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International Journal of Radiation... Jul 2024Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of...
FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease.
PURPOSE
Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared with conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared with standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities.
METHODS AND MATERIALS
Mice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted using a shoot-through technique with a 5-mm diameter circular collimator. Bulk RNA-sequencing was performed on nonirradiated samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks after a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2-dimensional echocardiograms at 8- and 30-weeks post-PRT.
RESULTS
Radiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily, and inflammatory response, and F-PRT primarily affected cytoplasmic translation, mitochondrion organization, and adenosine triphosphate synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in transforming growth factor β1 and α smooth muscle actin levels. Critically, F-PRT decreased collagen deposition and better preserved cardiac functionality compared with S-PRT.
CONCLUSIONS
This study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.
Topics: Animals; Fibrosis; Proton Therapy; Mice; Inflammation; Heart Diseases; Heart; Disease Models, Animal; Mice, Inbred C57BL; Radiation Injuries, Experimental; Male; Radiation Injuries
PubMed: 38364948
DOI: 10.1016/j.ijrobp.2024.01.224 -
Stem Cell Research & Therapy Sep 2023Though articular cartilage stem cell (ACSC)-based therapies have been demonstrated to be a promising option in the treatment of diseased joints, the wide variety of cell...
Human osteoarthritic articular cartilage stem cells suppress osteoclasts and improve subchondral bone remodeling in experimental knee osteoarthritis partially by releasing TNFAIP3.
BACKGROUND
Though articular cartilage stem cell (ACSC)-based therapies have been demonstrated to be a promising option in the treatment of diseased joints, the wide variety of cell isolation, the unknown therapeutic targets, and the incomplete understanding of the interactions of ACSCs with diseased microenvironments have limited the applications of ACSCs.
METHODS
In this study, the human ACSCs have been isolated from osteoarthritic articular cartilage by advantage of selection of anatomical location, the migratory property of the cells, and the combination of traumatic injury, mechanical stimuli and enzymatic digestion. The protective effects of ACSC infusion into osteoarthritis (OA) rat knees on osteochondral tissues were evaluated using micro-CT and pathological analyses. Moreover, the regulation of ACSCs on osteoarthritic osteoclasts and the underlying mechanisms in vivo and in vitro were explored by RNA-sequencing, pathological analyses and functional gain and loss experiments. The one-way ANOVA was used in multiple group data analysis.
RESULTS
The ACSCs showed typical stem cell-like characteristics including colony formation and committed osteo-chondrogenic capacity. In addition, intra-articular injection into knee joints yielded significant improvement on the abnormal subchondral bone remodeling of osteoarthritic rats. Bioinformatic and functional analysis showed that ACSCs suppressed osteoarthritic osteoclasts formation, and inflammatory joint microenvironment augmented the inhibitory effects. Further explorations demonstrated that ACSC-derived tumor necrosis factor alpha-induced protein 3 (TNFAIP3) remarkably contributed to the inhibition on osteoarhtritic osteoclasts and the improvement of abnormal subchondral bone remodeling.
CONCLUSION
In summary, we have reported an easy and reproducible human ACSC isolation strategy and revealed their effects on subchondral bone remodeling in OA rats by releasing TNFAIP3 and suppressing osteoclasts in a diseased microenvironment responsive manner.
Topics: Humans; Animals; Rats; Osteoarthritis, Knee; Cartilage, Articular; Osteoclasts; Tumor Necrosis Factor alpha-Induced Protein 3; Stem Cells; Bone Remodeling
PubMed: 37752608
DOI: 10.1186/s13287-023-03411-7 -
Cureus Feb 2024Thermal, electrical, chemical, or electromagnetic radiation can cause painful wounds or burns. Spilling hot liquids onto the skin can also cause these kinds of... (Review)
Review
Thermal, electrical, chemical, or electromagnetic radiation can cause painful wounds or burns. Spilling hot liquids onto the skin can also cause these kinds of injuries. The two biggest factors contributing to burn injuries in the elderly are smoking and exposure to open flames, while scalding is the primary cause of burn damage in children. Newborns and the elderly make up the majority of burn casualties. In India, there are estimated to be 6-7 million burn cases per year. The high incidence is attributed to the population's illiteracy, poverty, and lack of awareness of safety. The problem is made much worse by the fact that basic and secondary healthcare levels do not provide systematic burn care. Coagulation necrosis is caused by denaturing proteins due to heat from burns. Platelets clump together, arteries narrow, and partly perfused tissue (called the stasis zone) may spread out around the wound. In the stasis zone, tissue is hyperemic and inflammatory. When the skin's natural barrier is breached, microorganisms can enter the body and cause poor temperature regulation, fluid loss, and invasion. Intravascular volume loss is typically worsened by injured or edematous tissues. Significant heat loss may occur from the wounded dermis' lack of thermoregulation, particularly in exposed wounds. The severity determines the different treatments. Serious burns require considerable care, while lesser burns just require cleaning and painkillers. Just-partially thickened burns must be cleansed with soap and water before being clothed. For full-thickness burns, surgery, including skin grafting, is frequently required. Extensive intravenous fluid doses are often required to treat serious burns resulting from tissue edema and capillary fluid leakage.
PubMed: 38544618
DOI: 10.7759/cureus.54915 -
Biomedicine & Pharmacotherapy =... Sep 2023When activated by unconjugated bilirubin (UCB), inflammatory mediators such as IL - 18 and TNF contribute to the neurotoxicity and ototoxicity observed in severe...
When activated by unconjugated bilirubin (UCB), inflammatory mediators such as IL - 18 and TNF contribute to the neurotoxicity and ototoxicity observed in severe neonatal hyperbilirubinemia. However, in cell and molecular level, the regulation and mechanism of UCB-induced ototoxicity are remained unclear. In this study, 7-day-old mammary rats were exposed to various concentrations of UCB to imitate the infant auditory damage. The auditory brainstem response result (ABR) indicated severe hearing loss, which occurred with increasing concentration. Morphological analysis of organotypic cochlear cultures treated with different concentrations of UCB indicated that auditory nerve fibers (ANF) were demyelinated and the density of spiral ganglion neurons (SGN) were decreased. In addition, HEI-OC1 cells treated with different concentrations of UCB showed severe necrosis by Flow Cytometry. The morphologic feature of pyroptosis has been observed by scanning electronic microscope. Cleaved Caspase-1, GSDMD and NLRP3 expression were significantly increased in cochlear explants with UCB-induced. To further clarify the molecular mechanism of UCB-induced inner ear cell pyroptosis, specific inhibitors of pyroptosis were applied, the protein associated with pyrotosis such as Cleaved Caspase-1, GSDMD, ASC, IL-18 and NLRP3 were significantly lower than the group with UCB alone. All the data above indicated that ERK /NLRP3/GSDMD signaling pathway involved in UCB-induced ototoxicity.
Topics: Animals; Rats; Bilirubin; Caspase 1; Hyperbilirubinemia, Neonatal; NLR Family, Pyrin Domain-Containing 3 Protein; Ototoxicity; Pyroptosis; Animals, Newborn; Disease Models, Animal
PubMed: 37467648
DOI: 10.1016/j.biopha.2023.115162 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jul 2023Necroptosis is a cell death type mediated by receptor interacting protein 3 (RIP3)/mixed lineage kinase domain-like protein (MLKL). It has been reported that mammalian...
OBJECTIVES
Necroptosis is a cell death type mediated by receptor interacting protein 3 (RIP3)/mixed lineage kinase domain-like protein (MLKL). It has been reported that mammalian target of rapamycin plays a regulatory role in necroptosis. Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-eukaryotic initiation factor 4E (eIF4E) pathway is a key down streamer of mammalian target of rapamycin. However, whether 4EBP1-eIF4E pathway is involved in necroptosis is still unknown. This study aims to investigate the changes of 4EBP1-eIF4E pathway in necroptosis.
METHODS
TNF-α/SM-164/Z-VAD-FMK (TSZ), a necroptosis inducer, was used to induce necroptosis in murine fibroblastoid cell line L929. Cell necrosis was observed under an optical microscope. Then, TSZ was added to L929 cells with and gene knockout. Propidium iodide (PI) staining was used to observe cell necrosis. Real-time fluorescence quantitative PCR and Western blotting were used to determine the mRNA and protein expression of and , respectively.
RESULTS
After treating L929 cells with TSZ, the number of necrotic cells was increased, the mRNA and protein expression levels of were significantly downregulated, and the ratio of phosphorylated 4EBP1 (p-4EBP1) to 4EBP1 was increased (<0.05 or <0.01); the mRNA expression level of was significantly upregulated, and the ratio of phosphorylated eIF4E (p-eIF4E) to eIF4E was increased (both <0.01). After knocking out and in L929 cells, PI positive necrotic cells were significantly reduced, the mRNA and protein expression levels of were significantly upregulated, and the ratio of p-4EBP1 to 4EBP1 was decreased (<0.05 or <0.01); the mRNA expression level of was significantly downregulated, and the ratio of p-eIF4E to eIF4E was decreased (both <0.01).
CONCLUSIONS
4EBP1-eIF4E pathway is activated in the RIP3/MLKL mediated-necroptosis.
Topics: Animals; Mice; Cell Line; Eukaryotic Initiation Factor-4E; Fluorescence; Necroptosis; Protein Kinases; TOR Serine-Threonine Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37724400
DOI: 10.11817/j.issn.1672-7347.2023.230153 -
Journal of Neurosurgery. Case Lessons Nov 2023Focal cortical dysplasia is a structural cause of drug-resistant epilepsy commonly identified in childhood. In rare cases, radiation-induced injury has led to...
BACKGROUND
Focal cortical dysplasia is a structural cause of drug-resistant epilepsy commonly identified in childhood. In rare cases, radiation-induced injury has led to radiation-induced cortical dysplasia, also known as "focal neuronal gigantism."
OBSERVATIONS
The authors present a 53-year-old woman with recurrent status epilepticus events after she had radiation therapy and surgery for a left frontal meningioma several years prior. Imaging revealed findings consistent with radiation necrosis and possible recurrence. The patient's status epilepticus events required escalating therapies to manage. Scalp electroencephalography indicated that the seizure's origin was in the left hemisphere. A craniotomy was performed to remove the left frontal lesion, and histopathology was consistent with radiation-induced focal cortical dysplasia/neuronal gigantism. The patient's seizures ceased following the surgery, and she remains on maintenance antiseizure medications.
LESSONS
Radiation-induced focal cortical dysplasia/neuronal gigantism is an incredibly rare complication of therapy. However, it warrants consideration in the context of radiation necrosis and intractable epilepsy.
PubMed: 37992306
DOI: 10.3171/CASE23374 -
International Immunopharmacology Oct 2023To determine the effect of X-ray irradiation combined with PD-1 immune checkpoint inhibitor administration on lung tissue injury in a mouse model and its potential...
PURPOSE
To determine the effect of X-ray irradiation combined with PD-1 immune checkpoint inhibitor administration on lung tissue injury in a mouse model and its potential mechanism.
METHODS
In all, 20 C57BL/6J mice were randomly divided into four groups with five mice in each group: control group, PD-1 inhibitor group, irradiation group, and irradiation combined with PD-1 inhibitor group. Hematoxylin-eosin staining of the lung tissue was performed 30 days after the end of irradiation to evaluate the morphological and pathological changes in the tissue. Masson staining and analysis of hydroxyproline were used to evaluate the degree of pulmonary fibrosis. The levels of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor α(TNF-α) were evaluated by Enzyme-Linked immunosorbent assay (ELISA). CD3+, CD4+, and CD8+ T lymphocytes in the lung tissue were detected by immunohistochemistry. The expression levels of TGF-β1, Smad3, cGAS, and STING in the lung tissue were evaluated by Western blotting.
RESULTS
The lung injury scores and pulmonary fibrosis indices in the irradiation group were higher than those in the control group. Meanwhile, lung pneumonia score, pulmonary fibrosis index, percentage of CD4 cells and expression of TGF-β1, p-Smad3, and STING in the lung tissue of mice in irradiation combined with PD-1 inhibitor group were higher than those in the other three groups.
CONCLUSION
Lung injury and pulmonary fibrosis were induced by whole chest X-ray irradiation in mice, and PD-1 inhibitor could aggravate lung injury and pulmonary fibrosis in mice. Thus, radiotherapy combined with PD-1 inhibitors may affect the immune inflammatory microenvironment in the lung tissues of mice by activating TGF-β1/Samd3 and cGAS/STING signaling pathways, thus aggravating lung tissue damage induced by radiation.
Topics: Mice; Animals; Lung Injury; Immune Checkpoint Inhibitors; Transforming Growth Factor beta1; Pulmonary Fibrosis; X-Rays; Mice, Inbred C57BL; Lung
PubMed: 37562291
DOI: 10.1016/j.intimp.2023.110775 -
Yonsei Medical Journal Jan 2024Surgery, radiotherapy (RT), and chemotherapy have prolonged the survival of patients with anaplastic oligodendroglioma. However, whether RT induces long-term toxicity...
PURPOSE
Surgery, radiotherapy (RT), and chemotherapy have prolonged the survival of patients with anaplastic oligodendroglioma. However, whether RT induces long-term toxicity remains unknown. We analyzed the relationship between the RT dose to the fornix and symptomatic radiation necrosis (SRN).
MATERIALS AND METHODS
A total of 67 patients treated between 2009 and 2019 were analyzed. SRN was defined according to the following three criteria: 1) radiographic findings, 2) symptoms attributable to the lesion, and 3) treatment resulting in symptom improvement. Various contours, including the fornix, were delineated. Univariate and multivariate analyses of the relationship between RT dose and SRN, as well as receiver operating characteristic curve analysis for cut-off values, were performed.
RESULTS
The most common location was the frontal lobe (n=40, 60%). Gross total resection was performed in 38 patients (57%), and 42 patients (63%) received procarbazine, lomustine, and vincristine chemotherapy. With a median follow-up of 42 months, the median overall and progression-free survival was 74 months. Sixteen patients (24%) developed SRN. In multivariate analysis, age and maximum dose to the fornix were associated with the development of SRN. The cut-off values for the maximum dose to the fornix and age were 59 Gy (equivalent dose delivered in 2 Gy fractions) and 46 years, respectively. The rate of SRN was higher in patients whose maximum dose to the fornix was >59 Gy (13% vs. 43%, =0.005).
CONCLUSION
The maximum dose to the fornix was a significant factor for SRN development. While fornix sparing may help maintain neurocognitive function, additional studies are needed.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Vincristine; Radiation Dosage; Necrosis
PubMed: 38154474
DOI: 10.3349/ymj.2023.0112 -
European Radiology Experimental Dec 2023Renal ischemia-reperfusion injury (IRI) frequently occurs clinically. We investigated the value of contrast-enhanced ultrasonography (CEUS) in the evaluation of renal...
BACKGROUND
Renal ischemia-reperfusion injury (IRI) frequently occurs clinically. We investigated the value of contrast-enhanced ultrasonography (CEUS) in the evaluation of renal IRI levels in mice.
METHODS
Thirty-six healthy adult male C57BL/6 mice (20-22 g) were randomly divided into the sham, 10 min, 20 min, 30 min, 40 min, and 50 min groups based on the time of renal warm ischemia by blocking the left renal pedicle, approved by the Institutional Animal Ethics Committee. Time-intensity curve (TIC)-derived parameters such as peak enhancement (PE) and wash-in perfusion index (WiPI) were produced using CEUS at 1 h and 24 h after IRI. The severity of kidney injury was detected by the renal tubular necrosis rate which was analyzed by hematoxylin and eosin staining at 24 h after IRI. The Spearman correlation coefficient was used to describe the correlations between PE and WiPI values and the renal tubular necrosis rate.
RESULTS
The PE and WiPI values decreased after IRI in the groups with a warm ischemia time ≥ 20 min. The renal tubular necrosis rate was significantly correlated with the PE value at 1 h (ρ = -0.802) and 24 h (ρ = -0.861) after IRI and the WiPI value at 1 h (ρ = -0.814) and 24 h (ρ = -0.853) after IRI (all p < 0.001).
CONCLUSION
TIC-derived parameters, including PE and WiPI values, can be used to evaluate the severity of renal IRI in mice. CEUS is a safe and effective technology for the detection of renal IRI.
RELEVANCE STATEMENT
CEUS can evaluate the severity of renal ischemia-reperfusion injury by peak enhancement and wash-in perfusion index values selected from various time-intensity curve-derived parameters.
KEY POINTS
• Contrast-enhanced ultrasonography can evaluate the level of renal ischemia-reperfusion injury. • Peak enhancement and wash-in perfusion index are correlated with the renal tubular necrosis rate. • CEUS can detect changes in unilateral renal function without radiation.
Topics: Mice; Male; Animals; Mice, Inbred C57BL; Kidney; Reperfusion Injury; Ultrasonography; Necrosis
PubMed: 38110603
DOI: 10.1186/s41747-023-00392-3 -
Journal of Hazardous Materials Jun 2024Micro- and nanoplastics (MNPs) are ubiquitous in the environment, resulting in the uptake of MNPs by a variety of organisms, including humans, leading to particle-cell...
Micro- and nanoplastics (MNPs) are ubiquitous in the environment, resulting in the uptake of MNPs by a variety of organisms, including humans, leading to particle-cell interaction. Human macrophages derived from THP-1 cell lines take up Polystyrene (PS), a widespread plastic. The question therefore arises whether primary human macrophages also take up PS micro- and nanobeads (MNBs) and how they react to this stimulation. Major aim of this study is to visualize this uptake and to validate the isolation of macrophages from peripheral blood mononuclear cells (PBMCs) to assess the impact of MNPs on human macrophages. Uptake of macrophages from THP-1 cell lines and PBMCs was examined by transmission electron microscopy (TEM), scanning electron microscopy and live cell imaging. In addition, the reaction of the macrophages was analyzed in terms of metabolic activity, cytotoxicity, production of reactive oxygen species (ROS) and macrophage polarization. This study is the first to visualize PS MNBs in primary human cells using TEM and live cell imaging. Metabolic activity was size- and concentration-dependent, necrosis and ROS were increased. The methods demonstrated in this study outline an approach to assess the influence of MNP exposure on human macrophages and help investigating the consequences of worldwide plastic pollution.
Topics: Humans; Macrophages; Reactive Oxygen Species; Polystyrenes; THP-1 Cells; Microplastics; Leukocytes, Mononuclear; Nanoparticles; Cell Survival; Microscopy, Electron, Transmission; Particle Size
PubMed: 38642497
DOI: 10.1016/j.jhazmat.2024.134253