Phenomics. 2026 May 20;6(3):213-229. doi: 10.1007/s43657-026-00322-4. eCollection 2026 Jun.

ABSTRACT

Early cancer detection remains challenging due to the lack of reliable pan-cancer screening methods, particularly blood-based biomarkers. Using a novel three-tiered validation framework combining artificial intelligence (AI)-powered literature mining of 180,000 PubMed articles (1950-2024), multiomics integration across major databases, and extensive clinical validation, we identified macrophage migration inhibitory factor (MIF) as a promising blood-based biomarker for pan-cancer detection. Multiomics analysis revealed consistent MIF upregulation across 21 cancer types at the transcriptional level and across 12 cancer types at the protein level. Clinical validation in independent cohorts (n = 4,269) showed that serum MIF protein levels discriminated effectively between cancer patients and healthy controls (median AUC = 0.994) and between cancer and benign conditions (median AUC = 0.881). Notably, comparative analyses showed that MIF demonstrated superior or comparable performance to established cancer-specific markers, including AFP for hepatocellular carcinoma (MIF AUC = 0.885 vs. AFP AUC: 0.744-0.887) and CA125 for ovarian cancer (MIF AUC = 0.831 vs. CA125 AUC: 0.58-0.71). Meta-analysis of 28 cohorts (n = 5,347) confirmed the diagnostic efficacy of MIF (pooled AUC: 0.782). This cost-effective, blood-based ELISA approach establishes MIF as a valuable tool for broad applications in cancer screening.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s43657-026-00322-4.

PMID:42750739 | PMC:PMC13578188 | DOI:10.1007/s43657-026-00322-4

Crit Rev Oncol Hematol. 2026 Sep;225:105483. doi: 10.1016/j.critrevonc.2026.105483. Epub 2026 Jul 10.

ABSTRACT

Low-dose CT (LDCT) lung cancer screening significantly reduces mortality but has dramatically increased the detection of pulmonary nodules. Most of these nodules are benign, leading to a high false-positive rate that triggers unnecessary invasive procedures and patient anxiety, underscoring the need for more precise noninvasive diagnostic tools. Critically, single-modality liquid biopsy biomarkers, including circulating tumor cells, cell-free DNA mutations, or individual microRNAs, have demonstrated insufficient sensitivity or specificity for independent clinical deployment when used in isolation. This necessitates a paradigm shift toward multimodal molecular integration, wherein complementary biomarker classes are combined to overcome the inherent limitations of any single analyte. Traditional clinical prediction models (Mayo, VA, Brock, Herder) assist in estimating malignancy risk, yet their accuracy remains modest. Emerging approaches harness radiomics and artificial intelligence (AI) to extract high-dimensional imaging features from chest CT scans, improving risk stratification beyond human assessment alone. In parallel, minimally invasive liquid biopsy biomarkers offer complementary avenues to detect occult malignancy signals. Additionally, bronchial airway gene expression classifiers leverage the "field-of-injury" effect in normal respiratory epithelium to help identify lung cancer even when the nodule itself cannot be directly sampled via biopsy. Integrating these radiologic and molecular data streams into a multi-omics framework has the potential to enhance diagnostic precision for indeterminate pulmonary nodules, enabling more confident discrimination between benign and malignant lesions. However, most of these emerging tools have not yet been validated in large prospective trials and face technological barriers as well as challenges in real-world implementation. This review focuses primarily on LDCT screening detected pulmonary nodules, while incorporating evidence from incidentally detected and other indeterminate nodule cohorts when relevant to broader CT based management. By synthesizing advances in radiomics, AI, liquid biopsy, airway classifiers, and multi-omics integration, we highlight the need for prospective validation and multidisciplinary collaboration to translate these approaches into clinically useful pathways that improve early lung cancer detection, reduce unnecessary interventions, and enhance patient outcomes.

PMID:42431477 | DOI:10.1016/j.critrevonc.2026.105483

Front Pediatr. 2026 Mar 16;14:1770578. doi: 10.3389/fped.2026.1770578. eCollection 2026.

ABSTRACT

The neonatal lung, once considered sterile, is now recognized to harbor a dynamic and complex microbiome that plays a critical role in respiratory health and disease. This review synthesizes current evidence on the composition, development, and functional impact of the lung microbiome in neonates, with a focus on its involvement in key respiratory disorders such as bronchopulmonary dysplasia, respiratory syncytial virus infection, neonatal acute respiratory distress syndrome, cystic fibrosis, and asthma predisposition. We place particular emphasis on the bidirectional communication along the gut-lung axis as a central mechanism, wherein intestinal microbiota and their metabolites modulate pulmonary immunity and inflammation. Emerging multi-omics studies that integrate microbial data with host metabolomic and immune profiles are highlighted for their role in deciphering disease-specific dysbiotic signatures and mechanistic pathways. Critically, this review advances the discussion beyond association by evaluating the translational potential of the microbiome as both a diagnostic biomarker and a therapeutic target. We provide a critical appraisal of innovative microbiome-targeted strategies-including probiotics, postbiotics, phage therapy, and bacterial lysates-and discuss the unique challenges and future directions for translating these approaches into safe, effective clinical interventions for vulnerable neonates. By bridging foundational science with clinical implications, this work aims to inform the development of novel, ecology-informed therapeutics to prevent and mitigate neonatal respiratory diseases.

PMID:41918694 | PMC:PMC13033698 | DOI:10.3389/fped.2026.1770578

Front Pediatr. 2026 Mar 16;14:1770578. doi: 10.3389/fped.2026.1770578. eCollection 2026.

ABSTRACT

The neonatal lung, once considered sterile, is now recognized to harbor a dynamic and complex microbiome that plays a critical role in respiratory health and disease. This review synthesizes current evidence on the composition, development, and functional impact of the lung microbiome in neonates, with a focus on its involvement in key respiratory disorders such as bronchopulmonary dysplasia, respiratory syncytial virus infection, neonatal acute respiratory distress syndrome, cystic fibrosis, and asthma predisposition. We place particular emphasis on the bidirectional communication along the gut-lung axis as a central mechanism, wherein intestinal microbiota and their metabolites modulate pulmonary immunity and inflammation. Emerging multi-omics studies that integrate microbial data with host metabolomic and immune profiles are highlighted for their role in deciphering disease-specific dysbiotic signatures and mechanistic pathways. Critically, this review advances the discussion beyond association by evaluating the translational potential of the microbiome as both a diagnostic biomarker and a therapeutic target. We provide a critical appraisal of innovative microbiome-targeted strategies-including probiotics, postbiotics, phage therapy, and bacterial lysates-and discuss the unique challenges and future directions for translating these approaches into safe, effective clinical interventions for vulnerable neonates. By bridging foundational science with clinical implications, this work aims to inform the development of novel, ecology-informed therapeutics to prevent and mitigate neonatal respiratory diseases.

PMID:41918694 | PMC:PMC13033698 | DOI:10.3389/fped.2026.1770578

Cell Rep Med. 2026 Mar 30:102708. doi: 10.1016/j.xcrm.2026.102708. Online ahead of print.

ABSTRACT

Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.

PMID:41916296 | DOI:10.1016/j.xcrm.2026.102708

Am J Surg Pathol. 2026 Jun 1;50(6):695-704. doi: 10.1097/PAS.0000000000002533. Epub 2026 Mar 13.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

METHODS: We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

RESULTS: OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

CONCLUSION: The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

PMID:41824193 | DOI:10.1007/s10120-026-01718-x

Am J Surg Pathol. 2026 Mar 13. doi: 10.1097/PAS.0000000000002533. Online ahead of print.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

FASEB J. 2026 Mar 31;40(6):e71634. doi: 10.1096/fj.202503587R.

ABSTRACT

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target.

PMID:41808415 | PMC:PMC12976582 | DOI:10.1096/fj.202503587R