Nucleoporins (NUPs) constitute the nuclear pore complex (NPC) and are essentially involved in nuclear transport, chromatin organization, and context-dependent gene regulation. However, the role of NUPs in neuroendocrine (tumor)biology and related diagnostic potential is poorly defined. In this study, we comparatively analyzed immunohistochemical expression patterns of NUP98 and NUP153 (sharing structural and functional similarities) across a large variety of human tissues and tumors (total N > 600), with a focus on neuroendocrine neoplasms (NENs (n = 361)). While both NUPs showed a nuclear rim accentuated staining pattern, NUP98 exhibited ubiquitous and NUP153 a striking cell- and tissue/tumor-type-dependent immunoreactivity. More specifically, NUP153 immunoreactivity was consistently detectable in neuroendocrine tissues (e.g., pancreatic islets) and retained in neuroendocrine tumors (NETs) of the pancreas, lung, appendix, and small intestine, but almost completely absent in neuroendocrine carcinomas (NECs) and non-neuroendocrine carcinomas. Loss of NUP153 staining correlated with poorer clinical outcomes in pancreatic NETs. Further analyses revealed that NUP153 messenger ribonucleic acid (mRNA) and total protein levels were not significantly different between NETs and non-neuroendocrine carcinomas, as evaluated by quantitative real-time polymerase chain reaction and targeted proteomics. Differential isoform usage was ruled out by polymerase chain reaction and sequencing as another possible explanation for the discriminative immunohistochemical findings. Finally, a high density of post-translational modifications (PTMs) within the antigen sequence could be discovered and indicated PTM-dependent detection as the likely cause of differential staining. Collectively, our findings suggest that NUP153 is a differentiation-dependent and PTM-sensitive immunohistochemical marker in NENs with diagnostic and prognostic potential. It also emphasizes the importance of orthogonal molecular analyses for correct interpretation of IHC stainings.

Although immune checkpoint inhibition has proven highly effective in patients with metastatic or advanced squamous cell carcinomas, such as oral cancer, the role of innate immune responses in regulating oral cancer progression remains poorly understood. In this study, we examined the impact of innate immune responses in an orthotopic oral squamous cell carcinoma model (NR-S1-Luc cells) using bioluminescence imaging. In severe combined immunodeficiency mice lacking adaptive immune cells, CD11b+ Ly6Ghi Ly6Chi (Ly-6G+) myeloid cells accumulated more prominently than CD11b+ Ly6Gint Ly6Chi (Ly-6C+) cells within NR-S1-Luc tumors. Although Ly-6G+ myeloid cells were predominant in orthotopic NR-S1 tumors, in vivo depletion of Ly-6G+ cells did not alter tumor growth. Treatment with a Toll-like receptor 3 (TLR3) agonist (poly I:C) significantly inhibited tumor growth, accompanied by enhanced inflammation and upregulation of Ly-6C expression on Ly-6G+ myeloid cells. Moreover, depletion of Ly-6G+ cells partially impaired this TLR3-mediated effect. Transcriptomic analysis of Ly-6G+ myeloid cells from NR-S1-Luc tumor-bearing mice revealed that poly I:C treatment induced functional reprogramming of these cells, accompanied by broad alterations in immune-related and metabolic pathways within the orthotopic oral tumor microenvironment. Collectively, these findings suggest that tumor-infiltrating Ly-6G+ myeloid cells are functionally plastic and can be reprogrammed by TLR3 stimulation, thereby contributing to the regulation of tumor progression.

In this study, we engineered pH/glutathione dual-responsive nanoparticles (LP/CC-Cu-Cur NPs) based on a poly-γ-glutamic acid (γ-PGA)/chitosan (CS) core-shell architecture for synergistic chemo/chemodynamic therapy of glioma. The nanoparticles feature a core of CC-Cu-Cur NPs, formed via Cu2+-coordinated self-assembly of caffeic acid-grafted CS and curcumin (Cur), encapsulated within a phenylboronic acid-conjugated γ-PGA shell through pH-sensitive borate ester bonds. Surface modification with lactoferrin conferred brain-penetrating and glioma-targeting capabilities. The resulting spherical nanoparticles had a uniform size of 235.89 nm, a zeta potential of -22.66 mV, and high Cur loading (6.02%) and encapsulation efficiency (83.09%). Upon exposure to the acidic tumor microenvironment, the nanoparticle shell detaches, reversing surface charge from negative to positive, thereby enhancing cellular uptake and mitochondrial targeting. Intracellular glutathione then triggers core degradation, releasing Cur and Cu2+. Cur induces mitochondrial apoptosis, while Cu2+ catalyzes a Fenton-like reaction, converting endogenous hydrogen peroxide into highly cytotoxic reactive oxygen species. In vitro, the nanoparticles showed enhanced blood-brain barrier penetration, efficient lysosomal escape, and potent cytotoxicity against GL-261 cells (IC50 = 18.34 μg/mL) via a synergistic action of Cu2+ and Cur (CI = 0.28). In vivo, LP/CC-Cu-Cur NPs achieved superior brain accumulation and antitumor efficacy, highlighting their potential as a promising strategy for glioma therapy.

Acquired resistance limits the durability of programmed cell death protein-1 (PD-1) blockade in lung adenocarcinoma, yet the tumor-intrinsic programs and immune circuits that drive acquired resistance relapse remain poorly defined. The purpose of this study was to identify tumor-intrinsic mediators of acquired resistance and determine how they remodel antitumor immunity.

A woman in her early 20s at 30 weeks of gestation presented with elevated blood pressure, transaminitis, progressive dyspnoea, orthopnoea, exertional chest pain and peripheral oedema, raising concern for preeclampsia-associated cardiopulmonary disease or peripartum cardiomyopathy. Transthoracic echocardiography showed preserved left ventricular systolic function, normal left-sided filling pressures, right ventricular dilatation and an estimated right atrial pressure of 15 mmHg; N-terminal pro-brain natriuretic peptide was 57 pg/mL. Cross-sectional imaging revealed a large multi-cystic anterior mediastinal mass occupying the left hemithorax, displacing the heart and abutting/compressing major cardiopulmonary structures. Labour was induced at 34 weeks after clinical stabilisation. Three months postpartum, the patient re-presented with worsening dyspnoea and haemoptysis and underwent complete surgical resection. Pathology confirmed mature cystic teratoma and cardiopulmonary symptoms resolved after resection.

Antenatally detected cystic abdominal masses in neonates pose a diagnostic challenge, particularly in female infants where ovarian pathology is common but heterogeneous. We report a term female neonate with a large intra-abdominal cyst detected antenatally and persisting postnatally. Imaging revealed a well-defined, unilocular, avascular cyst without solid components, initially suggestive of an enteric duplication cyst. Postnatal imaging was non-specific as to the origin of the lesion. Given the size and persistence of the lesion, surgical exploration was undertaken. Intraoperatively, the mass was found to arise from the right adnexa, and histopathological examination confirmed a serous cystadenoma of the ovary. This rare diagnosis highlights the limitations of imaging in distinguishing benign abdominal cysts from uncommon ovarian neoplasms and underscores the importance of a structured diagnostic approach and timely surgical intervention in selected cases.

Although B-cell lymphomas are the most common malignancies in people living with HIV, T-cell lymphomas, such as anaplastic large cell lymphoma (ALCL), have also been described in people living with HIV, with frequent extranodal involvement and a poor prognosis when associated with a lack of anaplastic lymphoma kinase (ALK) expression. We present a case of a man in his late 30s with a 2 year history of HIV and adequate antiretroviral therapy (ART) adherence who presented with worsening oppressive low back pain radiating to the abdomen and constitutional symptoms. Imaging revealed retroperitoneal lymphadenopathy and biopsy showed CD30+and ALK-negative large atypical anaplastic lymphocytes consistent with ALK-negative ALCL. As expected in ALK-negative ALCL, the patient deteriorated quickly and died hours after starting chemotherapy. This case highlights the importance of including HIV-associated malignancies, including T-cell lymphomas, in our differential diagnosis to allow prompt initiation of targeted therapy in case of a rapidly progressing malignancy.

Many patients with N-methyl-D-aspartate receptor (NMDAR) encephalitis show persistent neurological or psychiatric symptoms, despite immunotherapy. The neuroanatomical basis of these symptoms remains uncertain. Morphological complexity analysis with fractal dimensionality has emerged as a sensitive neuroimaging method in related conditions, but remains unexplored in autoimmune encephalitis. We aimed to characterise morphological brain complexity, symptom trajectories from peak illness to the post-acute stage, and the relationship between structural brain changes and post-acute outcomes in patients with NMDAR encephalitis.

Trichloroethylene (TCE), a pervasive environmental contaminant, is epidemiologically linked to kidney, but the precise molecular mechanisms underlying this association remain insufficiently elucidated. To decipher the toxicological network, an integrated approach combining network toxicology, molecular docking, and in vitro validation was employed, resulting in the identification of TP53, ACTB, and CASP3 as pivotal hubs from 599 intersecting targets. Functional enrichment analyses implicated these targets in the dysregulation of cellular proliferation and apoptosis, predominantly mediated by the PI3K-Akt signaling cascade, while clinical correlation analysis revealed that their significant overexpression in tumor tissues was associated with advanced pathological staging, unfavorable prognosis, and heightened infiltration of immunosuppressive cell populations, including Tr1 cells, macrophages, and exhausted T cells. Furthermore, potential binding interactions between TCE and these proteins were predicted by molecular docking and subsequently validated by in vitro experiments, wherein TCE exposure dose-dependently upregulated TP53 and ACTB expression while concomitantly reducing cleaved CASP3 levels. Collectively, this study establishes a mechanistic framework demonstrating that TCE promotes kidney carcinogenesis by directly dysregulating TP53, ACTB, and CASP3, offering critical insights into environ-mental oncogenesis and potential therapeutic interventions.

BackgroundPathological fractures (PFs) are clinically important skeletal-related events in patients with bone metastases from solid tumors and may negatively affect survival. This meta-analysis aimed to quantify the association between PFs and overall survival (OS) in patients with metastatic solid cancers.MethodsThis systematic review and meta-analysis was conducted in accordance with PRISMA 2020 using a PICOS-defined protocol. PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 2025 without language restrictions. Eligible studies included adults with metastatic solid tumors, compared patients with and without PFs, and reported OS using hazard ratios (HRs). Tumor types were pooled a priori because the included studies evaluated the same exposure-comparator-outcome framework across metastatic solid tumors. Random-effects models were used, and heterogeneity was explored through moderator analyses and meta-regression. Two reviewers independently screened records, extracted data, and assessed risk of bias using MINORS for observational studies and the Cochrane tool for randomized trials.ResultsFrom 198 records, four studies comprising seven cohorts and 3,607 participants met the inclusion criteria. Random-effects pooling showed that PFs were significantly associated with poorer OS compared with no PFs (pooled HR 1.40, 95% CI 1.08-1.81; p = 0.010). However, heterogeneity was substantial (I2 = 92.6%), indicating that the pooled estimate should be interpreted cautiously. Meta-regression suggested a positive association between publication year and effect size (β = 0.041; p = 0.041), whereas primary cancer subgrouping was not a significant moderator. Funnel-plot asymmetry and Egger's test suggested possible small-study effects.ConclusionsPFs appear to be associated with worse OS in patients with metastatic solid tumors, highlighting the importance of fracture prevention, early identification of impending fractures, and multidisciplinary care. Nevertheless, the small evidence base, substantial heterogeneity, and possible publication bias warrant cautious interpretation. Prospective studies with standardized PF definitions and adjusted survival analyses are needed.

The response to neoadjuvant therapy in patients with locally advanced rectal cancer varies considerably among individuals. While some patients achieve a complete pathological response, others may even experience disease progression during treatment. The aim of the study was to investigate the predictive value of serum adipokines in determining the response to neoadjuvant therapy.

The prognostic value of tumor-infiltrating lymphocytes has been studied in several cancers, but in gastric cancer, their evaluation by standard hematoxylin-eosin staining remains controversial.

Isthmin-1, a recently discovered adipokine, was first characterized for its role in early brain development. Subsequent studies have demonstrated that isthmin-1 is involved in a broad range of biological processes, including metabolism, immunity, tumorigenesis, cellular proliferation, endothelial permeability, and organ development.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare yet highly aggressive subtype of non-small cell lung carcinoma (NSCLC) with limited therapeutic options. We conduct a comprehensive proteogenomic analysis of LCNEC using tumors and paired normal adjacent tissues from 107 patients (81 pure LCNEC and 26 combined LCNEC). APOBEC mutational signatures strongly correlate processes of tumor initiation and immune suppression, and KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC. A conflicting relationship is observed between neuroendocrine and immune phenotypes. We identify three LCNEC subtypes with unique prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets. Interleukin-33 (IL-33) emerges as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity. We further optimize recombinant IL-33 (rIL33) with site-directed mutagenesis and develop PEGylated rIL33, demonstrating its prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models. Overall, this study offers insights into LCNEC biology and provides promising innovative immunoagonist therapy strategies for lung cancer.

Myasthenia gravis (MG) presents a clinical challenge where autoantibody titers poorly predict disease severity, and thymectomy provides inconsistent benefits. We hypothesized that thymic B cells acquire survival mechanisms that bypass canonical tolerance checkpoints, enabling persistence independent of antigen-specific selection. Using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics to generate the largest MG atlas to date (237,661 cells), we identified a tolerance checkpoint swap in MG pathogenesis. Pathological class-switched B cells within thymic germinal centers exhibited reduced antigen presentation (CD74 and CD1C) and diminished CD40 costimulation while up-regulating TNFRSF17 to engage BAFF-driven survival. This shift allows polyclonal autoreactive B cells to evade stringent selection and seed peripheral sites. T follicular helper cells supported this reprogramming via increased TNFSF13B and CHGB expression, with the latter facilitating dopamine-mediated synaptic acceleration. These findings offer insight into clinical paradoxes in MG and point to the BAFF-BCMA axis as a potential therapeutic target and biomarkers for disease activity.

Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD-TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD-TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.

Glioblastoma (GBM) remains a lethal primary brain tumor, in part because therapeutic efficacy is limited by the blood-brain barrier (BBB) and the complex tumor microenvironment (TME). Sonodynamic therapy (SDT), i.e., use of ultrasound to activate chemical sensitizers and generate cytotoxic stress, offers a non-invasive strategy for treating deep-seated intracranial disease, but progress is constrained by the scarcity of validated sonosensitizers and the inefficiency of conventional in vitro screening methods. Here, we introduce a New Approach Methodology (NAM) that couples a neural network-based positive-unlabeled (PU) learning framework with a high-throughput, magnetic field-guided 3D bioprinting platform to accelerate identification and experimental validation of SDT-sensitizing agents. Using curated drug and small-molecule data and RDKit-derived molecular descriptors, the PU classifier identifies candidate ultrasound-responsive compounds without requiring reliable negative labels. We then validate the AI-based predictions in physiologically relevant U-87 MG glioblastoma spheroids that reproduce key TME features, including spatial heterogeneity and a hypoxic core. The NAM identifies two FDA-approved drugs, carboplatin (advanced ovarian cancer) and memantine hydrochloride (Alzheimer's disease), as effective ultrasound-responsive agents. In 3D spheroids, combining low-intensity pulsed ultrasound with either drug significantly reduces viability compared with drug-only controls, and both combinations outperform temozolomide (TMZ), the current standard chemotherapeutic. Time-resolved responses reveal distinct kinetics: memantine produces strong early cytotoxicity (24 h) enhanced by ultrasound, whereas carboplatin shows delayed but pronounced cytotoxicity (72 h), also improved by ultrasound. Together, these results establish an integrated computational-experimental NAM that enables rapid repurposing of approved drugs as SDT sensitizers and provides a scalable framework for advancing GBM therapeutic discovery while reducing reliance on animal studies.

Gastric cancer remains a major cause of cancer-related mortality worldwide, with tumor recurrence and distant metastasis being primary contributors to poor prognosis; however, the underlying molecular mechanisms are not fully understood. CD93, a type I transmembrane glycoprotein, has been implicated in tumor angiogenesis and metastasis in various solid cancers, yet its role in gastric adenocarcinoma (STAD) requires further elucidation.

As a 6-month waiting period is required to receive exception points to prioritize patients with hepatocellular carcinoma (HCC) for liver transplantation, prompt addition to the waitlist is critical in access to LT.