Citations

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.

Abstract Understanding how immune checkpoint inhibitors (ICIs) reshape human T-cell responses requires models that move beyond static transcriptomic snapshots and discrete cell-state classifications. Here, we present an integrative AI-enabled virtual cell framework that represents human CD8⁺ T-cell responses as dynamic and computable systems during ICI therapy. By integrating single-cell RNA sequencing with paired T-cell receptor sequencing within the C2S-scale foundation model, we construct a virtual representation of individual T cells, in which each cell is encoded by a unique functional identity that captures its transcriptional, signaling, and clonal characteristics. Using this framework, we identify a previously unrecognized dynamic latent effector state of CD8⁺ T cells characterized by intermediate expression of effector genes, distinct signaling activity, and ongoing clonal expansion. Across independent patient cohorts, the virtual cell model consistently indicates that ICI therapy mainly acts by unmasking pre-existing effector potential rather than inducing de novo effector differentiation. Notably, this latent effector population remains transcriptionally restrained despite active signaling and clonal expansion, revealing a hidden reservoir of antitumor immune capacity. More broadly, our study demonstrates how AI-enabled virtual cell modeling can reconstruct latent cellular states and their dynamic transitions from multidimensional single-cell data. By incorporating functional identity into virtual cell model, this framework uncovers biologically meaningful yet non-obvious T-cell effector program during cancer immunotherapy and provides a generalizable approach for studying immune dynamics in human disease.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) are prevalent disorders of gut–brain interaction with limited effective treatments. The vagus nerve exerts considerable influence on the gastrointestinal (GI) tract, indicating that noninvasive electrical neuromodulation targeting this nerve could provide a promising therapeutic avenue for both FC and IBS-C. This review explores several emerging noninvasive neuromodulation techniques involving the vagus nerve, such as transcutaneous auricular vagal nerve stimulation, percutaneous electrical nerve field stimulation, and transcutaneous electrical acustimulation. The clinical applications of these methods in managing FC and IBS-C are evaluated. Existing evidence supports the efficacy and safety of noninvasive neuromodulation in relieving symptoms of these conditions. Future investigations should aim to refine these techniques, advance device technology, and further clarify the mechanisms of action.

Variability in novel inflammatory markers (HBP and SAA) post-surgery could indicate ongoing perioperative inflammation. This pilot cohort study collected blood from 99 patients undergoing elective cardiac surgery at baseline, 24 hours, 7 days, and 3 months post-surgery. Inflammatory markers (HBP, SAA, PCT, CRP, IL-6) were measured with a point-of-care device. Demographic and clinical data were extracted from health records. Serum SAA increased significantly in the acute postoperative phase (M e [IQR];SAA baseline =81.1[87] vs SAA 24hr= 232.65[88.02];U[72]=2343,p<0.0001), remained elevated at 7 days (Me 7d =252.6[88.56];U[57]=1484,p<0.0001) and were still more pronounced than baseline at t 3m (Me 3m =118.44[101.52];U[38]=448,p=0.0008). HBP showed a significant rise at seven days (HBP baseline =45[26;89] vs HBP 7d =121[69.75;224.5]; U[56]=805,p<0.0001) then returned to near baseline by t 3m (Me 3m =32.5[15.75;98.5]). Traditional inflammatory markers PCT, CRP, and IL-6 demonstrated a rapid increase at t 24h and plateaued at t 7d . None of the biomarkers showed variability at baseline or postoperatively with preoperative status or postoperative complications. Cluster analysis of the inflammatory markers at 24 hours (t 24h ) identified distinct subgroups. Cluster #1-patients with a modest increase in all markers; Cluster#2 characterized with a robust increase in IL-6; Cluster #3 showed increase in CRP and decline in HBP; Cluster #4 showed a modest increase in IL-6 and decline in HBP; Cluster #5 represented a decline in both CRP and SAA. Patients in these clusters differ with respect to age, pre-existing peripheral artery disease, and borderline differences in perioperative acetaminophen use. SAA and HBP remain elevated longer than IL-6, CRP, and PCT after surgery, suggesting that inflammation may persist beyond 3 months.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Abstract Background The left anterior descending (LAD) coronary artery is a critical organ‐at‐risk in thoracic radiotherapy. In thoracic stereotactic body radiation therapy (SBRT), sharp dose gradients and poor LAD contrast on 4DCT scans introduce uncertainty in LAD dose assessment. Methods We evaluated the performance of an AI‐generated LAD region structure as a surrogate for manual LAD contours in early‐stage NSCLC. We used deep inspiration breath hold (DIBH) scans from 49 patients with manually delineated LADs; planning risk volume contours were expanded by 3 mm. Then, 96 lung SBRT dose maps were registered by matching the left anterior portion of the heart contours. Dice similarity coefficient (DSC), inclusion ratios (IR), dose–volume histogram (DVH) metrics, linear regression, and linear mixed models were used to compare the structures. The correlation of the AI LAD region and LAD dose to mean heart dose (MHD) was assessed. Results The AI LAD region showed strong correlation with manual LAD contours for maximum dose (D1%, R 2 = 0.93) and volume receiving ≥10 Gy (V10Gy, R 2 = 0.81). The planning risk volume also demonstrated high correlation to the AI LAD region. MHD was a poor predictor of LAD dose ( R 2 ≈0.4). Additional dose metric correlations were assessed. Discussion To investigate dose volume effects to the LAD during radiotherapy for stage I NSCLC, a robust segmentation paradigm must be established. It must be easily implementable on typical imaging acquired during treatment, with an emphasis on clinical translatability. Our model has shown that the AI LAD region has a strong correlation with LAD dose under typical lung SBRT doses and supports its use for further investigation into LAD dose volume constraints during lung SBRT. Conclusion AI LAD region provides a clinically feasible and scalable alternative to manual LAD contouring for dose estimation in lung SBRT. Its strong correlation with key dose metrics validates its use in large‐scale retrospective and prospective studies.

Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103 + dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR + dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage–dependent and EMT-inducing effects of ATR ATR promotes metastasis and immunosuppression through EMT process