Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer

npj Precision Oncology, Journal Year: 2025, Volume and Issue: 9(1)

Published: Jan. 17, 2025

Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine effective for unresectable locally advanced PDAC. This study aimed identify patient characteristics predictive of CIRT response. We utilized a panel human PDAC cell lines diverse genetic profiles determine their sensitivity compared γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 3.04. Increased radiosensitivity was linked impaired DNA double-strand break (DSB) repair, particularly in deficiencies the homologous recombination (HR) repair pathway and/or elevated genomic instability replication stress. Furthermore, pretreatment HR inhibitor B02 significantly enhanced radioresistant line when irradiated spread-out Bragg peak but not entry position beam. These findings suggest tumors mutations or high stress are more likely benefit while minimizing normal tissue toxicity.

Language: Английский

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Effect of FLASH proton therapy on primary bronchial epithelial cell organoids

Clinical and Translational Radiation Oncology, Journal Year: 2025, Volume and Issue: 52, P. 100927 - 100927

Published: Jan. 29, 2025

The effects of conventional (CONV) and FLASH proton therapy on primary bronchial epithelial cell (PBEC) organoids from individuals with chronic obstructive pulmonary disease (COPD) were investigated. objective was to compare the effect CONV COPD PBEC a focus DNA damage, organoid formation, gene expression. PBECs obtained six donors, cultured as three-dimensional (3D) exposed 2 8 Gy radiation at Holland Proton Therapy Center. damage assessed by γH2AX staining. Organoid formation capacity counting formed after reseeding irradiated cells 24 h 7 days. Bulk RNA sequencing (RNAseq) qPCR analyses performed identify pathways differences in response. foci analysis showed significant dose-dependent increase 1 for both treatments, without between two modalities. assays revealed decrease treatments. At days, FLASH-treated samples significantly reduced compared (p = 0.008). RNAseq identified FLASH-induced changes expression DNA-damage response apoptosis pathway genes. A upregulation MDM2, GDF15, DDB2, BAX, P21, AEN MKi67 confirmed analysis. No found or profiles FLASH. assay prolonged detrimental organoids, suggesting more complex interaction lung cells. results this study contribute advancement robust vitro human models investigating mechanisms action FLASH, potentially facilitating treatment NSCLC patients therapy.

Language: Английский

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Advancing Radiobiology: Investigating the Effects of Photon, Proton, and Carbon-Ion Irradiation on PANC-1 Cells in 2D and 3D Tumor Models

Current Oncology, Journal Year: 2025, Volume and Issue: 32(1), P. 49 - 49

Published: Jan. 18, 2025

Introduction: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, calling for enhanced research. ductal adenocarcinoma (PDAC) represents 70–80% all cases known its resistance to conventional therapies. Carbon-ion radiotherapy (CIRT) has emerged as a promising approach due ability deliver highly localized doses unique radiobiological properties compared X-rays. In vitro radiobiology relied on two-dimensional (2D) cell culture models so far; however, these are not sufficient replicate complexity in vivo tumor architecture. Three-dimensional (3D) become paradigm shift, surpassing constraints traditional by accurately re-creating morphological, histological, genetic characteristics well interaction tumour cells with microenvironment. Materials Methods: This study investigates survival pancreatic both 2D spheroids, 3D model, following photon, proton, carbon-ion irradiation means clonogenic, MTT, spheroid growth, vitality assays. Results: Our results demonstrate that carbon ions more efficient reducing photons protons. cultures, reduced approximately 15%, 45% 30% growth was similarly inhibited irradiation; overall rates were higher across modalities cultures. Carbon consistently showed highest efficacy viability models. Conclusions: research highlights pivotal role unraveling complexities radiobiology, offering new avenues designing effective precise treatment protocols.

Language: Английский

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AI in Radiopharmaceutical Development

Advances in computational intelligence and robotics book series, Journal Year: 2025, Volume and Issue: unknown, P. 93 - 116

Published: Feb. 28, 2025

Radiopharmaceuticals are a specialized class of compounds used in These compounds, which combine radioactive isotope with biologically active molecule, hold central role nuclear medicine. Their ability to diagnose, stage, and even treat diseases, particularly cancers, makes them invaluable tools the realm modern healthcare. The term “radiopharmaceutical” derives from two words: “radio” “pharmaceutical”. When administered patient, radiopharmaceuticals emit radiation that can be detected by imaging systems, allowing for visualization organ tissue function morphology. This technique is widely referred as or molecular imaging. generally categorized into primary types: diagnostic therapeutic radiopharmaceuticals. former designed help clinicians visualize evaluate condition organs tissues, aiding diagnosis disorders.

Language: Английский

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Multi-Target Inhibitor CUDC-101 Impairs DNA Damage Repair and Enhances Radiation Response in Triple-Negative Breast Cell Line

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(11), P. 1467 - 1467

Published: Nov. 1, 2024

Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation chemotherapeutic drugs management breast cancer. However, studies on HDACi and proton remain limited. CUDC-101 is multitarget inhibitor deacetylases (HDACs), epidermal growth factor receptor (EGFR), human 2 (HER-2). In this paper, effectiveness enhancing response to both was studied.

Language: Английский

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In vitro FLASH irradiation of A549 lung cancer cells and IMR90 healthy human fibroblasts in the synchrocyclotron room of a clinical proton therapy system

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Abstract Purpose This study aims to investigate the FLASH irradiation effect on lung tumor (A549) and healthy fibroblast (IMR90) cell lines using an station installed at synchrocyclotron room of a clinical proton facility without any permanent beamline modifications. Methods Materials An system composed lead scatterer 3D-printed positioning was designed fabricated operate within gap IBA Proteus One therapy after extraction beam from synchrocyclotron. A dosimetric analysis produced field carried out radiochromic films. conventional-rate irradiations were conducted relevant for cancer isocenter treatment room. Biological assessments post-irradiation included clonogenic viability assays survival, immunofluorescence p21 protein expression, flow cytometry cycle arrest evaluation. Results The successfully delivered homogeneous repeatable dose rates (>900 Gy/s) with accuracy 1 mm uniformity 10%. Clonogenic revealed no statistically significant differences in survival between conventional both A549 IMR90 lines, although trend towards higher observed cells under conditions. Flow demonstrated patterns doses above 7 Gy, FLASH-irradiated exhibiting decrease G2/M phase compared rates. Immunofluorescence expression showed modalities. Conclusions developed effectively facilitates radiotherapy experiments facility, achieving necessary hardware modification or extra tuning facility. Our reported notable alterations dynamics suggesting distinct biological responses cells. These findings contribute emerging understanding support potential its differential impact cancerous versus tissues.

Language: Английский

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