Search Results (21,023)

The 4T1 cell line is a widely used model for triple-negative breast cancer (TNBC) research due to its high metastatic potential and resemblance to clinical progression. However, its biological characteristics often limit the efficiency and reproducibility of conventional nucleic acid delivery protocols. Here, we present an optimized non-viral delivery framework for efficient cell-associated uptake in 4T1 cells. Five carrier systems—Xfect RNA polymer (Xfect), polyethyleneimine (PEI), chitosan (CHI), and gold nanoparticle conjugates (AuPEI and AuCHI)—were systematically evaluated using both standard (adherent) and reverse (suspension) delivery approaches. A fluorescently labeled oligonucleotide (5′-TYE563) served as a reporter cargo at final concentrations of 5 nM and 10 nM, comparing complexation times of 15 s and 15 min. The proposed protocol introduces a rapid complexation strategy combined with reverse delivery, significantly reducing preparation time while enhancing cell-associated uptake. Under optimized conditions (10 nM, 15 s, reverse), Xfect achieved near-complete cellular uptake with minimal cytotoxicity. Crucially, the colocalization of dual-fluorescence signals enabled the simultaneous validation of metabolic viability and internalized cargo within a single field of view, bypassing the need for independent bulk cytotoxicity assays. This methodology provides a rapid, reproducible, and cost-effective framework to standardize early-stage delivery conditions for difficult-to-transfect cell lines such as 4T1. Full article

This article describes the synthesis, structure confirmation, and evaluation of physico-chemical, pharmacological, and pharmacokinetic properties of new para-fluorophenylated dihydroimidazotriazinones. Based on the strategy of heteroannulation, and the concept of fluorine–hydrogen isosterism, an efficient and simple synthetic route was developed. The target heterobicycles (10–18) were obtained by the reaction of nucleophilic building blocks, i.e., 1-(R-phenyl)-2-hydrazinylideneimidazolidine hydroiodides (1–9), with an electrophilic two-carbon synthon, i.e., 2-(4-fluorophenyl)-2-oxoacetic acid. The structures of the new compounds were confirmed by spectroscopic data. The spectrum of anticancer activity, selectivity profile, and effect on caspase levels, as well as the haemolytic and antihaemolytic properties of the molecules were assessed in in vitro and ex vivo studies. Most compounds exhibited antiproliferative activity against human solid tumour and leukaemic cells (superior/comparable to anticancer drugs) with low toxicity to normal cells. Moreover, they revealed a broader spectrum of anticancer activity than previously obtained isosteres without fluorine substitution, suggesting that the isosteric replacement of hydrogen with fluorine was a fruitful modification. The most selective molecules were able to increase the levels of apoptotic caspases in lung, cervical, and breast cancer cells. Molecular docking results revealed that although all fluorophenylated fused triazinones exhibited affinity for the adenosine A_2A and A_2B receptors, ligands 13, 16, and 17 emerged as promising dual-target candidates due to their superior interaction profiles and stronger binding affinities for both receptor subtypes. All the compounds proved to be safe for red blood cells, as they did not induce any haemolytic effects. Additionally, most of them revealed protective effects on oxidatively stressed erythrocytes, and their antihaemolytic activity was better or comparable to that of antioxidant standards. In silico ADME (absorption, distribution, metabolism, excretion) profiling demonstrated favourable drug-like and pharmacokinetic properties of compounds. Lipophilicity of the molecules was measured by RP-HPLC on an ODS-2 column using an appropriately selected mobile phase. The retention factors, logs k, for most compounds showed a strong correlation with both in silico log P (logarithmic n-octanol/water partition coefficient) and log P_HSA (logarithmic human serum albumin/water partition coefficient) values. In summary, among the nine original fluorophenylated fused 1,2,4-triazinones studied, five molecules (11, 13, 14, 15, and 17) seem to be the most promising anticancer drug candidates suitable for further development. Full article

Background: Feline mammary carcinoma (FMC) is an aggressive neoplasm in cats and has attracted interest in comparative oncology because selected clinicopathological and molecular features overlap with human breast cancer. Methods: This integrative review synthesized literature was identified in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 30 March 2026, focusing on epidemiology, pathology, biomarkers, tumor microenvironment, omics, therapy, and comparative oncology. Feline-derived evidence was distinguished from the human breast cancer literature, and findings were synthesized qualitatively because of substantial methodological and clinical heterogeneity. Results: FMC shows recurrent associations with aggressive histological features, hormone receptor-negative phenotypes, HER2-related signaling, immune checkpoint pathways, and emerging molecular and liquid-biopsy biomarkers. However, differences in molecular classification, methodology, treatment, cohort size, and clinical validation limit direct cross-species inference. Conclusions: FMC may serve as a complementary, question-specific comparative oncology system for studying selected aspects of aggressive mammary tumor biology, metastasis, tumor–host interactions, biomarkers, and therapeutic response. Its translational relevance remains hypothesis-generating and requires standardized methods and independent clinical validation. Full article

Background: Anthracyclines have historically remained a cornerstone of treatment for early HER2-positive breast cancer. However, the emergence of dual HER2 blockade, antibody–drug conjugates, and response-adapted treatment strategies has changed the clinical context in which anthracycline use is considered. Whether anthracyclines continue to provide sufficient oncologic benefit to justify their additional cardiovascular toxicity remains uncertain. Objectives: This study aims to evaluate the contemporary role of anthracyclines in early HER2-positive breast cancer by synthesizing direct comparative evidence and contextual evidence from prospective de-escalation studies. Design: It involves a systematic review with narrative synthesis. Data Sources and Methods: PubMed, the Web of Science, and CENTRAL were searched for prospective studies published from January 2000 to 31 May 2026. A meta-analysis was initially planned, but only three clinically heterogeneous trials directly compared anthracycline-containing and anthracycline-free regimens. Direct comparative and contextual de-escalation evidence was therefore synthesized separately using a narrative approach. Results: Twelve studies were included. BCIRG-006, TRAIN-2, and TRYPHAENA provided direct comparative evidence; nine additional prospective trials provided contextual evidence on anthracycline-sparing or treatment de-escalation strategies. Direct comparisons generally indicated greater cardiac toxicity with anthracycline-containing regimens, although severe events were uncommon and cardiotoxicity definitions varied. Contextual studies supported the feasibility of contemporary anthracycline-sparing approaches in selected populations but did not provide direct estimates of the effect of anthracycline exposure. Conclusions: Anthracycline-containing regimens appear to confer greater cardiac risk than anthracycline-free regimens, but comparative evidence remains limited. The available evidence supports selective rather than routine anthracycline use, with treatment decisions guided by the anticipated oncologic benefit, cardiovascular risk, tumor characteristics, treatment setting, and patient preferences. Registration: PROSPERO CRD420261296599; registered on 29 January 2026. Full article

Background/Objectives: Digital breast tomosynthesis (DBT) provides quasi-three-dimensional breast imaging, but volumetric segmentation model development is constrained by limited expert-annotated clinical data. This proof-of-concept study evaluated the feasibility of synthetic-to-clinical breast tumor segmentation using synthetic model development, limited clinical fine-tuning, and heterogeneous ensemble learning, and aimed to establish a reproducible low-resource framework for volumetric DBT segmentation. Methods: Three architectures—3D U-Net, nnU-Net, and Attention U-Net—were evaluated using publicly available synthetic and clinical DBT datasets. Models initialized from the Mixed-size synthetic configuration were fine-tuned using 10 clinical development cases with five-fold cross-validation; 10 additional clinical cases were reserved for independent testing. Ensemble weights and threshold were evaluated from development-set out-of-fold predictions. Performance was assessed using Dice, Intersection-over-Union (IoU), precision, and recall, with paired non-parametric comparisons on the clinical test cohort. Results: nnU-Net achieved the highest mean Dice on the Large Tumor (0.864) and Mixed-size (0.841) synthetic test sets, while performance was lower in the Small Tumor configuration (0.560). On the independent clinical cohort, the ensemble achieved the highest mean Dice (0.518) and recall (0.630), compared with nnU-Net (Dice = 0.482), Attention U-Net (0.372), and 3D U-Net (0.367). After Holm correction, ensemble Dice was significantly higher than Attention U-Net and 3D U-Net, but not nnU-Net. Conclusions: Synthetic DBT data provided a useful source-domain foundation for volumetric segmentation under constrained annotation conditions, although a synthetic-to-clinical gap remained. Heterogeneous ensemble integration achieved the highest mean clinical Dice without demonstrating superiority over fine-tuned nnU-Net. Larger and more diverse clinical cohorts are required to establish generalizability. Full article

Background: Deep-learning artificial intelligence (AI) for mammographic screening moved from proof of concept to randomised evaluation in a single decade. We reviewed and meta-analysed its diagnostic accuracy and its effect on screening programmes, covering the literature published between 2015 and 2025. Methods: PubMed and Europe PMC were searched from 1 January 2015 to 31 December 2025, supplemented by ClinicalTrials.gov and by forward and backward citation searching (PRISMA 2020, PRISMA-DTA, PRISMA-S). Eligible studies evaluated a deep-learning system for cancer detection or triage in a screening population against a histopathological reference standard. Four syntheses were performed: standalone accuracy pooled on the logit-AUC scale (A), a bivariate sensitivity–specificity model (A2), cancer detection rate ratio for AI-integrated versus standard reading (B), and recall rate ratio (C). Random-effects models used restricted maximum likelihood with Knapp–Hartung intervals. Risk of bias was assessed with QUADAS-2 and QUADAS-C, and certainty with GRADE. Results: Twenty-six studies (27 reports, 2019–2025) were included. Pooled standalone AUC across 14 studies and 1,214,885 examinations was 0.890 (95% CI 0.858–0.915), with I² = 97.4% and a 95% prediction interval of 0.731–0.960. Neither publication year (p = 0.79) nor enriched versus consecutive sampling (p = 0.94) explained this dispersion in meta-regression. The bivariate model (k = 9) gave a summary sensitivity of 73.3% (64.5–80.6) at a specificity of 92.4% (86.8–95.8). Across randomised and paired prospective trials (k = 3), the pooled detection rate ratio was 1.13 (0.83–1.55), with the MASAI randomised trial alone reporting 1.29 (1.09–1.51) and a 44% reduction in screen reading. Non-randomised implementation studies (k = 5), which include a 463,094-women German programme evaluation, pooled to 1.22 (1.08–1.37) with little dispersion (I² = 19.0%). Recall changed little overall (0.95, 0.81–1.12). Certainty was very low for accuracy outcomes and moderate for the single randomised trial. Conclusions: A decade of evidence supports AI as a second reader and triage tool in organised screening, not as an autonomous replacement for the radiologist. Pooled accuracy is high on average but so dispersed that it cannot be transferred to a new programme; local validation before deployment remains necessary. The larger and more precise detection gains come from non-randomised designs, which is the pattern confounding would produce, so the randomised evidence remains the anchor. Interval-cancer and mortality endpoints are still awaited. Full article

Background: Breast cancer survivors frequently experience persistent sensory, psychosocial, and functional sequelae that may not be captured by pain measures alone. Understanding recovery trajectories throughout treatment and survivorship may help identify women at risk of long-term recovery-related difficulties. Objective: To investigate sensory, psychosocial, functional, and quality-of-life trajectories throughout breast cancer treatment. Methods: This prospective longitudinal study included women undergoing unilateral breast cancer surgery assessed at six time points before and after surgery, including before and after adjuvant treatments when applicable. Outcomes included sensory function, pain, upper-limb function, psychosocial variables, and quality of life. Results: Seventy-two women (57 ± 11 years) were included. Despite stable pain intensity and self-reported sensitization symptoms, fear of movement increased (TSK-11: MD [95%CI] = +9[0;22]), quality of life deteriorated (FACT-B: 3–12 month MD [95%CI] = −10[−19;−1]), and upper-limb function initially worsened before partially recovering. Objective sensory alterations suggested dynamic changes in somatosensory processing but were not consistently accompanied by greater pain intensity or self-reported sensitization symptoms. Conclusions: Recovery after breast cancer treatment is multidimensional and cannot be adequately reflected by pain intensity alone. Multidimensional assessment may help identify women at risk of persistent recovery-related difficulties and support personalized survivorship care. Full article

Breast cancer is the most common cancer and the second leading cause of cancer-related death among women worldwide. For accurate diagnosis, pathologists use immunohistochemical (IHC) staining for biomarkers such as human epidermal growth factor receptor 2 (HER2) as an auxiliary test, in addition to hematoxylin and eosin (H&E) staining for evaluating tissue morphology. Traditional IHC staining is limited by high cost, time, and labor, with a shortage of pathologists to meet demand. In this work, we propose a digital HER2 IHC staining algorithm based on tumor masks. The proposed model builds on the Dual Contrastive Learning Generative Adversarial Network (DCLGAN), adding tumor mask loss, structural similarity index measure (SSIM) loss, and a modified identity loss that differentiates between active and inactive regions. Performance was quantitatively assessed by comparing HER2 scores using the Fréchet Inception Distance (FID) and a grade classification model. Compared to DCLGAN, the proposed model achieved a 27.2% decrease in FID and a 2.57% increase in soft accuracy. Visual evaluation further showed that it prevents yellow discoloration and suppresses nonspecific region staining seen in unsupervised learning. These results indicate that effective learning is achievable even with limited and unaligned data, thereby accelerating digital pathology workflows. Full article

This study explored the potential of gold nanorods (AuNRs) functionalized with polyethylene glycol (PEG) and loaded with non-steroidal anti-inflammatory drugs (NSAIDs) fenamic acid (fenH) or its bromo-derivative (4′BrfenH) for targeted drug delivery and preclinical cancer research, given their pH-dependent drug-release profiles and in vitro cytotoxicity in breast cancer cell models. Both formulations demonstrated strong π–π stacking interactions with calf-thymus DNA, suggesting intercalation, and exhibited significant binding affinity to bovine and human serum albumins. Drug release was markedly higher at alkaline pH. As the fenamates are weak acids that are practically insoluble in their neutral form, this pH dependence is attributed principally to the ionization and solubility of the released drug rather than to a responsive carrier. Cytotoxicity assays revealed that AuNRs@PEG@4′BrfenH significantly reduced cell viability in both aggressive (MDA-MB-231) and less metastatic (MCF-7) breast cancer cell lines, particularly at higher concentrations, and caused structural disorganization in 3D spheroid cultures. These findings highlight the promise of AuNRs@PEG@4′BrfenH as a nanoplatform showing pH-dependent release and significant in vitro anticancer activity in breast cancer cell lines and spheroids, supporting its further investigation in relevant tumor models. Full article

Background and Clinical Relevance: The association between acute myeloid leukemia (AML) and monoclonal gammopathy of undetermined significance (MGUS) is rare and likely coincidental, due to the similar epidemiology of these two blood disorders in older AML patients who are not eligible for intensive chemotherapy or aggressive treatment, as they can be excessively myelosuppressive. Such treatments include those containing venetoclax, an easy-to-use all-oral form of decitabine–cedazuridine (DEC-C), which is now available and approved for AML in addition to standard parenteral DNA methyltransferase inhibitors, which have been commonly used in routine clinical practice for about two decades in patients unsuitable for intensive chemotherapy (IC). Case Presentation: A 71-year-old woman developed a therapy-related acute myeloid leukemia (t-AML) seven years after the discovery of the plasma cell dyscrasia. She had carried an asymptomatic and non-progressing IgG-λ MGUS since 2019 while affected by breast cancer, which was cured with chemotherapy and radiotherapy. BM smear and trephine biopsy at the time of t-AML diagnosis showed 30% myelomonoblasts and 8% plasma cells, while SPEP showed the presence of 15 g/L of monoclonal protein. However, considering her age and other medical and personal history, the patient was found unsuitable for IC as well as venetoclax treatment because of the myelosuppressive effect of the therapy. Therefore, she received DEC-C oral monotherapy. After four DEC-C cycles, she achieved CR with hematological incomplete recovery (CRi). During DEC-C monotherapy, serum immunofixation (IF) and BM evaluations after 12 months of treatment showed gradual clearance of the IgG-λ paraprotein and BM plasma cells. Maintenance therapy with oral DEC-C is ongoing for 18 months after achieving CRi, without any signs of toxicity or infection. Conclusions: This report describes the first anecdotal case of t-AML responding to DEC-C with concomitant clearance of the paraprotein associated with MGUS. Full article

Imines, commonly known as Schiff bases, are widely investigated compounds because of their structural versatility and biological properties. In this study, we aimed to evaluate the antioxidant potential of salicylaldehyde-derived imines and to determine how their reduction to the corresponding secondary amines affects their radical-scavenging activity and mechanism of action. Two series of phenolic derivatives, imines I1–I6 and amines A1–A6, were synthesized and assessed using an integrated experimental and theoretical strategy combining five in vitro antioxidant assays with density functional theory calculations. Antioxidant evaluation by DPPH, ABTS, FRAP, phenanthroline, and CUPRAC assays revealed distinct activity profiles for the two series. The imine derivatives were more effective in electron-transfer-based assays, whereas the reduced amines showed stronger DPPH radical-scavenging activity. Compound A6 exhibited the highest overall antioxidant activity, with IC₅₀ values (e.g., DPPH IC₅₀ = 26.7 ± 0.97 µM; ABTS IC₅₀ = 11.69 ± 0.43 µM) lower than BHT (DPPH IC₅₀ = 85.85 ± 3.69 µM) and BHA (DPPH IC₅₀ = 59.39 ± 1.9 µM) in most assays. DFT calculations in aqueous medium indicated that the phenolic OH groups govern antioxidant reactivity and identified SPLET as the dominant mechanism for A6, supported by a remarkably high rate constant (k = 1.40 × 10⁵ M⁻¹s⁻¹) and a 100% branching ratio (G), completely outcompeting the HAT mechanism (k = 2.28 × 10⁻² M⁻¹s⁻¹). In addition to the antioxidant investigation, cytotoxicity was assessed in MDA-MB-231 breast cancer cells and Vero normal cells, revealing that the chlorinated derivatives such as I5 combine moderate anticancer activity (MDA-MB-231 IC₅₀ = 122.6 ± 2.23 µM) with lower toxicity toward non-tumor cells (Vero IC₅₀ > 400 µM). Molecular docking studies were conducted to elucidate the binding modes of the active derivatives within the active sites of EGFR, Tubulin, and Topoisomerase IIβ, while subsequent 100 ns molecular dynamics simulations validated the structural stability and sustained interaction energies of these predicted complexes. Full article

SOX9 is a transcription factor linked to cellular plasticity and aggressive behavior in breast cancer. We investigated whether nuclear SOX9 expression correlates with short-term (5-year) survival outcomes in luminal breast cancer. In a retrospective cohort of 60 patients with estrogen receptor-positive invasive breast carcinoma, nuclear SOX9 expression was evaluated via immunohistochemical H-scores (0–300). Survival was analyzed continuously, by median-split dichotomy, and using a 1% nuclear-staining threshold via Kaplan–Meier and Cox regression models. Most tumors were luminal B (73.3%), and 45% were node-positive. Nuclear SOX9 was detected in 51.7% of cases (median positive H-score: 30). Over follow-up, 13 disease-free survival (DFS) and 12 overall survival (OS) events occurred. Continuous H-score did not correlate with clinicopathological variables, DFS (p = 0.576), or OS (p = 0.613). A median-split showed higher 5-year DFS for high-expression tumors (89.7% vs. 74.2%, p = 0.048), but this borderline protective trend was unconfirmed by Cox regression (p = 0.063) or the 1% threshold; ROC analysis showed no discrimination (AUC: 0.34–0.36). Standalone nuclear SOX9 expression has no significant impact on short-term (5-year) prognosis in early-stage luminal breast cancer; extended follow-up is warranted to assess potential late recurrence. Full article

Background/Objectives: This study aimed to evaluate the concordance of preoperative digital breast tomosynthesis (DBT)- and magnetic resonance imaging (MRI)-measured tumor size with the pathological gold standard in invasive breast cancer and how this varies by molecular subtype and breast density (BI-RADS). Methods: This single-center, retrospective cohort study included 55 patients with unifocal invasive breast cancer who underwent preoperative DBT and MRI (1.5 T) followed by surgery within ≤60 days. Agreement with pathological size was assessed using Pearson’s correlation, Lin’s CCC, and Bland–Altman analysis; measurements within ±20% of pathological size were classified as concordant, with DBT/MRI rates compared using McNemar’s test. Subgroup analyses were performed by molecular subtype and breast density. Results: The mean pathological tumor size was 21.7 ± 10.7 mm. Pearson’s r was 0.784 for DBT and 0.785 for MRI (Lin’s CCCs were 0.775 and 0.783). Bland–Altman bias was −1.16 mm for DBT and +0.10 mm for MRI, with wider limits of agreement for MRI. Concordance (±20% threshold) was 54.5% for DBT and 45.5% for MRI, a non-significant difference (McNemar p = 0.38). Subtype- and density-stratified findings were directionally consistent but based on small subgroups and are hypothesis-generating only. Conclusions: In this cohort, DBT showed correlation and agreement with pathology comparable to MRI, without a statistically significant difference in concordance rate. Subgroup heterogeneity suggests DBT may hold value as a complementary sizing tool where MRI is unavailable, pending confirmation in larger, prospective, multicenter studies with independent reader validation. Full article

Cardio-oncology explores the complex interplay between cancer biology and cardiovascular health, particularly the cardiotoxic effects of cancer therapies. Both microRNAs (miRNAs) and alarmins have emerged as key molecular mediators linking tumor progression and cardiac stress, representing promising biomarkers and therapeutic targets. In skin and breast cancer, specific miRNAs, including miR-21, miR-155, miR-34a, and the miR-200 family, regulate tumor proliferation, invasion, metastasis, and therapy resistance. Alarmins such as NPM, HMGB1, HSPs, IL-33, and S100 proteins modulate inflammatory signaling, oxidative stress, and tissue remodeling, contributing to both tumor progression and cardiomyocyte dysfunction. These molecules are also implicated in chemotherapy- and targeted therapy-induced cardiotoxicity, including apoptosis, fibrosis, and impaired cardiac function. This review highlights the dual role of miRNAs and alarmins in tumor biology and cardiovascular toxicity, emphasizing their potential as circulating biomarkers for early detection and monitoring. Therapeutic strategies targeting this axis—including miRNA mimics/inhibitors and alarmin modulators—may provide synergistic benefits by reducing cardiotoxicity while suppressing tumor growth. Understanding miRNA–alarmin relationships, including direct interactions such as the NPM/miR-200c axis, as well as their broader regulatory networks in cardio-oncology, offers novel avenues for precision medicine, enabling integrated approaches to monitor, prevent, and treat therapy-related cardiac complications in patients with skin and breast cancers. Full article

Obesity influences breast cancer risk, progression, and therapeutic response through endocrine, inflammatory, metabolic, stromal, and vesicular mechanisms. Circulating and extracellular vesicle (EV)-associated microRNAs are attractive liquid biopsy candidates; however, in obesity-associated breast cancer, they should not be interpreted as tumor-only biomarkers. This narrative review analyzes circulating/EV-miRNAs as mixed host–tumor signals and separates association-based biomarker evidence from functional EV-mediated transfer. We performed a narrative and integrative review of studies on miRNA biogenesis, circulating miRNA transport, EV biology, adipose tissue dysfunction, adipose-tumor communication, biomarker development, therapy response, and methodological reporting standards. The current literature is read along two independent axes: human relevance and source attribution, from non-breast models to obesity-stratified human cohorts, and mechanistic causality, from association only to EV-level function, miRNA-level function, and causality with rescue; clinical validation is treated as a separate qualifier rather than as the top of a single scale. For example, EV-let-7a in overweight/obese breast cancer patients mainly supports an obesity-stratified biomarker candidate. Breast adipose tissue-derived EV cargoes enriched in miR-155-5p, miR-10a-3p, and miR-30a-3p provide stronger functional support for metabolic reprogramming, whereas EV-associated miR-221/222 has mediator-level evidence in endocrine resistance but is not obesity specific. Conclusions: The main contribution of this review is an operational interpretation framework in which circulating miRNAs are evaluated according to probable source, evidence level, and clinical purpose. Future studies should report EV workflow quality, sample type, hemolysis and platelet control, normalization strategy, external validation, tumor subtype, and obesity phenotyping beyond BMI, including waist circumference or waist-to-hip ratio, insulin resistance, diabetes, menopausal status, and inflammatory markers. Full article