enhance anti-SARS-CoV-2 immune responses in KTR. However, the monovalent XBB.1.5 mRNA vaccine boost elicited recall of cross-reacting immune responses against the original Wuhan Spike without a clear advantage against Omicron subvariants, consistent with a predominant immunological imprinting.
Autoimmune encephalitis (AE) is an important and potentially reversible cause of subacute cognitive and neurological decline. A significant proportion of patients remain seronegative for known neuronal antibodies or harbor unclassified antibodies, posing diagnostic challenges. We report two cases of suspected AE associated with unclassified neuronal antibodies. The first case involved a 42-year-old male presenting with focal seizures followed by rapidly progressive cognitive decline, mutism, and spasticity. Magnetic resonance imaging revealed multifocal cortical-subcortical T2-FLAIR hyperintensities, while cerebrospinal fluid (CSF) and conventional autoimmune and paraneoplastic antibody panels were noncontributory. The second case was a 70-year-old male with insidious cognitive decline, Parkinsonism, autonomic dysfunction, and fluctuating cognition. Neuroimaging was unremarkable, and CSF showed elevated protein with lymphocytic predominance. In both cases, serum testing demonstrated unclassified neuronal antibodies. Both patients received immunomodulatory therapy including high-dose corticosteroids, intravenous immunoglobulin, rituximab, and plasmapheresis, resulting in clinical stabilization and cognitive improvement. These cases emphasize the importance of considering autoimmune encephalitis in patients presenting with gradually worsening cognitive and neurological symptoms, despite negative routine antibody panels. Early clinical suspicion and prompt immunotherapy are crucial for improved outcomes. RésuméL’encéphalite auto-immune (EA) est une cause importante et potentiellement réversible de déclin cognitif et neurologique subaigu. Cependant, une proportion significative de patients reste séronégative pour les anticorps neuronaux connus ou présente des anticorps non classés, ce qui pose des difficultés diagnostiques. Nous rapportons deux cas suspects d’EA associés à des anticorps neuronaux non classés. Le premier cas concernait un homme de 42 ans présentant des crises focales suivies d’un déclin cognitif rapidement progressif, d’un mutisme et d’une spasticité. L’imagerie par résonance magnétique a montré des hyperintensités T2-FLAIR corticales et sous-corticales multifocales, tandis que l’analyse du liquide céphalo-rachidien (LCR) et les panels d’anticorps auto-immuns et paranéoplasiques conventionnels étaient non contributifs. Le second cas concernait un homme de 70 ans présentant un déclin cognitif insidieux, un syndrome parkinsonien, une dysautonomie et des fluctuations cognitives. La neuro-imagerie était sans particularité, et le LCR montrait une hyperprotéinorachie avec prédominance lymphocytaire. Dans les deux cas, les tests sériques ont révélé des anticorps neuronaux non classés. Les deux patients ont été traités par immunothérapie, incluant des corticostéroïdes à forte dose, des immunoglobulines intraveineuses, du rituximab et des échanges plasmatiques, avec stabilisation clinique et amélioration cognitive. Ces cas soulignent que l’encéphalite auto-immune doit être envisagée chez les patients présentant des symptômes cognitifs et neurologiques subaigus ou progressifs, même lorsque les tests d’anticorps standards sont négatifs. Une suspicion clinique précoce et un traitement immunomodulateur rapide sont essentiels pour améliorer le pronostic.
Comprehensive mapping of drug-induced metabolic alterations is crucial for understanding the mechanisms of targeted therapies. Antibody-drug conjugates (ADCs) such as trastuzumab emtansine (T-DM1) have revolutionized targeted cancer therapy by combining antibody specificity with cytotoxic potency. However, the metabolic reprogramming underlying their therapeutic action and systemic effects remains poorly understood. Here, we applied high-performance liquid chromatography-mass spectrometry (HPLC-MS)-based metabolomics to profile tumor and plasma metabolic alterations in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model at 4- and 7-days following T-DM1 treatment, corresponding to the period of pronounced antitumor activity. A total of 32 significantly altered metabolites were identified in tumor tissues, mapping to pathways including tricarboxylic acid (TCA) cycle, pyrimidine metabolism and lipid metabolism, reflecting disruption in energy production and macromolecular biosynthesis. In plasma, 12 significantly altered metabolites were identified, predominantly affecting histidine, glutamine, taurine, tryptophan, and tyrosine metabolism. Integrated analysis further revealed two compartment-specific metabolites-hippuric acid and uric acid-showing opposite trends, with elevated levels in tumors and reduced levels in plasma. These bidirectional changes indicate a metabolic coupling between tumor and circulation, driven by differential utilization and excretion processes during T-DM1 response. Collectively, our findings demonstrate that T-DM1 elicits coordinated local and systemic metabolic reprogramming, providing mechanistic insights into its antitumor activity and the metabolic coupling between tumor and circulation.
Postoperative stimulated thyroglobulin (ps-Tg) is an established biomarker for assessing treatment response in papillary thyroid carcinoma (PTC), but optimal integration of biochemical parameters into the 2025 American Thyroid Association (ATA) recurrence risk stratification system remains undefined. We retrospectively analyzed 1,117 PTC patients who underwent first radioactive iodine (RAI) therapy at the First Affiliated Hospital of Jinan University between 2015 and 2021. Two models were built to estimate the probability of achieving an excellent response (ER) 1 year after RAI: Model 1 included all variables selected by LASSO (pathological N stage, 2025 ATA recurrence risk stratification, ps-Tg, ps-Tg/thyroid-stimulating hormone [TSH] ratio, and thyroglobulin antibody [TgAb]); Model 2 served as a control, including only pathological N stage and recurrence risk stratification. Model performance was evaluated using receiver operating characteristic (ROC) analysis, LASSO regression, decision curve analysis (DCA), and net reclassification improvement (NRI). ROC analysis identified optimal cut-off values of 4.10 ng/mL for ps-Tg and 0.07 for the ps-Tg/TSH ratio (area under the curve [AUC] 0.856 and 0.843, respectively). In the training cohort, Model 1 outperformed Model 2 (AUC 0.862 vs. 0.614; R2 0.531 vs. 0.056) and significantly improved reclassification (IDI 0.389; overall NRI 0.297; event NRI 0.163). DCA demonstrated greater clinical net benefit for Model 1 across risk thresholds of 0.02-0.80, and findings in the validation cohort were consistent. Based on ps-Tg, the ps-Tg/TSH ratio, TgAb, pathological N stage, and the ATA 2025 recurrence risk stratification, the combined model showed good predictive value for 1-year ER after RAI therapy in patients with PTC. This model may serve as a complementary tool to existing postoperative risk assessment and provide additional support for follow-up stratification and individualized management.
Plasma neurofilament light chain (NfL) has been identified as a promising early-stage Alzheimer's disease (AD) biomarker, reflecting neuroaxonal degeneration at preclinical stages. However, its extremely low concentration in blood presents a major analytical challenge. Although single-molecule array (Simoa) assays provide exceptional sensitivity, they remain costly, instrumentation-intensive, and difficult to implement in decentralized settings. Here, we report the identification and engineering of high-affinity DNA aptamers against NfL using capillary electrophoresis-SELEX. Solution-phase fluorescence polarization was used to evaluate the binding capability of the aptamer candidates and the effect of aptamer truncation. Molecular modelling provided structural insights into aptamer-protein interactions, thereby supporting the rational optimization of aptamer design. The optimized truncated aptamers were integrated onto microfabricated gold electrodes to construct electrochemical aptasensors, exhibiting a Kd value of 1.67 ± 0.47 nM. To further enhance analytical performance, the aptamers were implemented in ion-gated organic electrochemical transistors (iOECTs), yielding an ultrasensitive and highly selective platform capable of detecting NfL in 0.1 × human serum with an ultralow limit of detection of 9 aM. This work establishes a scalable, minimally invasive, cost-effective alternative to antibody-based assays and provides a versatile biosensing strategy for early neurodegenerative disease diagnostics.