Proliferative fasciitis (PFA) and proliferative myositis (PM) are related benign neoplasms that show large ganglion-like neoplastic cells and harbor recurrent FOS fusions. Proliferative funiculitis (PFU) is a benign mesenchymal lesion of the spermatic cord, with small ganglion-like cells and unknown etiology. Ischemic fasciitis (IFA) is a possibly reactive lesion that shows cytomorphologic overlap with PFA/PM. Here, we assessed FOS and FOSB immunohistochemistry (IHC) in PFA (adult and pediatric), PM, PFU, and IFA. Diffuse nuclear FOS expression was detected in adult PFA (15/26 cases; 58%) and PM (6/10; 60%), while FOSB was consistently negative (19 adult PFA, 5 PM). FOS FISH demonstrated rearrangement in only 4 of 12 tested adult PFA/PM, all of which were FOS-positive by IHC. A FOS fusion (FOS::TSHZ2) was detected in only 1 of 9 adult PFA/PM (11%) tested by RNA sequencing (RNAseq); 5 tumors without detected FOS fusions by RNAseq were FOS-positive by IHC. The pediatric PFA lacked expression of FOS (all 9 tumors) and FOSB (4 tested tumors) by IHC. Compared with FOS-positive PFA/PM, pediatric PFA and adult FOS-negative PFA/PM were more frequently cellular, and pediatric tumors were less infiltrative. DNA sequencing demonstrated FOSL1::RELA fusions in 2 of 5 tested pediatric PFAs, both in infants. Six of 18 PFU (33%) expressed FOS and/or FOSB by IHC. FISH demonstrated FOSB rearrangement in 1 of 6 PFU, while all 6 tested PFU were negative for FOS rearrangement. Nine of 20 IFA (45%) expressed FOS and/or FOSB; 2 tested tumors were negative for FOS or FOSB fusions by RNAseq. We conclude that about 60% of adult PFA/PM strongly express FOS, and 5 of these tumors were proven to harbor FOS rearrangements, including a novel FOS::TSHZ2 fusion. Some PFU and pediatric PFA harbored alterations in related genes FOSB and FOSL1, respectively. RNAseq and FISH might have imperfect sensitivity for FOS alterations in PFA/PM, likely due to the low relative neoplastic cell content in these tumor types.

Pilocytic astrocytomas (PAs) are central nervous system tumors that predominantly occur during the first two decades of life and typically arise in the cerebellum, optic pathways, hypothalamus, or brainstem. Intraventricular PAs are extremely uncommon, accounting for less than 4% of all cases, and adult presentations are particularly rare. We report the first documented case of an intraventricular PA in an adult patient in Brazil and highlight its clinical and therapeutic relevance.

A 32-year-old Brazilian woman presented with a secondary epileptic seizure. Magnetic resonance imaging revealed an expansive lesion in the left lateral ventricle. The tumor was surgically resected, and histopathological examination showed a biphasic neoplasm with eosinophilic granular bodies and microcystic areas. Immunohistochemical analysis demonstrated positivity for glial fibrillary acidic protein (GFAP) and oligodendrocyte transcription factor 2 (OLIG2), with no expression of mutant isocitrate dehydrogenase 1 protein (IDH1 R132H). Expression of 5'-methylthioadenosine phosphorylase (MTAP), alpha-thalassemia/mental retardation syndrome X-linked (ATRX), and the tumor suppressor protein p16 (INK4a) was retained. The Ki-67 (MIB-1) proliferation index was low, at approximately 1%, consistent with a WHO Grade 1 glioma.

This case illustrates a rare intraventricular PA in an adult, confirmed through clinical, radiological, and histopathological integration. It emphasizes the importance of including PA in the differential diagnosis of intraventricular tumors in adults and may contribute to guiding recognition and management of rare ventricular tumors in this population.

Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed "conjunctional targeting", in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex, immunosuppressive tumor microenvironment (TME) that contributes to poor clinical outcomes and resistance to therapy. To replicate the human TME in vitro, we develop a 3D pentaculture model incorporating five human cell types: malignant HGSOC cells and primary fibroblasts, mesothelial cells, adipocytes, monocytes. Monocytes differentiate into macrophages without exogenous cytokines in the pentacultures. Bulk RNA sequencing and deconvolution with single-cell RNA data from patient biopsies reveal that macrophage clusters within the pentacultures replicate those found in human HGSOC metastases, and proportions of individual clusters vary according to the malignant cell line. The pentacultures enable detailed analysis of malignant cell-macrophage interactions and highlight the influence of malignant cell genomic, transcriptomic and proteomic heterogeneity on the TME. Furthermore, targeting of "do-not-eat-me" signals with anti-CD47 and anti-CD24 monoclonal antibodies demonstrate differential effects on macrophage activity and cancer cell viability, again depending on the individual malignant cell line. Real-time microscopic monitoring of the pentacultures confirms dynamic modulation of macrophage behavior. We conclude that this pentaculture model offers a platform to study malignant cell control of TME elements and in particular their interactions with myeloid cells.

Cancer progression involves coordinated regulation of oncogenes and tumor suppressors. This study explores the interplay of ENOX2 (ecto-NADH oxidase disulfide-thiol exchanger 2), MMP2 (matrix metalloproteinase-2), and regulatory genes Ras Association Domain Family Member 1, Isoform A (RASSF1A), WAP Four-Disulfide Core Domain Protein 10A (WFDC10A), and Methyltransferase-Like Protein 7A (METTL7A) across multiple cancer cell lines, and evaluates the anticancer potential of repurposed mebendazole.

Eight human cell lines, including breast (MCF7 and MDAMB231), colorectal, pancreatic, lung, hepatocellular, leukemia, and endothelial models, were profiled by qRT-PCR and Western blotting. Expression was assessed under basal conditions and following mebendazole exposure (0.7 µM).

Basal expression revealed elevated ENOX2 and MMP2 in aggressive cancers (MDA-MB-231, PANC1). Mebendazole significantly downregulated ENOX2 in HEPG2 (p < 0.01) and K562 (p < 0.05), and suppressed MMP2 in MDA-MB-231 (p < 0.05) and MCF7 (p < 0.01), indicating anti-invasive effects. Tumor suppressors were selectively induced: RASSF1A increased >200-fold in endothelial cells (p < 0.01) and was upregulated in HEPG2 and HT29 (p < 0.05), while WFDC10A was strongly elevated in MDA-MB-231 (>40-fold, p < 0.001). METTL7A displayed endothelial enrichment with heterogeneous tumor-specific regulation. Collectively, these findings reveal cell-type-specific modulation of oncogenic and suppressor pathways.

This multi-cancer investigation identifies ENOX2-MMP2 signaling as a functional driver of invasion and metastasis and demonstrates that mebendazole reprograms oncogenic-tumor suppressor networks. By integrating biomarker profiling with drug repurposing, our study highlights the translational potential of mebendazole as a cost-effective anticancer agent and supports the development of multi-gene biomarkers for diagnosis and therapy in aggressive malignancies.

Gliomas are primary brain tumors that develop from glial cells within the central nervous system and are among the deadliest human cancers. Glioblastoma (GBM) is the most malignant form of glioma. NLRX1 is an innate immune pattern recognition receptor that exhibits tumor-suppressive or tumor-promoting effects that may be cancer type- and context-dependent, aided by differences in the microenvironment. Here, we report that NLRX1 is differentially expressed in microglia, astrocytes, GBM cell lines, and glioma patient tissues. siRNA-mediated silencing of NLRX1 induces metabolic stress in GBM cells, as observed by an increased number of tunneling nanotubes (TNTs) formation between GBM cells and decreased expression of autophagy markers. Moreover, silencing of NLRX1 decreases the ability of the GBM cell lines, LN-229 and LN-18, to proliferate and migrate. si-NLRX1 GBM cells exhibit attenuated ability to generate 3D spheroids. In summary, our findings indicate that NLRX1 positively regulates GBM pathophysiology by supporting GBM cell metabolism, proliferation, migration, and anchorage-independent growth. We believe our understanding of NLRX1 in GBM pathophysiology paves the way for potential development of GBM-targeting therapeutics that may delay disease progression and/or improve survival.

The Protein Phosphatase Methylesterase 1 (PPME1) is a methylesterase specific to phosphatase 2A, a tumor suppressor, and plays a key role in tumor development. Its impact on pan-cancer diagnosis, prognosis, and immune regulation is still uncertain.

We analyzed PPME1 expression across multiple carcinomas using TCGA, GEO, and other datasets, focusing on its transcriptional profile, prognostic value, genetic and epigenetic alterations, and immunological role. To substantiate our findings, we evaluated PPME1 expression and protein levels in breast cancer tissues through RT-qPCR, Western blotting, and immunohistochemical techniques. The role of PPME1 in tumor progression was evaluated in vitro using CCK-8, colony formation, wound healing, and Matrigel transwell assays, and in vivo using xenograft tumor models.

Our pan-cancer analysis demonstrates that PPME1 is upregulated in the majority of tumors and exhibits heterogeneous expression across immune and molecular subtypes. Elevated levels of PPME1 constitute an independent risk factor in various cancers, including BLCA, BRCA, HNSC, KICH, LIHC, and UVM, and are associated with a poor prognosis. It has moderate to high diagnostic accuracy and can impact the tumor microenvironment by modifying genomic stability, affecting immunotherapy outcomes, and altering the immune response from anti-tumor to tumor-promoting. Functional enrichment analysis indicates PPME1's involvement in DNA damage and repair, pathway activation, substance metabolism, protein modification, and immune regulation. In breast cancer, PPME1 mRNA and protein levels are elevated in tumor tissues compared to adjacent normal tissue. Functional experiments revealed that suppression of PPME1 significantly inhibits the migration, invasion, and tumor growth of breast cancer cells, suggesting that PPME1 may serve as a potential therapeutic target for breast cancer progression.

Overall, our data indicate that PPME1 acts as an oncogenic driver in multiple cancer types, promoting BRCA progression by enhancing pro-tumorigenic pathways.

Mycotoxins are toxic secondary metabolites produced predominantly by fungal genera, such as Aspergillus, Fusarium, and Penicillium, and represent major foodborne contaminants responsible for chronic human exposure worldwide. While aflatoxin B1 (AFB1) is a well-established hepatocarcinogen, increasing evidence indicates that multiple mycotoxins contribute to tumorigenesis across diverse organ systems through shared biochemical and molecular mechanisms. At the molecular level, mycotoxins undergo cytochrome P450-mediated bioactivation, generating reactive intermediates that induce DNA adduct formation, oxidative stress, genomic instability, and disruption of redox homeostasis. These events converge on dysregulation of key signaling pathways governing cell-cycle control, apoptosis, immune surveillance, and epigenetic regulation, including aberrant DNA methylation, histone modification, and non-coding RNA expression. Importantly, emerging data support a "dual-hit" paradigm in which mycotoxin exposure synergizes with oncogenic viral infections, such as hepatitis B virus (HBV), human papillomavirus (HPV), and Epstein-Barr virus (EBV), amplifying genotoxic stress, immune evasion, and epigenetic instability. This review synthesizes current mechanistic insights into mycotoxin-induced carcinogenesis, emphasizing molecular toxicological endpoints that link exposure to cancer risk. In addition, advances in biosensing, detoxification, and preventive strategies are discussed, highlighting the need for mechanism-driven interventions to mitigate mycotoxin-associated carcinogenicity and its public health burden.