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The combination of carbon ion radiotherapy and anti-PD-1 antibody represents a new approach to treating thoracic tumors. However, the lung damage caused by this combination therapy may limit its use, and the potential mechanisms for this are worthy of investigation. The objective of this research was to examine the potential involvement of repulsive guidance molecule b (RGMb) in lung damage promoted by the utilization of carbon ion irradiation combined with an anti-PD-1 antibody. The C57BL/6 mice have been randomly separated into four distinct groups: control, anti-PD-1, whole thorax carbon ion irradiation, and irradiation in combination with anti-PD-1 treatment groups (combination group). Detection of pathological changes in lung tissue using HE staining. Detection of pulmonary fibrosis by Masson staining and the hydroxyproline assay. ELISA to detect TNF-α, TGF-ß, IL-6, and IL-1ß expression levels within lung homogenates. The expression of RGMb, p38 MAPK, and Erk1/2 pathways was detected using a fully automated digital Western blotting system WES (ProteinSimple, USA). Flow cytometry was employed to analyze tissue-resident memory T cells (TRM) within the lung. Subsequently, the siRNA gene was employed to induce the downregulation of RGMb in mice in order to validate the involvement of RGMb in radiation-immune lung injury. The present study observed a significant increase in both inflammatory and fibrotic indicators within the mice group's lung tissue that received the combination treatment. The combination group exhibited elevated levels of TGF-ß, TNF-α, IL-6, and IL-1ß in lung homogenates. Anti-PD-1 antibody and carbon ion irradiation, upregulated RGMb, phospho-p38 MAPK and phospho-Erk1/2. The results obtained from the flow cytometry analysis indicated that the combination group was significantly higher in the number of clonal expansion TRMs, which were predominantly characterized by the expression of CD8+CD103+CD69-TRMs. The downregulate of RGMb via siRNA in mice resulted in a decrease in phospho-p38 MAPK and phospho-Erk1/2. The combination group exhibited a reduction in TNF-α, TGF-ß, IL-6, and IL-1ß in their lung tissues, and the number of CD8+CD103+CD69-TRM was significantly reduced. The combination group exhibited a significant improvement in inflammatory and fibrotic indicators within the lung tissues. Anti-PD-1 antibody and carbon ion irradiation synergistically regulate RGMb, leading to strong clonal expansion of lung TRM through the p38 MAPK and Erk1/2 pathways. The present study offers valuable insights into the treatment of lung injury due to the combined administration of carbon ion radiotherapy and anti-PD-1 antibody therapy.
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Lesão Pulmonar , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Camundongos , Fator de Necrose Tumoral alfa , Interleucina-6 , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta , RNA Interferente Pequeno , CarbonoRESUMO
BACKGROUND: The lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown. METHODS: The expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells. Flow cytometry and Western blotting were conducted to measure the level of apoptosis. The binding relationship between the lncRNA H19 and miR-130a-3p was determined by a dual-luciferase reporter assay. A binding relationship was also identified between miR-130a-3p and With-No-Lysine Kinase 3 (WNK3). RESULTS: Expression patterns of lncRNAs revealed that the lncRNA H19 was upregulated in radioresistant NSCLC (A549-R11) cells compared with A549 cells. Knockdown of the lncRNA H19 enhanced the sensitivity of NSCLC cell lines to X-ray and carbon ion irradiation. Mechanistically, the lncRNA H19 serves as a sponge of miR-130a-3p, which downregulates WNK3 expression. The lncRNA H19-miR-130a-3p-WNK3 axis modulates radiosensitivity by regulating apoptosis in NSCLC cell lines. CONCLUSION: Knockdown of the lncRNA H19 promotes the sensitivity of NSCLC cells to X-ray and carbon ion irradiation. Hence, the lncRNA H19 might function as a potential therapeutic target that enhances the antitumor effects of radiotherapy in NSCLC.
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BACKGROUND: Controversy persists about whether additional induction chemotherapy (ICT) before neoadjuvant chemoradiation (NCRT) yields improved oncological outcomes. We performed a systematic review and meta-analysis to compare ICT+ NCRT+ surgery(S) with NCRT+ S in patients with locally advanced rectal cancer (LARC). METHODS: We searched the PubMed, EMBASE, Cochrane Library, and China Biology Medicine (CBM) databases. The data were analyzed with Stata version 12.0 software. RESULTS: We identified 9 relevant trials that enrolled 1538 patients. We detected no significant difference in the 5-year overall survival (OS) (OR 1.50, 95% CI 0.48-4.64), disease-free survival (DFS) (OR 1.03, 95% CI 0.73-1.46), local recurrence (LR) (OR 0.80, 95% CI 0.45-1.43), and distant metastasis (DM) rates (OR 1.03, 95% CI 0.55-1.93) between patients who did and did not receive ICT. The addition of ICT before NCRT had a similar pathological complete response rate compared to NCRT (OR 1.26, 95% CI 0.90-1.77). Our findings suggest that between the ICT + NCRT+S and NCRT+S groups, ICT improved the incidence of grade 3 to 4 toxicity effects (OR 4.81, 95% CI 2.38-9.37), but between the ICT + NCRT+S and NCRT+S+ adjuvant chemotherapy (ACT) groups, ICT might reduce toxicity (OR 0.19, 95% CI 0.08-0.50). ICT had no significant impact on surgical complications (OR 0.97, 95% CI 0.63-1.51). CONCLUSIONS: The addition of ICT before NCRT seemingly shows no survival benefit on patients with LARC, and might increase the toxicity.
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Terapia Neoadjuvante , Neoplasias Retais , Quimiorradioterapia , Quimiorradioterapia Adjuvante , China , Humanos , Quimioterapia de Indução , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Retais/terapia , Resultado do TratamentoRESUMO
This Systematic Review summarizes the literatures of clinical trials on the efficacy and safety of carbon ion therapy for gynecological carcinomas. The protocol is detailed in the online PROSPERO database, registration no. CRD42019121424, and a final set of eight studies were included. In the treatment of cervical carcinomas, both carbon ion therapy alone and carbon ion therapy concurrent chemotherapy have presented good efficacy. Besides, the efficacy of inoperable endometrial carcinomas and gynecological melanoma are similar to that of surgical treatment. In terms of safety, gastrointestinal and genitourinary toxicities are low and could be controlled by limiting the volume and dose of intestinal tract and bladder. Carbon ion radiotherapy could be considered a safe, effective and feasible therapy for gynecological carcinomas.
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Neoplasias dos Genitais Femininos/terapia , Radioterapia com Íons Pesados , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Feminino , Neoplasias dos Genitais Femininos/diagnóstico , Radioterapia com Íons Pesados/métodos , Humanos , Resultado do TratamentoRESUMO
Core scan is the instrument used for core spectrum and pictures detection that has been developed in recent years. Cores' data can be digitized with this equipment, then automatic core catalog can be achieved, which provides basis for geological research, mineral deposit study and peripheral deposit prospecting. Meanwhile, an online database of cores can be established by the means of core digitalization to solve the cost problem caused by core preservation and share resources. Quality of core data measurement directly affects the mineral identification, reliability of parameter inversion results. Therefore it's very important to quasi-manage the assessment of data quality with the instrument before cores' spectrum testing services. Combined with the independent R&D of CSD350A type core scan, and on the basis of spectroscopy basic theory, spectrum analysis methods, core spectrum analysis requirements, key issues such as data quality assessment methods, evaluation criteria and target parameters has been discussed in depth, and comprehensive assessment of independent R&D of core scan has been conducted, which indicates the reliability and validity of spectrum measurements of the instrument. Experimental tests show that the methods including test parameters and items can perfectly response the measurements of reflectance spectrum, wavelength accuracy, repeatability and signal to noise ratio with the instrument. Thus the quality of core scan data can be evaluated correctly, and the foundation of data quality for commercial services can be provided. In the case of the current lack of relevant assessment criteria, the method this study proposes for the assessment has great value in the work of core spectrum measurements.
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Purpose: Although active spot scanning irradiation technique is theoretically superior to passive-scattered broad beam irradiation with respect to normal tissue sparing, corroborations of the clinical benefit of carbon-ion spot scanning have remained scarce. This study aims to investigate the feasibility and clinical implementation of an active spot scanning beam calculation algorithm in a homemade carbon-ion treatment planning system by comparing it with a conventional passive uniform scanning technique. Methods and Materials: Carbon-ion plans were initially formulated using spot/uniform scanning methods in 22 participants enrolled in a prospective observational clinical trial. Subsequently, 2 additional plans were designed, resulting in 3 carbon-ion plans for each participant: uniform and spot scanning with miniridge filters of 2 mm and 4 mm, respectively. Results: The findings revealed no significant differences in dose homogeneity; however, significant differences in dose conformity were found between the active and passive scanning plans. For dose drop-off outside the target volume, the average gradient index values were 1.94 (95% CI, 1.79%-2.09%), 1.87 (95% CI, 1.73%-2.01%), and 3.20 (95% CI, 2.80%-3.61%) for the miniridge filters of 2 mm and 4 mm, and uniform scanning plans, respectively. The pretreatment tumor volume was 124.7 cm3 (range, 54.2-234 cm3), and the average shrinkage observed was 38.4% (95% CI, 17.6%-59.4%). Seven participants experienced grade 1 acute toxicity, and 4 experienced grade 2 acute toxicity. However, none of the patients developed grade 3 acute toxicity. Conclusions: Increasing evidence suggests that potential clinical advantages of spot scanning delivery underlie its technical characteristics. As one among the few institutions currently using carbon-ion radiation therapy, the investigation also provides promising safety and efficacy outcomes from the initial groups of treated participants, thereby contributing to the established clinical evidence supporting the effectiveness and superiority of carbon-ion therapy.
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BACKGROUND: Gliomas are characterized by aggressive behavior, leading to severe disability and high mortality. Ubiquitin-like modifier activating enzyme 2 (UBA2) is a subunit of the E1-activating enzyme involved in the SUMOylation (SUMO, small ubiquitin-related modifier) of numerous proteins. Although the abnormality of UBA2 is linked to the progression of various tumor types, the role of UBA2 in glioma is still unknown. METHODS: A bioinformatic analysis using several public databases was conducted to examine the expression level, clinicopathological correlations, and prognostic significance of UBA2 in glioma. The correlation between UBA2 expression and drug sensitivity in cancers was also explored. Multiple cellular experiments were conducted to validate the role of UBA2 in glioma. RESULTS: Analysis of multiple databases and cellular experiments revealed that UBA2 was overexpressed in glioma tissues and cell lines, respectively. UBA2 expression in gliomas correlated with World Health Organization (WHO) grade, IDH gene status, 1p19q deletion, histological type, and immune cell infiltration in glioma. UBA2 expression in carcinomas also correlated with drug sensitivity. Kaplan-Meier analysis revealed that high expression of UBA2 predicted poorer survival in glioma patients. A nomogram model containing UBA2 expression was constructed for clinical practice. Knockdown of UBA2 was observed to suppress glioma cell progression and sensitize glioma cells to irradiation in vitro. CONCLUSION: Overall, this research showed that UBA2 might be involved not only in the development of glioma but also in the regulation of immunity, drug sensitivity, and radiosensitivity. Therefore, UBA2 may be a potential target for therapy and a candidate biomarker for glioma diagnosis and prognosis.
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Biomarcadores Tumorais , Glioma , Enzimas Ativadoras de Ubiquitina , Glioma/diagnóstico , Glioma/imunologia , Glioma/mortalidade , Glioma/terapia , Linhagem Celular Tumoral , Prognóstico , Enzimas Ativadoras de Ubiquitina/análise , Enzimas Ativadoras de Ubiquitina/metabolismo , Imunoterapia , Tolerância a Radiação , Progressão da DoençaRESUMO
This study explored the role of 14-3-3σ in carbon ion-irradiated pancreatic adenocarcinoma (PAAD) cells and xenografts and clarified the underlying mechanism. The clinical significance of 14-3-3σ in patients with PAAD was explored using publicly available databases. 14-3-3σ was silenced or overexpressed and combined with carbon ions to measure cell proliferation, cell cycle, and DNA damage repair. Immunoblotting and immunofluorescence (IF) assays were used to determine the underlying mechanisms of 14-3-3σ toward carbon ion radioresistance. We used the BALB/c mice to evaluate the biological behavior of 14-3-3σ in combination with carbon ions. Bioinformatic analysis revealed that PAAD expressed higher 14-3-3σ than normal pancreatic tissues; its overexpression was related to invasive clinicopathological features and a worse prognosis. Knockdown or overexpression of 14-3-3σ demonstrated that 14-3-3σ promoted the survival of PAAD cells after carbon ion irradiation. And 14-3-3σ was upregulated in PAAD cells during DNA damage (carbon ion irradiation, DNA damaging agent) and promotes cell recovery. We found that 14-3-3σ resulted in carbon ion radioresistance by promoting RPA2 and RAD51 accumulation in the nucleus in PAAD cells, thereby increasing homologous recombination repair (HRR) efficiency. Blocking the HR pathway consistently reduced 14-3-3σ overexpression-induced carbon ion radioresistance in PAAD cells. The enhanced radiosensitivity of 14-3-3σ depletion on carbon ion irradiation was also demonstrated in vivo. Altogether, 14-3-3σ functions in tumor progression and can be a potential target for developing biomarkers and treatment strategies for PAAD along with incorporating carbon ion irradiation.
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Proteínas 14-3-3 , Camundongos Endogâmicos BALB C , Neoplasias Pancreáticas , Reparo de DNA por Recombinação , Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/radioterapia , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Regulação para Baixo , Tolerância a Radiação/genética , Exorribonucleases/metabolismo , Exorribonucleases/genética , Radioterapia com Íons Pesados , Carbono , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Masculino , Dano ao DNA , FemininoRESUMO
Purpose: Head and neck adenoid cystic carcinoma (HNACC) is a radioresistant tumor. Particle therapy, primarily proton beam therapy and carbon-ion radiation, is a potential radiotherapy treatment for radioresistant malignancies. This study aims to conduct a meta-analysis to evaluate the impact of charged particle radiation therapy on HNACC. Methods: A comprehensive search was conducted in Pubmed, Cochrane Library, Web of Science, Embase, and Medline until December 31, 2022. The primary endpoints were overall survival (OS), local control (LC), and progression-free survival (PFS), while secondary outcomes included treatment-related toxicity. Version 17.0 of STATA was used for all analyses. Results: A total of 14 studies, involving 1297 patients, were included in the analysis. The pooled 5-year OS and PFS rates for primary HNACC were 78% (95% confidence interval [CI] = 66-91%) and 62% (95% CI = 47-77%), respectively. For all patients included, the pooled 2-year and 5-year OS, LC, and PFS rates were as follows: 86.1% (95% CI = 95-100%) and 77% (95% CI = 73-82%), 92% (95% CI = 84-100%) and 73% (95% CI = 61-85%), and 76% (95% CI = 68-84%) and 55% (95% CI = 48-62%), respectively. The rates of grade 3 and above acute toxicity were 22% (95% CI = 13-32%), while late toxicity rates were 8% (95% CI = 3-13%). Conclusions: Particle therapy has the potential to improve treatment outcomes and raise the quality of life for HNACC patients. However, further research and optimization are needed due to the limited availability and cost considerations associated with this treatment modality.
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Carcinoma Adenoide Cístico , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma Adenoide Cístico/radioterapia , Carcinoma Adenoide Cístico/mortalidade , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/mortalidade , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/métodos , Resultado do TratamentoRESUMO
Objective: Osteosarcomas are derived from bone-forming mesenchymal cells that are insensitive to radiation. This study aimed to investigate the radiosensitization of osteosarcoma cells (U2OS and K7M2) using the PARP inhibitor olaparib combined with X-rays or carbon ions (C-ions). Methods: The effect of olaparib on the proliferation of osteosarcoma cells after irradiation was assessed using CCK-8 and clone formation assays. Cells were treated with olaparib and/or radiation and the effects of olaparib on the cell cycle and apoptosis were analysed by flow cytometry after 48h. Immunofluorescence was used to stain the nuclei, γ-H2AX, 53BP1, and Rad51 proteins, and the number of γ-H2AX, 53BP1, and Rad51 foci was observed under a fluorescence microscope. The effect of olaparib combined with radiation on double-stranded DNA breaks in osteosarcoma cells was evaluated. Results: At the same radiation dose, olaparib reduced the proliferation and colony formation ability of irradiated osteosarcoma cells (P < 0.05). Olaparib monotherapy induced minimal apoptotic effects and G2/M phase arrest in osteosarcoma cells and irradiation alone induced moderate apoptosis and G2/M phase arrest. However, radiation combined with olaparib significantly increased the percentage of apoptotic cells and G2/M phase arrest in osteosarcoma cells (P < 0.05). Immunofluorescence experiments showed that compared to the radiation group, the formation of γ-H2AX and 53BP1 foci was significantly increased in the combined group (P < 0.05). The expression levels of Rad51 foci in the irradiated group were higher than those in the control group (P < 0.05). However, the number of Rad51 foci in the combined group was significantly decreased (P < 0.05). Conclusion: The PARP inhibitor olaparib combined with irradiation (X-rays or C-ions) enhanced the radiosensitivity of osteosarcoma cell lines (U2OS and K7M2). Our findings provide a potential theoretical basis for the clinical application of olaparib in overcoming radiation resistance in osteosarcoma.
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Background and goal: Carbon ion beam is radio-biologically more efficient than photons and is beneficial for treating radio-resistant tumors. Several animal experiments with tumor-bearing suggest that carbon ion beam irradiation in combination with immunotherapy yields better results, especially in controlling distant metastases. This implies that carbon ion induces a different anti-tumor immune response than photon beam. More complex molecular mechanisms need to be uncovered. This in vivo and in vitro experiment was carried out in order to examine the radio-immune effects and the mechanism of action of carbon ion beam versus X-ray in combination with PD-1 inhibitors. Methods and Materials: Lewis lung adenocarcinoma cells and C57BL/6 mice were used to create a tumor-bearing mouse model, with the non-irradiated tumor growing on the right hind leg and the irradiated tumor on the left rear. 10Gy carbon ion beam or X-ray radiation, either alone or in combination with PD-1 inhibitor, were used to treat the left back tumor. The expression of molecules linked to immunogenicity and the infiltration of CD8+ T lymphocytes into tumor tissues were both identified using immunohistochemistry. IFN-ß in mouse serum was measured using an ELISA, while CD8+ T cells in mouse peripheral blood were measured using flow cytometry. Lewis cells were exposed to different dose of X-ray and carbon ion. TREX1, PD-L1, and IFN-ß alterations in mRNA and protein levels were identified using Western blot or RT-PCR, respectively. TREX1 knockdown was created by siRNA transfection and exposed to various radiations. Using the CCK8 test, EdU assay, and flow cytometry, changes in cell viability, proliferation, and apoptosis rate were discovered. Results: Bilateral tumors were significantly inhibited by the use of carbon ion or X-ray in combination with PD-1, particularly to non-irradiated tumor(p<0.05). The percentage of infiltrating CD8+ T cells and the level of IFN-ß expression were both raised by 10Gy carbon ion irradiation in the irradiated side tumor, although PD-L1 and TREX1 expression levels were also elevated. Lewis cell in vitro experiment further demonstrated that both X-ray and carbon ion irradiation can up-regulate the expression levels of PD-L1 and TREX1 with dose-dependent in tumors, particularly the trend of up-regulation TREX1 is more apparent at a higher dose in carbon ion, i.e. 8 or 10Gy, while the level of IFN-ß is decreased. IFN-ß levels were considerably raised under hypofractionated doses of carbon ion radiation by gene silencing TREX1. Conclusions: By enhancing tumor immunogenicity and increasing CD8+T infiltration in TME through a threshold dosage, X-ray or carbon ion radiation and PD-1 inhibitors improve anti-tumor activity and cause abscopal effect in Lewis lung adenocarcinoma-bearing mice. TREX1 is a possible therapeutic target and prognostic marker.
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Radiotherapy is one of the main treatments for cervical cancer. Early cervical cancer is usually considered postoperative radiotherapy alone. Radiotherapy combined with cisplatin is the standard treatment for locally advanced cervical cancer (LACC), but sometimes the disease will relapse within a short time after the end of treatment. Tumor recurrence is usually related to the inherent radiation resistance of the tumor, mainly involving cell proliferation, apoptosis, DNA repair, tumor microenvironment, tumor metabolism, and stem cells. In the past few decades, the mechanism of radiotherapy resistance of cervical cancer has been extensively studied, but due to its complex process, the specific mechanism of radiotherapy resistance of cervical cancer is still not fully understood. In this review, we discuss the current status of radiotherapy resistance in cervical cancer and the possible mechanisms of radiotherapy resistance, and provide favorable therapeutic targets for improving radiotherapy sensitivity. In conclusion, this article describes the importance of understanding the pathway and target of radioresistance for cervical cancer to promote the development of effective radiotherapy sensitizers.
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MOF-74 (metal-organic framework) is utilized as a filler in mixed-matrix membranes (MMMs) to improve gas selectivity due to its unique one-dimensional hexagonal channels and high-density open metal sites (OMSs), which exhibit a strong affinity for CO2 molecules. Reducing the agglomeration of nanoparticles and improving the compatibility with the matrix can effectively avoid the existence of non-selective voids to improve the gas separation efficiency. We propose a novel, layer-by-layer modification strategy for MOF-74 with graphene oxide. Two-dimensional graphene oxide nanosheets as a supporting skeleton creatively improve the dispersion uniformity of MOFs in MMMs, enhance their interfacial compatibility, and thus optimize the selective gas permeability. Additionally, they extended the gas diffusion paths, thereby augmenting the dissolution selectivity. Compared with doping with a single component, the use of a GO skeleton to disperse MOF-74 into Pebax®1657 (Polyether Block Amide) achieved a significant improvement in terms of the gas separation effect. The CO2/N2 selectivity of Pebax®1657-MOF-74 (Ni)@GO membrane with a filler concentration of 10 wt% was 76.96, 197.2% higher than the pristine commercial membrane Pebax®1657. Our results highlight an effective way to improve the selective gas separation performance of MMMs by functionalizing the MOF supported by layered GO. As an efficient strategy for developing porous MOF-based gas separation membranes, this method holds particular promise for manufacturing advanced carbon dioxide separation membranes and also concentrates on improving CO2 capture with new membrane technologies, a key step in reducing greenhouse gas emissions through carbon capture and storage.
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Carbon-ion radiotherapy (CIRT) enhanced local control in patients with malignant melanoma. In several in vitro studies, carbon ions (C ions) have been also shown to decrease the metastatic potential of melanoma cells. CXC motif 10 (CXCL10) has been shown to play a crucial role in regulating tumor metastasis and it significantly increase in human embryonic kidney cells after heavy ion irradiations. This study sought to explore the regulatory effect of C ions on melanoma metastasis, emphasizing the role of CXCL10 in this process. To explore the potential regulatory effect of C ions on tumor metastasis in vivo, we developed a lung metastasis mouse model by injecting B16F10 cells into the footpad and subjected all mice to treatment with X rays and C ions. Subsequently, a series of assays, including histopathological analysis, enzyme-linked immunosorbent assay, real-time PCR, and western blotting, were conducted to assess the regulatory effects of C ions on melanoma. Our results showed that mice treated with C ions exhibited significantly less tumor vascularity, enhanced tumor necrosis, alleviated lung metastasis, and experienced longer survival than X-ray irradiated mice. Moreover, VEGF expression in B16F10 cells was significantly reduced by C-ion treatment, which could be alleviated by CXCL10 knockdown in vitro. Further investigations revealed that co-culturing with HUVECs resulted in a significant inhibition of proliferation, migration, and tube formation ability in the C-ion treated group, while the opposite effect was observed in the C-ion treated with si-CXCL10 group. In conclusion, our findings demonstrate that treatment with carbon-ion radiation can suppress angiogenesis and lung metastases in melanoma by specifically targeting CXCL10. These results suggest the potential utility of carbon ions in treating melanoma.
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Neoplasias Pulmonares , Melanoma , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Melanoma/radioterapia , Melanoma/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Cutâneas/patologia , Raios X , Carbono , Linhagem Celular Tumoral , Quimiocina CXCL10RESUMO
High-grade gliomas are the most common intracranial malignancies, and their current prognosis remains poor despite standard aggressive therapy. Charged particle beams have unique physical and biological properties, especially high relative biological effectiveness (RBE) of carbon ion beam might improve the clinical treatment outcomes of malignant gliomas. We systematically reviewed the safety, efficacy, and dosimetry of carbon-ion or proton radiotherapy to treat high-grade gliomas. The protocol is detailed in the online PROSPERO database, registration No. CRD42021258495. PubMed, EMBASE, Web of Science, and The Cochrane Library databases were collected for data analysis on charged particle radiotherapy for high-grade gliomas. Until July 2022, two independent reviewers extracted data based on inclusion and exclusion criteria. Eleven articles were eligible for further analysis. Overall survival rates were marginally higher in patients with the current standard of care than those receiving concurrent intensity-modulated radiotherapy plus temozolomide. The most common side effects of carbon-ion-related therapy were grade 1-2 (such as dermatitis, headache, and alopecia). Long-term toxicities (more than three to six months) usually present as radiation necrosis; however, toxicities higher than grade 3 were not observed. Similarly, dermatitis, headache, and alopecia are among the most common acute side effects of proton therapy treatment. Despite improvement in survival rates, the method of dose-escalation using proton boost is associated with severe brain necrosis which should not be clinically underestimated. Regarding dosimetry, two studies compared proton therapy and intensity-modulated radiation therapy plans. Proton therapy plans aimed to minimize dose exposure to non-target tissues while maintaining target coverage. The use of charged-particle radiotherapy seems to be effective with acceptable adverse effects when used either alone or as a boost. The tendency of survival outcome shows that carbon ion boost is seemingly superior to proton boost. The proton beam could provide good target coverage, and it seems to reduce dose exposure to contralateral organs at risk significantly. This can potentially reduce the treatment-related dose- and volume-related side effects in long-term survivors, such as neurocognitive impairment. High-quality randomized control trials should be conducted in the future. Moreover, Systemic therapeutic options that can be paired with charged particles are necessary.
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Dermatite , Glioma , Terapia com Prótons , Humanos , Adulto , Prótons , Glioma/radioterapia , Glioma/tratamento farmacológico , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Cefaleia/tratamento farmacológico , Cefaleia/etiologia , Carbono/uso terapêutico , Alopecia/tratamento farmacológico , Alopecia/etiologia , Necrose/etiologia , Dermatite/etiologiaRESUMO
OBJECTIVE: This study aimed to evaluate and conduct a meta-analysis on the efficacy and safety of proton beam therapy (PBT) for rhabdomyosarcoma (RMS). METHODS: We searched for articles using PubMed, Embase, Cochrane Library, and Web of Science databases from their inception to December 22, 2022. Two researchers independently screened literature and extracted data. Statistical analyses were performed using STATA version 14.0. RESULTS: We got 675 candidate articles, of which 11 studies were included in our study according to the inclusion and exclusion criteria. Of the 544 RMS patients who received PBT. The local control (LC) rate at 1, 2, 3, 4, and 5 years were 96% (95% confidence interval (CI) 0.91-1.01), 93% (95% CI 0.86-1.00), 78% (95% CI 0.71-0.85), 85% (95% CI 0.78-0.92), and 84% (95% CI 0.74-0.95), respectively. The progression-free survival (PFS) rate at 1, 2, 3, 4, and 5 years were 82% (95% CI 0.72-0.92), 73% (95% CI 0.61-0.84), 63% (95% CI 0.47-0.79), 64% (95% CI 0.54-0.74), and 76% (95% CI 0.59-0.94), respectively. The overall survival (OS) rate at 1, 2, 3, 4, and 5 years were 93% (95% CI 0.86-1.00), 85% (95% CI 0.76-0.95), 80% (95% CI 0.63-0.96), 71% (95% CI 0.62-0.80), and 82% (95% CI 0.71-0.94), respectively. Acute and late toxicities were mainly grades 1 to 2 in all studies. CONCLUSION: As an advantageous RT technique, PBT is an emerging option for patients with RMS, particularly children and adolescents patients. The data showed that PBT is a feasible, safe, and effective modality for RMS, showing promising LC, OS, PFS, and lower acute and late toxicities. PROSPERO registration number: CRD42022329154.
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Terapia com Prótons , Rabdomiossarcoma , Adolescente , Criança , Humanos , Terapia com Prótons/efeitos adversos , Bases de Dados Factuais , Intervalo Livre de Progressão , Projetos de Pesquisa , Rabdomiossarcoma/radioterapiaRESUMO
Chromatin-modifying enzymes are commonly altered in cancers, but the molecular mechanism by which they regulate cancers remains poorly understood. Herein, we demonstrated that Lysine acetyltransferase 7 (KAT7) was upregulated in breast cancer. KAT7 expression negatively correlated with the survival of breast cancer patients, and KAT7 silencing suppressed breast cancer radioresistance in vitro. Mechanistically, KAT7 activated Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) transcription, leading to enhanced PI3K/AKT signaling and radioresistance. Overexpression of AKT or PIK3CA restored radioresistance suppression induced by KAT7 inhibition. Moreover, overexpression of KAT7, but not KAT7 acetyltransferase activity-deficient mutants promoted AKT phosphorylation at the Ser473 site, PIK3CA expression and radioresistance suppression due to KAT7 inhibition. In conclusion, KAT7 has huge prospects for clinical application as a new target for predicting radioresistance in breast cancer patients.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/radioterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Histona Acetiltransferases/metabolismoRESUMO
Background: Esophagus cancer is a malignant tumor with a high incidence rate, and radiation is an important modality for esophageal cancer therapy. However, therapeutic failure in the treatment of ESCC is often attributed to an inherent radio-resistance of the tumor cells. This study discusses effect and mechanism of carbon ion exerts tumor-inhibiting proliferation via down-regulation of LIF in esophageal squamous cell carcinoma. Methods: Colony formation, CCK8 and EdU assays were used to detect cell survival and proliferation after 0 and 2Gy carbon ion irradiation of ECA109 cells. Proteomics changes were probed in response to carbon ion irradiation using quantitative proteomics approach incorporating TMT isotope tags. Then, candidate genes were identified via bioinformatics analysis methods and microarray results were verified by real-time qPCR. Paired ESCC tumor tissues and adjacent non-tumor samples from 17 patients were collected and used for detecting expression by immunohistochemistry. Furthermore, small interfering RNA (siRNA) was transfected into ECA109 and KYSE150 cells and cell proliferation was analyzed by EdU assay. Flow cytometry and Western blot were performed to measure the and apoptosis and JAK-STAT3 protein expression level of ECA109 and KYSE150 cells combined drugs after siLIF transfection. Results: When compared with the control (0Gy), Inhibition of ECA109 cell proliferation and clonogenic survival by 2 Gy carbon ions, radiation group screened 360 differentially expressed proteins, 156 of which were up-regulated and 144 were down-regulated. Downregulation of LIF expression by siRNA enhances apoptotic in the ECA109 and KYSE150 cells, significantly inhibited esophageal squamous cell carcinoma cells proliferation. In ESCC cells, the JAK/STAT3 signaling pathway is inhibited in a LIF-dependent manner, resulting in the expression of STAT3 downstream target genes. Carbon ions combined with siLIF inhibited cell proliferation more significantly. The inhibitory cell proliferation effect was more pronounced by the combined intervention of carbon ion irradiation with siLIF. LIF expression was 18.51±9.84 and 5.82±4.50 in 17 paired ESCC tissues and adjacent non-cancerous tissues, respectively. LIF protein expression was lower in ESCC than in the adjacent normal tissue. Conclusion: The findings of this study reveal that Carbon ion knockdown was shown to downregulate LIF in ESCC cells. LIF is involved in ESCC proliferation and inhibited the ESCC cell proliferation by activating the STAT3 signaling pathways.
RESUMO
BACKGROUND AND PURPOSE: Particle therapy, mainly including carbon-ion radiotherapy (CIRT) and proton beam therapy (PBT), has dose distribution advantages compared to photon radiotherapy. It has been widely reported as a promising treatment method for early non-small cell lung cancer (NSCLC). However, its application in locally advanced non-small cell lung cancer (LA-NSCLC) is relatively rare, and its efficacy and safety are inconclusive. This study aimed to provide systematic evidence for evaluating the efficacy and safety of particle therapy for inoperable LA-NSCLC. METHODS: To retrieve published literature, a systematic search was conducted in PubMed, Web of Science, Embase, and Cochrane Library until September 4, 2022. The primary endpoints were local control (LC) rate, overall survival (OS) rate, and progression-free survival (PFS) rate at 2 and 5 years. The secondary endpoint was treatment-related toxicity. The pooled clinical outcomes and 95% confidence intervals (CIs) were calculated by using STATA 15.1. RESULTS: Nineteen eligible studies with a total sample size of 851 patients were included. The pooled data demonstrated that the OS, PFS, and LC rates at 2 years of LA-NSCLC treated by particle therapy were 61.3% (95% CI = 54.7-68.7%), 37.9% (95% CI = 33.8-42.6%) and 82.2% (95% CI = 78.7-85.9%), respectively. The pooled 5-year OS, PFS, and LC rates were 41.3% (95% CI = 27.1-63.1%), 25.3% (95% CI = 16.3-39.4%), and 61.5% (95% CI = 50.7-74.6%), respectively. Subgroup analysis stratified by treatment type showed that the concurrent chemoradiotherapy (CCRT, PBT combined with concurrent chemotherapy) group had better survival benefits than the PBT and CIRT groups. The incidence rates of grade 3/4 esophagitis, dermatitis, and pneumonia in LA-NSCLC patients after particle therapy were 2.6% (95% CI = 0.4-6.0%), 2.6% (95% CI = 0.5-5.7%) and 3.4% (95% CI = 1.4-6.0%), respectively. CONCLUSIONS: Particle therapy demonstrated promising efficacy and acceptable toxicity in LA-NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia com Prótons , Humanos , Intervalo Livre de Progressão , Terapia com Prótons/efeitos adversos , QuimiorradioterapiaRESUMO
Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.