Search Results (2,605)

Human Epidermal Growth Factor Receptor 2 (HER2) is a key therapeutic target in breast cancer. However, the application of existing anti-HER2 antibody drugs is limited by such issues as large molecular weight and poor stability. In this study, a series of small protein minibinders targeting HER2 domain IV were de novo designed using the RFdiffusion method. Candidate molecules were selected through a combination of ProteinMPNN and AlphaFold2 screening, and their binding capabilities were further evaluated using Escherichia coli surface display coupled with flow cytometry analysis. By integrating molecular dynamics simulations, confocal fluorescence imaging, and isothermal titration calorimetry (ITC) experiments, a highly efficient minibinder (0_703_6) with nanomolar affinity and a smaller molecular size was finally identified. Compared with the existing drug molecules, the identified minibinder exhibited approximately threefold higher affinity and a threefold reduction in molecular size. This study provides strong support for the development of novel, stable, and easily expressible HER2-targeted therapeutic molecules and also offers new insights into the rapid development of robust breast cancer drugs that may serve as ideal alternatives to monoclonal antibodies. Full article

The biophysical characteristics of cellular membranes, particularly their electrical properties in the $\alpha$-dispersion frequency domain, offer valuable insights into cellular states and are increasingly important for cancer diagnostics through epidermal growth factor receptor (EGFR) expression analysis. However, a critical limitation in these electrical measurements is the confounding effect of morphological changes that inevitably occur during prolonged observation periods. These shape alterations significantly impact measured capacitance values, potentially masking true biological responses to epidermal growth factor (EGF) stimulation that are essential for cancer detection. In this study, we attempted to address this fundamental challenge by developing a deep learning method that establishes a direct computational relationship between cellular morphology and electrical properties. We combined optical trapping technology and capacitance measurements to generate a comprehensive dataset of HeLa cells under two different experimental conditions: (i) DPBS treatment and (ii) EGF stimulation. Our convolutional neural network (CNN) architecture accurately predicts 401-point capacitance spectra (0.1–2 kHz) from binary morphological images at low frequencies (0.1–0.8 kHz, < 10% error rate). This capability allows for the identification and subtraction of morphology-dependent components from measured capacitance changes, effectively isolating true biological responses from morphological artefacts. The model demonstrates remarkable prediction performance across diverse cell morphologies in both experimental conditions, validating the robust relationship between cellular shape and electrical characteristics. Our method significantly improves the precision and reliability of EGFR-based cancer diagnostics by providing a computational framework for a morphology-induced measurement error correction. Full article

Background/Objectives: TP53 mutations in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer could worsen prognosis. Therefore, we aimed to investigate the clinical significance of TP53 mutations and p53 expression in these patients. Methods: Patients with advanced/metastatic EGFR-mutated lung adenocarcinoma treated with first-line tyrosine kinase inhibitors were retrospectively enrolled. Sanger sequencing was performed to detect TP53 mutations and immunohistochemical staining was used to verify p53 protein expression levels. Kaplan-Meier and Cox proportional hazards analyses were used to estimate survival and hazard ratio (HR) with 95% confidence interval (CI). Results: The study involved 83 patients with adequate tumor samples for TP53/p53 analysis. Patients with tumor p53 immunostaining ≥50% showed significantly better overall survival (OS) (HR: 0.49 [95% CI: 0.30–0.81], p < 0.001), but TP53 mutations were not associated with inferior progression-free survival (PFS) or OS (missense vs. wild-type [PFS, HR: 0.68 (95% CI: 0.40–1.15), p = 0.151; OS, HR: 0.88 (95% CI: 0.56–1.42), p = 0.599]). Areas under the receiver operating characteristic curves of TP53 mutations with different cut-off values for p53 positivity were 0.51–0.56. The Kaplan-Meier survival analysis revealed significant survival benefits in patients with EGFR L858R substitution and tumor p53 immunostaining ≥50% (median PFS: 8.0 vs. 5.3; median OS: 20.4 vs. 15.3 months; log-rank p = 0.025 and 0.049, respectively). Conclusions: Tumor p53 immunostaining (≥50%) was associated with better OS, especially in patients with TP53 mutations or L858R. Prospective clinical trials are required to explore the prognostic significance of p53 expression in the genomic era of TP53 mutations. Full article

Background/Objectives: Older adults with breast cancer may suffer from over- and undertreatment if intensity of therapy does not align with their physiologic age. We sought to evaluate the association between physiologic age, chronologic age, and treatment patterns in women ≥ 70 years with non-metastatic breast cancer. Methods: Patients ≥ 70 diagnosed with non-metastatic breast cancer 10/2021–3/2024 who had received surgical therapy and frailty (Geriatric-8) and life expectancy (Schonberg index) screening at our institution were identified from our institutional database. Descriptive analyses were run using chi-square tests of proportion. In the largest subgroup (patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2)-disease), multivariate logistic regression adjusting for patient- and disease-level characteristics was used to assess the relationship between life expectancy < 10 years and the omission of sentinel lymph node biopsy (SLNB) and radiation therapy (RT). Results: Of 272 patients, 104 (38.2%) screened positive for frailty and 64 (23.5%) had a life expectancy of <10 years. On bivariate analysis, a higher proportion of frail patients (44 (42.3%) had a life expectancy < 10 years, while 20 (11.9%) robust patients had a life expectancy < 10 years (p < 0.001). Most patients (226, 83.1%) had HR+/HER-2 negative disease; 10 (3.7%) had HER2+ disease; and 33 (12.1%) had triple-negative breast cancer (TNBC) (p < 0.001). Life expectancy was not significantly associated with omission of SLNB (life expectancy < 10 years: reference; life expectancy ≥ 10 years: OR 0.81 95% CI [0.20–3.28]) or RT (life expectancy < 10 years: reference; life expectancy ≥ 10 years: OR 1.14, 95% CI 0.44–2.93]) in patients with stage I–II HR+/HER-2− disease on adjusted analysis. Conclusions: While patients at risk for frailty and limited life expectancy are relatively common in our population, these measures may not significantly influence patient and clinician treatment decision making. Future efforts to tailor therapy by measures of physiologic age are needed. Full article

Background: Recent landmark clinical trials have introduced the role of targeted therapy with surgery for resectable non-small cell lung cancers (NSCLCs). Methods: This narrative review summarizes data from recent clinical trials and retrospective studies to highlight the evolving interplay between targeted therapy and resectable NSCLC. Results: For patients with epidermal growth factor receptor (EGFR) mutations, the ADAURA trial demonstrated significant improvements in disease-free and overall survival with adjuvant osimertinib after complete resection. The NeoADAURA trial expanded the role of osimertinib to neoadjuvant treatment as it showed benefit in major pathologic response rates when compared to chemotherapy alone. Neoadjuvant osimertinib may facilitate surgical resection, especially for patients with lymph node involvement. Furthermore, the ALINA trial established the role of adjuvant alectinib, another targeted therapy, for patients with anaplastic lymphoma kinase (ALK) positive resectable NSCLC. Given the evidence for use of these novel targeted therapies in patients with resectable lung cancer, early molecular profiling is critical for patients with NSCLC to help guide pre- and postoperative treatment. The use of targeted therapies may even expand to stage IV NSCLC as clinical trials are ongoing and could possibly redefine the role of surgery in advanced disease. Conclusions: While there are ongoing trials to clarify the optimal timing of targeted therapies and surgical resection, current data supports the use of targeted therapies as part of multimodality care in surgically resectable NSCLC. Full article

Galactic cosmic ray (GCR) radiation is a major barrier to human space exploration beyond Earth’s magnetic field protection. Mesenchymal stem cells (MSCs) are found in all organs and play a critical role in repair and regeneration of tissue. We engineered bone marrow-derived MSCs and evaluated their response to ionizing radiation exposure. Epidermal growth factor receptor (EGFR) expression by certain types of cancers has been shown to induce radioresistance. In this study, we tested the feasibility of transfecting MSCs to overexpress EGFR (eMSC-EGFR) and their capacity to tolerate and recover from X-ray exposure. Quantitative real-time PCR (qRT-PCR) and immunoblotting results confirmed the efficient transfection of EGFR into MSCs and EGFR protein production. eMSC-EGFR maintained characteristics of human MSCs as outlined by the International Society for Cell & Gene Therapy. Then, engineered MSCs were exposed to various dose rates of X-ray (1–20 Gy) to assess the potential radioprotective role of EGFR overexpression in MSCs. Post-irradiation analysis included evaluation of morphology, cell proliferation, viability, tumorigenic potential, and DNA damage. eMSC-EGFR showed signs of radioresistance compared to naïve MSCs when assessing relative proliferation one week following exposure to 1–8 Gy X-rays, and significantly lower DNA damage content 24 h after exposure to 4 Gy. We establish for the first time the efficient generation of EGFR overexpressing MSCs as a model for enhancing the human body to tolerate and recover from moderate dose radiation injury in long-term manned space travel. Full article

Background/Objectives: This meta-analysis aimed to evaluate the efficacy of combining CDK4/6i with ET, compared with ET alone, in improving invasive disease-free survival (iDFS), distant recurrence-free survival (DRFS), and overall survival (OS) in early-stage hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) breast cancer. Given the inconclusive findings of previous meta-analyses, an updated synthesis of the latest phase III trial data was performed. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Randomized Controlled Trials (RCTs) comparing CDK4/6i plus ET versus ET alone were identified through PubMed, Scopus, and ClinicalTrials.gov. Hazard ratios and adverse events were analyzed using appropriate statistical models. Results: Four RCTs (monarchE, NATALEE, PENELOPE-B, PALLAS) including 17,749 patients were analyzed. CDK4/6 inhibitors improved iDFS (HR 0.80; 95% CI: 0.67–0.96; p = 0.01), while a strong trend toward improved DRFS was observed (HR 0.79; 95% CI: 0.61–1.02; p = 0.07), suggesting a potential clinically relevant benefit that requires longer follow-up to confirm. The effect on OS (HR 0.95; 95% CI: 0.79–1.16; p = 0.63) remains inconclusive. Adverse events, including neutropenia and diarrhea, were more frequent with CDK4/6i. Conclusions: The addition of CDK4/6i to ET improves iDFS and shows a favorable trend in DRFS in early-stage HR+/HER2− breast cancer, highlighting the need for longer follow-up to clarify their long-term benefit. Full article

Background and Method: The overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is correlated with accelerated tumor progression and an unfavorable clinical outcome. Since the introduction of trastuzumab in 2002, the treatment of HER2-positive breast cancer has been revolutionized, leading to significant improvements in survival. This retrospective, multicenter study aimed to describe the characteristics of patients with HER2-positive metastatic breast cancer (MBC) who maintained disease control for a minimum of three years after first-line therapy with trastuzumab and/or pertuzumab combined with chemotherapy. Results: Among 280 eligible patients, 48 (17.5%) were classified as long-term responders. The study population primarily consisted of women with a median age of 56.7 years at diagnosis; de novo metastatic presentation was observed in approximately 70% of cases. An objective response rate of nearly 90% was observed, with a median duration of response of 5.8 years. Median progression-free survival was 11.0 years [95% CI: 6.6—not reached], and median overall survival was not reached [95% CI: 10.9—not reached]. Furthermore, about 15% of patients were able to discontinue systemic therapy without immediate disease progression. Discussion and Conclusions: These findings indicate the potential of achieving prolonged disease control in a subset of patients with HER2-positive MBC, raising questions about therapeutic intensification and potential treatment discontinuation strategies. This study underscores the need for future research to identify predictive factors of durable response and assess the feasibility of adaptive treatment strategies, including planned treatment discontinuation. Full article

Introduction: The aim of the study was to analyse the results and potential complications of local treatment with HDR (high dose-rate) brachytherapy of liver metastases from colorectal cancer, depending on the targeted therapy used and considering RAS gene mutation and chemotherapy in individual treatment lines. Material and methods: The study included 142 patients with oligoprogressive liver metastases who underwent HDR brachytherapy without changing the line of treatment, based on a retrospective analysis of 270 patients treated between 2015 and 2022. The impact of RAS gene mutations, lines of chemotherapy depending on the treatment regimens used, PFS (progression free survival), OS (overall survival), LC (local control) and the degree of radiological response were analysed. The impact of these drugs on hepatotoxicity and the risk of haemorrhagic complications was also analysed. Results: The presence of mutations in KRAS/NRAS genes (exons 2, 3, 4) had a statistically significant impact on PFS in the first, third and fourth lines of treatment, and on OS and LC in the third and fourth lines of treatment. In the third and fourth lines of treatment, patients with a mutation in the RAS gene had a poorer radiological response to treatment regardless of the chemotherapy used. PFS, OS and LC differed depending on the line of treatment and amounted to 17.5, 11, 8.5, 6 and 4 months, 27, 19, 13, 11 and 11 months, and 27, 19, 11, 6 and 6 months, respectively. The greatest benefit in terms of PFS was achieved by patients treated with first-line chemotherapy combined with epidermal growth factor receptor (EGFR) inhibitors, in the absence of RAS gene mutations. In the third line, the greatest benefit was achieved by patients treated with trifluridine/tipiracil in the absence of RAS gene mutations. The greatest percentage reduction in the volume of treated lesions and the highest percentage of control were observed in the first three lines of treatment. The toxicity of the treatment was low; only in the third and fourth lines of treatment were differences in the decrease in albumin levels found depending on the type of treatment used. Conclusions: A mutation in the RAS genes worsens the prognosis, regardless of the line of treatment and the systemic treatment used. The greatest benefit from brachytherapy is seen in patients in the first three lines of treatment without RAS mutations, treated with anti-EGFR chemotherapy in the first line and trifluridine/tipiracil in the third line. Combining brachytherapy of liver metastases with systemic treatment is safe, regardless of the systemic treatment used. 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

Therapies targeting human epidermal growth factor receptor 2 (HER2) have substantially improved overall survival in patients with HER2-positive metastatic breast cancer. Approximately 31% of these patients develop brain metastases, representing a significant therapeutic challenge. This review classifies anti-HER2 therapies into three categories: monoclonal antibodies (MABs), antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs). The mechanisms of action and clinical impacts of these agents are examined, with particular attention to intracranial efficacy. The introduction of trastuzumab increased overall survival (OS) from 20.3 to 25.1 months compared to chemotherapy alone. The addition of pertuzumab further extended survival to 57.1 months, as demonstrated in the CLEOPATRA trial. Among ADCs, T-DM1 improved OS to 29.9 months versus 25.9 months in the EMILIA trial, while T-DXd extended OS to 52.6 months in DESTINY-Breast03. T-DXd also demonstrated notable intracranial activity, achieving a 64.9% objective response rate in patients with active brain metastases. In the HER2CLIMB trial, tucatinib reduced intracranial progression by 68% and improved OS (24.7 vs. 19.2 months) in patients with active brain metastases. Recent advances have increased median OS from approximately 20 months prior to trastuzumab to over 50 months with current therapies. Future research should focus on optimizing treatment sequencing, refining biomarker-driven approaches, and developing targeted strategies for brain metastases to further improve long-term survival outcomes. Full article

Radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression might permit the selection of patients for EGFR-targeting therapies. Designed ankyrin repeat protein (DARPin) E01 with a high affinity to the ectodomain III of the EGFR is a possible EGFR imaging probe. The goal of this study was to evaluate the potential of radiolabeled DARPin E01 for in vivo imaging of EGFR. DARPin E01 containing the (HE)₃-tag was site-specifically labeled with a residualizing ^99mTc (using ^99mTc]Tc(CO)₃). Two methods providing non-residualizing ¹²³I labels, direct electrophilic radioiodination and indirect radioiodination using [¹²³I]I-para-iodobenzoate (PIB), were tested. [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB preserved specific binding to EGFR-expressing cells and affinity in the single-digit nanomolar range. Direct labeling with ¹²³I resulted in a substantial loss of binding. In vitro cellular processing studies showed that both [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB had rapid binding and relatively slow internalization. Evaluation of [^99mTc]Tc-(HE)₃-E01 biodistribution in normal CD1 mice showed that its hepatic uptake was non-saturable, suggesting that this tracer does not bind to murine EGFR. A side-by-side comparison of biodistribution and tumor targeting of [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB was performed in Nu/j mice bearing EGFR-positive A-431 and EGFR-negative Ramos human cancer xenografts. Both radiolabeled DARPins demonstrated EGFR-specific tumor uptake. However, [¹²³I]I-(HE)₃-E01-PIB had appreciably lower uptake in normal organs compared to [^99mTc]Tc-(HE)₃-E01, which provided significantly (p < 0.05) higher tumor-to-organ ratios. Gamma-camera imaging confirmed that [¹²³I]I-(HE)₃-E01-PIB demonstrated a higher imaging contrast in preclinical models than [^99mTc]Tc-(HE)₃-E01. In conclusion, DARPin (HE)₃-E01 labeled using a non-residualizing [¹²³I]I-para-iodobenzoate (PIB) label is the preferred radiotracer for in vivo imaging of EGFR expression in cancer. Full article

Wound healing is a complex, multi-phase process involving hemostasis, inflammation, proliferation, and tissue remodeling. Syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans, serve as co-receptors for growth factors, cytokines, and ECM components, playing critical roles in cell adhesion, migration, proliferation, and angiogenesis. Among them, SDC-1 and SDC-4 are key regulators of skin wound healing. Due to their distinct spatial and temporal expression across various cell types—such as epithelial cells, fibroblasts, and immune cells—SDCs are well-positioned to coordinate regenerative responses. This review focuses on the spatial regulation of SDCs during skin wound healing, highlighting their roles in epidermal and dermal repair, modulation of intracellular signaling, and remodeling of the wound microenvironment. Overall, SDCs are emerging as central modulators of skin wound healing, with promising implications for regenerative medicine in the skin and beyond. Full article

Lung cancer (LC) remains a leading cause of cancer mortality worldwide, where accurate and early identification of gene mutations such as epidermal growth factor receptor (EGFR) is critical for precision treatment. However, machine learning-based radiomics approaches often face challenges due to the small and imbalanced nature of the datasets. This study proposes a comprehensive framework based on Generic Sparse Regularized Autoencoders with Kullback–Leibler divergence (GSRA-KL) to generate high-quality synthetic radiomics data and overcome these limitations. A systematic approach generated 63 synthetic radiomics datasets by tuning a novel kl_weight regularization hyperparameter across three hidden-layer sizes, optimized using Optuna for computational efficiency. A rigorous assessment was conducted to evaluate the impact of hyperparameter tuning across 63 synthetic datasets, with a focus on the EGFR gene mutation. This evaluation utilized resemblance-dimension scores (RDS), novel utility-dimension scores (UDS), and t-SNE visualizations to ensure the validation of data quality, revealing that GSRA-KL achieves excellent performance (RDS > 0.45, UDS > 0.7), especially when class distribution is balanced, while remaining competitive with the Tabular Variational Autoencoder (TVAE). Additionally, a comprehensive statistical correlation analysis demonstrated strong and significant monotonic relationships among resemblance-based performance metrics up to moderate scaling (≤1.0*), confirming the robustness and stability of inter-metric associations under varying configurations. Complementary computational cost evaluation further indicated that moderate kl_weight values yield an optimal balance between reconstruction accuracy and resource utilization, with Spearman correlations revealing improved reconstruction quality (MSE $\rho =-0.78$, $p<0.001$) at reduced computational overhead. The ablation-style analysis confirmed that including the KL divergence term meaningfully enhances the generative capacity of GSRA-KL over its baseline counterpart. Furthermore, the GSRA-KL framework achieved substantial improvements in computational efficiency compared to prior PSO-based optimization methods, resulting in reduced memory usage and training time. Overall, GSRA-KL represents an incremental yet practical advancement for augmenting small and imbalanced high-dimensional radiomics datasets, showing promise for improved mutation prediction and downstream precision oncology studies. 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