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Results for “benchmark dose analysis”

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PubMed2026

Differential Mutagenic Response of Rat Liver and Lung to Nicotine-Derived Nitrosamine Ketone (NNK).

Nitrosamines (NA) are chemical impurities that are present in tobacco, foods, more recently in some pharmaceuticals and are associated with genotoxicity and carcinogenicity. We evaluated the in vivo mutagenicity of nicotine-derived nitrosamine ketone (NNK) or 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone, a model compound used as an anchor molecule to estimate carcinogenic potency of unknown nitrosamine impurities. Big Blue rats were treated with NNK at doses ranging from 0.001 to 30 mg/kg for 28 days, following which liver and lung tissue were harvested 3 days later for nuclear genomic DNA isolation. Mutations in liver and lung were assessed with the cII transgene assay and endogenous genomic loci using Duplex Sequencing (DupSeq), a highly validated error-corrected sequencing (ECS) technology. The no genotoxic effect level (NOGEL) was 1 mg/kg in liver and 0.1 mg/kg in lung while the benchmark dose (BMD) analysis for cII mutagenicity determined a BMDL50 of 1.3 mg/kg in liver and 0.12 mg/kg in lung, consistent with lung being the more sensitive target organ for carcinogenicity for NNK. ECS-derived mutagenicity was highly correlated with cII-derived mutagenicity. Interestingly, the types of mutations formed appeared to be tissue-specific with higher C > T transitions and lower T > G transversions in lung compared to liver, differences that may reflect tissue-specific DNA repair capacity and/or metabolic differences. Collectively, these data support the use of in vivo mutagenicity data─from both TGR cII and ECS methods─for human health and cancer risk characterization of nitrosamines and for estimating acceptable daily intakes for unknown nitrosamine drug substance related impurities.

Animals↗
PubMed2025

BMDx2: A Tool for Integrating Toxicogenomics-Based Dose-Dependency Analysis and AOP-Based Mechanistic Insights.

Despite the advent of mechanistic toxicology using omics data to link molecular perturbations with systemic outcomes, regulatory toxicology still lacks the application of mechanism-anchored metrics from such data. This is partially because traditional gene-centric analysis often falls short of linking molecular changes to adverse outcomes. To address this gap, BMDx2, an open-source tool that transforms multi-dose toxicogenomics datasets into quantitative, mechanistic evidence for human chemical safety assessment is developed. BMDx2 couples benchmark-dose modeling with Adverse Outcome Pathway (AOP) enrichment to derive transcriptomic-based points of departure, enabling potency ranking, chemical prioritization, and mechanistically anchored explanations of the effect of chemical exposures. BMDx2 can process a broad range of data, including DNA microarray and RNA sequencing studies. Here, case studies are used to illustrate the versatility of BMDx2 in characterizing the mechanism of action of chemicals. An initial case study on carbon nanotubes exposure applies integrative analysis of transcriptomics and genome-wide DNA methylation data, uncovering cellular reprogramming processes underlying fibrosis. A second case study on bleomycin exposure demonstrate how transcriptomic data alone can be mapped to fibrosis-related AOPs in a standardized, regulatory appropriate manner. Together, these examples show how BMDx2 supports the regulatory application of toxicogenomics and accelerates mechanism-based chemical safety evaluation.

Toxicogenetics↗
PubMed2026

scGPA: an LLM-assisted workflow for directional virtual gene perturbation analysis from single-cell transcriptomes.

BACKGROUND: Existing virtual perturbation methods can often infer directional changes by comparing predicted post-perturbation expression profiles with control cells. However, workflows that directly return direction-specific downstream candidate genes together with confidence scores, evidence support and interpretable summaries remain limited. We developed scGPA, an LLM-assisted workflow system for directional single-cell virtual gene perturbation analysis. METHODS: scGPA starts from raw single-cell RNA sequencing data and performs quality control, normalization, dimensionality reduction, clustering and cell-group selection. It then constructs cell-group-specific wild-type regulatory networks using repeated subsampling, principal component regression (PCR)/Ridge-based network inference and CP tensor denoising. Based on these networks, scGPA simulates dose-aware virtual knockdown of the target gene and applies signed perturbation propagation to estimate the magnitude and direction of downstream transcriptional responses. LLM assistance is used for marker-based cell-type annotation, evidence-guided candidate prioritization and user-facing biological summarization. RESULTS: We benchmarked scGPA across five public Perturb-seq datasets and compared its performance with GEARS, scGPT and a random baseline. The overall correct prediction rate of scGPA was 23.0%, exceeding those of GEARS (20.7%), scGPT (15.1%) and the random baseline (13.6%). These results indicate that scGPA achieved a higher correct prediction rate than the two comparator models and the random baseline. We subsequently evaluated scGPA using a public osteosarcoma single-cell dataset and performed qRT-PCR validation in 143B osteosarcoma cells. Among genes with significant experimental changes, scGPA achieved a directional concordance of 76.9%. When all tested downstream genes were counted, 37.0% were directionally correct, 51.9% showed no significant change and 11.1% changed in the opposite direction. CONCLUSIONS: scGPA provides a practical workflow system for predicting and prioritizing direction-specific downstream transcriptional responses after target-gene perturbation. By integrating single-cell regulatory network inference, signed virtual perturbation and LLM-assisted interpretation, scGPA supports target-gene function inference and downstream mechanistic investigation from single-cell transcriptomic data.

Single-Cell Gene Expression Analysis↗
PubMed2026

Neonatal gene therapy with AAV2/8-LSPhGAA improves hypertrophic cardiomyopathy in the Gaac.1826dupA knock-in murine model.

Pompe disease (PD) results from lysosomal acid α-glucosidase (GAA) deficiency, causing lysosomal glycogen accumulation in cardiac and skeletal muscles. We previously characterized a murine model carrying the orthologous human infantile-onset PD (IOPD) pathogenic variant, c.1826dupA (p.Y609*), introduced into the mouse Gaa gene. Compared to wild-type (WT; C57BL/6NJ) controls, Gaac.1826dupA mice exhibit reduced GAA activity and develop early-onset hypertrophic cardiomyopathy-evidenced by increased left ventricular wall thickness and left ventricular mass index (LVMI)- as well as impaired grip strength and gait abnormalities. To benchmark the model's disease fidelity and assess its responsiveness to established therapeutic intervention, Gaac.1826dupA mice received a single retro-orbital dose of AAV2/8-LSPhGAA (2 × 109 vg/g body weight) at postnatal day 12-14. Twelve weeks post-treatment, mice exhibited supraphysiological GAA enzymatic activity in the heart (550% of WT) and liver (400% of WT) with a 93% reduction in cardiac glycogen. No sex-dependent differences in therapeutic efficacy were observed. Echocardiography revealed robust reversal of cardiac pathology, with wall thicknesses and LVMI values approaching WT levels. In contrast to this profound cardiac rescue, skeletal muscle improvements were modest; while forelimb grip strength remained unchanged, automated gait analysis showed benefit limited to hind paw base of support. These findings demonstrate that the Gaac.1826dupA model mirrors the critical cardiomyopathy characteristic of IOPD. While systemic AAV treatment yields definitive cardiac correction, the partial skeletal muscle response highlights a clear need for optimization. Consequently, the Gaac.1826dupA mouse serves as a high-fidelity platform for evaluating next-generation genomic correction strategies targeting both cardiac and refractory neuromuscular manifestations of PD.

Acid α-glucosidase↗
PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

Humans↗