Complete resection can be curative for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), but occult systemic or central nervous system (CNS) disease may cause relapse. ALINA and ELEVATE provide positive randomized adjuvant evidence that must be interpreted alongside negative findings, emerging neoadjuvant strategies, and practical barriers to care. This narrative review centers on adjuvant ALK inhibition after complete resection within the evolving perioperative landscape. In ALINA, alectinib or platinum chemotherapy was assigned before any postoperative systemic therapy; ELEVATE assigned ensartinib or placebo after surgery and any selected chemotherapy. Both improved disease-free survival and CNS outcomes within their randomized comparisons; neither ranked the agents nor isolated chemotherapy’s incremental contribution. The negative E4512 crizotinib trial reinforces the need for agent- and setting-specific evidence. Early neoadjuvant studies report pathologic regression and surgical feasibility, but do not establish whether adding a preoperative phase improves long-term outcomes. ADAURA provides lessons in survival and off-treatment follow-up in epidermal growth factor receptor (EGFR)-mutated NSCLC without determining ALK-specific timing or duration. Access encompasses molecular diagnosis before systemic treatment, coordination of investigational preoperative care, and sustained postoperative treatment and monitoring. Residual-disease biology, molecular residual disease (MRD), and paired tissue-plasma analysis at relapse inform the translational discussion; MRD-guided treatment adaptation remains investigational. Current adjuvant decisions should follow the relevant randomized evidence, pathologic anatomy, prior treatment, and patient-specific feasibility. Perioperative research should test the incremental value of preoperative treatment, chemotherapy sequencing, duration, and MRD-guided strategies using appropriate surgical and long-term endpoints. Timely molecular testing and access to treatment are essential to implementation.
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and heart transplantation, exhibiting marked genetic and clinical heterogeneity. Truncating variants in TTN represent the most common identifiable genetic cause of DCM; however, the mechanisms linking variant position, molecular consequences, and systemic metabolic remodeling remain incompletely understood. We integrated genetic analysis with targeted plasma metabolomics to investigate genotype-associated metabolic signatures in families with inherited DCM. Two unrelated multigenerational families affected by inherited DCM (11 affected and 19 unaffected relatives) underwent clinical phenotyping, whole-exome sequencing, segregation analysis, and targeted plasma LC–MS/MS metabolomic profiling, the latter performed on 28 individuals (9 affected, 19 unaffected) following exclusion of two participants whose blood was sampled after heart transplantation. Differential metabolite analysis, multivariate modeling, pathway enrichment, and exploratory machine-learning approaches were applied to identify genotype-associated metabolic signatures. Whole-exome sequencing identified two ultra-rare heterozygous. TTN frameshift variants (p.(Pro28946Leufs*6) and p.(Glu29179Asnfs*8)) that co-segregated with DCM and were located in constitutively expressed (high-PSI) distal A-band exons. Pooled comparison of affected individuals (n = 9) and unaffected relatives (n = 19), following exclusion of two participants whose blood was sampled after heart transplantation, identified three amino acids — glutamic acid, alanine, and proline — as significantly lower in affected individuals (all FDR < 0.05), with pathway enrichment implicating amino-acid and nitrogen-handling pathways rather than fatty-acid β-oxidation; no acylcarnitine reached FDR-corrected significance in this comparison. Within-family analyses revealed a mixed signature in the family carrying the more proximal variant (four amino acids lower, five acylcarnitines higher relative to controls), whereas the family carrying the more distal variant showed no metabolite reaching significance. Direct comparison between the two families identified seven differentially abundant metabolites, including arginine (higher in the distal-variant family; FDR = 0.0146). Exploratory multivariate and machine-learning analyses supported discrimination both between affected individuals and controls (Random Forest AUC = 0.91, 95
Tumors employ diverse mechanisms to reshape the tumor microenvironment (TME), leading to immune escape and therapeutic resistance. A key mechanism underlying this reshaping is epigenetic alterations, such as DNA modification, RNA modification, histone modification, chromatin remodeling, and non-coding RNA regulation. Among these, N6-methyladenosine (m6A), the most prevalent internal chemical modification in eukaryotic mRNA, exerts crucial roles in numerous physiological and pathological processes, including tumorigenesis. Divergent m6A modifications have been demonstrated in various tumors, influencing nearly every stage of tumor development. Furthermore, emerging evidence suggests that m6A modifications also serve as key determinants in regulating the TME. This review generalizes recent advances on the role of how m6A modifications reshape the TME, focusing on immune cells, stromal cells, and non-cellular compositions, and discusses the potential implications for cancer therapy. Deciphering the biological logic by which m6A modifications reshape the TME will offer promising strategies for cancer prevention and treatment.
Preoperative prediction of BRAF V600E mutation status in papillary thyroid carcinoma (PTC) may support individualized treatment planning, but molecular testing is not always immediately available. This study developed and validated an interpretable pathomics framework for predicting BRAF V600E status from routine Wright-stained fine-needle aspiration cytology (FNAC) whole-slide images. This retrospective study included 209 patients with histologically confirmed PTC and PCR-confirmed BRAF V600E status from two centers. Center 1 contributed 156 patients, which were divided into a training set (n = 109) and an internal test set (n = 47). Center 2 provided 53 patients for external validation, including one representative slide per patient as external test set 1 and additional slides as external test set 2. Nuclei were segmented and classified into five cytological channels: Tumor, MTumor, Follicle, MFollicle, and Heterocyte. For each channel, deep, shape, intensity, and texture features were extracted and aggregated into whole slide image (WSI)-level representations. Single-channel models were developed using 5-fold cross-validation with 20 repeats across 117 feature selector-classifier combinations, and a fusion model was constructed by integrating the prediction scores of the five single-channel models. The fusion model achieved encouraging discrimination across datasets, with area under the receiver operating characteristic curve (AUC) of 0.947 in the cross-validation training set, 0.933 in the internal test set, 0.962 in external test set 1, and 0.889 in external test set 2. In the pooled independent test datasets, the fusion model achieved an AUC of 0.925. Same-patient slice-sensitivity analysis showed moderate-to-good agreement between reference and additional slides, with a classification agreement of 85.4
Traffic noise is an established environmental risk factor for cardiometabolic disease, yet controlled human evidence on acute daytime exposure and feasible mitigation remains limited. The hypothalamic-pituitary-thyroid (HPT) axis, a key metabolic regulator, has been virtually unexplored in noise research. In this randomized crossover trial, 26 healthy adults completed three 24-hour conditions in a metabolic chamber: a fixed quiet reference day (≈ 46.5 dBA) and, in randomized order with 24-hour washout, 14-hour daytime traffic noise (≈ 76.2 dBA, 08:00–22:00) and equal-level natural-sound masking (≈ 76.2 dBA). Outcomes encompassed HPT-, sympathoadrenal (SAM)-, and hypothalamic–pituitary–adrenal (HPA) hormones, cardiovascular parameters, glucose-insulin homeostasis, substrate oxidation, salivary melatonin, and self-reported scales, analyzed by linear mixed-effects models. Traffic noise selectively activated the HPT axis (TSH + 0.26 µIU/mL, FT4 + 0.94 pmol/L, FT3 + 0.42 pmol/L; all P < 0.05) and SAM axis (metanephrine + 5.77 pg/mL, normetanephrine + 7.71 pg/mL; both P < 0.05) without measurable HPA-axis activation. This was accompanied by elevated heart rate (+ 3.34 bpm, P < 0.001), diastolic blood pressure (+ 1.66 mmHg, P = 0.040), venous glucose (+ 0.45 mmol/L, P = 0.021), insulin (+ 12.78 µIU/mL, P = 0.004), and fat oxidation (+ 0.01 g/min, P = 0.013), with borderline late-day trends in energy expenditure. Natural-sound masking significantly reversed noise-driven elevations of FT3 (-0.27 pmol/L; P = 0.015), FT4 (-0.70 pmol/L; P = 0.003), insulin (-10.71 µIU/mL; P = 0.010), and self-reported anxiety (P < 0.001), and showed borderline attenuation of heart rate and diastolic blood pressure, while SAM-axis catecholamine output was not measurably reduced. Acute daytime traffic noise triggers selective, coordinated HPT- and SAM-axis activation without classical HPA engagement, producing early subclinical cardiometabolic alterations including increased fat oxidation. Natural-sound masking selectively attenuated free-thyroid-hormone, insulin, and anxiety responses but did not normalize all physiological endpoints. These findings advance mechanistic understanding of traffic noise as an environmental cardiometabolic risk factor and support natural-sound masking as a feasible mitigation strategy in urban environments where source-level noise reduction is difficult. Chinese Clinical Trial Register (ChiCTR), ChiCTR250098645. Registered 12 March 2025.
