Mucosal melanomas (MMs) are rare, aggressive cancers with poor outcomes and limited response to standard therapies. A significant knowledge gap exists regarding their genomic landscape and corresponding druggable targets. This study explores this issue through a multi-omic analysis, including whole exome-, RNA-, and targeted sequencing, of unique sinonasal mucosal melanoma (SN-MM) cell lines. SN-MM cell lines showed a low tumour mutational burden and low genomic instability, suggesting that their DNA repair mechanisms are largely intact. However, they exhibited a high prevalence of structural variants, likely from catastrophic genomic events. We also found novel, clinically actionable variants, including oncogenic fusion transcripts. Key findings, such as fusion transcripts and single-nucleotide variants, were validated on diagnostic biopsies. Moreover, using a break-apart FISH assay, we identified BRAF rearrangements as recurrent events in MM, supporting their biological relevance. The MAPK pathway was found to have a significant functional role, sustained by variants such as BRAF p.Asn581Ser, NRAS p.Gly12Asp, and the MKRN1::BRAF fusion. This pathway activation was effectively inhibited by the MEK inhibitor trametinib. This genomic and functional profiling unveiled novel molecular hubs in MM. The findings propose that MEK inhibitors may represent a relevant therapeutic option for BRAF fusions and non-V600 BRAF mutant tumours, providing a novel strategy for this challenging disease. Further molecular and functional validation of novel variants, and particularly of BRAF rearrangements, may reveal additional clinically relevant therapeutic targets. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Pancreatic polypeptide (PP) and neuropeptide Y4 receptor (Y4R) are part of a conserved system that is involved in appetite regulation, gastrointestinal functions, and energy homeostasis. Experimental evidence suggests that PP-Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP-Y4R crosstalk in hepatocellular carcinoma (HCC) was unknown and has been addressed in this study. We found that the ligand (PP) and the receptor (Y4R) were markedly overexpressed in HCC cells and in patient-derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal-regulated kinase (ERK) signaling. Knockdown of Y4R or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1-cell cycle arrest and cellular senescence. Conversely, activation of the PP-Y4R axis was sufficient to overcome both spontaneous and sorafenib-induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro-tumorigenic roles of PP and Y4R in HCC, indicating that PP-Y4R crosstalk might represent a potential novel therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.
Invasion and metastasis in multiple solid tumors are promoted by collective invasion which is organized by leader and follower cells. Yet in colorectal cancer (CRC), biomarkers and mechanisms that specify leader cells remain undefined. Here we identify biomarkers of leader cells and elucidate how they drive CRC collective invasion and metastasis. Using a 3D photoconvertible CRC spheroid model, we isolated leader and follower cells. Transcriptomic, functional and in vivo assays show that GLUT1, PLOD2, and CCL5 in leader cells are indispensable for collective invasion. CCL5 activates PI3K/AKT signaling to up-regulate GLUT1 and PLOD2 in leader cells. Moreover, GLUT1 and CCL5 could serve as specific biomarkers for leader cells in CRC collective invasion, and their co-expression correlates with poor prognosis. Pharmacologic inhibition of GLUT1 and CCL5-CCR5 impairs collective invasion. CCL5 and GLUT1 may define the leader cells and are required for CRC collective invasion as potential key regulators of metabolic shifts and collagen deposition. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Reliable detection of structural variants (SVs) and copy number variations (CNVs) is crucial in the contemporary diagnostics of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, limitations of commonly used conventional and molecular cytogenetic methods may hinder the accurate genetic characterization of patients. Optical genome mapping (OGM) offers a reliable alternative by enabling high-resolution, genome-wide detection of CNVs and SVs. Chromosomal aberrations were screened using OGM in 51 children with B-ALL. The results were compared with those of karyotyping, fluorescence in situ hybridization (FISH), digital multiplex ligation-dependent probe amplification (digitalMLPA), and targeted RNA sequencing (RNA-seq). OGM data showed high congruency with karyotyping and FISH findings, detecting clinically relevant variants beyond G-banding results and unraveling a complex KMT2A fusion undetected by FISH. Gene fusions involved in complex ETV6::RUNX1 translocations, but not detected by RNA-seq, were confirmed using FISH. Normalization of OGM copy number values with DNA-index-improved concordance with FISH-derived copy numbers in near-tri/tetraploid cases. In the peripheral regions of OGM variants (fringe-zones), a novel evaluation strategy called 'FriZone' was applied, which significantly improved the concordance between OGM and digitalMLPA. In addition, a co-segregation analysis revealed strong associations between ETV6::RUNX1 fusion and deletions of ETV6, RAG2, and NR3C2. OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of the patients. The FriZone analysis and normalization by DNA-index provide a refined, more accurate approach to OGM variant interpretation, facilitating the efficient application of OGM in clinical diagnostics. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Epstein-Barr virus associated gastric carcinoma (EBVaGC) represents a distinct molecular subtype of gastric cancer with prognostic and therapeutic significance. Current diagnostic practice relies on Epstein-Barr virus-encoded small RNA (EBER) in situ hybridization, which is rarely performed on initial biopsy specimens. We developed a deep learning-based diagnostic pipeline that predicts EBV status directly from H&E-stained gastric biopsy slides. Our method incorporates a multiple bag instance learning (MBIL) framework, which groups spatially adjacent tumor patches to address the inherent heterogeneity of biopsy samples and improve predictive performance. A pathology foundation model was employed to distinguish tumor from normal regions with minimal pathologist annotation, enabling robust tumor detection and contributing to downstream model accuracy. The model was trained on 744 biopsy cases from three general hospitals using 5-fold cross-validation and evaluated on an independent external cohort of 157 cases. MBIL-based models consistently outperformed single-bag approaches. The DSMIL-MB model achieved the best performance, with an area under the receiver operating characteristic curve (AUC) of 0.907 ± 0.044 in internal validation and 0.870 in external testing. TransMIL also showed improved performance with MBIL, with external AUC increasing from 0.701 to 0.853. This framework may serve as a practical prescreening tool for EBV status prediction in routine gastric biopsy specimens prior to EBER-ISH testing, supporting preoperative decision-making and facilitating broader implementation of EBV screening in gastric cancer diagnostics. © 2026 The Pathological Society of Great Britain and Ireland.
Thyroid cancer (TC) is the most common endocrine malignancy. While papillary thyroid cancer (PTC) generally has a favorable prognosis, anaplastic thyroid cancer (ATC) is rare but highly aggressive, with limited treatment options, highlighting the urgent need for novel therapeutic targets. Macrophages are a major component of the immune infiltrate in TC, and their abundance is associated with poor prognosis. We recently identified upregulation of the immune checkpoint TIM3 (T-cell immunoglobulin and mucin-domain containing protein 3) on M2-like macrophages both in vitro and in ATC xenografts. In addition, we have shown that transforming growth factor β1 (TGFβ1) promotes macrophage polarization toward an M2-like phenotype. However, the role and clinical significance of TGFβ1 in regulating TIM3 expression in TC-associated macrophages remains unclear. We found that TGFβ1 secreted by ATC cells significantly increased HAVCR2 (TIM3) mRNA expression in human monocytes. Analysis of patient samples demonstrated elevated TIM3 expression in both PTC and ATC tissues compared with adenoma and normal thyroid counterparts. Analysis of publicly available single-cell RNA sequencing datasets further showed increased TIM3 expression in T cells from both tumor types. Notably, TIM3 upregulation was also localized to M2-like macrophages within the thyroid tumor microenvironment (TME), and positively correlated with TGFB1/CD163 expression, suggesting the involvement of a TGFβ-TIM3 axis in macrophages in TC. Combined targeting of the TIM3 and PD1 pathway in an immunocompetent mouse model of ATC led to a significant reduction in tumor growth. Together, these findings highlight TIM3 as a promising immunotherapeutic target in TC, with the potential to suppress macrophage-mediated pro-tumor activity while enhancing T-cell-driven anti-tumor immunity within the thyroid TME. © 2026 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.
Impaired bile secretion disrupts the gut microbiome and perpetuates cholestatic liver injury. Vancomycin (VCM) has been shown to improve cholestasis in human patients, but its biological effects remain unclear. This study aimed to investigate the therapeutic effects of VCM on microbiome modulation and the restoration of liver function. VCM was administered in a modified Abcb11 knockout (KO) mice model with pre-existing cholestasis to examine its therapeutic effects and microbiome changes. After 2 weeks of treatment, VCM significantly decreased serum bilirubin while maintaining stable transaminase in the KO mice. Three-dimensional imaging of pan-CK expression by immunofluorescence revealed improvement of the disrupted biliary epithelium and interconnected bile duct network, as evidenced by increased coverage and cumulative duct length in the liver. Gene expression and hepatic bile acid profiling demonstrated that VCM enhanced canalicular/sinusoidal bile acid export while repressing bile acid synthesis, with a reduction in tauro-β-muricholic acid, the predominant bile acid in mice, in KO livers. Fecal microbial analysis using next-generation sequencing identified Parabacteroides goldsteinii (PG) as the predominant species after VCM treatment. KO mice fed PG demonstrated improved cholestasis, with significantly reduced direct bilirubin, alkaline phosphatase, total bile acids in serum, as well as fewer reactive ductules in the liver. In vitro culture of ductal organoids suggested that PG directly promoted the growth of cholangiocytes. RNA sequencing results suggested that PG suppressed pro-inflammatory Lyz1 (mouse orthologous gene of human LYZ) and Aqp4 and increased pro-proliferative Muc6 and Chrm3. This study highlights the therapeutic potential of VCM in cholestasis by enriching PG in the gut and improving biliary structures in the liver, identifying PG as a potential probiotic with beneficial effects in cholestasis. © 2026 The Pathological Society of Great Britain and Ireland.
Platelet-derived microparticles (PMPs) constitute the majority of circulating microparticles in blood. PMPs carry cargo including RNA, protein, and miRNA, and play key pathophysiologic intercellular signaling roles in cardiovascular, autoimmune, and liver diseases. Most methods use fresh platelets treated with an agonist to generate PMPs, which has restricted the size and feasibility of human studies. With the rise of large biobanks, such as the UK Biobank (https://www.ukbiobank.ac.uk/), and because microparticles are retained in cryopreserved plasma, this study aimed to develop an efficient and reproducible method to isolate PMPs from banked cryopreserved human plasma to investigate their communication with target cells. We employed flow cytometry using 180-1,300 nm size calibration beads and the platelet-specific marker CD41 to identify and sort PMPs based on size and CD41 positivity. Following isolation, microparticle size and morphology were validated by electron microscopy and nanoparticle tracking analysis. To assess the utility of the microparticles for studies of cell-cell interactions, we visualized microparticle uptake into human umbilical vein endothelial cells and THP-1 cells. Our method enables the isolation and downstream analysis of human PMPs in cell-cell interactions, facilitating translational studies in large populations and rare diseases. © 2026 The Pathological Society of Great Britain and Ireland.
High-resolution spectroscopy allows the probing of weak interactions and subtle phenomena. Although such measurements are routinely performed in the gas phase and in crystalline materials, studies of adsorbed species on surfaces have previously fallen short of the ultimate spectral resolution, where dephasing is eliminated and the transition linewidth is determined by the excited-state lifetime. In this work, we devise an approach to surface preparation and deposition that provides access to Fourier-limited electronic transitions in single molecules on the surface of an organic crystal. By performing spectroscopy and super-resolution microscopy at liquid helium temperature, we shed light on the spectral and spatial features of the adsorbed species. Our results pave the way for investigations in solid-state physics, where angstrom spatial resolution can be combined with high-resolution laser spectroscopy.
Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor Invasive Border Index (TIBI), a novel and reproducible method that quantifies the proportion of tumor stroma and adipose tissue within a hotspot at the deepest point of invasion. TIBI was evaluated in two CRC cohorts (n = 1,100 and n = 776) and analyzed in relation to tumor and patient features. Molecular correlates of an infiltrative growth pattern were explored in The Cancer Genome Atlas (TCGA) CRC cohorts (n = 350), with key features validated independently. High TIBI, indicating an infiltrative border, was associated with advanced disease, tumor budding, lymphovascular invasion, and an immune microenvironment characterized by lower M1-like macrophage and granulocyte densities. High TIBI independently predicted higher CRC-specific mortality, with multivariable hazard ratios of 1.52 (95% CI 1.07-2.17) in cohort 1 and 2.45 (95% CI 1.37-4.37) in cohort 2. Molecular analysis revealed associations with mismatch repair proficiency, TP53 and KRAS mutations, MYC signaling downregulation, and epithelial-mesenchymal transition upregulation. L1CAM and DSG3 were among the genes showing high expression in infiltrative tumors. As experimental validation, we identified a CRC cell line with high expression of L1CAM and DSG3 and demonstrated that silencing them reduced invasion in vitro. A TIBI-associated gene signature also predicted infiltrative growth and adverse outcome in the TCGA gastric cancer cohort. These findings highlight molecular characteristics of tumor border configuration and establish TIBI as a clinically relevant tumor biomarker. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Spontaneous emission is inherently associated with spectral broadening mechanisms, resulting in finite bandwidth in the emitted light. Narrowing this linewidth toward the monochromatic limit has long been a central pursuit in photonics, as it determines the ultimate color purity of nonstimulated light sources. Organic luminescent materials offer facile wavelength tunability but typically exhibit broad emission bands (>40 nanometers). The emergence of multiple-resonance emitters has provided a promising route to overcome this limitation, yet most reported systems remain within 20 to 30 nanometers. We present a molecular design strategy that amplifies the multiple-resonance effect through molecular repetition, yielding fluorescence with linewidths of 6.9 nanometers in toluene, 5.5 nanometers in 3-methylpentane, and 9.1 nanometers in a doped polymer film, placing this molecular framework among the narrowest-band organic luminophores reported.
Near Oceanic populations harbor substantial cultural, phenotypic, and genetic diversity yet are drastically underrepresented in human genomics. We generated 177 high-coverage Near Oceanian whole genomes and analyzed them alongside 1284 worldwide genomes, revealing major distinctions among and within islands, including long-term isolation and strong population bottlenecks. We reconstructed 1.897 billion base pairs of the archaic genome, including 831.9 million base pairs of Denisovan sequence, and found evidence for introgression from three Denisovan-like groups in Near Oceanians and adaptive Denisovan introgression at TRPS1 , a skeletal development gene also under selection in central African rainforest hunter-gatherers and highland Ecuadorians. We then performed a massively parallel reporter assay and discovered 3127 high-frequency introgressed expression-modulating variants, finding an enrichment of functional impacts on genes in the interferon-γ signaling pathway including JAK1 , GBP2 , and OAS1 .
Previous brain-wide association studies (BWAS) have linked specific environmental and behavioral variables to brain variability. In this work, we mapped 649 variables to children's brains and compared the resultant BWAS maps with each other and with neurobiological reference patterns. Socioeconomic status (SES) showed the strongest brain-wide associations. The SES associations were strongest in motor and sensory but not cognitive regions, a pattern shared across many BWAS maps, including intelligence quotient (IQ). A single, common BWAS brain pattern existed across variables that was most reflective of a child's socioeconomics. Adjusting for SES weakened brain-IQ associations, eliminating the BWAS motor and sensory pattern. Brain-with-IQ associations also did not generalize when trained on higher-SES subsamples. Thus, children's brains vary the most with SES, potentially through SES-dependent sleep deprivation and stress.
Improved rangeland grazing could mitigate climate change through carbon dioxide (CO2) sequestration in soils and vegetation. However, altering grazing practices to increase ecosystem carbon storage may also decrease livestock production and/or increase greenhouse gas emissions through the supply chain, such that the net emissions impacts remain unclear. Here, we assess the global net mitigation potential of improving grazing intensity by quantifying potential CO2 sequestration alongside systems-level impacts of plant productivity changes, livestock emissions, feed requirements, and production constraints. Improving grazing intensity in global rangelands could sequester 2.2 ± 0.43 gigatons of carbon dioxide equivalent (Gt/CO2eq) per year in the near term, but maintaining livestock production through supplemental feeding would reduce net mitigation by 2 to 31% (to 1.8 ± 0.45 GT/CO2eq per year). Our results suggest that neglecting systems-level emissions impacts may substantially overestimate the global climate benefits of improved grazing.
Labor is mediated proximately by prostaglandin signaling within gestational tissues and must be tightly regulated for birth to occur after appropriate fetal development. Metabolic changes accompanying gestational aging have been postulated as a determinant of birth timing, but specific nutrients, sensors, and messengers remain obscure. We report that placental nicotinamide adenine dinucleotide (NAD+) dynamically tunes gestational length. Depletion of placental NAD+ in mice provoked labor onset, mediated by the role of NAD+ as a cofactor for 15-hydroxy prostaglandin dehydrogenase, an enzyme responsible for suppressing prostaglandin accumulation. Augmentation of placental NAD+ prolonged gestation at baseline and in a model of preterm labor. These findings suggest a central role for metabolic exhaustion in provoking labor and reveal potential therapeutic avenues for preterm labor and the optimization of labor induction.
Arbuscular mycorrhizal fungi form symbioses with ~70% of plant species, building hyphal networks that exchange nutrients for host-derived carbon. These tubular networks move ~1 billion metric tons of carbon per year into Earth's soils. However, we have no quantitative understanding of the hyphal infrastructure required to carry out this resource transfer. We assembled data from 322 studies representing more than 16,000 soil cores across nine biomes and developed machine-learning models to predict hyphal densities globally. With robotic imaging of more than 300,000 hyphae, we calibrated a biomass model from our spatial predictions. We estimate that global topsoils contain 1.10 × 1017 ± 0.13 × 1017 SD kilometers of living hyphae, weighing ~300 ± 60 SD megatons, ~4- to 6-fold the biomass of humans. Our uncertainty analyses identified undersampled ecosystems that require additional empirical attention.
Plants can move rapidly without muscles, as seen in the Venus flytrap's snapping lobes-a long-standing puzzle in plant biomechanics. Trap closure involves an elastic instability, but the active mechanical driver has remained elusive. Using in situ hydraulic and mechanical measurements, we identified the motor driving this transition. Closure occurs too quickly to be explained by water transport, revealing a distinct, nonhydraulic mechanism: a rapid (about one second) softening of the epidermal cell wall, releasing elastic energy stored in the trap. This represents the fastest modulation of wall mechanics reported in plants. Our finding reveals a mode of plant motility based on dynamic tuning of material properties, suggesting principles for muscle-free, bioinspired actuation.
Large-scale artificial intelligence training demands ultralow-latency, energy-efficient interconnects for massive graphics processing unit clusters. In intensity-modulation/direct-detection links, digital signal processing (DSP) equalization is limited by nonideal equalization caused by phase loss as well as tight power and latency budgets. We present an integrated, programmable optical signal processor (OSP) that functions as a nonlinear universal equalizer and performs all-optical, DSP-free, real-time equalization. A deep reservoir with all-optical readout enables a Vernier scheme with ~1-picosecond (ps) sampling resolution and a tunable memory window. The OSP simultaneously equalizes eight wavelength-division-multiplexing (WDM) channels, delivering 1.6-terabits/second aggregate throughput with <60-picoseconds latency and tens of femtojoules/bit energy consumption. Operating before detection, it provides superior chromatic dispersion compensation, mitigates transceiver bandwidth limits and fiber nonlinearity, and expands the usable WDM window by a factor of 6.8.
Anthropogenic ocean warming affects ecosystem functioning but is not necessarily the primary climate driver regulating tropical seas. Tropical semi-enclosed marine ecosystems are poorly understood, geographically distinct, and influenced by compounding impacts from global warming, cyclones, monsoons, freshwater influx, and massive sea-level and circulation variability. We unify climate risk understanding of these large-scale integrated ocean-atmosphere-biological systems, showing that compound climate events expose resident species to larger, prolonged fluctuations, causing reconfigured spatial patterns and lack of sustained hydrological connectivity. We attribute changes in species' abundance in these systems to complex and cumulative combinations of extreme temperatures, exposure, turbidity, and hydrologic connections. We describe evidence of such climate-induced physical and biological regime shifts in tropical marine ecosystems in northern Australia and identify implications for other systems.
