Search Results (4,049)

In vitro cultured biomass of Rindera graeca, a rare endemic plant, is an efficient renewable source of bioactive naphthoquinones, e.g., rinderol, a potential bioactive inducer of apoptosis in cancer cells. Bioengineering strategies, as biomass immobilization on functionalized biomaterial-based scaffolds, elicitation by chitosan, and in situ extraction of metabolites, are tested for intensifying naphthoquinones production in R. graeca hairy roots. The aim of the study was to investigate the effects of hybrid poly(lactic)–chitosan scaffolds on biomass proliferation and rinderol production in R. graeca hairy roots. Effects of chitosan origin (fungal or squid), molecular mass (350–1800 kDa), and concentration (up to 45%) in the developed hybrid scaffolds have been quantitatively identified, and the results were compared to the reference culture system containing an unmodified PLA-based construct. Applying PLA–chitosan scaffold containing 33% of fungal chitosan resulted in 635 times higher rinderol production (3660 µg g_DW⁻¹) than the application of reference scaffolds. Among the tested parameters, the chitosan concentration in the hybrid scaffolds revealed significant importance in rinderol production. To sum up, the developed hybrid PLA-chitosan scaffold may be recognized as a functional key element supporting the production of naphthoquinones in cultures of R. graeca biomass. 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

High-intensity focused ultrasound (HIFU) has recently emerged as a novel non-invasive treatment modality in dermatology, offering precise ablation of cutaneous lesions with minimal damage to surrounding tissue. Originally developed for deep-seated tumors, dermatological HIFU platforms operating at ~20 MHz enable submillimeter-scale treatment of thermal or mechanical injuries localized to the epidermis and superficial dermis, making them suitable for managing benign, premalignant, and malignant skin conditions. This review outlines the mechanistic basis of HIFU—including thermal coagulation, acoustic cavitation, and immunomodulatory effects—and presents the current evidence for its efficacy in treating actinic keratoses and basal cell carcinomas (BCCs), where early studies report clearance rates of 70–97% and excellent cosmetic outcomes. Compared to conventional therapies such as surgery, photodynamic therapy, or cryotherapy, HIFU offers reduced procedural pain, faster healing, and the ability to treat multiple lesions in a single session. Its role in field cancerization and potential utility in prophylaxis for high-risk skin areas are also explored. While promising, long-term oncologic outcomes and standardized treatment protocols remain under investigation. HIFU represents a significant advancement in non-invasive skin cancer management, aligning oncologic efficacy with patient-centered care.
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Background: Personalized medicine in breast cancer surgery aims to tailor therapeutic strategies not only to tumor biology but also to patient-specific risk factors and surgical outcomes. The Alexis^® retractor, originally designed for abdominal and pelvic surgery, may represent an innovative tool to optimize axillary surgical procedures in selected patients. Its atraumatic design and protective sheath provide enhanced visibility, minimized tissue trauma, and a potentially lower risk of postoperative complications, thus contributing to individualized surgical care. Methods: We conducted a retrospective, single-center study at Fondazione Policlinico Universitario Agostino Gemelli IRCCS between January 2024 and April 2025. Patients undergoing breast-conserving surgery or mastectomy with axillary access were included. The Alexis^® retractor was used for axillary tissue retraction in procedures such as sentinel lymph node biopsy and axillary dissection. Outcomes were assessed at 7, 14, and 30 days postoperatively, with particular focus on complication rates and surgical efficiency. Results: Thirty-seven patients (38 procedures) were analyzed. Seromas occurred in four patients (10.8%) and were managed with ultrasound-guided aspiration. Wound dehiscence occurred in two patients (5.4%) and was treated with advanced dressings. No infections, hemorrhages, or flap necrosis were observed. No systemic complications occurred. Conclusions: The preliminary results suggest that the Alexis^® retractor may support a more personalized approach to axillary surgery in breast cancer, by reducing early postoperative complications and improving surgical ergonomics. Its atraumatic design and protective sheath may help tailor surgical management to individual patient risk profiles, minimizing tissue damage and infection risk while enhancing intraoperative visibility and efficiency. Further prospective, controlled studies with larger cohorts are needed to confirm its role in precision breast surgery and to define which patient subgroups may benefit the most. Full article

Collagens comprise a large, diverse family of proteins that are abundantly expressed throughout most tissues. As a main component of the extracellular matrix (ECM), it is becoming increasingly appreciated how vital collagens are to tumor development, progression, and metastasis. COL6A3, which encodes the alpha 3 chain of type VI collagen, is a unique member of the collagen family that encodes a C-terminal peptide with powerful signaling capabilities, named endotrophin (ETP). Expression of COL6A3 is required for the survival, migration, and invasion of many cancer cell lines, including breast, bladder, liver, and colorectal cancers. ETP, which was originally discovered to be enriched in the adipocytes of mammary tumors, is a powerful oncopeptide that can alter signaling of tumor and stromal cells. ETP has greater signaling potential than the parental COL6A3 as it can induce EMT and promote chemoresistance, metastasis, and stemness in an TGF-β-like manner. ETP can also function independently of TGF-β to recruit endothelial cells and macrophages. In this review, we examine the molecular implications of COL6A3 and ETP expression and their effects on tumor growth, metastasis, and therapeutic response. Finally, we speculate on the potential of serum ETP as a prognostic biomarker in both carcinomas and sarcomas. In summary, COL6A3 and ETP are powerful drivers of tumor growth that have potential as noninvasive diagnostic and prognostic tools for the clinical management of cancer. Full article

Background: Human papillomavirus (HPV)-associated oral and oropharyngeal squamous cell carcinomas have risen dramatically in incidence over recent decades. Yet, unlike cervical neoplasia, there is no established screening paradigm for HPV-driven oropharyngeal dysplasia, as precursor lesions are often occult and are not easily accessible for examination. This drives an urgent need for non-invasive biomarkers to enable early detection, risk stratification, and timely intervention. Objective of this review is to highlight advances in liquid biopsy modalities, specifically saliva- and blood-based biomarkers—in the context of HPV-driven oral carcinogenesis—and to evaluate their utility in early cancer detection, prognostic, post-treatment surveillance, and recurrence monitoring. Methods: We performed a narrative review of PubMed-indexed studies (2015–2025) focusing on HPV-positive oral and oropharyngeal squamous cell carcinomas. and liquid biopsy analytes. Key sources were high-impact original studies and meta-analyses from 2020–2025 examining circulating tumor DNA (ctDNA), viral nucleic acids, circulating tumor cells (CTCs), extracellular vesicles (EVs), and related biomarkers in saliva and blood. Reported data on assay performance, biases, and validation were reviewed to highlight how oral cancer findings align with trends seen in other solid tumors. Results: In reviewing recent studies (2015–2025), we found consistent evidence that saliva best captures locoregional tumor signals while plasma circulating tumor HPV DNA (ctHPV DNA) reflects systemic disease, and that using both matrices improves detection over either alone. Dual-fluid testing will potentially enable earlier identification of molecular residual disease with clinically meaningful lead time before radiographic recurrence, supporting risk-adapted surveillance. Overall, literature favors standardized pre-analytics and combined saliva plus plasma workflows to enhance early detection and follow-up in HPV-positive oral and oropharyngeal squamous cell carcinomas. Conclusions: Liquid biopsy approaches offer promising tools for the early, non-invasive detection and real-time monitoring of HPV-associated oral cancers. Realizing their full clinical potential will require robust prospective validation and standardization of pre-analytical protocols. Integrating salivary and blood biomarkers into tailored surveillance programs may further support earlier intervention and improved patient outcomes, while potentially reducing reliance on unnecessary invasive procedures. Full article

Background/Objectives: Access to genetic counselling and BRCA1/2 germline testing is standard of care for patients with high-grade serous ovarian carcinoma (HGSOC). While tumour testing reliably detects pathogenic variants in hereditary cancer genes, it cannot distinguish somatic from germline variants. Concurrent testing of non-cancerous (normal) tissue obtained during surgery may improve triage for germline testing and clinical genetics referral. This study evaluated the concordance of inherited variant detection among tumour, normal tissue, and blood to determine whether archived normal tissue can reliably identify germline pathogenic variants. Methods: Patients with HGSOC who had a pathogenic variant identified by targeted Next Generation Sequencing (NGS) tumour testing and underwent germline hereditary cancer gene panel (HCP) testing between April 2019 and November 2020 were included. HCP testing was performed on formalin-fixed, paraffin-embedded normal tissue from the original resection. Variant results were compared across tumour, normal tissue, and germline (blood) samples to determine concordance, false-negative, and false-positive rates. Results: Forty-one patients had confirmed tumour variants in BRCA1/2 or other HCP genes. Of these, 24 harboured a corresponding germline pathogenic variant. Archived normal tissue was available for 23 of these 24 cases, and all germline variants were detected in normal tissue, showing 100% concordance. Among the 17 patients without germline variants, all corresponding normal tissue samples were negative, also demonstrating 100% concordance. No false positives or negatives were identified. Conclusions: NGS testing of normal tissue at surgical resection reliably identifies germline pathogenic variants in patients with HGSOC. Incorporating this approach may help triage patients for clinical genetics assessment. Full article

This study proposes a high-contrast photoacoustic (PA) imaging methodology based on a dual-wavelength confocal metalens, designed to monitor the dissemination of cancer cells and to inform subsequent cancer treatment strategies. The metalens is composed of two metasurfaces that perform filtering and focusing functions, effectively reducing the cross-talk between the two wavelengths of light in space and achieving a confocal effect. Furthermore, to minimize process complexity, a uniform material system of silicon dioxide (SiO₂) and titanium dioxide (TiO₂) is employed across the different metasurfaces of the metalens. The designed metalens has a radius of 25 µm and an operational focal length of 98.5 µm. The results confirm that this dual-metasurface design achieves high focusing efficiency alongside precise focusing capability, with the deviations of the actual focal lengths for both beams from the design values being within 1.5 µm. Additionally, this study developed a skin tissue model and simulated multi-wavelength photoacoustic imaging of cancer cells within the human body by integrating theories of radiative transfer, photothermal conversion, and the wave equation. The results demonstrate that the enhancement trend of the reconstructed signal closely matches the original signal, confirming the model’s excellent fitting performance. The sound pressure values generated by cancer cells are significantly higher than those of normal cells, proving that this method can effectively distinguish cancerous tissue from healthy tissue. This research provides new theoretical support and methodological foundations for the clinical application of multi-wavelength photoacoustic imaging technology. Full article

The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions—from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy of the head and neck area, with a propensity to spread to local lymph nodes. Epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) play a well-documented role in the progression of the disease. In this study, we developed and characterised multicellular tumour spheroids (MCTS) composed of patient-derived metastatic cSCC cell lines—each exhibiting distinct phenotypes—combined with either dermal- or lymph node-derived fibroblasts. We aimed to investigate how these cellular combinations influence MCTS formation, spatial architecture, and invasive behaviour. We hypothesised that the interplay between different cSCC and fibroblast cell combinations would differentially influence spheroid formation and invasion. Methods: Using live-cell microscopy we assessed the spatial architectures specific to each cell line-fibroblast combination and evaluated the expression of EMT and CAF markers. Furthermore, we utilised MCTS in invasion models to investigate associations between the mode of invasion and the EMT phenotype of the cancer cell line. Results: We show that metastatic cSCC/fibroblast MCTS self-organise into distinct spatial architectures. They also invade through collagen in a manner influenced by fibroblasts but dominated by the EMT status of the originating cancer cells. Conclusions: These findings highlight the physiological relevance and utility of MCTS as models for investigating tumour–stroma interactions and invasion dynamics in metastatic cSCC. Full article

Assisted reproductive technologies (ARTs) have revolutionized infertility treatment, leading to the birth of over 10 million children worldwide. Despite their success, increasing concerns have been expressed regarding the potential long-term outcomes of ART-conceived individuals, particularly in relation to imprinting disorders (IDs). IDs result from the abnormal expression of imprinted genes, which are expressed in a parent-of-origin-specific manner and regulated by epigenetic mechanisms (e.g., DNA methylation). Disruption of these processes, through environmental, genetic, or procedural factors, can lead to disorders such as Beckwith–Wiedemann syndrome (BWS), Silver–Russell syndrome (SRS), Angelman syndrome (AS), and Prader–Willi syndrome (PWS). These syndromes are characterized by distinct clinical features, including growth abnormalities, neurodevelopmental delay, endocrine dysfunction, and cancer predisposition. ART procedures, especially ovarian hyperstimulation, in vitro fertilization (IVF), and embryo culture, coincide with critical periods of epigenetic reprogramming and may contribute to epimutations in imprinting control regions. In this review, we explored epidemiology, molecular mechanisms, and prenatal diagnostic strategies related to these four IDs in the context of ART. The findings suggest a higher prevalence of BWS and SRS in ART-conceived children. The data regarding AS and PWS are more controversial, with conflicting results across populations and methodologies. Although a causal link between ART and IDs remains debated, evidence suggests the potential contribution of ART procedures to epigenetic dysregulation in susceptible individuals. Further large-scale, methodologically rigorous studies will be essential to clarify this association and inform safer ART practices. Full article

Highly degraded sterols belonging to the incisterol group have been identified in a large set of microorganisms. The leading product in the family is demethylincisterol A3 (DM-A3), isolated from various fungi and endowed with marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, essentially from fungi. An overview of these products, their bio-origin, chemical synthesis, and associated pharmacological properties is presented. The series includes diverse incisterol and demethylincisterol derivatives, chaxines, volemolide, different analogues (salimyxins, phellinignincisterols, daedatrin D, inonotoide F, aplykurodinone-1, dendrodoristerol), and a glycoside derivative (xyloneside), all bearing a tetracyclic incisterol framework. An analysis of the anticancer mechanism of the action of DM-A3 underlined the three main components of its activity associated with the (i) inhibition of β-catenin and the Wnt signaling pathway, (ii) inhibition of tyrosine phosphatase SHP2 (IC₅₀ = 6.75 µM) implicated in cancer cell survival and differentiation, and (iii) blockade of α7nAchR activation coupled with inhibition of acetylcholinesterase (IC₅₀ = 11.16 µM). A comprehensive picture of the DM-A3 mechanism of action is discussed, highlighting the uniqueness of the compound as a dual SHP2/AchE inhibitor able to attenuate an inflammatory response through the cholinergic anti-inflammatory pathway. The review shed light on this little-known category of incisterol-type natural products, with the objective of promoting further research into this neglected group of anticancer agents. Full article

Background: Dynamic whole-body (D-WB) FDG PET/CT is a novel technique that enables the direct reconstruction of multiparametric images representing the FDG metabolic uptake rate (MR_FDG) and “free” FDG (DV_FDG). Applying complementary parameters with distinct characteristics compared to static SUV images, the aims of this study are as follows: (1) to determine the threshold values of SUV, MR_FDG, and DV_FDG for malignant and benign lesions; (2) to compare the specificity of MR_FDG and DV_FDG images with static SUV_bw images; and (3) to assess whether any of the dynamic imaging parameters correlate more significantly with malignancy or non-malignancy in the examined lesions based on the measured values obtained from D-WB FDG PET/CT. Methods: The study was a retrospective analysis of D-WB PET/CT data from 43 patients (23 males and 20 females) included both in the context of primary staging as well as imaging performed due to suspicion of post-therapeutic relapse or recurrence. Standard scanning was performed using a multiparametric PET acquisition protocol on a Siemens Biograph Vision 600 PET/CT scanner. Pathological findings were manually delineated, and values for SUV_bw, MR_FDG, and DV_FDG were extracted. The findings were classified and statistically evaluated based on their was histological verification of a malignant or benign lesion. Multinomial and binomial logistic regression analyses were used to find parameters for data classification in different models, employing various combinations of the input data (SUV_bw, MR_FDG, DV_FDG). ROC curves were generated by changing the threshold p-value in the regression models to compare the models and determine the optimal thresholds. Results: Patlak PET parameters (MR_FDG and DV_FDG) combined with mean SUV_bw achieved the highest diagnostic accuracy of 0.82 (95% CI 0.75–0.89) for malignancy detection (F1-score = 0.90). Sensitivity reached 0.85 (95% CI 0.77–0.91) and specificity 0.93 (95% CI 0.87–0.98). Classification accuracy in tumors was 0.86 (95% CI 0.78–0.92) and in lymph nodes 0.81 (95% CI 0.73–0.88). Relative contribution analysis showed that DV_FDG accounted for up to 65% of the classification weight. ROC analysis demonstrated AUC values above 0.8 for all models, with optimal thresholds achieving sensitivities of around 0.85 and specificities up to 0.93. Thresholds for malignancy detection were, for mean values, SUV_bw > 5.8 g/mL, MR_FDG > 0.05 µmol/mL/min, DV_FDG > 68%, and, for maximal values, SUV_bw > 8.7 g/mL, MR_FDG > 0.11 µmol/mL/min, DV_FDG > 202%. Conclusions: The D-WB [¹⁸F]FDG PET/CT images in this study highlight the potential for improved differentiation between malignant and benign lesions compared to conventional SUV_bw imaging in patients with locally advanced head and neck cancers presenting with cervical lymphadenopathy and carcinoma of unknown primary origin (CUP). This observation may be particularly relevant in common diagnostic dilemmas, especially in distinguishing residual or recurrent tumors from post-radiotherapy changes. Further validation in larger cohorts with histopathological confirmation is warranted, as the small sample size in this study may limit the generalizability of the findings. Full article

Cholangiocarcinoma (CC) is a rare and aggressive malignancy that arises from the epithelial cells (cholangiocytes) of the biliary tree. Biliary tract cancers (BTC) include both CC and gall bladder cancer. Surgical resection is considered the only curative treatment. Recently, however, a fundamental shift in the understanding of the molecular profiles of these tumors has led to a molecular-targeted approach with improved survival rates in some patients with these tumors. In patients with local or limited regional disease, neoadjuvant therapies offer a way to downstage tumors, assess tumor biology, potentially achieve R0 resection, and potentially prevent both locoregional and distant recurrence by treating occult micrometastatic disease. Because BTC are rare and surgery is the standard of care for patients with non-metastatic disease, there is very little data evaluating neoadjuvant strategies in resectable disease. Immunotherapies and molecularly targeted agents originally developed for advanced disease in the adjuvant or palliative settings are now being considered for neoadjuvant use. This review aims to summarize the data and provide a rationale for the role of neoadjuvant treatment in patients with resectable BTC. While there is no high-level evidence, studies show that neoadjuvant therapy that incorporates targeted treatments and immunotherapies under multidisciplinary oversight benefits select patients and is a valuable tool in the treatment of BTC. We favor molecular testing to guide neoadjuvant therapy for patients with BTC, when feasible, to prevent unnecessary operations and minimize the risk of recurrence or metastasis. Full article

Background: Multifocal (MF) and multicentric (MC) breast cancers, defined by the presence of multiple synchronous tumor foci within the same breast, present important diagnostic, therapeutic, and prognostic challenges. Historically considered a contraindication for breast-conserving therapy (BCT), advances in imaging, surgical techniques, and adjuvant therapy have reshaped management strategies. Methods: A narrative literature review was conducted through PubMed, Web of Science, and Scopus, prioritizing ISI-indexed articles published within the last 10–15 years. More than 55 relevant studies, including systematic reviews, meta-analyses, and large cohorts, were analyzed to evaluate epidemiology, pathological features, imaging modalities, treatment outcomes, and prognosis of MF/MC breast cancers. Results: The reported incidence of MF/MC breast cancers ranges from 10% to 24%, increasing when MRI or whole-organ pathology is applied. MRI can detect otherwise occult additional foci in up to 30% of patients, improving staging accuracy but raising concerns of overdiagnosis. MF/MC presentation is strongly associated with lobular histology, younger age at diagnosis, and higher rates of axillary involvement—nodal positivity is observed in up to 45% of MF/MC cases versus 28% in unifocal tumors. Pathological analyses demonstrate frequent clonal origin of MF lesions, whereas MC lesions may represent independent primaries, occasionally with receptor heterogeneity that alters systemic therapy selection. From a prognostic perspective, older series suggested shorter breast cancer-specific survival (e.g., median 154 vs. 204 months for MF/MC vs. unifocal disease), and higher local recurrence with BCT. However, contemporary analyses, including a 2022 meta-analysis of 15,703 patients, demonstrated no significant difference in overall or disease-free survival once adjusted for tumor size and nodal status. Local recurrence remains slightly higher with BCT in MF/MC (5.6% vs. 4.2%), but outcomes are equivalent to mastectomy when radiotherapy is appropriately delivered. Five-year survival in early-stage MF/MC exceeds 90% with guideline-concordant multimodal therapy. Conclusions: MF/MC breast cancers represent a biologically heterogeneous entity. Optimal outcomes rely on precise imaging, complete excision, tailored systemic therapy, and multidisciplinary management, with increasing acceptance of breast conservation in selected patients. Full article