Ann Surg Oncol. 2025 Oct 14. doi: 10.1245/s10434-025-18556-3. Online ahead of print.

ABSTRACT

BACKGROUND: Familial pancreatic cancer (FPC) will be enriched for germline mutations (GLMs), particularly in homologous recombination repair (HRR) genes, but its distinction from sporadic pancreatic cancer (PC) remains unclear.

METHODS: We retrospectively analyzed 111 resected PCs, including 13 patients with FPC (11.8%) and 98 with non-FPC (88.2%). Whole-exome sequencing targeted 151 cancer-related genes, with parallel gene expression profiling. GLMs were assessed by ClinVar and in silico tools. Homologous recombination deficiency (HRD) scores, COSMIC signatures, immune deconvolution, and survival were compared.

RESULTS: Patients with FPC and non-FPC were comparable in age, sex, tumor stage, and receipt of adjuvant chemotherapy. ClinVar-annotated GLMs were found in 2/13 patients with FPC (15.4%) and 4/98 patients with non-FPC (4.1%). FPC cases more often carried pancreatitis-associated variants (SPINK1, CFTR), whereas non-FPC included HRR-related variants (PALB2, FANCG). When potentially pathogenic HRR-related variants were considered together, prevalence was similar (23.1% vs. 12.2%, p = 0.380). HRD scores did not differ (median 22 vs. 19, p = 0.591), and high HRD scores (≥ 42) were observed only in two non-FPC cases, including one with PALB2. Differential expression analysis revealed no significant differences after false discovery rate correction. Multivariate analysis indicated that FPC status was not an independent prognostic factor (hazard ratio 1.73, p = 0.084).

CONCLUSIONS: Transcriptomic profiles and HRD status were similar between patients with FPC and patients with non-FPC. A spectrum of GLMs was observed in both groups, suggesting that hereditary risk variants are not exclusive to FPC and underscoring the importance of germline testing in all patients with PC.

PMID:41085800 | DOI:10.1245/s10434-025-18556-3

Front Med (Lausanne). 2025 Sep 26;12:1648612. doi: 10.3389/fmed.2025.1648612. eCollection 2025.

ABSTRACT

Small airways-defined as bronchioles <2 mm in internal diameter that lack cartilaginous support-are frequently involved in the earliest stages of chronic obstructive pulmonary disease (COPD). While COPD is defined per GOLD by persistent post-bronchodilator airflow limitation, small-airway dysfunction can precede spirometric abnormality, motivating earlier, imaging- and physiology-based detection (Agustí et al., 2023). Pathological progression typically begins with loss and stenosis of terminal bronchioles, followed by mucus retention/plugging, fibrotic remodeling, chronic inflammation, microvascular abnormalities, and cellular senescence, ultimately resulting in irreversible impairment of gas exchange. Early diagnosis remains difficult, but a suite of advanced non-invasive modalities-including impulse oscillometry system/forced oscillation techniques (IOS/FOT), single- and multiple-breath washout tests, high-resolution CT with parametric response mapping (PRM), nuclear medicine approaches (e.g., SPECT), dynamic measurements of lung compliance, and Fluorine-19 (¹⁹F) MRI-combined with artificial intelligence markedly improve the sensitivity and specificity for detecting small-airway disease. Therapeutic strategies that target cellular senescence and fibrotic pathways-such as senolytics and antifibrotic interventions-are showing promise, particularly approaches that clear senescent cells or block pro-fibrotic signaling. The integration of single-cell omics, high-resolution microvascular imaging, and molecularly targeted therapies is expected to accelerate precision diagnostics and enable personalized early interventions. This review summarizes recent insights into small-airway physiology, key pathophysiological and molecular mechanisms, and current pharmacological strategies, and emphasizes the clinical principle of "early detection, early diagnosis, early intervention" for managing COPD-related small-airway disease.

PMID:41080967 | PMC:PMC12510933 | DOI:10.3389/fmed.2025.1648612

Nat Commun. 2025 Oct 7;16(1):8892. doi: 10.1038/s41467-025-63921-1.

ABSTRACT

Though open chromatin may promote active transcription, gene expression responses may not be directly coordinated with changes in chromatin accessibility. Most existing methods for single-cell multi-omics data focus only on learning stationary, shared information among these modalities, overlooking modality-specific information delineating cellular states and dynamics resulting from causal relations among modalities. To address this, the epigenome-transcriptome relationship can be characterized in relation to time as coupled (changing dependently) or decoupled (changing independently). We propose the framework HALO, adopting a causal approach to model these temporal causal relations on two levels. On the representation level, HALO factorizes these two modalities into both coupled and decoupled latent representations, revealing their dynamic interplay. On the individual gene level, HALO matches gene-peak pairs and characterizes their changes over time. HALO discovers analogous biological functions between modalities, distinguishes epigenetic factors for lineage specification, and identifies temporal cis-regulation interactions relevant to cellular differentiation and human diseases.

PMID:41057364 | PMC:PMC12504611 | DOI:10.1038/s41467-025-63921-1

Pneumologie. 2025 Oct;79(10):701-711. doi: 10.1055/a-2625-4648. Epub 2025 Oct 6.

ABSTRACT

Genetics and pathobiology were addressed at the 7^th World Symposium on Pulmonary Hypertension in Task Forces 2 and 3. The Genetics Task Force also focused on precision medicine approaches, and the Pathobiology working group concentrated heavily on new omics technologies. Therefore, the following not only summarises the current state of knowledge on genetics, genetic testing methods, and molecular pathophysiological changes, but also places it in context and critically discusses it. In addition, the importance of national and international biobanks and cohorts, as well as the active involvement of patients and families, is emphasized.

PMID:41052524 | DOI:10.1055/a-2625-4648