Search Results (2,556)

Uterine smooth muscle tumors (USMTs) represent a diagnostically and clinically challenging subset of uterine mesenchymal neoplasms. Up to 5% of these tumors exhibit ambiguous histological features that preclude definitive classification as either benign leiomyomas or malignant leiomyosarcomas. This review provides a comprehensive synthesis of the evolving diagnostic criteria, histopathological variants, and recent advancements in immunohistochemical and molecular profiling of smooth muscle tumors with uncertain malignant potential (STUMPs). The review traces the historical development of diagnostic criteria, from the original mitotic thresholds to the “Stanford criteria,” which incorporate mitotic index, cytological atypia, and tumor cell necrosis. Contemporary WHO guidelines largely uphold these principles, with nuanced refinements for spindle, myxoid, and epithelioid subtypes. However, recent studies suggest additional morphologic indicators, such as atypical mitoses, infiltrative margins, and vascular invasion, may provide prognostic insight. Notably, necrosis remains the most reliable histologic predictor of recurrence, while mitotic activity and atypia, though important, are less specific. In conclusion, STUMPs represent a heterogeneous group with unpredictable behavior that requires long-term clinical follow-up. While existing histological and molecular tools aid classification, definitive prognostic markers remain elusive. Further studies integrating histopathology, immunohistochemistry, and molecular biology are essential to refine diagnosis and improve therapeutic decision-making in this diagnostically ambiguous group of uterine tumors. Full article

Background: The tumor microenvironment (TME), composed of diverse immune and stromal cells, plays a key role in cancer progression. Among its components, tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR) have emerged as important modulators of tumor behavior. While each has been extensively studied, their interrelationship and association with tumor grade and clinicopathological parameters remain unclear. Aim: This hypothesis-generating study aimed to explore the relationship between the presence of TANs, various types of DR, the grade of tumor malignancy, and other fundamental clinicopathological characteristics commonly studied in daily clinical practice. Materials and Methods: The study included a cohort of 65 cancer patients (N = 65). The average number of TANs was recorded. In hematoxylin and eosin (H&E)-stained sections, “hot spots” representing areas with the highest neutrophil density were first identified. The tumor-associated polymorphonuclear neutrophils were then counted in ten consecutive high-power fields (HPFs). In the same specimens, the DR was assessed and classified according to stromal texture. Results: TANs did not follow a normal distribution across any clinicopathological category (p < 0.05). Significant differences in TAN levels were observed among DR types (Kruskal–Wallis H = 9.890, p = 0.007), with higher counts in myxoid compared to mature stroma (Mean Rank = 41.58 vs. 24.80, p = 0.006). TAN levels also varied significantly with tumor grade (H = 22.384, p < 0.001), increasing from Grade 1 to Grade 3 (p < 0.013–0.001). Higher TAN counts were associated with cellular erythroblastic oncogene B2 (c-erbB2) positivity (H = 6.547, p = 0.038), perineural invasion (Mann–Whitney U = 179.5, p < 0.001), and ER/PR negativity (p = 0.016 and p = 0.044, respectively). No significant association was found with necrosis (p = 0.083). A near-significant relationship was identified between DR type and tumor differentiation grade (χ² = 9.448, p = 0.051), with mature stroma most common in Grade 1 tumors, keloid-like stroma in Grade 2, and myxoid stroma in Grade 3. Conclusions: High TAN levels were linked to aggressive tumor features and specific DR patterns. The association of myxoid stroma with elevated TAN infiltration may reflect a highly aggressive TME. These preliminary results warrant validation in larger, prospective studies. Full article

The evolving tumor microenvironment (TME) plays a critical role in breast cancer tumorigenesis, growth, and metastatic potential. This study focuses on two key components of the TME: tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR). We will analyze their multifaceted functions, emphasizing the significant mutual relationships among them, which dramatically affect disease outcomes and the effectiveness of treatments. TANs can either suppress or promote tumors, demonstrating notable functional flexibility in response to signals from their immediate environment. Concurrently, the proliferation of myofibroblasts and the extensive deposition of extracellular matrix (ECM), which characterize the DR, substantially alter the tumor’s physical properties, increasing its stiffness. This increased stiffness significantly obstructs immune system cells from accessing the tumor, ultimately limiting the effectiveness of therapies and contributing to a more clinically aggressive tumor behavior. A comprehensive understanding of the interactions among TANs, the desmoplastic stroma, and other elements of the TME is critical for developing new predictive biomarkers and establishing more effective targeted therapies. Full article

Prader–Willi (PWS) and Angelman (AS) syndromes were the first examples in humans with errors in genomic imprinting, usually from de novo 15q11-q13 deletions of different parent origin (paternal in PWS and maternal in AS). Dozens of genes and transcripts are found in the 15q11-q13 region, and may play a role in PWS, specifically paternally expressed SNURF-SNRPN and MAGEL2 genes, while AS is due to the maternally expressed UBE3A gene. These three causative genes, including their encoding proteins, were targeted. This review article summarizes and illustrates the current understanding and cause of both PWS and AS using strategies to include the literature sources of key words and searchable web-based programs with databases for integrated gene and protein interactions, biological processes, and molecular mechanisms available for the two imprinting disorders. The SNURF-SNRPN gene is key in developing complex spliceosomal snRNP assemblies required for mRNA processing, cellular events, splicing, and binding required for detailed protein production and variation, neurodevelopment, immunodeficiency, and cell migration. The MAGEL2 gene is involved with the regulation of retrograde transport and promotion of endosomal assembly, oxytocin and reproduction, as well as circadian rhythm, transcriptional activity control, and appetite. The UBE3A gene encodes a key enzyme for the ubiquitin protein degradation system, apoptosis, tumor suppression, cell adhesion, and targeting proteins for degradation, autophagy, signaling pathways, and circadian rhythm. PWS is characterized early with infantile hypotonia, a poor suck, and failure to thrive with hypogenitalism/hypogonadism. Later, growth and other hormone deficiencies, developmental delays, and behavioral problems are noted with hyperphagia and morbid obesity, if not externally controlled. AS is characterized by seizures, lack of speech, severe learning disabilities, inappropriate laughter, and ataxia. This review captures the clinical presentation, natural history, causes with genetics, mechanisms, and description of established laboratory testing for genetic confirmation of each disorder. Three separate searchable web-based programs and databases that included information from the updated literature and other sources were used to identify and examine integrated genetic findings with predicted gene and protein interactions, molecular mechanisms and functions, biological processes, pathways, and gene-disease associations for candidate or causative genes per disorder. The natural history, review of pathophysiology, clinical presentation, genetics, and genetic-phenotypic findings were described along with computational biology, molecular mechanisms, genetic testing approaches, and status for each disorder, management and treatment options, clinical trial experiences, and future strategies. Conclusions and limitations were discussed to improve understanding, clinical care, genetics, diagnostic protocols, therapeutic agents, and genetic counseling for those with these genomic imprinting disorders. Full article

Background/Objectives: Accurate preoperative TN staging is essential for guiding surgical and adjuvant treatment decisions in colorectal cancer (CRC), yet conventional imaging still faces limitations in reliably distinguishing early from advanced disease. This study aimed to evaluate whether CT-based radiomics combined with machine learning can noninvasively predict both tumor (T) and nodal (N) stages of CRC, and to identify which feature groups most contribute to each task. Methods: Fifty-three patients (55 tumors) with histologically confirmed CRC who underwent preoperative contrast-enhanced CT were retrospectively analyzed. A total of 107 radiomic features were extracted using PyRadiomics version 3.1.0, including shape, first-order, and texture features. Multiple preprocessing strategies—z-score normalization, PCA, and SMOTE—were tested across 11 machine learning classifiers. Results: For T staging, logistic regression using shape-based features achieved a mean sensitivity of 0.721, a specificity of 0.68, a balanced accuracy of 0.70, and an AUC of 0.751. For N staging, the AdaBoost model using texture-based features achieved a sensitivity of 0.742, a specificity of 0.622, a balanced accuracy of 0.682, and an AUC of 0.750. Shape features predominantly contributed to T prediction, while texture matrices drove N prediction, reflecting morphological and microstructural correlates of invasiveness and lymphatic dissemination. Conclusions: CT-based radiomics can quantitatively capture both morphological and textural patterns of tumor behavior, providing a noninvasive framework for preoperative TN staging in CRC. Full article

Regulatory T cells (Tregs) are central mediators of immune tolerance, yet within tumors they adopt specialized phenotypes that confer the potent suppression of anti-tumor immune responses. Emerging evidence indicates that this functional plasticity is not driven by genetic alterations but instead arises from dynamic and context-dependent epigenetic reprogramming. While individual epigenetic mechanisms controlling Treg development and stability have been described, how tumor-derived cues reshape Treg epigenetic states, how these programs differ across cancer types, and which features distinguish tumor-infiltrating Tregs from their peripheral counterparts remain incompletely understood. In this review, we synthesize recent advances in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation that govern Treg identity and function with a particular emphasis on tumor-specific epigenetic adaptations. We highlight emerging epigenetic hallmarks of intratumoral Tregs, discuss unresolved mechanistic questions, and evaluate the therapeutic potential and limitations of targeting epigenetic pathways to selectively modulate Tregs in cancer. By integrating mechanistic, cancer-specific, and translational perspectives, this review aims to provide a conceptual framework for understanding how epigenetic regulation shapes Treg behavior in the tumor microenvironment and how it may be exploited for cancer immunotherapy. Full article

Background: Triple-negative breast cancers (TNBCs) are among the most aggressive breast tumors, due not only to the absence of clinically functional biomarkers used in other molecular subtypes, but also their marked heterogeneity and pronounced migratory and invasive behavior. The search for new molecules of interest for risk prediction, diagnosis and therapy stems from the class of long non-coding RNAs (lncRNAs), which often display context-dependent (“dual”) functions and tissue specificity. Among them, lncRNA LINC01133 stands out for its dysregulation across cancer, although its molecular role in TNBC remains unclear. Methods: In the present study, we used the human TNBC cell line Hs578T to generate a cell panel comprising the parental line (Hs578T_wt), the control line (Hs578T_ctr), and the LINC01133 knockout line (Hs578T_ko). Subsequently, we performed bulk RNA-Seq to identify KO-associated Differentially Expressed Genes (DEGs) using ko_vs_ctr as the primary contrast. Functional interpretation was achieved by Over-Representation Analysis (ORA) using Gene Ontology. We then conducted a comparative patient-cohort analysis using TCGA-BRCA Basal-like/TNBC cases (TCGA/BRCA n = 1098; Basal-like/TNBC n = 199), classified with the AIMS algorithm, and evaluated concordance between KO-associated signatures and patient tumor expression patterns via trend-based analyses across the LINC01133 expression levels and associated genes. Results: A total of 265 KO-dominant DEGs were identified in Hs578T_ko, reflecting transcriptional changes consistent with tumor progression, with enrichment of pathways associated with LINC01133 knockout including cell adhesion, cell–cell interactions, epithelial–mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. The main DEGs included ITIH5, GLUL, CACNB2, PDX1, ASPN, PTGER3, MFAP4, PI15, EPHB6, and CPA3 with additional candidates, such as KAZN and the lncRNA gene SSC4D, which have been implicated in migration/invasion, ECM remodeling, or signaling across multiple tumor contexts. Translational analyses in TCGA-BRCA basal-like tumors suggested a descriptive association in which lower LINC01133 levels were accompanied by shifts in the expression trends of genes linked to ECM/EMT programs and modulation of genes related to cell adhesion and protease inhibition. Conclusions: These results suggest a transcriptional model in which LINC01133 is associated with TNBC-related gene expression programs in a concentration-dependent manner, with loss of LINC01133 being associated with a transcriptomic shift toward pro-migratory/ECM remodeling signatures. While functional validation is required to establish causality, these data support LINC01133 as a molecule of interest in breast cancer research. Full article

A four-compartment tumor–immune interaction model is studied in a belief-based uncertain framework. The deterministic dynamics for tumor cells, natural killer cells, dendritic cells, and cytotoxic CD8${}^{+}$ T lymphocytes are extended to an uncertain differential system driven by a canonical Liu process, with therapeutic effects represented through treatment-related parameters acting on the respective populations. The analysis establishes well-posedness in the biologically relevant positive orthant under structural conditions compatible with the model nonlinearities, and it characterizes stability properties in the sense appropriate to uncertain dynamical systems. Sufficient conditions are derived for the existence of a global attracting set describing the long-time behavior of trajectories. The analytical results are complemented by numerical experiments based on $\alpha$-path dynamics to illustrate uncertainty-aware therapeutic scenarios and to connect the qualitative theory with observable system behavior. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by molecular heterogeneity and poor clinical prognosis. Lysyl oxidase-like 3 (LOXL3) is frequently upregulated in GBM, but its mechanistic contribution remains insufficiently defined. Here, we investigated the functional role of LOXL3 in GBM using CRISPR-Cas9-mediated LOXL3 knockdown in two genetically distinct GBM cell lines: U87MG (wild-type TP53) and U251 (mutant TP53). Reduced LOXL3 expression markedly reduced α-tubulin acetylation, particularly in U87MG cells, and downregulated genes involved in cell cycle progression and proliferation. Both cell lines exhibited mitotic defects, including delayed cell cycle progression and spindle abnormalities; however, cell fate diverged according to TP53 status. U87MG cells, sustained spindle checkpoint activation triggered a p53-dependent spindle checkpoint response culminating in apoptosis, while U251 cells underwent mitotic slippage and senescence. Transcriptomic analyses confirmed differential regulation of apoptosis versus senescence pathways in accordance with TP53 functionality. Additionally, reduced LOXL3 expression markedly impaired adhesion and migration in U87MG cells, whereas U251 cells were minimally affected, consistent with more pronounced microtubule destabilization. Collectively, these findings identify that LOXL3 is a key regulator of microtubule homeostasis, mitotic fidelity, adhesion, and invasive behavior in GBM. Targeting LOXL3 may therefore provide a therapeutic opportunity for genotype-informed intervention in GBM. Full article

Background/Objectives: Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. The classic variant (cPTC) is characterized by indolent behavior and excellent prognosis. However, rare subtypes of PTC most often exhibit adverse clinical behavior. The aim of the study was to assess the aggressiveness of rare variants of PTC by analyzing clinicopathological characteristics (CPCs) and survival outcomes. Methods: We analyzed 80 patients with rare PTC variants treated between 2009 and 2019 who were compared with cPTC and matched with a control group for age and tumor size. The variants were categorized into high-risk (HRV: tall cell, diffuse sclerosing, columnar cell, and hobnail variants), intermediate-risk (IRV: solid variant (SV)), and low-risk (LRV: oncocytic (OV) and Warthin-like (WLV)) variants. Different CPCs (capsule and blood vessel invasion, lymphonodal metastases, microscopic and macroscopic extrathyroid extension, multifocal and bilateral presentation) and survival outcomes—overall (OS), disease-specific (DSS), and disease-free survival (DFS) were compared. Results: HRVs exhibited significantly more aggressive CPCs and worse OS, DSS, and DFS compared to cPTC (p < 0.001). IRVs showed no significant difference in CPCs or survival outcomes compared to cPTC. LRVs showed excellent survival but were associated with several unfavorable CPCs. Multivariate analysis identified classification in HRVs as the only independent predictor of recurrence (p = 0.014). Conclusions: Tumors in the HRV group should retain their status as aggressive PTC variants due to unfavorable behavior and poorer prognosis. SVs, despite earlier assumptions, do not exhibit aggressive characteristics. Although the OV and WLV have similar survival to cPTC, their potential for adverse CPCs requires caution. Full article

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of injury. This review summarizes principles of ECM organization, mechanotransduction, and pathological remodeling and highlights translational opportunities for ECM-targeted therapies, biomaterial platforms, and precision diagnostics. We conducted a narrative synthesis of foundational and recent literature covering ECM composition and turnover, stiffness-dependent signaling, and disease-associated remodeling across fibrosis/cardiovascular disease, cancer, and metabolic disorders, together with advances in ECM-based biomaterials, drug delivery, and ECMderived biomarkers and imaging. Across organs, a self-reinforcing cycle of altered matrix composition, excessive crosslinking, and stiffness-dependent mechanotransduction (including integrin–FAK and YAP/TAZ pathways) sustains fibroinflammation, myofibroblast persistence, and progressive tissue dysfunction. In tumors, aligned and crosslinked ECM promotes invasion, immune evasion, and therapy resistance while also shaping perfusion and drug penetration. Translational strategies increasingly focus on modulating ECM synthesis and crosslinking, normalizing rather than ablating matrix architecture, and targeting ECM–cell signaling axes in combination with anti-fibrotic, cytotoxic, or immunotherapeutic regimens. ECM biology provides a unifying framework linking pathogenesis, therapy, and precision diagnostics across chronic diseases. Clinical translation will benefit from standardized quantitative measures of matrix remodeling, mechanism-based biomarkers of ECM turnover, and integrative imaging–omics approaches for patient stratification and treatment monitoring. Full article

This review highlights the anti-inflammatory and antioxidant effects of probiotics and their complex health-related impacts. The main health areas targeted are gastrointestinal inflammation, neuroinflammation, systemic metabolic disorders, and liver conditions. Probiotics work mechanistically to regulate key inflammatory pathways by suppressing nuclear factor (NF-κb) and mitogen-activated protein kinase (MAPK) pathways and activating antioxidant defenses through nuclear erythroid 2-related factor (Nrf2). They stimulate anti-inflammatory cytokines (including interleukin 10 (IL-10) and inhibit pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), partly through the regulation of T cells. Probiotics also produce antioxidant metabolites (e.g., exopolysaccharides and short-chain fatty acids), which enhance the host’s resistance to oxidative stress. Supplementation with probiotics improves intestinal inflammation and oxidative injury in gut disorders. Clinical trials suggest that probiotic supplements may reduce neuroinflammation and oxidative stress, while improving cognitive or behavioral outcomes in neurodegenerative disorders. Overall, this review underscores that probiotics have potent anti-inflammatory and antioxidant effects within the gut–brain axis and across various organ systems, supporting their use as valuable adjunctive therapies for inflammatory and oxidative stress-related conditions. It further emphasizes that additional mechanistic research and controlled clinical trials are essential to translate these findings into the most effective therapeutic strategies. Full article

Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulfide bond-forming enzyme with both disulfide isomerase and oxidoreductase activities. It plays an important role in protein folding, stability, and secretion. Growing evidence demonstrates that QSOX1 is upregulated in multiple cancer types and influences key behaviors of cancer cells, including proliferation, migration, invasion, and metastasis. Elevated QSOX1 expression is also associated with tumor malignancy and disease relapse. However, the molecular mechanisms by which QSOX1 drives cancer progression remain incompletely understood. In this review, we summarize current knowledge of QSOX1 expression and regulation in cancer, discuss its functional roles, and highlight key unanswered questions to warrant further investigation. Full article

MicroRNAs are key post-transcriptional regulators in breast cancer, but their time-dependent dynamics and downstream oncogenic effects are not fully understood. miR-548c-3p has been proposed as a tumor suppressor, yet its temporal behavior and impact on cell cycle drivers remain unclear. This study investigated the time-dependent expression of miR-548c-3p and its post-transcriptional regulation of E2F3 and FOXM1 in MCF-7 breast cancer cells. Cells were analyzed at multiple time points (2–72 h) by quantitative real-time PCR to assess dynamic changes in miR-548c-3p, E2F3, and FOXM1 mRNA levels. Bioinformatic validation using TCGA-BRCA datasets and public platforms evaluated gene expression, promoter methylation, and prognostic significance. miR-548c-3p showed a progressive time-dependent decline, with the lowest levels at 72 h, whereas E2F3 and FOXM1 were significantly upregulated over time, supporting a post-transcriptional derepression mechanism. TCGA-based analyses confirmed overexpression and hypomethylation of E2F3 and FOXM1 in breast cancer, particularly in triple-negative tumors, and high expression of both genes was associated with poor survival. These findings indicate that time-dependent loss of miR-548c-3p contributes to E2F3 and FOXM1 activation through a post-transcriptional regulatory mechanism, highlighting this miRNA–oncogene axis as a potential prognostic signature and therapeutic target in breast cancer. Full article

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences between tumor subtypes and malignancy. We performed an integrative analysis of DNA methylation (Illumina EPIC 850K) and gene expression profiles (Affymetrix microarrays) in 24 PPGLs, comparing these with The Cancer Genome Atlas (TCGA) data, to delineate cluster- and malignancy-specific epigenetic patterns. Comparison between pseudohypoxic Cluster I and kinase-signaling Cluster II tumors revealed 13 differentially methylated CpG sites, with a specific CpG within DSCAML1 showing hypermethylation in Cluster II accompanied by increased expression, suggesting context-dependent gene body methylation effects. Benign versus malignant comparisons identified 101 differentially methylated CpGs, including hypermethylated CpG in BAIAP2L1 and hypomethylated CpG in SHANK1 in malignant tumors. Pathway enrichment of differentially methylated genes revealed alterations in Notch signaling, adherens junctions, cytoskeletal regulation, and intracellular transport. Gene expression analysis demonstrated partial overlap between clusters, with malignant tumors exhibiting distinct transcriptional profiles involving RNA processing, metabolism, and adhesion pathways. Correlation between methylation and expression was generally limited, emphasizing that methylation-dependent gene regulation is a locus-specific and context-dependent regulation. These findings illustrate a complex interplay between epigenetic modifications and transcriptional programs in PPGLs, enhancing our understanding of molecular heterogeneity and tumor classification, and identifying candidate biomarkers and therapeutic targets for malignant progression. Full article