Biological Effects Research Articles

Characterisation of LPS+ bacterial extracellular vesicles along the gut-hepatic portal vein-liver axis.

Gut microbiome dysbiosis is a major contributing factor to several pathological conditions. However, the mechanistic understanding of the communication between gut microbiota and extra-intestinal organs remains largely elusive. Extracellular vesicles (EVs), secreted by almost every form of life, including bacteria, could play a critical role in this inter-kingdom crosstalk and are the focus of present study. Here, we present a novel approach for isolating lipopolysaccharide (LPS)+ bacterial extracellular vesicles (bEVLPS) from complex biological samples, including faeces, plasma and the liver from lean and diet-induced obese (DIO) mice. bEVLPS were extensively characterised using nanoparticle tracking analyses, immunogold labelling coupled with transmission electron microscopy, flow cytometry, super-resolution microscopy and 16S sequencing. In liver tissues, the protein expressions of TLR4 and a few macrophage-specific biomarkers were assessed by immunohistochemistry, and the gene expressions of inflammation-related cytokines and their receptors (n=89 genes) were measured using a PCR array. Faecal samples from DIO mice revealed a remarkably lower concentration of total EVs but a significantly higher percentage of LPS+ EVs. Interestingly, DIO faecal bEVLPS showed a higher abundance of Proteobacteria by 16S sequencing. Importantly, in DIO mice, a higher number of total EVs and bEVLPS consistently entered the hepatic portal vein and subsequently reached the liver, associated with increased expression of TLR4, macrophage markers (F4/80, CD86 and CD206), cytokines and receptors (Il1rn, Ccr1, Cxcl10, Il2rg and Ccr2). Furthermore, a portion of bEVLPS escaped liver and entered the peripheral circulation. In conclusion, bEV could be the key mediator orchestrating various well-established biological effects induced by gut bacteria on distant organs.

Golgi apparatus-targeted BODIPY-based photosensitizer synergized with glutaminase inhibition for enhanced photodynamic therapy

Photodynamic therapy (PDT) is a precise and less toxic side effect treatment strategy. However, the inherently short lifespan and constrained diffusion range of reactive oxygen species within the cellular milieu can attenuate the therapeutic efficacy of cytoplasmic photosensitizers. Organelle-targeted PDT is thus proposed. Although the essence of PDT is the photosensitization reaction accompanied by biological effects involving aerobic molecules, mitochondria-targeted PDT may lead to the emergence of drug resistance in tumor cells triggered by mitochondrial damage. Thus, developing more types of organelle-targeted PDT strategies is the key to avoiding this problem. Herein, a fluoroboron dipyrrole-based photosensitizer, OFBDP, with Golgi apparatus-targeted and PDT ability is designed and synthesized. Furthermore, considering the effect of high concentrations of reduced glutathione in tumor cells, the addition of glutaminase inhibitor, compound 968 (C968), synergistically enhanced the PDT efficacy of OFBDP by indirectly inhibiting intracellular glutathione synthesis through its effect on glutamine metabolism. The OFBDP/C968 combination has demonstrated an enhanced tumor ablation capability. This work generally provides a strategy for the potential of organelle-targeted PDT to improve treatment outcomes, but also contribute to the burgeoning field of subcellular photosensitizer research.

The Potentials of Phytoestrogen Compounds in Aquaculture – A Review

Abstract All organisms require the ability to engage in either sexual or asexual reproduction in order to ensure their own survival. In aquaculture, when one sex outgrows the other faster, farmers use hormones to stimulate growth. Furthermore, the production of fish based on sexual dimorphism is predominantly executed through the utilization of estrogens and androgens. Environmentally, these compounds may pollute the ecosystem and cause endocrine system alterations that cause harmful effects; thus, they must be handled carefully to assure environmental, biological, and food safety. Phytoestrogens as natural non-steroidal phenolic plant chemicals that resemble 17-β-estradiol, could be employed as a safe alternative source of natural estrogens. The phytoestrogens have many biological effects due to their ability to compete with estrogen receptors, but they may negatively affect fish production, reproduction, and behaviors under controlled conditions. Thus, the current literature emphasizes on the beneficial effects of phytoestrogens on aquatic animal performance, behaviors, and some reproductive features.

Research on the Relationship between Exosome Production and Atherosclerosis.

Atherosclerosis (AS) is the leading cause of cardiovascular disease, causing a major burden on patients as well as families and society. Exosomes generally refer to various lipid bilayer microvesicles originating from different cells that deliver various bioactive molecules to the recipient cells, exerting biological effects in cellular communication and thereby changing the internal environment of the body. The mechanisms of correlation between exosomes and the disease process of atherosclerosis have been recently clarified. Exosomes are rich in nucleic acid molecules and proteins. For example, the exosome miRNAs reportedly play important roles in the progression of atherosclerotic diseases. In this review, we focus on the composition of exosomes, the mechanism of their biogenesis and release, and the commonly used methods for exosome extraction. By summarizing the latest research progress on exosomes and atherosclerosis, we can explore the advances in the roles of exosomes in atherosclerosis to provide new ideas and targets for atherosclerosis prevention, diagnosis, and treatment.

Hollow mesoporous calcium peroxide nanoparticles for drug-free tumor calcicoptosis therapy

Calcium ions (Ca2+) participate in the regulation of cellular apoptosis as a second messenger. Calcium overload, which refers to the abnormal elevation of intracellular Ca2+ concentration, is a factor that can lead to cell death. Here, based on the unique biological effects of Ca2+, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed by a facile hydrolysis-precipitation method for drug-free tumor calcicoptosis therapy. The average pore size of the optimized HMCPN17 is 6.4 nm, and the surface area is 81.3 m2/g, which enables HMCPN17 with high drug loading capability. The Ca2+ release from HMCPN17 is much faster at pH 6.8 than that at pH 7.4, which can be ascribed to the acid-triggered conversion of HMCPN17 to Ca2+ and H2O2, indicating a pH-responsive decomposition behavior of HMCPN17. The high drug loading contents of doxorubicin (DOX) and/or sorafenib (SFN) indicate that HMCPN17 can be employed as a generic drug delivery system (DDS). The in vitro and in vivo results reinforce the high calcicoptosis therapeutic efficacy of tumors by our HMCPN17 without drug loading, which can be attributed to the efficient accumulation in tumors and the ability of H2O2 and Ca2+ production at acidic TME. Our HMCPN17 has broad application prospect for construction of multi-drug-loaded composite nanomaterials with diversified functions for the treatment of tumors. Statement of significanceThe combination of hollow mesoporous nanomaterials and calcium peroxide nanoparticles has a wide range of applications in the synergistic treatment of tumors. In this study, hollow mesoporous calcium peroxide nanoparticles (HMCPN) were developed based on a simple hydrolysis-precipitation method for tumor calcicoptosis therapy without drug loading. The high drug loading contents of DOX and/or SFN indicate that our HMCPN can serve as a generic DDS. The experimental results demonstrated the high calcicoptosis therapeutic efficacy of HMCPN on tumors even without drug loading.

The biological effect of ultradisperse zinc particles and phybiotics based on essential oils on the carp organism

The biological effect of ultradisperse zinc particles and phybiotics based on essential oils on the carp organism

, , Roshaan , ,

Background: Microbial resistance to various drugs is a significant challenge in treating infectious diseases, necessitating the development of new drugs. Pyrimidine, with diverse biological effects, is an effective component in antimicrobial drugs. Despite significant progress over the last decade in studying pyrimidine as an antimicrobial agent, a bibliometric analysis in this area is lacking. This analysis aims to fill that gap and provide insights into the field's evolution. Methods: A comprehensive examination of the available literature published between 2015 and 2023 on pyrimidine derivatives as antimicrobial agents was done across the Scopus database. Microsoft Excel 365 was employed to analyze the quantitative variables, such as publications and citation counts, for the authors, institutions, countries, and journals. Furthermore, the network visualization and analysis of co-authorship, co-occurrence, and co-citation among countries, institutions, authors, and keywords were facilitated by VOSviewer. Results: A total of 934 articles were selected for the study. The years 2019 and 2022 exhibited the highest volume of published papers on pyrimidine derivatives as antimicrobial agents between 2015 and 2023, with 125 publications each. A total of 53 countries contributed to the topic, with India leading in publications, followed by Egypt, China, Saudi Arabia, and the United States. Among journals, the Journal of Heterocyclic Chemistry had the highest number of publications (n = 50), followed by the European Journal of Medicinal Chemistry with 37 publications. Conclusion: The findings offer crucial insights for researchers in choosing specific compounds for future studies, highlighting the importance of bibliometric analysis in advancing pyrimidine antimicrobial research.

Effects of discharge plasma on seed germination and volatile compounds content of Agropyron Mongolicum

To investigate the effects of discharge plasma on Agropyron mongolicum seeds, various treatments including direct exposure to discharge plasma, combined treatment with discharge plasma and plasma-activated water (PAW) were applied to the seeds. The changes in germination rate, MDA content, and volatile compound levels of Agropyron mongolicum seeds after different treatments were examined. The results showed that the direct effect of plasma had no significant effect on the MDA content or germination rate of Agropyron mongolicum seeds due to the limited penetration depth. However, the combined effect of plasma and activated water could cause active nitrogen and oxygen particles to enter the seeds and cause oxidative stress damage. After 18 h of combined treatment, the MDA content increased significantly, and the germination rate decreased to below the semilethal dose, which was 33.44 %. After plasma treatment, 55 volatile compounds, mainly alcohols, aldehydes and ketones, were identified from the seeds of Agropyron mongolicum. Due to the oxidation and modification of the plasma, the content of most aldehydes increased with increasing reaction time. After screening, 13 volatile organic compounds could be used as potential markers to distinguish between different treatment methods. These results reveal the mechanism underlying the biological effects of plasma treatment on Agropyron mongolicum seeds.

Relationships of intestinal microbiota metabolites with biomarkers of oxidative stress in type 2 diabetes mellitus. Review

The review is devoted to the analysis of modern data on the relationships between pathogenetic mechanisms in dysmetabolic conditions (metabolic syndrome, type 2 diabetes mellitus) and the functional activity of the intestinal microbiota, which produces low‑molecular compounds classified by biological effects into two types: 1) beneficial for maintaining metabolic homeostasis and antioxidant system in the body, such as short‑chain fatty acids (SCFAs), bile acids and 2) so‑called «dangerous» metabolites, including endotheliotoxic trimethylamine‑N‑oxide (TMAO) and endotoxemia factors lipopolysaccharides (LPS). The molecular mechanisms that mediate SCFAs effects as mediators of oxidative eustress and cytoprotection in various pathologies have been considered. In addition to the role of energy substrates, SCFAs play the role of ligands of G protein‑coupled membrane fatty acid receptors, the activation of which triggers nuclear erythroid 2‑related factor 2 (NRF2) signaling pathways. This transcription factor plays a crucial role in the response to cellular stress, suppressing the expression of inflammatory cytokine and chemokine genes and contributing to the maintenance of redox homeostasis under physiological conditions. The second type of microbial metabolites, on the contrary, corresponds to the definition of oxidative distress factors that exhibit cytotoxic properties, contributing to the processes of atherogenesis and chronic inflammation, especially under the conditions of a dysbiotic state. For example, it has been shown that TMAO can affect mitochondrial and lysosomal signaling pathways, thereby increasing the concentration of reactive oxygen species and malondialdehyde. In addition, TMAO modulates the expression of microRNAs, which promotes the expression of pro‑inflammatory interleukins and blood coagulation factors. Other toxic metabolites, LPS, have a high pro‑inflammatory potential, they increase the permeability of the intestinal mucosa and provoke inflammation and oxidative stress in various tissues of the body. Thus, there is a significant progress in the study of the molecular mechanisms of positive and negative effects of microbial metabolites, which argues for the importance of correcting the composition of the intestinal microbiota and monitoring its functional activity in the process of complex treatment of diabetes mellitus and prevention of the development of cardiometabolic complications associated with oxidative stress.

COW COLOSTRUM IS A PROMISING RAW MATERIAL FOR THE PRODUCTION OF FUNCTIONAL FOOD PRODUCTS

The article presents studies of the quality of cow colostrum. To date, a promising direction in the development of food functional products technology is the processing of cow colostrum as an additional source of protein, immunoglobulins, lipids, vitamins, minerals and other biologically active substances. It has been established that the physico-chemical composition of colostrum depends on the time elapsed since the calving of the cow. According to the conducted studies, it was found that the protein content is significantly higher in colostrum obtained immediately after calving than in colostrum collected after 24 hours and 36 hours after calving. The article provides data on the study of dry cow colostrum obtained by freeze-drying. In this regard, the authors of the article investigated the chemical composition of dry colostrum, namely, the concentration of protein, fat and ash was determined depending on the time of collection of colostrum. The authors found that colostrum obtained immediately after calving also has low humidity, which makes it possible to increase the shelf life. The article substantiates the ways of its subsequent use in the production of food products with high nutritional and biological value and possible immunomodulatory effect.

COW COLOSTRUM IS A PROMISING RAW MATERIAL FOR THE PRODUCTION OF FUNCTIONAL FOOD PRODUCTS

The article presents studies of the quality of cow colostrum. To date, a promising direction in the development of food functional products technology is the processing of cow colostrum as an additional source of protein, immunoglobulins, lipids, vitamins, minerals and other biologically active substances. It has been established that the physico-chemical composition of colostrum depends on the time elapsed since the calving of the cow. According to the conducted studies, it was found that the protein content is significantly higher in colostrum obtained immediately after calving than in colostrum collected after 24 hours and 36 hours after calving. The article provides data on the study of dry cow colostrum obtained by freeze-drying. In this regard, the authors of the article investigated the chemical composition of dry colostrum, namely, the concentration of protein, fat and ash was determined depending on the time of collection of colostrum. The authors found that colostrum obtained immediately after calving also has low humidity, which makes it possible to increase the shelf life. The article substantiates the ways of its subsequent use in the production of food products with high nutritional and biological value and possible immunomodulatory effect.

Studies of spectroanalytical and the biological effectiveness of the Azo compound (J25) prepared from Ethyl p-aminobenzoate

Studies of spectroanalytical and the biological effectiveness of the Azo compound (J25) prepared from Ethyl p-aminobenzoate

Analysis of the essential oils in leaves and rhizomes with roots of angelica Archangelica growing in Ukraine

Essential oils, comprised of volatile compounds, have a wide range of biological effects, making them valuable in medicine, industry, and agriculture. They exhibit properties such as antimicrobial, anti-inflammatory, antiviral, antioxidant, anti-obesity, antidiabetic, and smooth muscle relaxation. In this aspect, plants belonging to the genus Angelica show promise. One of these essential oil plants is Angelica archangelica. There is insufficient information in the literature on the essential oils of the leaves and rhizomes with roots of Angelica archangelica. The aim. The aim of our study was to identify and determine the quantitative content of essential oils by GC/MS method in Angelica archangelica leaves and rhizomes with roots grown in Ukraine. Materials and methods. The determination of the essential oils composition of Angelica archangelica was conducted using Agilent Technologies 6890 chromatograph with mass spectrometric detector 5973 (Agilent Technologies, USA). Results. The leaves of Angelica archangelica were found to contain twenty-three components in their essential oil, while the rhizomes and roots of this plant contained fifteen components. Eleven components were common to both parts of the plant, namely cis-Pinane, α-Farnesene, α-Curcumene, α-Caryophyllene, Copaen, β-Bisabolene, δ-Amorphene, α-Muurolene, trans-Chrysanthemal, β-Guaiene, α-Elemene. Twelve components such as α-Pinene, β-Myrcene, 3-p-Menthene, Isoborneol, Anisole, Bornyl acetate, (Z)-β-Elemene, Caryophyllene, (-)-Spathulenol, α-Bergamotene, γ-Muurolene, α-Bisabolol were present only in leaves, and four components namely p-Isopropenylacetophenone, β-Cubebene, α-Zingiberene, Hexahydrofarnesyl acetone were present only in rhizomes with roots. Conclusions. The component composition of the essential oil in the leaves and the rhizomes with roots of Angelica archangelica growing in Ukraine was investigated using the GS/MC method. We have defined for the first time the chemical composition of the essential oils of the leaves of Angelica archangelica, 23 components of essential oil were identified. In the rhizomes with roots, 15 components of essential oils were identified. The following pharmacologically important components, cis-Pinane and α-Farnesene, were found in both samples of the essential oil of Angelica archangelica in significant quantities. These results have been cross-analyzed and are particularly important for planning and defining the process of cultivation and use of this species plant in traditional and official medicine

Analysis of the essential oils in leaves and rhizomes with roots of angelica Archangelica growing in Ukraine

Essential oils, comprised of volatile compounds, have a wide range of biological effects, making them valuable in medicine, industry, and agriculture. They exhibit properties such as antimicrobial, anti-inflammatory, antiviral, antioxidant, anti-obesity, antidiabetic, and smooth muscle relaxation. In this aspect, plants belonging to the genus Angelica show promise. One of these essential oil plants is Angelica archangelica. There is insufficient information in the literature on the essential oils of the leaves and rhizomes with roots of Angelica archangelica. The aim. The aim of our study was to identify and determine the quantitative content of essential oils by GC/MS method in Angelica archangelica leaves and rhizomes with roots grown in Ukraine. Materials and methods. The determination of the essential oils composition of Angelica archangelica was conducted using Agilent Technologies 6890 chromatograph with mass spectrometric detector 5973 (Agilent Technologies, USA). Results. The leaves of Angelica archangelica were found to contain twenty-three components in their essential oil, while the rhizomes and roots of this plant contained fifteen components. Eleven components were common to both parts of the plant, namely cis-Pinane, α-Farnesene, α-Curcumene, α-Caryophyllene, Copaen, β-Bisabolene, δ-Amorphene, α-Muurolene, trans-Chrysanthemal, β-Guaiene, α-Elemene. Twelve components such as α-Pinene, β-Myrcene, 3-p-Menthene, Isoborneol, Anisole, Bornyl acetate, (Z)-β-Elemene, Caryophyllene, (-)-Spathulenol, α-Bergamotene, γ-Muurolene, α-Bisabolol were present only in leaves, and four components namely p-Isopropenylacetophenone, β-Cubebene, α-Zingiberene, Hexahydrofarnesyl acetone were present only in rhizomes with roots. Conclusions. The component composition of the essential oil in the leaves and the rhizomes with roots of Angelica archangelica growing in Ukraine was investigated using the GS/MC method. We have defined for the first time the chemical composition of the essential oils of the leaves of Angelica archangelica, 23 components of essential oil were identified. In the rhizomes with roots, 15 components of essential oils were identified. The following pharmacologically important components, cis-Pinane and α-Farnesene, were found in both samples of the essential oil of Angelica archangelica in significant quantities. These results have been cross-analyzed and are particularly important for planning and defining the process of cultivation and use of this species plant in traditional and official medicine

Palmitoylethanolamide-Incorporated Elastic Nano-Liposomes for Enhanced Transdermal Delivery and Anti-Inflammation

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application.

Integrated Analysis of Transcriptome Profiles and lncRNA–miRNA–mRNA Competing Endogenous RNA Regulatory Network to Identify Biological Functional Effects of Genes and Pathways Associated with Johne’s Disease in Dairy Cattle

Integrated Analysis of Transcriptome Profiles and lncRNA–miRNA–mRNA Competing Endogenous RNA Regulatory Network to Identify Biological Functional Effects of Genes and Pathways Associated with Johne’s Disease in Dairy Cattle

Mechanisms of biological effectiveness of ionic forms of metals of variable valence in respiratory medicine

Background: The task to develop new drugs containing metals of variable valence requires systematization of our knowledge, experimental and clinical studies. The aim of the study: To investigate the mechanisms of the effectiveness of the mineral complex containing metals of variable valence in the treatment of respiratory diseases, to conduct preclinical trials and clinical testing of a new inhalation mineral solution. Materials and methods: The ability of cerium (III) ions to exhibit reducing properties was demonstrated by carrying out chemical reactions of cerium (III) chloride and sulfate with potassium permanganate in the presence of sodium hydroxide or sulfuric acid (respectively). Preclinical studies of acute toxicity were carried out on laboratory mice and rats in accordance with the rules of bioethics and with generally accepted ethical standards for the treatment of animals, based on the standard operating procedures of the university, which comply with the rules adopted by the European Convention for the Protection of Vertebrate Animals used for research and other scientific purposes (Strasbourg, 1986). Clinical testing of two forms of the mineral complex for inhalation (1. Inhalation solution for nebulizer – Renerium; 2. intranasal spray) was carried out on 6 groups of volunteers in compliance with human rights and the principles of conducting medical research involving a person as a subject, declared on the 18th General Assembly of the World Medical Association (Helsinki, Finland), voluntary informed consent, approved by the local ethical committee. Results: Mineral preparation for inhalation therapy of patients with acute respiratory diseases does not show acute toxicity in preclinical studies on laboratory animals. The mechanism of action of the drug is most likely associated with the regulation of redox reactions at the level of the cell membrane, mitochondria and cell nucleus, which is manifested by anti-inflammatory and regenerative activity in the mucous membrane of the respiratory tract and alveolar apparatus. Both forms of the drug are well tolerated. A pronounced clinical efficacy of the drug Renerium in the form of inhalation through a compressor inhaler was noted in the case of a 5-day course of treatment, 5 ml once a day. Conclusion: Experimental and clinical data have demonstrated pronounced anti-inflammatory and regenerative properties of a new mineral complex based on cerium (III), the mechanism of which is due to the regulation of redox reactions.

The Impact of Virgin and Aged Microstructured Plastics on Proteins: The Case of Hemoglobin Adsorption and Oxygenation.

Plastic particles, particularly micro- and nanoparticles, are emerging pollutants due to the ever-growing amount of plastics produced across a wide variety of sectors. When plastic particles enter a biological medium, they become surrounded by a corona, giving them their biological identity and determining their interactions in the living environment and their biological effects. Here, we studied the interactions of microstructured plastics with hemoglobin (Hb). Virgin polyethylene microparticles (PEMPs) and polypropylene microparticles (PPMPs) as well as heat- or irradiation-aged microparticles (ag-PEMPs and ag-PPMPs) were used to quantify Hb adsorption. Polypropylene filters (PP-filters) were used to measure the oxygenation of adsorbed Hb. Microstructured plastics were characterized using optical microscopy, SAXS, ATR-FTIR, XPS, and Raman spectroscopy. Adsorption isotherms showed that the Hb corona thickness is larger on PPMPs than on PEMPs and Hb has a higher affinity for PPMPs than for PEMPs. Hb had a lower affinity for ag-PEMPs and ag-PPMPs, but they can be adsorbed in larger amounts. The presence of partial charges on the plastic surface and the oxidation rate of microplastics may explain these differences. Tonometry experiments using an original method, the diffuse reflection of light, showed that adsorbed Hb on PP-filters retains its cooperativity, but its affinity for O2 decreases significantly.

Cumulative Dose from Recurrent CT Scans: Exploring the DNA Damage Response in Human Non-Transformed Cells.

Recurrent computed tomography (CT) examination has become a common diagnostic procedure for several diseases and injuries. Though each singular CT scan exposes individuals at low doses of low linear energy transfer (LET) radiation, the cumulative dose received from recurrent CT scans poses an increasing concern for potential health risks. Here, we evaluated the biological effects of recurrent CT scans on the DNA damage response (DDR) in human fibroblasts and retinal pigment epithelial cells maintained in culture for five months and subjected to four CT scans, one every four weeks. DDR kinetics and eventual accumulation of persistent-radiation-induced foci (P-RIF) were assessed by combined immunofluorescence for γH2AX and 53BP1, i.e., γH2AX/53BP1 foci. We found that CT scan repetitions significantly increased both the number and size of γH2AX/53BP1 foci. In particular, after the third CT scan, we observed the appearance of giant foci that might result from the overlapping of individual small foci and that do not associate with irreversible growth arrest, as shown by DNA replication in the foci-carrying cells. Whether these giant foci represent coalescence of unrepaired DNA damage as reported following single exposition to high doses of high LET radiation is still unclear. However, morphologically, these giant foci resemble the recently described compartmentalization of damaged DNA that should facilitate the repair of DNA double-strand breaks but also increase the risk of chromosomal translocations. Overall, these results indicate that for a correct evaluation of the damage following recurrent CT examinations, it is necessary to consider the size and composition of the foci in addition to their number.

Quantifying the Dosimetric Impact of Proton Range Uncertainties on RBE-Weighted Dose Distributions in Intensity-Modulated Proton Therapy for Bilateral Head and Neck Cancer

Background: In current clinical practice, intensity-modulated proton therapy (IMPT) head and neck cancer (HNC) plans are generated using a constant relative biological effectiveness (cRBE) of 1.1. The primary goal of this study was to explore the dosimetric impact of proton range uncertainties on RBE-weighted dose (RWD) distributions using a variable RBE (vRBE) model in the context of bilateral HNC IMPT plans. Methods: The current study included the computed tomography (CT) datasets of ten bilateral HNC patients who had undergone photon therapy. Each patient’s plan was generated using three IMPT beams to deliver doses to the CTV_High and CTV_Low for doses of 70 Gy(RBE) and 54 Gy(RBE), respectively, in 35 fractions through a simultaneous integrated boost (SIB) technique. Each nominal plan calculated with a cRBE of 1.1 was subjected to the range uncertainties of ±3%. The McNamara vRBE model was used for RWD calculations. For each patient, the differences in dosimetric metrices between the RWD and nominal dose distributions were compared. Results: The constrictor muscles, oral cavity, parotids, larynx, thyroid, and esophagus showed average differences in mean dose (Dmean) values up to 6.91 Gy(RBE), indicating the impact of proton range uncertainties on RWD distributions. Similarly, the brachial plexus, brain, brainstem, spinal cord, and mandible showed varying degrees of the average differences in maximum dose (Dmax) values (2.78–10.75 Gy(RBE)). The Dmean and Dmax to the CTV from RWD distributions were within ±2% of the dosimetric results in nominal plans. Conclusion: The consistent trend of higher mean and maximum doses to the OARs with the McNamara vRBE model compared to cRBE model highlighted the need for consideration of proton range uncertainties while evaluating OAR doses in bilateral HNC IMPT plans.