搜索结果：Toxics

N-Nitrosodimethylamine (NDMA) is present in food, water, and drugs and is considered a probable human carcinogen by the International Agency for Research on Cancer. The mechanism of action of NDMA involves the generation of carcinogenic methyl lesions such as 3-methyladenine (3MeA) on DNA bases. Alkyladenine DNA Glycosylase (AAG; a.k.a. N-methylpurine DNA glycosylase, MPG) removes 3MeA to initiate Base Excision Repair, leaving an abasic site that is resolved by backbone cleavage, nucleotide insertion, and backbone ligation. The intermediate steps following base removal produce potentially toxic and mutagenic abasic sites and single-strand DNA breaks. Here, we explored differences between males and females regarding downstream DNA damage, toxicity, mutations and cancer arising from 3MeA in the livers of WT, Aag-/-, and Aag-overexpressing (AagTg) mice. We found that males were more susceptible to NDMA-induced mutations (WT and Aag-/-) and cancer (all genotypes). In contrast, AagTg females were more prone to micronucleus induction. As we showed in our prior analyses where data were pooled for males and females, Aag-/- mice were significantly more susceptible to NDMA-induced mutations and cancer, and AagTg mice displayed significantly greater toxicity. Building on these findings, our analyses of sex-related differences show that Aag deficiency and maleness are both susceptibility factors for NDMA-induced hepatic cancer, while Aag overexpression drives toxicity, potentially with a greater effect in females. This study reveals a deeper understanding of the underpinnings for a well-known increased risk of hepatic cancer in men versus women by demonstrating a higher susceptibility of male mice to both mutations and cancer.

We conducted a phase II study of fludarabine, thiotepa, reduced dose melphalan conditioning for allogeneic transplantation using alternate donors. Thirty-eight patients with hematological malignancies were enrolled. Conditioning included fludarabine 160 mg/m2, thiotepa 10 mg/kg (dose adjusted to 5 mg/kg for age >60 years) and melphalan 100 mg/m2. Sixteen patients (42%) received reduced intensity thiotepa (5 mg/kg). Twenty-one patients (55%) had acute myeloid leukemia, rest had acute lymphoblastic leukemia, myelodysplastic syndrome, myelofibrosis and relapsed high-risk lymphomas. Twenty-eight (74%) underwent haplo-identical transplants-rest received double cord blood grafts. With median follow up of 38 months, Day +100 marrow demonstrated morphologic complete remission in 34/38 evaluable patients. Progression-free survival at 1-, 2- and 3-year was 68%, 63% and 63%, respectively. Overall survival at 1-, 2- and 3-year was 76%, 71% and 64%, respectively. One-year non-relapse mortality was 21% and relapse rate was 11%. Twelve patients received post-transplant maintenance therapy. We conclude that fludarabine/thiotepa/low dose melphalan can induce durable long-term remissions in patients with advanced disease.

Methyl red (MR) is a widely used azo dye in various industries, and its uncontrolled discharge into aquatic ecosystems poses serious health and environmental concerns owing to its persistence, toxicity, and resistance to conventional treatment methods. Therefore, the development of efficient and sustainable technologies for MR removal has become an important research priority. This review critically summarizes recent advances in the catalytic reduction and photocatalytic degradation of MR using metal nanoparticles and semiconductor-based materials. The synthesis strategies and characterization techniques employed for metal nanoparticles and photocatalysts are discussed which emphasis on their structural, morphological, optical, and electronic properties. Various catalytic systems like mono-metallic, bi-metallic, tri-metallic, and tetra-metallic nanoparticles are comprehensively evaluated for NaBH4-assisted reduction of MR, while semiconductor photocatalysts and hybrid nanocomposites are examined for photocatalytic and oxidative degradation applications. The fundamental mechanisms governing electron transfer, hydrogen atom transfer, reactive oxygen species generation, and azo bond cleavage are critically analyzed. Moreover, the influence of operational parameters like catalyst composition, light intensity, pH, catalyst loading, particle size, dye concentration, temperature, and oxidant dosage on reaction efficiency is systematically discussed. Particular attention is given to catalyst stability, recyclability, thermodynamic aspects, and the role of support materials in enhancing catalytic performance. Current challenges like incomplete mineralization, metal leaching, nanoparticle aggregation, and limitations associated with real wastewater treatment which are also highlighted. Finally, future perspectives focusing on multifunctional nanomaterials, solar-driven processes, green synthesis approaches, and scalable treatment technologies are presented. This review provides a comprehensive framework for the rational design of highly efficient and sustainable catalysts for MR remediation in wastewater treatment systems.

Postmarketing safety surveillance data identify safety issues not identified in preapproval clinical trials. We describe the frequency of new safety issues overall and by labeling section and the relationship of the most commonly added safety issues with the cumulative number of prescriptions dispensed via retail pharmacies. Using publicly available sources, we determined the frequency of the most common safety issues added after approval overall and by labeling section (Boxed Warning, Warnings and Precautions, and Adverse Reactions) for new molecular entities (NMEs) and new therapeutic biologics (NTBs) approved between 10/1/2002 and 12/31/2014. There were 339 products in the cohort (278 NMEs and 61 NTBs) with a median follow up of 13.1 years. There were 5,161 new safety issues overall. The most frequently added to the product labeling were anaphylactic reaction, angioedema, Stevens-Johnson syndrome (SJS), hypersensitivity, and toxic epidermal necrolysis (TEN), which were added to the labeling of at least 12% of the 339 products. This was similar between NMEs and NTBs, except for cardiac failure, which was among the five most frequent adverse reactions (AR) added to NTBs, while TEN was less frequently added. Most other ARs were added to 10% or fewer products. Among drugs used primarily in the outpatient setting, the mean number of cumulative dispensed prescriptions exceeded 1 million at the time a safety issue was added to the labeling. Many of the most frequently added ARs are drug hypersensitivities. These findings are relevant to practitioners and patients, who should be alerted to the possibility of such reactions.

To evaluate dose-volume histogram metrics and preliminary toxicity of prostate cancer (PC) patients affected by postoperative locoregional relapse treated with moderately hypofractionated salvage radiotherapy (sRT) using AI-assisted daily adaptive RT. This is a prospective observational study (4181CESC, NCT05884632) on adaptive hypofractionated sRT in PC. Eligible patients (up to 80&#xa0;years old, post-prostatectomy, PSMA PET-CT confirmed M0) received 20 daily fractions up to 59&#xa0;Gy for macroscopic relapse and 55&#xa0;Gy for biochemical-only relapse. When indicated, pelvis was included with a dose of 45&#xa0;Gy. The treatment was administered using Ethos&#x2122; system which generates two plans: scheduled and adapted. The scheduled plan includes a dose recalculation on daily synthetic CT (generated from daily CBCT). The adapted plan consists on a reoptimization based on the daily anatomy. The user then select the preferred one for treatment. This is an interim analysis reporting on DVH metrics (scheduled versus adapted plan) and toxicity outcome. The results of the first 840 treatment fractions in 42 patients are reported. Sixteen (37.2%) had biochemical relapse only, while 27 (62.8%) had macroscopic relapse. We reported a significant improvement between scheduled and adapted plan for rectum V52.8Gy (16.9% versus 12.8%); p&#xa0;&#x2264;0.0001), rectum Dmean per fraction (1.54Gy/fraction versus 1.42&#xa0;Gy/fraction; p&#xa0;&#x2264;0.0001), prostate bed PTV95%, (92.1% versus 98.5%; p&#xa0;&#x2264;0.0001), pelvis PTV95% (<0.0001), pelvis PTV107% (<0.0001), and bowel Dmax (<0.0001). There was no difference for prostate bed PTV107%, bladder Dmean, and bladder V40.8Gy. Grade 2 GI toxicity (overall) was 4.8%. Grade 2 GU toxicity (overall) was 9.5% of cases. In the univariate analysis, the only factor associated with diarrhea onset was the inclusion of the pelvis (p&#xa0;=&#xa0;0.002). There was no difference between treatment dose and toxicity. Preliminary data seems to show minimal acute toxicity. A longer follow up is needed to confirm these data and evaluate late toxicity.

Soil salinity poses a major threat to global food security, impairing plant physiology through ionic toxicity, osmotic stress, and oxidative damage. However, conventional breeding and genetic engineering approaches face limitations due to the complexity of stress responses and regulatory hurdles. Nanotechnology, through the unique properties of nanomaterials (NMs), offers a promising alternative. This review synthesizes recent advances in nanoscale strategies for early salt stress sensing, the regulation of ion homeostasis, and reactive oxygen species scavenging. It further examines how NMs enhance nutrient use efficiency under saline conditions and discusses emerging applications in microbiome engineering and nontransgenic genetic improvements. The integration of machine learning to optimize NM design and application is also discussed. By synthesizing insights across these disciplines, this review provides a holistic framework for developing next-generation, nanotechnology-driven solutions to mitigate salinity stress, bridging the fundamental research with field-scale application for sustainable agriculture.

Natural killer (NK) cells are promising off-the-shelf cancer immunotherapies, but their scalable deployment requires effective cryopreservation. Conventional dimethyl sulfoxide (DMSO)-based methods are associated with toxicity and persistent post-thaw functional impairment, and the mechanisms underlying NK cell cryoinjury remain incompletely understood. We investigated NK cell dysfunction following cryopreservation and evaluated DMSO-free cryoprotectant formulations as alternative strategies. DMSO-free formulations were optimized using a differential evolution algorithm. Cryopreserved NK-92 cells were assessed post-thaw for viability, recovery, proliferation, and cytotoxicity over 5 days. Raman cryomicroscopy and flow cytometry were used to characterize cytolytic granule localization and integrity during cooling and freezing. Pre-freezing chemical degranulation was performed to probe granule-mediated injury. Both DMSO-based and DMSO-free formulations had immediate post-thaw recovery and viability over 80% but had notable cell loss over 24 h. Although proliferation resumed by 48 h, expansion remained attenuated, and cytotoxic function was reduced by &#x2265; 20% and did not recover after 3-5 days. Imaging revealed temperature- and cryoprotective agent (CPA)-induced granule redistribution and destabilization. Pre-freeze degranulation improved short-term recovery and proliferation. These findings support cytolytic granule redistribution and destabilization as contributors to persistent NK cell dysfunction and may inform future cryopreservation strategies for NK cell therapies.

Relapsed or refractory (RR) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presents increasing therapeutic complexity in the era of targeted agents. Frontline use of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax-based fixed-duration (FD) or minimal residual disease-guided regimens has led to deeper remissions, yet many patients will eventually require subsequent therapy. Management of first relapse should integrate clinical status, prior therapy, progression kinetics, and assessment for Richter transformation, along with genomic re-evaluation (particularly acquired resistance mutations and TP53 aberrations).Multiple effective options exist for relapsing disease. Second-generation cBTKi (acalabrutinib, zanubrutinib) continuous therapy provides durable disease control with improved tolerability over ibrutinib, whereas continuous venetoclax monotherapy or FD venetoclax-rituximab achieves high response rates and prolonged remission, with retreatment feasible for selected patients. Noncovalent BTKis (ncBTKis) such as pirtobrutinib offer meaningful activity in patients previously exposed to cBTKi. Cellular therapies, particularly lisocabtagene maraleucel, have demonstrated substantial efficacy in heavily pretreated patients, and allogeneic hematopoietic cell transplantation remains an option for select individuals with double-class refractory disease. Emerging therapies-including BTK degraders, next-generation BCL2 inhibitors, and bispecific antibodies-will likely reshape the therapeutic landscape for RR CLL/SLL. With broadening treatment options for RR CLL/SLL, optimal sequencing requires consideration of disease biology, depth and duration of prior response, comorbidities, toxicity profiles, patient preferences, and logistical factors. As therapeutic options expand, individualized treatment planning and clinical trial participation remain essential for improving outcomes in RR CLL/SLL.

Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role. A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations. Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials. Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with metabolic and environmental factors. We investigated associations between urinary tryptophan-pathway metabolites and essential/toxic trace elements in children with ASD and healthy controls. In a cross-sectional cohort of 216 children (149 ASD, 67 controls), urinary tryptophan metabolites were quantified by LC-MS/MS and normalized to creatinine. Trace elements were assessed by ICP-MS. Matching yielded 1:1 (n&#x2009;=&#x2009;57/57) and 1:2 (n&#x2009;=&#x2009;30/60) age- and sex-matched subsets. Correlations (Pearson or Spearman, FDR-adjusted) and group comparisons were performed; autism severity (CARS) was analyzed within ASD. Creatinine-normalized tryptamine, 5-hydroxyindoleacetic acid, and N-acetyltryptophan showed moderate, positive correlations with essential elements (Mg, Zn, Se; r&#x2009;&#x2248;&#x2009;0.5-0.7; N-acetyltryptophan and IAA correlated modestly with toxic elements (Tl, Cs; r&#x2009;&#x2248;&#x2009;0.3-0.4). Group differences in individual metabolites and elements were modest; however, the composite toxic element index was significantly lower in ASD (P&#x2009;=&#x2009;.002). CARS scores did not show robust, FDR-corrected associations. Essential trace elements are closely linked to tryptophan metabolism, suggesting cofactor-dependent modulation in ASD. N-acetyltryptophan may serve as a sensor for specific toxic elements. Intervention studies are warranted to clarify causality.

BACKGROUND: Environmental exposures to toxicants, such as per- and polyfluoroalkyl substances (PFAS), during gestation can disrupt immune development, causing long-term impacts on a child's ability to generate a well-regulated, protective immune response. T-cells coordinate with all immune cell types to orchestrate both cellular and antibody-mediated responses. While there is compelling evidence that PFAS alters immunity in humans, the specific effects of early life PFAS exposure on infant T-cell development are unreported. Because of their central role in immunity, altered T-cell development in infants would have implications on immune responses broadly and long-term. OBJECTIVES: We seek to model longitudinal changes in the frequency of functionally distinct CD4+ T-cell subpopulations from birth through 12 months and their association with in utero PFAS exposure. METHODS: Maternal-infant dyads were recruited as part of the UPSIDE-ECHO cohort during the first trimester between 2015 and 2019 in Rochester, New York; dyads were followed through the infant's first birthday. Maternal PFAS concentrations (PFOS, PFOA, PFNA, PFHXS and PFDA) were quantified in serum during the second trimester using high-performance liquid chromatography and tandem mass spectrometry. Infant lymphocyte frequencies were assessed at birth, 6- and 12-months using mass cytometry and high-dimensional clustering methods. Linear mixed-effects models were employed to analyze the relationship between maternal PFAS concentrations and CD4+ T-cell subpopulations (n = 200). All models included a PFAS and age interaction and were adjusted for parity, infant sex, and prepregnancy body mass index. RESULTS: In utero PFAS exposure correlated with multiple CD4+ T-cell subpopulations in infants. The greatest effect sizes were seen in T follicular helper (Tfh) and T-helper 2 (Th2) cells at 12 months. A log2-unit increase in PFOS was associated with lower Tfh [0.17% (95% CI: -0.30, -0.40)] and greater Th2 [0.27% (95% CI: 0.18, 0.35)] cell percentages at 12 months. Similar trends were observed for PFOA, PFNA, PFHXS, and PFDA. DISCUSSION: Maternal PFAS exposures correlate with cell-specific changes in the infant T-cell compartment, including key CD4+ T-cell subpopulations that play central roles in coordinating well-regulated protective immunity. Future studies into the role of PFAS-associated T-cell distribution and the risk of adverse immune-related health outcomes in children are warranted.

Tropomyosin kinase B (TrkB) is an attractive target for cancer treatment and is emerging as a target for the treatment of neurological disorders, specifically epilepsy, due to its role in regulating neuronal degeneration and inflammation. However, current medications frequently suffer from toxicity, resistance, and poor metabolism. In the present study, four new series of tetrazole annulated benzopyridodiazepine derivatives (26 examples) were synthesized in two steps: intramolecular cyclization with various sets of amines to produce benzopyridodiazepinone derivatives, and then, in the second step, the tetrazole ring was introduced by the reaction of imidoyl chloride with azide. All four synthesized series were assessed for in vitro inhibitory activity against tropomyosin kinase (TrkB) using both enzyme and cellular assays. To further evaluate the biological efficacy of the synthesized derivatives, we conducted ROS measurements, fluorescence-based microscopy, and flow cytometry to determine the mode of action and the induction of apoptosis. Molecular docking, ADMET, and DFT studies supported the binding at the TrkB site and suggested favorable pharmacokinetic profiles. Overall, the results indicate that the synthesized compounds are highly promising candidates, especially 14h, which shows significant inhibition of TrkB in neuroblastoma cells. Thus, the tetrazole annulated benzopyridodiazepine is an interesting molecule for exploration in the management of cancer and neurological disorders.

Primary malignant tumors of the lacrimal gland are very rare. The standard treatment typically involves wide surgical excision, which may include orbital bone resection and enucleation of the eyeball, followed by adjuvant radiotherapy. Recent advancements in hadron therapy, particularly carbon-ion radiotherapy, enable highly precise dose delivery to the tumor while minimizing exposure to surrounding healthy tissues, which could reduce toxicity. We report the case of a 70-year-old man diagnosed with asymptomatic primary ductal adenocarcinoma of the lacrimal gland. After a conservative microsurgical excision, residual disease remained, prompting the patient to undergo carbon-ion radiotherapy, which resulted in complete resolution of the tumor with minimal toxicity.

Pseudomonas aeruginosa (PA) is isolated in up to 12% of post-operative head and neck cancer patients, capable of surgical site tissue invasion triggering acute inflammation, thrombus formation, and localized microcirculatory collapse. This may result in flap failure and delay post-operative radiotherapy due to extended hospital stays. This report reviews literature on acetic acid washouts as adjunctive treatment for post-surgical PA infection and presents a single-centre case series. A systematic review protocol was registered with PROSPERO, and a comprehensive literature search on acetic acid use in PA infection was conducted. A retrospective single-centre review of head and neck patients undergoing ablative and reconstructive surgery with microvascular free tissue transfer (2020-2023) was performed. Patients with clinical and biochemical evidence of PA infection received 2-3 daily bedside washouts with 0.05% acetic acid for 7-14 days, alongside intravenous antibiotics. Six patients with post-operative PA infection were identified. Acetic acid washouts were administered for 1-2 weeks alongside IV antibiotics based on susceptibility testing. Four patients required return to theatre (mean days post-op=20.5; range=5-44). Post-operative inpatient stays ranged from 9 to 38 days. No flap failures or metal-work removals occurred. Our literature search found no comparable studies. Acetic acid is an easily available, non-toxic, inexpensive topical agent, with bedside washout courses costing &#xa3;28-&#xa3;84 per patient. This modest expense is outweighed by the substantial health and psychological benefits of avoiding flap failure. Its low side effect profile supports its use in managing PA-infected surgical sites post-operatively in head and neck cases.

The evidence linking long-term exposure to air pollution and the development of chronic obstructive pulmonary disease (COPD) is still controversial. Furthermore, most studies have investigated associations with particulate matter (PM) and nitrogen dioxide (NO2), disregarding their emission source and other relevant air pollutants, such as ultrafine particles (UFP) and elemental carbon (EC). This study aimed to assess associations between long-term residential exposure to PM2.5, NO2, UFP, and EC and the risk of COPD, distinguishing the effects of air pollution from local traffic and other sources. We pooled data from two large Danish cohorts, the Diet, Cancer, and Health cohort and the Danish National Health Survey. For all participants (N = 159,769), we estimated long-term air pollution exposure to total, local traffic, and other contributions, based on complete address histories. We used Cox proportional hazards models to estimate associations between 10-year time-weighted averaged air pollution and incident COPD, adjusting for demographic, socioeconomic, and lifestyle factors, including smoking. We evaluated the possible modification of these associations by sex, smoking status, and previous asthma diagnosis. Long-term exposures to PM2.5, NO2, UFP, and EC were associated with higher risk of COPD. The highest hazard ratio (HR) per interquartile range of total contributions was observed for PM2.5 (HR: 1.11 [95% confidence interval: 1.05, 1.17]), followed by NO2 (1.08 [1.04, 1.13]), UFP (1.05 [0.99, 1.11]), and EC (1.02 [1.00, 1.05]), after full adjustment. PM2.5 from other sources than local traffic was more strongly associated with COPD than PM2.5 from local traffic, while for UFP and EC, the contributions from local traffic seemed to be the most harmful. Effect modification analyses showed stronger associations among women, never smokers, and those with an asthma diagnosis. Our findings suggest that air pollution from local traffic and other sources contributes to COPD risk, with variations depending on the pollutant type. Further research is needed to validate these findings across different populations and geographical settings.

Breast cancer represents a major public health burden in Sudan, where most patients are diagnosed at advanced stages and access to comprehensive diagnostic and molecular services remains limited. Current treatment strategies are largely extrapolated from non-African populations, despite the substantial genetic diversity across African populations that may significantly influence drug response, efficacy, and toxicity. Pharmacogenomics offers a promising approach to optimize breast cancer therapy through genetically informed treatment decisions; however, its clinical application in Sudan and across Africa remains limited. This narrative review synthesizes published evidence on pharmacogenetic determinants influencing breast cancer treatment, with a particular focus on African and Sudanese populations. Relevant studies published between 2005 and 2026 were identified through searches of PubMed, Google Scholar, and PharmGKB. A qualitative synthesis was conducted to summarize key pharmacogenes, population-specific genetic variability, and their potential clinical and therapeutic implications. Considerable interethnic variability has been reported in pharmacogenes involved in drug metabolism and transport, including CYP2D6, CYP3A4, CYP2B6, DPYD, and ATP-binding cassette transporter genes. African populations exhibit distinct allele frequency patterns that may substantially affect drug disposition, therapeutic efficacy, and toxicity, particularly for endocrine therapies and commonly used chemotherapeutic agents. These differences limit the direct applicability of pharmacogenomic data derived from European and Asian populations and underscore the need for population-specific evidence. Integrating pharmacogenomics into breast cancer management has the potential to improve treatment effectiveness and safety in Sudan. Achieving this goal requires the generation of locally relevant pharmacogenomic data, strengthened diagnostic and laboratory infrastructure, and a stepwise, context-appropriate incorporation of pharmacogenomic principles into clinical practice. Such an approach is important to support equitable and effective precision oncology for Sudanese and African populations.

Adoptive T cell therapy requires T cells to infiltrate vascular tissues and preserve immune function. In solid tumor treatment, however, the surrounding microenvironment produces abnormal vasculature that impedes T cell infiltration. An approach that enables vascular normalization and enhances adoptive T cell function in parallel is essential for effective therapy but has not been reported. Here, we report the use of lenvatinib (LEN) to induce transient vascular normalization, thereby facilitating T cell infiltration. Moreover, LEN enhances T cell persistence by promoting the differentiation of T cells toward a memory phenotype. Our results indicate that the differentiation is by suppressing the PI3K-AKT-mTOR pathway, which drives effector differentiation, and by activating FOXO1, a transcription factor that promotes memory formation. To coordinate the transient vascular normalization and T cell enhancement, we link LEN-loaded, PD-L1-blocking micelles to T cells through acid-labile click chemistry, forming pH-responsive T cell-nanodrug conjugates. The conjugates synchronize the intratumoral release of LEN and the PD-L1 antagonist peptide OPBP-1, thereby coordinating vascular normalization, T cell differentiation, and checkpoint blockade. In vivo, the conjugates increased intratumoral CD8+ T cells and splenic memory T cells by over sixfold in B16-OVA tumors and achieved complete regression in a subset of MC38-OVA tumors without systemic toxicity, providing a promising strategy for solid tumor immunotherapy.

The clinical successes of chimeric antigen receptor (CAR) T cells represent a major shift in immunotherapy. However, there is also increasing emphasis on potential long-term effects of CAR T cell therapy, especially using preclinical xenogeneic models. It has been previously demonstrated that only na&#xef;ve, and not memory, peripheral blood human T cells can mediate a rapid and acute xenogeneic graft-versus-host disease (xenoGVHD). Here, we demonstrate that simply by altering the donor T cells in the process of generating CAR T cells, in which they are all memory phenotype, that the xenoGVHD outcome was markedly altered. Following tumor clearance with CAR T cell administration, we observed a significantly delayed (up to 200 days post-transfer with some donors) occurrence of lethal xenoGVHD, marked by profound scleroderma and multi-organ pathology consistent with chronic, not acute, GVHD. Notably, this novel chronic xenoGVHD occurred in the absence of B cells, which are classically associated with mediating chronic GVHD pathology. TCR-repertoire constriction during disease and the lack of disease using MHCI/II double-knockout NSG recipient mice confirmed the observed pathology was xenoGVHD and mediated by human-TCR:murine-MHC interactions. Interestingly, despite the consistent expansion of CAR-positive T cells during early tumor-clearance, a later emergence of CAR-negative populations during xenoGVHD also resulted. Our findings highlight xenoGVHD as a problem that makes long-term assessment of CAR T efficacy or toxicity highly problematic in xenograft models due to the artefact of xenoreactivity which is not representative of autologous clinical usage, and the profound effect that T cell alterations have in GVHD pathophysiology.

While lead exposure is hypothesized to promote Th2-type allergic responses, large-scale epidemiological data on its link to adult allergic rhinitis (AR) are scarce. This study aimed to explore the association between serum lead levels and AR risk and immunoglobulin E (IgE) levels in the general adult population of the United States. Using data from the 2005-2006 National Health and Nutrition Examination Survey, a cross-sectional study included 2876 participants aged&#x2005;&#x2265;&#x2005;20 years, 682 AR patients and 2194 controls. AR was defined as having a positive serum-specific IgE (&#x2265;0.35 kU/L) and reporting pollen-related or non-cold-related nasal symptoms in the past 12 months. Serum lead levels was measured using inductively coupled plasma mass spectrometry, and the natural logarithm of serum lead levels (Ln Pb) was adopted. Multivariable logistic regression, linear regression, and Cox regression models were employed to assess the associations after stepwise adjustment for demographic characteristics, lifestyle factors, and laboratory indicators, along with subgroup analyses and restricted cubic spline (RCS) tests for dose-response relationships. Blood lead levels were significantly negatively associated with the risk of AR. Quartile analysis indicated that the highest exposure group (Q4) had a 53% lower risk of AR compared to the lowest group (Q1) (adjusted odds ratio [aOR]&#x2005;=&#x2005;0.467, 95% confidence interval [CI]: 0.269 to 0.811, P for trend&#x2005;=&#x2005;.014). RCS analysis suggested a linear trend in this association (P-non-linear&#x2005;=&#x2005;.954). Additionally, Ln Pb was positively associated with serum total IgE levels (&#x3b2;&#x2005;=&#x2005;1.179, 95% CI: 1.005 to 1.383, P&#x2005;=&#x2005;.045), indicating that lead exposure may promote Th2-type immune responses. Higher blood lead levels were also significantly associated with an increased risk of all-cause mortality (HR&#x2005;=&#x2005;2.535, 95% CI: 1.509 to 4.261, P&#x2005;<&#x2005;.001). Subgroup analyses showed that the negative association between lead and AR was consistent across most populations, but was most pronounced in nondrinkers (HR&#x2005;=&#x2005;0.53, P&#x2005;=&#x2005;.003), with borderline interaction effects related to smoking status (P for interaction&#x2005;=&#x2005;0.039). The dissociation between reduced AR risk and elevated IgE levels suggests a complex immunomodulatory effect of lead. Furthermore, lead exposure was confirmed as a significant risk factor for all-cause mortality, underscoring its broader systemic toxicity.