Oncogenic mutations shape colorectal cancer (CRC) biology, yet their impact on transcriptional phenotypes remains incompletely understood, and their individual prognostic value is limited. Here, we perform a pooled single-cell transcriptomic screen of over 100,000 CRC cells with a comprehensive barcoded library of oncogenic variants across genetically diverse CRC lines. Using a variational autoencoder-based interpretable factor model, we identify ten conserved oncogene-driven transcriptional modules (TMOs) representing core cancer phenotypes such as cellular plasticity, inflammatory response, replicative stress, and epithelial-to-mesenchymal transition. Engagement of these modules can be context-dependent, reflecting interactions between oncogene-induced driver pathways and background genetics. TMO activity in patient tumors stratifies CRC cohorts into high- and low-risk groups, improving relapse-free survival prediction beyond existing classification systems. Our study systematically links oncogenic signaling to transcriptional states and clinical outcomes, establishing a functional framework for module-based patient stratification in precision oncology.
Background In patients with primary hyperparathyroidism (pHPT), the importance of oxyphil cells for hormonal activity is uncertain. Methods This retrospective observational study analyzed the histopathological findings of postoperative specimens from patients with pHPT (single gland disease). The indication for surgery was based on increased plasma intact parathyroid hormone (iPTH) concentrations and the presence of symptoms typical of pHPT. To quantify approximate oxyphil cell content (OCC), we determined the percentage of oxyphil cells observed in each specimen. To quantify the approximate lesion volume, we determined the diameters of the fresh specimen (length, width, and height). Multiplying the lesion volume by the approximated relative OCC yielded an estimate of absolute OCC. Approximated absolute and relative OCC were then compared with preoperative plasma iPTH and calcium concentrations. Associations between these parameters were calculated using logistic or linear regression analysis. Results We studied 76 patients with pHPT. Increasing approximate relative OCC predicted slightly lower calcium concentration (indirect non-linear association, adjusted estimate 0.71, 95% confidence interval (CI) 0.19-1.40, p = 0.044). However, only in large lesions (> 1.5 cm(3)) was high approximate OCC (> 10%) associated with lower iPTH levels (adjusted odds ratio for "volume by content" interaction 0.02, 95% CI 0.01-0.52, p = 0.018). Qualitatively similar results were obtained with approximated absolute OCC as the variable of interest. Conclusion In patients with pHPT, a higher approximate OCC was associated with slightly lower calcium concentrations, possibly mediated by a counter regulatory effect on iPTH production, especially in large lesions.
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is now recognized as the most prevalent chronic liver disease worldwide, driven by the rise in obesity, type 2 diabetes, and metabolic syndrome. The evolving nomenclature and understanding of MASLD necessitate updated insights into its pathophysiology, diagnostics, and internal medicine management. A comprehensive literature review was conducted using PubMed, Scopus, Web of Science, and Cochrane databases for articles published between 2018 and 2025. Eligible studies included human-based clinical or translational research addressing MASLD pathogenesis, diagnostics, and management. Non-invasive scoring systems, pharmacotherapies, and multidisciplinary management strategies were evaluated. The pathological progression of MASLD spans from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Key pathogenic mechanisms involve insulin resistance, adipokine imbalance, gut-liver axis dysregulation, and genetic polymorphisms such as PNPLA3. Diagnostic approaches have shifted toward non-invasive tools, including Fibrosis-4 (FIB-4), NAFLD Fibrosis Score, Enhanced Liver Fibrosis (ELF) score, Vibration-Controlled Transient Elastography (VCTE), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Lifestyle modification remains the cornerstone of management, but promising pharmacologic therapies, such as glucagon-like peptide-1 (GLP-1) receptor agonists, vitamin E, pioglitazone, and resmetirom, are emerging. Multidisciplinary risk factor control, including diabetes, lipid, and blood pressure management, is critical. Emerging biomarkers and multi-omics technologies, alongside artificial intelligence, are redefining MASLD stratification and therapeutic monitoring. Early identification and comprehensive management of MASLD are essential to prevent advanced liver disease and associated comorbidities. With evolving nomenclature, non-invasive diagnostics, and emerging therapies, internal medicine practitioners must adopt an integrative, multidisciplinary approach to care. Future research should prioritize personalized treatment strategies and health system integration to address the growing MASLD burden.
BACKGROUND:Fine-needle aspiration biopsy (FNAB) of lymph nodes is a widely used method for evaluating lymphadenopathy. FNAB offers general advantages of rapid turnaround time, low cost and minimal morbidity, and more specific advantages in various clinical situations, such as deeply located lymph nodes or patients with significant comorbidities. The FNAB sample can be utilized for a wide range of ancillary tests, including microbiological studies, immunocytochemistry for primary and metastatic neoplasms and flow cytometry immunophenotyping in cases of lymphoid-rich samples, where there is a suspicion for lymphomas. SUMMARY:The increasing application of FNAB in lymph node pathology has led to the development of a standardized reporting system, formalized in the World Health Organization (WHO) Reporting System for Lymph Node, Spleen and Thymus Cytopathology (WHO System). This system is equally applicable to lymph node, spleen and thymus; however, this article focuses on lymph nodes. The WHO System was established through a joint project of the WHO, the International Agency for Research on Cancer (IARC) and the International Academy of Cytology (IAC) and is structured into five diagnostic categories: inadequate/insufficient/non-diagnostic, benign, atypical, suspicious for malignancy, and malignant. The WHO System provides a standardized and reliable means of categorizing various lymph node lesions based on cytopathology findings and enables pathologists to make more accurate and reproducible diagnoses, thereby improving clinical management and treatment decisions. Integrating cellular morphology and clinical-imaging data help distinguish benign from malignant lesions, significantly reducing diagnostic variability. The primary goal was to reduce diagnostic uncertainty and improve patient outcomes through greater consistency and clarity in lymph node cytopathology reports. The WHO System emphasizes the use of rapid on-site assessment (ROSE) to improve diagnostic accuracy and reduce the need for additional diagnostic procedures. The risk of malignancy (ROM) varies by diagnostic category, with higher risks of malignancy in the "Suspicious for malignancy" and "Malignant" categories. The system also includes recommendations for ancillary tests and performance of additional biopsies when further clarification is needed. The WHO System represents a significant advancement in the standardization of lymph node, spleen, and thymus cytopathology, facilitating interdisciplinary communication and improving risk stratification. However, diagnostic challenges remain, particularly in managing inadequate samples and interpreting atypical lesions, necessitating a multidisciplinary approach that integrates clinical, imaging, ancillary testing and, in some cases, core needle, or excision biopsy material. KEY MESSAGES:The WHO System serves as a crucial tool for refining the diagnosis of the broad range of inflammatory, infectious, metastatic, and lymphomatous processes in lymph node pathologies. In addition, it is suitable for high income as well as most obviously low- and middle-income countries leading to optimizing therapeutic decision-making.
