Search Results (969)

Background/Objectives: Large language models (LLMs) have been proposed as a means of converting unstructured electronic medical records (EMRs) into structured datasets. However, concerns regarding the reliability of these models in non-English clinical text and their capacity to generate novel insights remain unresolved. We aimed to utilize an LLM to identify a hypothetical “Luminal B poor-prognosis” breast cancer subgroup (LPP) based on progesterone receptor (PR), the Ki-67 proliferation index, and grade characteristics, while concurrently validating the LLM’s accuracy. Methods: We retrospectively compiled the EMRs on 7756 female breast cancer patients from five Moscow oncology centers. An LLM with a domain-engineered prompt extracted eight clinicopathological variables (Ki-67, estrogen receptor (ER)/PR Allred status, HER2 status, grade, relapse dates, and multiple primaries). The accuracy of the model was validated in 366 randomly sampled cases against oncologist annotations using Intraclass Correlation Coefficient (ICC) and weighted κ. Following data post-processing, the complete-case cohort (n = 2347) and the HR+/HER2− stage I–III sub-cohort (n = 1419) were analyzed. Survival was estimated with Kaplan–Meier/log-rank and modeled with Cox regression (adjusted for age, stage, and treatment). Ki-67 was modeled continuously; prespecified LPP definitions were compared. Results: LLM–human agreement was high (Ki-67 ICC = 0.882; grade κ = 0.887; ER κ = 0.997; PR κ = 0.975; HER2 κ = 0.935). Date extraction was characterized by a high degree of missing data. In HR+/HER2− stage I–III disease, ER < 5 was non-prognostic; however, PR < 4 and Ki-67 ≥ 40% were indicative of inferior survival (HR 2.25 and 1.85). The most effective LPP definition (PR < 4 and Ki-67 ≥ 40%) identified a subgroup (~5.3%) of patients with markedly poorer outcomes (age, stage, and treatment adjusted HR 2.60, 95% CI 1.53–4.43) compared to the Luminal B (HER2−) subgroup. Conclusions: The developed LLM has demonstrated the ability to reliably structure non-English EMRs and enable discovery of clinically meaningful subgroups. The discovered LPP phenotype defines a small, high-risk subset warranting external validation. Given the retrospective, single-system design of the study, it is imperative to interpret the discovered phenotype features as hypothesis-generating, rather than as definitive evidence. Full article

Integrin αvβ3, a key member of the integrin family, plays a crucial role in cell localization, mobilization, and signal transduction through collaborating with extracellular proteins. Its unique expression and activation in tumor cells and rapidly dividing endothelial cells suggest its potential role in cancer cell growth and metastasis, making it a promising therapeutic target. In genomic pathways, estrogen binds to its receptors to form transcription complexes that bind to the promoters of steroid hormone-receptive genes. Conversely, G protein-coupled estrogen receptor 1 (GPER) and integrin αvβ3 have been shown to play oles in non-genomic actions that contribute to estrogen-induced cancer growth. The molecular mechanisms of these non-genomic functions involve signal transduction via focal activated kinase (FAK), mitogen-activated protein kinase (ERK1/2), and phosphatidylinositol 3-kinase (PI3K), as well as the differential expression of multiple genes associated with various cellular processes. As a hormone receptor, integrin αvβ3, collaborating with ER-α and GPER, exhibits a wide range of cellular effects relevant to cancer biology. Full article

Background/Objectives: Organic UV filters are chemical compounds that are commonly used in sunscreen products to absorb UV radiation from the Sun. To date, the filters have been detected in aquatic environments worldwide, as well as in aquatic organisms, including fish and coral. Hydroxy-4-methoxybenzophenone (BP-3) is a common organic UV filter and it is well documented to be among the filters that are detectable worldwide in water samples and aquatic organisms. Long-term exposure in vivo studies have demonstrated that high doses of BP-3 can cause endocrine-disrupting effects in aquatic organisms. Methods: Using gonadal cell culture and quantitative RT-PCR, our study aimed to ascertain the effect of environmentally relevant doses of BP-3 (detected in aquatic systems) on the gene expression of reproductive targets, estrogen and growth hormone receptors (ERs and GHRs), in Mozambique tilapia (Oreochromis mossambicus) after an acute 24 h treatment. Results/Conclusions: Our study is the first to use an in vitro design to investigate the mechanism of the action of BP-3 on gonadal tissue in fish. Our results show that BP-3 does not induce gene regulation directly on the gonads of tilapia at doses that are comparable to what is detectable in aquatic environments after 24 h. We do verify, as seen in other teleost species, homologous regulation of ERβ in male tilapia gonadal tissue. Full article

Background/Objectives: Prognostic assessment in endometrial cancer (EC) is based on clinical and pathological features such as histological type, FIGO stage, tumor grade, LVSI, P53 status, and hormone receptor expression. Recent molecular research has distinguished four EC subtypes, with MMR status (pMMR vs. dMMR) providing clinically relevant stratification due to its predictive value for immunotherapy. The present study aims to compare dMMR and pMMR tumors in terms of the prevalence of adverse histopathological prognostic factors. Methods: This retrospective study included 179 patients with endometrioid endometrial carcinoma (EEC) treated at the authors’ institution (1 January 2023–31 August 2025). Patients were classified by MMR status (pMMR vs. dMMR) based on immunohistochemistry, and clinicopathological variables, including FIGO stage, myometrial invasion depth, tumor grade, LVSI, ER/PR expression, and P53 status, were analyzed. Normality was assessed using the Shapiro–Wilk test. Categorical variables were tested with chi-square or Fisher’s exact tests, reporting odds ratios with 95% CI, while continuous variables were compared using the Mann–Whitney test and presented as median (IQR) with the Hodges–Lehmann difference and 95% CI. Multivariable logistic regression with Wald tests was performed. Results: dMMR tumors accounted for 29.05% of all cases. Patients in the dMMR group were significantly more likely to present with FIGO stage III/IV disease (p = 0.036) and to exhibit LVSI (p = 0.008). No differences were observed between the groups with respect to tumor grade, estrogen receptor positivity, progesterone receptor positivity, or the prevalence of deep myometrial invasion. The most frequent pattern of protein loss in the dMMR population was concurrent loss of MLH1 and PMS2. Conclusions: In the studied population, dMMR tumors more frequently exhibited adverse prognostic features of EC, such as advanced stage of disease and lymphovascular space invasion. This suggests the potential for effective immunotherapy in this patient group. Full article

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that stabilizes numerous oncogenic proteins and supports tumor survival. Small molecules targeting HSP90 offer a novel approach to overcome drug resistance and immune suppression in breast cancer. Methods: A novel thiazolyl benzodiazepine (TB) containing a hydrazone moiety was evaluated in breast cancer cell lines (ER⁺ MCF-7, TNBC MDA-MB-231, and HER2⁺ SK-BR-3). Cytotoxicity was assessed using the CCK-8 assay, followed by PCR sequencing, flow cytometry, RT-qPCR, protein profiling, and HSP90 binding assays. Results: TB showed the strongest activity in MCF-7 cells (IC₅₀ = 7.21 µM) compared to MDA-MB-231 (IC₅₀ = 28.07 µM) and SK-BR-3 (IC₅₀ = 12.8 µM) cells. Mechanistic studies showed that TB binds to HSP90 (Kd = 3.10 µM), leading to disruption of the oncogenic signal. TB induced G2/M cell cycle arrest, promoted apoptosis via Bax and Caspase-3 activation, and suppressed cancer stem cell markers (NANOG, OCT4, SOX2). Additionally, TB activated immune-related pathways via ERK/MAPK signaling and upregulated genes such as SMAD2, SMAD3, and JUN.Conclusions: TB functions as an HSP90 inhibitor with dual anticancer and immunomodulatory properties in Estrogen Receptor-Positive (ER⁺) breast cancer cells. These findings suggest that TB represents a promising scaffold for the development of multi-targeted breast cancer therapies. Full article

Cancer development in BRCA1 carriers is a multi-step process, which is triggered by several factors and mechanisms that are not clearly understood. Most BRCA1 carriers develop triple-negative breast cancer (TNBC)—estrogen receptor (ER)-, progesterone receptor (PR)-, and HER2 -negative cancers—which originates from ER/PR/HER2-negative breast progenitor cells. Due to a lack of ER/PR/HER2-negative cell models with BRCA mutations, the processes inducing cancer development in BRCA carriers have not been comprehensively studied. Thus, studies characterizing ER/PR/HER2-negative cells carrying a BRCA1 germline mutation are needed to gain more in-depth knowledge about the steps leading to cancer initiation in BRCA1 carriers. To study the cancer development in these patients, we established a protocol for the generation of human ER/PR/HER2-negative breast organoids carrying a BRCA1 germline mutation. We confirmed that these organoids are unresponsive to estrogen, can self-renew, and express the stem/progenitor marker CD44. In addition, we observed that these organoids contain outgrowths that resemble the mature ductal and lobular units of the mammary gland, thus making it a suitable model system to study how cancer develops in ER/PR/HER2-negative mammary cells that carry a BRCA1 germline mutation. Full article

Background/Objectives: Conventional two-dimensional (2D) cell cultures offer valuable insights into cancer cell biology; however, they lack in replicating the complex interactions present in solid tumors. Therefore, research has shifted towards the development of three-dimensional (3D) cell models that recapitulate the dynamic cell–cell and cell–matrix interactions within the complex tumor microenvironment (TME), better resembling tumor growth and initial stages of dissemination. Extracellular matrix, a key component within the TME, regulates cell morphology and signaling, influencing key functional properties. Breast cancer remains the most frequently diagnosed cancer type in women and a leading cause of cancer-related mortality. Methods: The aim of the present study was the development of breast cancer cell-derived spheroids, utilizing two breast cancer cell lines with differential estrogen receptor (ER) expression profile, and their characterization in terms of morphology, functional properties, and expression of epithelial-to-mesenchymal transition (EMT) markers and matrix signatures implicated in breast cancer progression. To this end, the ERα-positive MCF-7, and ERβ-positive MDA-MB-231 breast cancer cell lines were utilized. Results: Our findings revealed notable phenotypic transitions between 2D and 3D cultures, which were further supported by differential EMT markers expression. Moreover, spheroids exhibited distinct expression profiles of key receptors [ERs, epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGF1R)] and matrix molecules (syndecans, and matrix metalloproteinases), accompanied by altered functional cell properties. Bioinformatic tools further emphasized the interplay between the studied matrix regulators and their prognostic relevance in breast cancer. Conclusions: Overall, this study introduces a simple yet informative 3D breast cancer model that captures key TME features to better predict cell behavior in vitro. Full article

Triple-negative breast cancer (TNBC) remains a leading cause of cancer-related mortality in women, characterized by its aggressive nature and limited therapeutic options. TNBC is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, which excludes patients from targeted endocrine and HER2-directed therapies, contributing to poor prognosis. This study investigates BKS-112, a potent histone deacetylase 6 (HDAC6) inhibitor, for its anticancer activity against TNBC using MDA-MB-231 cells. We assessed HDAC protein expression and their prognostic implications, alongside in vitro experiments analyzing cell viability, apoptosis, autophagy, and colony formation. BKS-112 exhibited dose- and time-dependent reductions in cell viability, significant morphological alterations, and decreased colony formation. The compound increased the acetylation of histones H3, H4, and α-tubulin while downregulating HDAC6 expression and activity. Additionally, BKS-112 reduced cell migration, demonstrating anti-metastatic potential. It induced G1 phase cell cycle arrest and modulated key regulators, including cyclins and cyclin-dependent kinases (CDKs). Apoptosis was promoted through mitochondrial pathways, evidenced by changes in Bcl-2, Bax, and caspase activation. BKS-112 also elevated reactive oxygen species (ROS) levels, affecting apoptosis-related PI3K/AKT signaling. Autophagy was triggered by upregulating LC3 and Atg-7 expression. Collectively, these findings suggest that BKS-112 exerts robust anticancer effects by inducing cell cycle arrest, apoptosis, and autophagy, highlighting its therapeutic promise for TNBC treatment. Full article

Mancozeb is a broad-spectrum fungicide used extensively in agriculture to protect crops against a wide range of plant diseases. Although its capacity to induce oxidative stress is well documented, the cytotoxic effects of mancozeb on red blood cells (RBCs) remain poorly characterized. The present study aimed to investigate the cytotoxic effects of mancozeb on isolated RBCs, with particular focus on oxidative stress-induced cellular and molecular alterations. Human RBCs were exposed to mancozeb (0.5–100 µM) for 24 h. No hemolytic activity was observed across the tested concentrations. However, 10 and 100 µM mancozeb induced a significant increase in intracellular reactive oxygen species (ROS), leading to lipid and protein oxidation and impaired Na⁺/K⁺-ATPase and anion exchanger 1 (AE1) function. These changes resulted in altered RBC morphology, reduced deformability, and increased methemoglobin levels. Alterations in glycophorin A distribution, anion exchanger 1 (AE1) clustering and phosphorylation, and α/β-spectrin and band 4.1 re-arrangement indicated disrupted membrane–cytoskeleton interactions. A release of extracellular vesicles (EVs) positive for glycophorin A and annexin-V was also observed, consistent with plasma membrane remodeling. Despite increased intracellular calcium, eryptosis remained minimal, possibly due to activation of protective estrogen receptor (ER)-mediated pathways involving ERK1/2 and AKT signaling. Activation of the cellular antioxidant system and the glutathione redox system (GSH/GSSG) occurred, with catalase (CAT) playing a predominant role, while superoxide dismutase (SOD) activity remained largely unchanged. These findings offer mechanistic insights regarding the potential health impact of oxidative stress induced by pesticide exposure. Full article

More than 70% of breast cancers are estrogen receptor-positive (ER⁺). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 inhibition, as these tumors rely heavily on CDK4/6 activity for survival under endocrine therapy. Full article

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organofluorines linked to cancer, organ dysfunction, and other health problems. This study used quantitative structure–property relationship (QSPR) and quantitative structure–activity relationship (QSAR) modeling to examine the binding of PFAS to estrogen receptor alpha (ERα) and beta (ERβ). Molecular docking of 14,591 PFAS compounds was performed, and docking scores were used as a measure of receptor affinity. QSPR models were built for two datasets: the ERα and ERβ top binders (TBs), and a set of commonly exposed (CE) PFAS. These models quantified how chemical descriptors influence binding affinity. Across the models, higher density and electrophilicity indicated positive correlations with affinity, while surface tension indicated negative correlations. Electrostatic descriptors, including HOMO energy and positive Fukui index (F⁺ max), were part of the models but showed inconsistent trends. The CE QSPR models displayed correlations that conflicted with those of the TB models. Following QSPR analysis, 66 QSAR models were developed using a mix of top binders and experimental data. These models achieved strong performance, with R² values averaging 0.95 for training sets and 0.78 for test sets, that indicated reliable predictive ability. To improve generalizability, large-set QSAR models were created for each receptor. After outlier removal, these models reached R² values of 0.68–0.71, which supports their use in screening structurally diverse PFAS. Overall, QSPR and QSAR analyses reveal key chemical features that influence PFAS–ER binding. This predictive approach provides a scalable framework to assess the binding interactions of structurally diverse PFAS to ERs and other nuclear receptors. All the codes, data, and the GUI visualization of the results are freely available at sivaGU/QSPR-QSAR-Molecular-Visualization-Tool. Full article

Background and Objectives: Breast cancer is one of the most common cancers in women and the most common cause of cancer death. Hormone receptors, specifically the estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor-2 (Her2), are tumor-specific markers used to guide breast cancer therapy. The purpose of this study is to evaluate the impact of tumor biology, including ER, PR, and Her2 expression, on survival in female breast cancer. Materials and Methods: This retrospective cohort study represents an analysis of 2016 female breast cancer cases using anonymized data. We reviewed cases of female breast cancer diagnosed from 1 January 2010 to 31 December 2021, in the Clinic of Obstetrics and Gynecology, Diakoneo Diak Klinikum Schwäbisch Hall, Germany. Data on clinical, pathology, immunohistochemistry, and follow-up characteristics were retrieved from the clinic’s database. To interpret the data, we used the software IBM SPSS Statistics 20, and, to account for multiple comparisons, we used a Bonferroni-adjusted significance level of 0.004. In the survival analysis, the Kaplan–Meier method and the log-rank test of equality of survival distributions were applied. Results: Among 2016 female breast cancer cases, 84.5% (1703/2016) were hormone receptor (HR)-positive. The 5-year overall survival was 0.873 (95% CI (0.851, 0.895); 99.6% CI (0.841, 0.905)) for HR-positive patients and 0.760 (95% CI (0.713, 0.807); 99.6% CI (0.691, 0.829)) for HR-negative patients (p < 0.001). Statistically significant differences were observed among HR+/HER2+, HR+/HER2−, HR−/HER2+, and triple-negative subtypes (p = 0.003). When comparing survival distributions based solely on HER2 expression (positive vs. negative), no statistically significant difference was observed (p = 0.29). Conclusions: Statistically significant differences in unadjusted overall survival distributions were observed among breast cancer molecular subtypes. HR-positive breast cancers demonstrated better overall survival than HR-negative cancers, while no statistically significant difference in unadjusted survival was observed between HER2-positive and HER2-negative groups. Full article

Breast cancer gene 1 (BRCA1) is a tumor suppressor gene essential for DNA repair, and its mutations are linked to aggressive breast cancers with poor prognosis. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit some patients with BRCA1-mutant, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, issues such as limited efficacy and drug resistance persist. This is especially critical for triple-negative breast cancer (TNBC), which lacks targeted therapies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as abemaciclib—FDA-approved for estrogen receptor (ER)-positive/HER2-negative breast cancer—are emerging as potential treatments for TNBC. We evaluated abemaciclib in BRCA1-mutant TNBC cell lines (SUM149, HCC1937, and MDA-MB-436) and found them to be sensitive to the drug. However, treatment induced cellular senescence and Interleukin-6 (IL-6) secretion, which may promote drug resistance. To address this, we inhibited IL-6 signaling using bazedoxifene or glycoprotein 130 (GP130) siRNA, and both of which enhanced abemaciclib sensitivity. Combination treatment with bazedoxifene and abemaciclib synergistically inhibited cell migration and invasion, and induced apoptosis. In a mammary fat pad TNBC tumor model, the combination treatment significantly suppressed SUM149 tumor growth more than either agent alone. These findings support co-targeting IL-6 and CDK4/6 as a novel therapeutic strategy for BRCA1-mutant TNBC. Full article

Adipocyte cell models are essential for investigating adipogenesis, yet methodological inconsistencies pose challenges to obtaining reproducible and physiologically relevant results. Murine cell lines, such as 3T3-L1 and OP9, are commonly utilized due to their established adipogenic capabilities. However, differences in its metabolic, genetic regulation, and receptor signaling raise concerns about their applicability to human adipose biology. Human-derived models, including mesenchymal stem cells (hMSCs) and preadipocyte cell lines, offer a closer approximation to in vivo adipogenesis but display significant variability in differentiation efficiency. This variability is often compounded by heterogeneous differentiation protocols, variations in cell confluence, and unstandardized pharmacological induction strategies. A pivotal factor influencing adipogenic potential is the receptor toolkit, which dictates cellular responses to differentiation stimuli. This study systematically evaluates key receptors—PPARγ, glucocorticoid receptors (GR), insulin receptor (IR), thyroid hormone receptors (TR), estrogen receptors (ER), and adenosine receptors (AR)—across commonly used adipocyte models to assess their roles in adipogenic regulation. Additionally, we examine the impact of pharmacological agents capable of inducing adipogenesis (adipogens) and the methodological inconsistencies that contribute to variations in adipocyte differentiation. By addressing these factors, we aim to elucidate the extent to which receptor variability influences experimental outcomes and propose a more structured approach to interpreting adipogenesis research. This critical assessment underscores the need for greater methodological transparency and receptor profiling to enhance the reliability of adipocyte models in metabolic research. Standardizing differentiation methodologies while accounting for receptor diversity will be essential for refining in vitro models and improving their translational potential in the study of obesity, diabetes, and other metabolic disorders. Full article