Search Results (9,342)

Breast carcinoma is a major cause of cancer-related mortality among women worldwide. Identifying novel molecular targets remains essential, particularly for aggressive triple-negative breast cancer (TNBC). Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been linked to tumor progression and angiogenesis, but its molecular mechanisms in breast cancer are poorly defined. We evaluated the effects of recombinant human LRG1 (rhLRG1) on cell viability and migration in MDA-MB-231 TNBC cells and performed transcriptomic profiling followed by functional enrichment analyses using GenArise, Cytoscape, and R-based tools. RhLRG1 treatment significantly increased cell viability and migration. Transcriptomic analysis revealed activation of key oncogenic cascades, including the PI3K/AKT, MAPK, and RAS signaling pathways. Hub-gene analysis identified upregulated genes involved in proliferation (NRAS, STAT5B, IGF2), angiogenesis (PGF, ANGPT2), and apoptosis (CASP8, BAD), whereas downregulated genes were associated with apoptotic resistance (BCL2, MCL1) and adhesion (LAMB1, ITGB4). Functional enrichment highlighted LRG1’s role in the bioinformatic analysis of differentially expressed genes that were obtained from microarray assays. LRG1 remodels the tumor microenvironment by promoting proliferation, angiogenesis, and apoptotic sensitivity while repressing resistance-related genes. These findings position LRG1 as a potential diagnostic biomarker and therapeutic target for advanced breast carcinoma. Full article

Background: Neoadjuvant chemotherapy (NAC) is widely used in the management of stage I–III breast cancer, with tumor regression serving as an important surrogate for long-term outcome. Identifying reliable pathological biomarkers predictive of residual disease remains clinically relevant. Methods: We conducted a retrospective cohort study of 165 patients with non-metastatic breast cancer treated with neoadjuvant chemotherapy followed by surgery between 2019 and 2022. Pathological response was assessed using the Residual Cancer Burden (RCB) index. The primary study endpoint was extensive residual disease (RCB-III), defined as the poorest category of tumor regression, indicating treatment resistance. Associations between the Nottingham Score together with other histopathological parameters, immunohistochemical markers (ER, PR, HER2), Ki67 proliferation index, and RCB were analyzed using univariate and multivariable logistic regression. Results: In univariate analysis, higher Nottingham scores (OR = 1.807, p = 0.0017), negative ER expression (OR = 3.017, p = 0.0255), the absence of lymphovascular invasion (OR = 0.1877, p = 0.0069) and elevated Ki67 (OR = 1.034, p = 0.0003) were significantly associated with RCB III. In multivariable analysis, only Ki67 and lymphovascular invasion remained independent predictors of RCB III, while Nottingham score and ER expression lost statistical significance. Correlation analysis demonstrated strong associations between Nottingham score, Ki67, hormone receptor loss, and tumoral necrosis. Conclusions: Ki67 is an independent predictor of poor tumor regression following neoadjuvant chemotherapy and appears to capture much of the prognostic information traditionally attributed to histologic grade and Nottingham score. However, the absence of lymphovascular invasion remains a significant positive prognostic factor. These observations support further investigation into the integration of proliferation markers into multivariable predictive models to improve response stratification in breast cancer. Full article

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are major risk factors for lung cancer and other diseases, acting through the aryl hydrocarbon receptor (AHR). Alveolar macrophages (AMs) help regulate the lung microenvironment by responding to inhaled toxicants and resident microbiota. Although small extracellular vesicles (sEVs, aka exosomes) released by AMs mediate intercellular communication and immune responses, the influence of lung microbiota on sEV biogenesis and the mechanisms underlying sEV dysregulation during PAH exposure remain unknown. Here, we investigated the interplay between AMs, B[a]P, and lung microbiota, focusing on sEV-associated miRNAs (exo-miRNAs). Murine AMs (MH-S) were exposed to varying B[a]P concentrations in the presence or absence of murine lung microbiota with or without an AHR antagonist. sEVs from each condition were characterized and profiled for miRNA. Distinct miRNA signatures emerged: high-dose B[a]P enriched miRNAs linked to cancer progression, whereas lung microbiota alone or with low-dose B[a]P induced tumor-suppressor miRNAs that limit proliferation and metastasis and promote apoptosis, an effect enhanced by AHR antagonism. Lung microbiota appeared to counteract high-dose B[a]P by modulating tumor-suppressive exo-miRNAs. This study demonstrates that lung microbiota-induced exo-miRNAs critically shape AM-derived sEV-miRNA signaling during PAH exposure. The identified exosomal miRNAs could serve as important exposure biomarkers and therapeutic targets for mitigating B[a]P-induced toxicity and cancer development. Full article

Breast cancer (BRCA) is the most common cancer worldwide, with an incidence exceeding that of lung cancer. Protein lactylation, a newly identified post-translational modification involving the binding of lactic acid to lysine residues, plays an important role in BRCA. However, its role in BRCA progression remains largely unexplored. This study aims to identify and characterize the lactylation-related genes involved in BRCA biology. Transcriptomic and clinical data of BRCA and normal breast tissues were obtained from TCGA and GEO. Lactylation-related genes were curated from literature and intersected with BRCA datasets to identify candidates. A prognostic risk model was constructed using LASSO and Cox regression. Functional enrichment was performed using KEGG, GSVA, and GSEA. Immune correlations were evaluated by ESTIMATE, CIBERSORT. Single-cell RNA-seq data were integrated to assess gene expression heterogeneity across tumor and immune compartments. In vitro, MDA-MB-231 cells were treated with sodium L-lactate and lactylation-inducing agents, and gene expression was validated by Western blot and RT-qPCR, while EdU and wound healing assays evaluated proliferation and migration. We identified six hub genes associated with the immune microenvironment. Notably, S100A4 is significantly underexpressed, suggesting their potential regulatory roles in BRCA. Further analysis demonstrated that lactylation-related genes are closely linked to immune regulation in BRCA, indicating a possible crosstalk between metabolic modification and tumor immunity. Additionally, we found that lactylation significantly influences gene expression patterns and immune infiltration in BRCA. Importantly, lactic acid ions were shown to upregulate lactylation levels in BRCA cells, underscoring the functional impact of metabolic signals on post-translational modifications in tumorigenesis. Our findings indicate a potential mechanism wherein lactylation affects BRCA progression via lactic acid-driven regulation of the immune microenvironment; they also highlight the possible involvement of S100A4 in this process and offer new insights that could contribute to the diagnosis and treatment of BRCA. Full article

Extracellular vesicles (EVs) facilitate intercellular communication in glioblastoma (GBM) by transferring microRNAs (miRNAs). GBM is the most aggressive primary brain tumor in adults, and despite multimodal therapy, the median survival remains approximately 15 months. Current diagnostic approaches, including contrast-enhanced MRI, are insufficient to reliably distinguish true tumor progression from pseudoprogression. Moreover, therapeutic efficacy is limited by intratumoral heterogeneity, acquired resistance, and the restrictive nature of the blood–brain barrier (BBB). In this context, EV-associated miRNAs (EV-miRNAs) contribute to GBM progression by regulating proliferation, angiogenesis, invasion, therapeutic resistance, and immune evasion. Notably, several EV-miRNAs are dysregulated in both GBM and neurodegenerative diseases (NDDs), suggesting shared molecular pathways across central nervous system (CNS) disorders. Circulating tumor-derived EV-miRNAs represent promising liquid biopsy biomarkers for diagnosis, prognosis, and longitudinal treatment monitoring. Beyond their biomarker potential, EVs can be engineered as nanocarriers capable of crossing the BBB to deliver therapeutic cargo, including inhibitors of oncogenic miRNAs (e.g., miR-21) or tumor-suppressive miRNAs (e.g., miR-124). This review summarizes the molecular functions, biomarker applications, and therapeutic strategies of EV-miRNAs in GBM. We further discuss current challenges related to methodological standardization, scalable production, and clinical translation. Collectively, advancing the understanding and clinical implementation of EV-miRNAs may provide new opportunities for precision diagnostics and therapeutic innovation in GBM. Full article

This case highlights a novel genotype–phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal < 1.8 µg/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G>A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C>G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C>T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype–phenotype association, which, to our best knowledge, has not been previously reported. Full article

Plant foods have been the cornerstone of human diets since ancient times, fueling civilization and shaping cultures. Plants became central to sustainable food systems, offering diverse and nutritious options for the future. Sea buckthorn (Hippophae rhamnoides L.) has attracted growing scientific interest due to the presence of bioactive compounds, polyphenols, fatty acids, phytosterols, carotenoids, vitamins, and minerals in its fruit, seeds, and leaves. Moreover, sea buckthorn exhibit antioxidant, anti-inflammatory, antimicrobial, antidiabetic, antihyperlipidemic, anticancer, hepatoprotective, neuroprotective, and metabolic regulatory properties supported by in vitro and in vivo models. The biological activity of these phytochemical compounds plays a crucial role in regulating the AMP-activated protein kinase (AMPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathways, as well as pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), cell proliferation, and apoptosis. Furthermore, its potential against microbial growth, including S. aureus, S. epidermidis, S. intermedius, and S. pyogenes, among others, not only expands its applications in the pharmaceutical industry but also attracts researchers to incorporate it into food products. This could lead to the discovery of plant-based therapeutic products without significant adverse effects. However, further exploration of each component’s potential side effects is necessary to support the commercialization of formulated products in either the pharmaceutical or food industries, ensuring the highest safety standards for consumers. Including studies on bioavailability and pharmacodynamics could further strengthen the scientific evidence supporting the specific phytochemicals in sea buckthorn and their mechanistic interactions. Full article

Chimeric antigen receptor–natural killer (CAR-NK) cell therapy is a promising immunotherapy for hematological malignancies. While engineered interleukin15 (IL15) variants like membrane-bound IL15 (mbIL15) and the IL15/IL15Rα heterodimer (RLI) can enhance NK cell activity, their relative efficacy and safety as armor for CAR-NK cells remain unclear. This study systematically evaluated primary human CAR-NK cells co-expressing an anti-CD19 CAR (19ζ) with soluble IL15, mbIL15, or RLI. We found that 19ζ-RLI CAR-NK cells exhibited superior IL15 secretion, proliferation, cytotoxicity, and migration in vitro, and effectively controlled tumors in vivo. However, all IL15-armored constructs, particularly 19ζ-RLI, induced lethal toxicity in mice, characterized by CAR-NK hyperproliferation and elevated systemic IL15. Transcriptomic analysis revealed that this toxicity correlated with a hyperactive molecular state driven by persistent IL15 signaling. In conclusion, this study suggests that constitutive IL15 armoring can be a potent but risky strategy for enhancing CAR-NK cells, with RLI being the most potent yet toxic exemplar of this general principle. Our findings highlight the necessity of incorporating safety-optimized strategies, such as inducible cytokine expression, into the design of cytokine-armored CAR-NK therapies for clinical translation. Full article

Objectives: The mechanism of action of genes related to lactate metabolism in papillary thyroid carcinoma (PTC) is still unclear. In this study, key genes that play a role in PTC were selected from the known genes related to lactate metabolism, and their roles in promoting lactate metabolism in PTC cells were investigated. Methods: Through bioinformatics analysis and cell experiments, the roles of the relevant genes in lactate metabolism and their roles in the occurrence and development of PTC were verified. Results: Through bioinformatics analysis, 12 candidate genes were obtained. Through qRT-PCR experiments, it was confirmed that the expressions of TIMP1 and DPP4 were higher in thyroid papillary carcinoma than in normal PTC cells. By inhibiting the expression of TIMP1 and DPP4 using siRNA, the invasion and proliferation abilities of PTC could be reduced. Compared with normal thyroid cells, the contents of lactic acid and LDHA in PTC cells were higher. Knocking down the expression of TIMP1 and DPP4 would reduce the lactate production ability of PTC cells, and TIMP1 and DPP4 promoted the accumulation of lactate in PTC cells.Conclusions: In this study, by screening the differentially expressed lactate metabolism genes in PTC, different prognostic subtypes were constructed based on the molecular expression patterns. Multi-group student’s t-tests were conducted on the differential signaling pathways and tumor immune regulation of the prognostic subtypes, and a PTC prognosis prediction model was constructed. It was further confirmed that the lactate metabolism genes TIMP1 and DPP4 are highly expressed in PTC and can regulate the proliferation, invasion, metastasis and lactate metabolism of PTC cells. Full article

Background/Objectives: Endometrial cancer frequently develops resistance to apoptosis-based therapies, highlighting the need for alternative strategies that control tumor growth independently of cell death induction. Three-dimensional (3D) tumor models more accurately recapitulate tumor architecture, cellular interactions, and treatment resistance compared to conventional two-dimensional (2D) cultures. This study aimed to investigate whether imatinib-based combination treatments can enforce sustained cytostatic responses in a 3D endometrial cancer model. Methods: Ishikawa spheroids were treated with imatinib alone or in combination with lithium chloride or medroxyprogesterone acetate. Proliferation was assessed by bromodeoxyuridine incorporation, cell cycle distribution by flow cytometry, and apoptosis by Annexin V/propidium iodide staining over 96 h. Results: Imatinib monotherapy produced modest antiproliferative effects, whereas combination treatments resulted in sustained suppression of DNA synthesis, increased G₀/G₁ accumulation, and reduced S-phase entry. Despite strong growth inhibition, apoptotic fractions remained low across all groups. Conclusions: Imatinib-based combinations suppress 3D endometrial cancer growth predominantly through sustained cell cycle arrest rather than apoptosis induction. Targeting apoptosis-resistant proliferation through cytostatic mechanisms may represent a complementary therapeutic strategy for hormone-responsive endometrial cancer and warrants further translational evaluation. Full article

Background: Lung cancer recurrence and metastasis are major causes of cancer-related mortality, but the molecular determinants underlying these processes remain incompletely understood. This study aimed to identify key regulators of lung cancer progression through integrative analyses of bulk and single-cell transcriptomic datasets. Methods: Bulk transcriptomic and single-cell RNA sequencing data from multiple cohorts were integrated to identify genes associated with survival, recurrence, and metastasis. Tumor microenvironment features were further analyzed to prioritize core progression-related genes. ANLN was subsequently evaluated in independent single-cell datasets, followed by functional validation using CRISPR–Cas9-mediated gene knockout in lung cancer cells. Network-based drug prediction and molecular docking were performed to identify candidate compounds targeting ANLN-related programs. Results: ANLN was identified as a core progression-related gene associated with poor prognosis. ANLN was upregulated in recurrent and metastatic lung tumors and correlated with worse overall survival. Single-cell analyses showed that ANLN was predominantly expressed in epithelial and proliferating tumor cells and was associated with microenvironment remodeling, enhanced proliferative and migratory programs, and progression toward an invasive phenotype. These findings were validated in an independent single-cell dataset capturing the transition from in situ to invasive lung cancer. Functional experiments showed that ANLN deletion reduced proliferation and promoted apoptosis in lung cancer cells. Drug prediction and molecular docking identified several candidate compounds, among which Trifluridine and Monobenzone showed favorable binding potential and pro-apoptotic effects in lung cancer cells. Conclusions: ANLN is a potential regulator of lung cancer recurrence and metastasis and marks a conserved invasion-prone epithelial state. ANLN-associated pathways may represent potential therapeutic targets in lung cancer. Full article

Background and Clinical Significance: Nodular fasciitis is a benign, self-limited myofibroblastic proliferation that frequently mimics malignant soft-tissue tumors both clinically and radiologically. Although it has been well described in the extremities, its uncommon occurrence in the submandibular region poses a diagnostic challenge. Case Presentation: We report the case of a 22-year-old male patient, presenting with a rapidly enlarging painless swelling in the left submandibular region. Ultrasound demonstrated a well-defined subcutaneous lesion, while magnetic resonance imaging revealed heterogeneous enhancement with diffusion restriction, suggesting inflammatory or neoplastic pathology. Fine-needle aspiration cytology showed spindle-cell proliferation with pseudosarcomatous features, warranting histological examination to exclude malignancy. Surgical resection was performed. Histopathological examination demonstrated a myofibroblastic proliferation with tissue culture-like morphology. Immunohistochemistry showed diffuse SMA positivity while many other immunohistological markers were negative, arguing against several histologic mimics. Fluorescence in situ hybridization confirmed USP6 gene rearrangement, establishing the diagnosis of nodular fasciitis. Conclusions: This case highlights the diagnostic challenges posed by nodular fasciitis in the head and neck region and emphasizes the importance of correlating imaging, cytology, histopathology, and molecular findings to avoid overtreatment. The literature review further supports the benign clinical course of this rare entity in the submandibular region and underscores the value of including it in the differential diagnosis of submandibular masses. Full article

Theaflavin-3,3′-digallate (TF3), a flavan-3-ol derivative found in black tea, exhibits anti-tumor activity, but its mechanism of action in hepatocellular carcinoma (HCC) remains to be elucidated. Here we systematically delineate how TF3 targets Pin1 to suppress HCC through an integrated approach combining computational simulations, enzyme assay and cell-based assays. TF3 spontaneously occupies the active site of Pin1 with a docking score of −8.9 kcal/mol, inhibiting its PPIase activity (IC₅₀ = 60.33 μmol/L) and yielding a binding constant (K_a) of 3.1 × 10⁵ mol/L. Drug affinity responsive target stability (DARTS) assays further corroborated that TF3 directly engages Pin1 within HCC cells. Functionally, TF3 potently suppressed the viability of HepG2, SK-Hep-1 and Huh-7 cells in both dose- and time-dependent manners (IC₅₀ = 61.22, 14.09 and 69.85 μmol/L at 24 h, respectively), and exhibited a modest selectivity window against the viability of L02 and THLE-2 cells (IC₅₀ = 133.43 and 90.29 μmol/L at 24 h, respectively). In addition, TF3 triggers mitochondrial-mediated apoptosis, evidenced by ROS accumulation, loss of mitochondrial membrane potential, an elevated Bax/Bcl-2 ratio, cytochrome c release and enhanced PARP cleavage, and induces G₂/M phase arrest. It also robustly inhibits HCC cell proliferation, invasion and migration, coinciding with downregulation of proteins governing cell cycle progression and invasive behavior. Transcriptome profiling coupled with enrichment analysis discovered that TF3 treatment differentially regulated 5009 genes, which were prominently enriched in pathways linked to apoptosis, cell cycle control, MAPK and PI3K/AKT signaling pathways. Western blotting analysis revealed that TF3 selectively suppresses phosphorylation of p38 and the PI3K/AKT cascade, activating JNK phosphorylation. In summary, our findings indicate that TF3 suppresses HCC proliferation by targeting Pin1, with attendant modulation of the MAPK and PI3K/AKT pathways, thereby presenting a potential candidate for targeted HCC therapy. Full article

Antiretroviral therapy (ART) effectively controls Human Immunodeficiency Virus Type-1 (HIV-1) infection in people with HIV-1 (PWH), preventing the progression of their infections to AIDS. However, as PWH age, they experience lifestyle- and age-related diseases, notably various types of cancer beyond those traditionally associated with AIDS, with greater incidence and mortality than their non-HIV-1-positive counterparts, despite effective arrest of HIV-1 infection by ART. Dysregulation of redox enzymes presents an underexplored linkage between HIV-1 infection and cancer comorbidity, impacting reactive oxygen/nitrogen species (RONS) management, inflammation, immune function, and mitochondrial function. Chronic HIV-1 infection increases both RONS production and RONS neutralization responses, accelerating development of a sustained RONS-rich environment that still possesses sufficient dampening to prevent outright cytotoxic effects. Such an environment promotes both tumor proliferation and resistance adaptations to chemo- and radiotherapies. This review considers the effects of chronic HIV-1 infection on redox enzyme function and links these effects to tumorigenic mechanisms as potentially shared pathways. We then examine current methods of modulating redox function, consider how these could potentially impact both HIV-1 infection and cancer progression, and lastly propose future methods of co-treatment that could be explored. Full article

Purpose: Cannabidiol (CBD) is a primary bioactive, non-intoxicating cannabinoid found in the cannabis plant. Studies have shown that CBD causes anticancer activity by inhibiting the expression of growth factors and inducing apoptosis, leading to cell cycle arrest. In this study, we aimed to determine how CBD influences the expression of genes that affect cancer pathways in doxorubicin-sensitive (MCF-7) and doxorubicin-resistant (MCF-7/Adr) breast cancer cells. Materials and Methods: IC₅₀ concentrations of CBD in MCF-7 and MCF-7/Adr cell lines were determined by the MTT cell cytotoxicity assay. RNA isolation and subsequent cDNA synthesis were performed for qPCR experiments with the determined IC₅₀ values. The effects of CBD on the cell cycle and apoptosis were studied using flow cytometry. IC₅₀ values of CBD were determined in MCF-7 and MCF-7/Adr breast cancer cell lines at eight different concentrations and at three different incubation periods (24 h, 48 h, and 72 h) with different doses. RT-qPCR was used to investigate the molecular mechanisms underlying the expression of genes involved in cancer pathway analysis. Results: Treatment with CBD at concentrations of 17.57 μM (MCF-7) and 11.41 μM (MCF-7/Adr) for 48 h decreased colony formation, induced apoptosis, and inhibited cell invasion in both cell lines. In addition, we observed significant alterations of angiogenesis, apoptosis, cell cycle, cellular senescence, DNA damage and repair, epithelial-to-mesenchymal transition, hypoxia, metabolism, telomeres, and telomerase in both cell lines. Conclusions: Our research indicates that CBD could be an effective natural bioactive compound for breast cancer treatment, inhibiting tumor cell proliferation and inducing apoptosis. Full article