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1.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201963

RESUMO

Pancreatic ductal adenocarcinoma is a devastating disease with a 5-year overall survival of 9% for all stages. Gemcitabine-based chemoradiotherapy for locally advanced pancreatic cancer is highly toxic. We conducted an in vitro study to determine whether poly(ADP-ribose) polymerase-1 inhibition radiosensitized gemcitabine-based chemotherapy. Human pancreatic cancer cell lines, MIA PaCa-2, AsPC-1, BxPC-3 and PANC-1 were treated with gemcitabine (10 nM) and/or olaparib (1 µM). Low-LET gamma single dose of 2, 5 and 10 Gy radiations were carried out. Clonogenic assay, PAR immunoblotting, cell cycle distribution, γH2Ax, necrotic and autophagic cell death quantifications were performed. Treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines, particularly at high dose per fraction A non-cytotoxic concentration of gemcitabine radiosensitized cells, but less than olaparib. Interestingly, olaparib significantly enhanced gemcitabine-based radiosensitization in PDAC cell lines with synergistic effect in BxPC-3 cell line. All cell lines were radiosensitized by the combination of gemcitabine and olaparib, through an increase of unrepaired double-strand, a G2 phase block and cell death. Radiosensitization was increased with high dose of radiation. The combination of olaparib with gemcitabine-based chemoradiotherapy could lead to an enhancement of local control in vivo and an improvement in disease-free survival.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Histonas/metabolismo , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Radiossensibilizantes/farmacologia
2.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202550

RESUMO

In this study, we determined the potential of polyethylene glycol-encapsulated iron oxide nanoparticles (IONPCO) for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to enhance the cytotoxic effects of ionizing radiation. The biological effects of IONP and X-ray irradiation (50 kV and 6 MV) were determined in HeLa cells using the colony formation assay (CFA) and detection of γH2AX foci. Data are presented as mean ± SEM. IONP were efficiently internalized by HeLa cells. IONPCO radiomodulating effect was dependent on nanoparticle concentration and photon energy. IONPCO did not radiosensitize HeLa cells with 6 MV X-rays, yet moderately enhanced cellular radiosensitivity to 50 kV X-rays (DMFSF0.1 = 1.13 ± 0.05 (p = 0.01)). IONPDOX did enhance the cytotoxicity of 6 MV X-rays (DMFSF0.1 = 1.3 ± 0.1; p = 0.0005). IONP treatment significantly increased γH2AX foci induction without irradiation. Treatment of HeLa cells with IONPCO resulted in a radiosensitizing effect for low-energy X-rays, while exposure to IONPDOX induced radiosensitization compared to IONPCO in cells irradiated with 6 MV X-rays. The effect did not correlate with the induction of γH2AX foci. Given these results, IONP are promising candidates for the controlled delivery of DOX to enhance the cytotoxic effects of ionizing radiation.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Compostos Férricos , Nanopartículas Metálicas , Tolerância a Radiação/efeitos dos fármacos , Relação Dose-Resposta à Radiação , Portadores de Fármacos/química , Compostos Férricos/química , Células HeLa/efeitos dos fármacos , Células HeLa/patologia , Células HeLa/efeitos da radiação , Células HeLa/ultraestrutura , Humanos , Nanopartículas Metálicas/química , Radiação Ionizante
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202589

RESUMO

BACKGROUND: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. METHODS: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. RESULTS: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. CONCLUSION: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.


Assuntos
Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Purinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Proteínas Supressoras de Tumor/metabolismo
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208417

RESUMO

In the present study, we analyze the nuclear magnetic resonance (NMR) blood serum metabolic profiles of 106 head and neck squamous cell carcinoma (HNSCC) patients during radio (RT) and concurrent radio-chemotherapy (CHRT). Four different fractionation schemes were compared. The blood samples were collected weekly, from the day before the treatment until the last week of CHRT/RT. The NMR spectra were acquired on A Bruker 400 MHz spectrometer at 310 K and analyzed using multivariate methods. Seven metabolites were found significantly to be altered solely by radiotherapy: N-acetyl-glycoprotein (NAG), N-acetylcysteine, glycerol, glycolate and the lipids at 0.9, 1.3 and 3.2 ppm. The NMR results were correlated with the tissue volumes receiving a particular dose of radiation. The influence of the irradiated volume on the metabolic profile is weak and mainly limited to sparse correlations with the inflammatory markers, creatinine and the lymphocyte count in RT and the branched-chain amino-acids in CHRT. This is probably due to the optimal planning and delivery of radiotherapy improving sparing of the surrounding normal tissues and minimizing the differences between the patients (caused by the tumor location and size).


Assuntos
Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/radioterapia , Espectroscopia de Ressonância Magnética , Metabolômica , Dosagem Radioterapêutica , Adulto , Idoso , Análise Discriminante , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas
5.
Molecules ; 26(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199757

RESUMO

The innovative strategy of using nanoparticles in radiotherapy has become an exciting topic due to the possibility of simultaneously improving local efficiency of radiation in tumors and real-time monitoring of the delivered doses. Yttrium oxide (Y2O3) nanoparticles (NPs) are used in material science to prepare phosphors for various applications including X-ray induced photodynamic therapy and in situ nano-dosimetry, but few available reports only addressed the effect induced in cells by combined exposure to different doses of superficial X-ray radiation and nanoparticles. Herein, we analyzed changes induced in melanoma cells by exposure to different doses of X-ray radiation and various concentrations of Y2O3 NPs. By evaluation of cell mitochondrial activity and production of intracellular reactive oxygen species (ROS), we estimated that 2, 4, and 6 Gy X-ray radiation doses are visibly altering the cells by inducing ROS production with increasing the dose while at 6 Gy the mitochondrial activity is also affected. Separately, high-concentrated solutions of 25, 50, and 100 µg/mL Y2O3 NPs were also found to affect the cells by inducing ROS production with the increase of concentration. Additionally, the colony-forming units assay evidenced a rather synergic effect of NPs and radiation. By adding the NPs to cells before irradiation, a decrease of the number of proliferating cell colonies was observed with increase of X-ray dose. DNA damage was evidenced by quantifying the γ-H2AX foci for cells treated with Y2O3 NPs and exposed to superficial X-ray radiation. Proteomic profile confirmed that a combined effect of 50 µg/mL Y2O3 NPs and 6 Gy X-ray dose induced mitochondria alterations and DNA changes in melanoma cells.


Assuntos
Melanoma/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ítrio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Melanoma/terapia , Mitocôndrias/efeitos dos fármacos , Nanopartículas , Tamanho da Partícula , Fotoquimioterapia , Proteômica
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071406

RESUMO

Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-ß binding sites of A549 cells. Treatment with 1-25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.


Assuntos
Alcaloides de Berberina/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células A549 , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Humanos , Microscopia Confocal , Radiação Ionizante , Radiossensibilizantes/farmacologia
7.
Mutat Res ; 787: 108350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083048

RESUMO

Radiation triage and biological dosimetry are two initial steps in the medical management of exposed individuals following radiological accidents. Well established biodosimetry methods such as the dicentric (DC) assay, micronucleus (MN) assay, and fluorescence in-situ hybridization (FISH) translocation assay (for residual damage) have been used for this purpose for several decades. Recent advances in scoring methodology and networking among established laboratories have increased triage capacity; however, these methods still have limitations in analysing large sample numbers, particularly because of the ∼ 48 h minimum culture time required prior to analysis. Hence, there is a need for simple, and high throughput markers to identify exposed individuals in case of radiological/nuclear emergencies. In recent years, a few markers were identified, one being phosphorylated histone 2AX (γ-H2AX), which measured a nuclear foci or nuclear staining intensity that was found to be suitable for triage. Measurement of γ-H2AX foci formed at and around the sites of DNA double-strand breaks is a rapid and sensitive biodosimetry method which does not require culturing and is thus promising for the analysis of a large number of samples. In this review, we have summarized the recent developments of γ-H2AX assay in radiation triage and biodosimetry, focusing chiefly on: i) the importance of baseline frequency and reported values among different laboratories, ii) the influence of known and unknown variables on dose estimation, iii) quality assurance such as inter-laboratory comparison between scorers and scoring methods, and iv) current limitations and potential for future development.


Assuntos
Histonas/metabolismo , Triagem/métodos , Biodiversidade , Relação Dose-Resposta à Radiação , Histonas/genética , Humanos , Testes para Micronúcleos/métodos , Radiação Ionizante , Radiometria
8.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067339

RESUMO

Dephosphorylation inhibitor calyculin A (cal A) has been reported to inhibit the disappearance of radiation-induced γH2AX DNA repair foci in human lymphocytes. However, other studies reported no change in the kinetics of γH2AX focus induction and loss in irradiated cells. While apoptosis might interplay with the kinetics of focus formation, it was not followed in irradiated cells along with DNA repair foci. Thus, to validate plausible explanations for significant variability in outputs of these studies, we evaluated the effect of cal A (1 and 10 nM) on γH2AX/53BP1 DNA repair foci and apoptosis in irradiated (1, 5, 10, and 100 cGy) human umbilical cord blood lymphocytes (UCBL) using automated fluorescence microscopy and annexin V-FITC/propidium iodide assay/γH2AX pan-staining, respectively. No effect of cal A on γH2AX and colocalized γH2AX/53BP1 foci induced by low doses (≤10 cGy) of γ-rays was observed. Moreover, 10 nM cal A treatment decreased the number of all types of DNA repair foci induced by 100 cGy irradiation. 10 nM cal A treatment induced apoptosis already at 2 h of treatment, independently from the delivered dose. Apoptosis was also detected in UCBL treated with lower cal A concentration, 1 nM, at longer cell incubation, 20 and 44 h. Our data suggest that apoptosis triggered by cal A in UCBL may underlie the failure of cal A to maintain radiation-induced γH2AX foci. All DSB molecular markers used in this study responded linearly to low-dose irradiation. Therefore, their combination may represent a strong biodosimetry tool for estimation of radiation response to low doses. Assessment of colocalized γH2AX/53BP1 improved the threshold of low dose detection.


Assuntos
Apoptose/efeitos dos fármacos , Sangue Fetal/efeitos dos fármacos , Histonas/metabolismo , Linfócitos/efeitos dos fármacos , Toxinas Marinhas/farmacologia , Oxazóis/farmacologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta à Radiação , Sangue Fetal/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/metabolismo , Microscopia de Fluorescência/métodos , Fosforilação/efeitos dos fármacos
9.
Mayo Clin Proc ; 96(5): 1157-1164, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958052

RESUMO

OBJECTIVE: To determine whether biological effective dose (BED) was predictive of obliteration after stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs). PATIENTS AND METHODS: We studied patients undergoing single-session AVM SRS between January 1, 1990, and December 31, 2014, with at least 2 years of imaging follow-up. Excluded were patients with syndromic AVM, previous SRS or embolization, and patients treated with volume-staged SRS. Biological effective dose was calculated using a mono-exponential model described by Jones and Hopewell. The primary outcome was likelihood of total obliteration defined by digital subtraction angiography or magnetic resonance imaging (MRI). Variables were analyzed as continuous and dichotomous variables based on the maximum value of (sensitivity-[1-specificity]). RESULTS: This study included 352 patients (360 AVM, median follow-up, 5.9 years). The median margin dose prescribed was 18.75 Gy (interquartile range [IQR]: 18 to 20 Gy). Two hundred fifty-nine patients (71.9%) had obliteration shown by angiography (n=176) or MRI (n=83) at a median of 36 months after SRS (IQR: 26 to 44 months). Higher BED was associated with increased likelihood of obliteration in univariate Cox regression analyses, when treated as either a dichotomous (≥133 Gy; hazard ratio [HR],1.52; 95% confidence interval [CI], 1.19 to 1.95; P<.001) or continuous variable (HR, 1.00, 95% CI, 1.0002 to 1.005; P=.04). In multivariable analyses including dichotomized BED and location, BED remained associated with obliteration (P=.001). CONCLUSION: Biological effective dose ≥133 Gy was predictive of AVM obliteration after single-session SRS within the prescribed margin dose range 15 to 25 Gy. Further study is warranted to determine whether BED optimization should be considered as well as treatment dose for AVM SRS planning.


Assuntos
Fístula Arteriovenosa/radioterapia , Malformações Arteriovenosas Intracranianas/radioterapia , Radiocirurgia , Eficiência Biológica Relativa , Adulto , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Resultado do Tratamento
10.
Anticancer Res ; 41(5): 2575-2581, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952486

RESUMO

BACKGROUND/AIM: Few previous studies have evaluated the effectiveness of single-isocenter multitarget (SIMT) stereotactic radiosurgery (SRS) in clinical practice. PATIENTS AND METHODS: Gross tumor volumes of 113 metastases in 13 patients were measured by contrast-enhanced magnetic resonance imaging. Prescribed doses were set at 20-24 Gy. Based on tumor reduction rates (TRRs) measured before and after SIMT SRS, tumor shrinkage effect was categorized into four grades; almost disappeared: TRR=1, decreased: 0.3≤TRR<1, stable: -0.2

Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiocirurgia/métodos , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Intervalo Livre de Doença , Relação Dose-Resposta à Radiação , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Radiocirurgia/efeitos adversos
11.
Anticancer Res ; 41(5): 2625-2635, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952493

RESUMO

BACKGROUND/AIM: To evaluate the impact of virtual tumor absorbed dose (vTAD) on tumor response in patients with hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization. PATIENTS AND METHODS: The institutional review board approved this retrospective single center study, which comprised 100 patients with nodular HCC who underwent yttrium-90 radioembolization between November 2015 and December 2019. The vTAD was calculated assuming that all infused microspheres were distributed only in the tumor. The ability of mean absorbed dose (mAD) and vTAD in predicting complete response were evaluated by receiver operating characteristic (ROC) curve analyses. RESULTS: The mAD was 263.9 Gy ± 125.8, and the mean vTAD was 2005.8 Gy ± 2348.9. In terms of tumor response, 63 patients had complete response, 25 partial response, and 12 stable disease. For predicting complete response, ROC curve analyses revealed that the area under the curve (AUC) value of the vTAD was significantly higher (p<0.001) than that of the mAD. Multivariate analysis revealed that Child-Pugh class A5, unilobar disease, and vTAD (>952 Gy) were significant factors in predicting complete response. CONCLUSION: High vTAD (>952 Gy) plays a significant role in complete response in patients with nodular HCC.


Assuntos
Carcinoma Hepatocelular/radioterapia , Relação Dose-Resposta à Radiação , Neoplasias Hepáticas/radioterapia , Radioisótopos de Ítrio/administração & dosagem , Idoso , Área Sob a Curva , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Interface Usuário-Computador , Radioisótopos de Ítrio/efeitos adversos
12.
Free Radic Biol Med ; 171: 126-134, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33992676

RESUMO

Although reactive oxygen species (ROS) play important roles in immune responses, excessive ROS production and accumulation might enhance the risk of inflammation-related diseases. Moreover, impaired immune function and the acceleration of pre-clinically persistent inflammation due to aging and radiation exposure have been observed in atomic bomb (A-bomb) survivors more than 60 years post-exposure. Meanwhile, the effects of aging and radiation exposure on ROS production in immune cells have not been characterized. This study investigated the relationship between intracellular ROS (H2O2 and O2•-) levels in blood cells or T cell subsets and serum iron, ferritin, and C-reactive protein (CRP) levels, as well as how these variables are affected by age and radiation exposure in A-bomb survivors. We examined 2495 Hiroshima A-bomb survivors. Multiple linear regression models adjusted for confounding factors indicated that intracellular O2•- levels in monocytes, granulocytes, and lymphocytes, and particularly in memory CD8+ T cells, including effector memory and terminally differentiated effector memory CD8+ T cells, increased with radiation dose. Additionally, serum iron, ferritin, and CRP levels affected intracellular ROS levels in specific blood cell types and T cell subsets. Serum CRP levels increased significantly with increasing age and radiation dose. Finally, when divided into three groups according to serum CRP levels, dose-dependent increases in the intracellular O2•- levels in blood cells and central memory and effector memory CD8+ T cells were most prominently observed in the high-CRP group. These results suggest that an increase in the levels of certain intracellular ROS, particularly after radiation exposure, might be linked to enhanced inflammatory status, including elevated serum CRP levels and reduced serum iron levels. This study reveals that aging and radiation exposure increase oxidative stress in blood cells, which is involved in impaired immune function and accelerated pre-clinically persistent inflammation in radiation-exposed individuals.


Assuntos
Guerra Nuclear , Exposição à Radiação , Envelhecimento , Sobreviventes de Bombas Atômicas , Linfócitos T CD8-Positivos , Relação Dose-Resposta à Radiação , Humanos , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Sobreviventes
14.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802822

RESUMO

Future space missions will include a return to the Moon and long duration deep space roundtrip missions to Mars. Leaving the protection that Low Earth Orbit provides will unavoidably expose astronauts to higher cumulative doses of space radiation, in addition to other stressors, e.g., microgravity. Immune regulation is known to be impacted by both radiation and spaceflight and it remains to be seen whether prolonged effects that will be encountered in deep space can have an adverse impact on health. In this study, we investigated the effects in the overall metabolism of three different low dose radiation exposures (γ-rays, 16O, and 56Fe) in spleens from male C57BL/6 mice at 1, 2, and 4 months after exposure. Forty metabolites were identified with significant enrichment in purine metabolism, tricarboxylic acid cycle, fatty acids, acylcarnitines, and amino acids. Early perturbations were more prominent in the γ irradiated samples, while later responses shifted towards more prominent responses in groups with high energy particle irradiations. Regression analysis showed a positive correlation of the abundance of identified fatty acids with time and a negative association with γ-rays, while the degradation pathway of purines was positively associated with time. Taken together, there is a strong suggestion of mitochondrial implication and the possibility of long-term effects on DNA repair and nucleotide pools following radiation exposure.


Assuntos
Radiação Cósmica , Metaboloma/efeitos da radiação , Exposição à Radiação , Baço/metabolismo , Baço/efeitos da radiação , Animais , Ciclo do Ácido Cítrico/efeitos da radiação , Relação Dose-Resposta à Radiação , Modelos Lineares , Masculino , Camundongos Endogâmicos C57BL , Análise Multivariada , Purinas/metabolismo
15.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807089

RESUMO

Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9-2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.


Assuntos
Biomarcadores , Fator de Crescimento Insulin-Like I/metabolismo , Miocárdio/metabolismo , Lesões por Radiação/metabolismo , Transdução de Sinais/efeitos da radiação , Animais , Células Sanguíneas/metabolismo , Células Sanguíneas/efeitos da radiação , Peso Corporal/efeitos da radiação , Colágeno/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Fibrose/etiologia , Regulação da Expressão Gênica/efeitos da radiação , Frequência Cardíaca/efeitos da radiação , Hematopoese/efeitos da radiação , Metabolismo dos Lipídeos/efeitos da radiação , Especificidade de Órgãos/efeitos da radiação , Lesões por Radiação/genética , Suínos
16.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924205

RESUMO

Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-ß1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability.


Assuntos
Autorrenovação Celular/efeitos da radiação , Raios gama , Proteínas de Homeodomínio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Técnicas de Inativação de Genes , Humanos , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Tolerância a Radiação , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anticancer Res ; 41(4): 1951-1958, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813401

RESUMO

BACKGROUND/AIM: This study focused on the hybrid-volumetric modulated arc therapy (hVMAT) for stage I esophageal cancer and compared the effects on dose distribution induced by changes in the ratio of three-dimensional conformal radiotherapy (3DCRT) to VMAT. PATIENTS AND METHODS: Fifteen patients who underwent 3DCRT for cT1bN0M0 esophageal cancer at Kanagawa Cancer Center from January 2014 to April 2019 were included in the study. The dose-volume histogram (DVH) parameters of the target volume and normal organs were evaluated in the 3DCRT, hVMAT, and VMAT treatment plans. RESULTS: The homogeneity index of the target volume was significantly lower for hVMAT. In hVMAT, as the ratio of VMAT increased, the volume of low-dose region in the heart and lung increased, whereas the volume of the middle- to high-dose region decreased. As the ratio of VMAT increased, the mean dose in the heart decreased, whereas the mean dose in the lung increased. CONCLUSION: Favorable dose concentration was obtained for the target volume in hVMAT for stage I esophageal cancer. Altering the ratio of VMAT significantly changed the DVH parameters in normal organs.


Assuntos
Adenocarcinoma/radioterapia , Neoplasias Esofágicas/radioterapia , Planejamento da Radioterapia Assistida por Computador , Radioterapia Conformacional , Adenocarcinoma/patologia , Relação Dose-Resposta à Radiação , Neoplasias Esofágicas/patologia , Coração/efeitos da radiação , Humanos , Pulmão/efeitos da radiação , Análise por Pareamento , Estadiamento de Neoplasias , Órgãos em Risco , Radiometria/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Conformacional/efeitos adversos , Estudos Retrospectivos , Carga Tumoral/efeitos da radiação
18.
Nat Commun ; 12(1): 2187, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846346

RESUMO

The RNA-sensing pathway contributes to type I interferon (IFN) production induced by DNA damaging agents. However, the potential involvement of RNA sensors in DNA repair is unknown. Here, we found that retinoic acid-inducible gene I (RIG-I), a key cytosolic RNA sensor that recognizes RNA virus and initiates the MAVS-IRF3-type I IFN signaling cascade, is recruited to double-stranded breaks (DSBs) and suppresses non-homologous end joining (NHEJ). Mechanistically, RIG-I interacts with XRCC4, and the RIG-I/XRCC4 interaction impedes the formation of XRCC4/LIG4/XLF complex at DSBs. High expression of RIG-I compromises DNA repair and sensitizes cancer cells to irradiation treatment. In contrast, depletion of RIG-I renders cells resistant to irradiation in vitro and in vivo. In addition, this mechanism suggests a protective role of RIG-I in hindering retrovirus integration into the host genome by suppressing the NHEJ pathway. Reciprocally, XRCC4, while suppressed for its DNA repair function, has a critical role in RIG-I immune signaling through RIG-I interaction. XRCC4 promotes RIG-I signaling by enhancing oligomerization and ubiquitination of RIG-I, thereby suppressing RNA virus replication in host cells. In vivo, silencing XRCC4 in mouse lung promotes influenza virus replication in mice and these mice display faster body weight loss, poorer survival, and a greater degree of lung injury caused by influenza virus infection. This reciprocal regulation of RIG-I and XRCC4 reveals a new function of RIG-I in suppressing DNA repair and virus integration into the host genome, and meanwhile endues XRCC4 with a crucial role in potentiating innate immune response, thereby helping host to prevail in the battle against virus.


Assuntos
Proteína DEAD-box 58/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais/imunologia , Células A549 , Animais , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA por Junção de Extremidades/efeitos da radiação , Reparo do DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Genoma Humano , Células HEK293 , Humanos , Camundongos , Radiação Ionizante , Retroviridae/metabolismo , Replicação Viral/efeitos da radiação
19.
Environ Res ; 197: 111041, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33794170

RESUMO

This paper argues that Edward B. Lewis served as a type of independent academic radiation LNT-cancer risk assessment-stalking horse for the BEAR Genetics Panel, a task for which he had no expertise or experience (e.g. radiation, leukemia, epidemiology and statistical modelling). His efforts produced an insufficiently documented, strongly biased, and high-profile paper in Science (May 17, 1957), whose principal conclusions had not been proven, he asserted privately, in writing. This inconclusive perspective was well camouflaged in the published paper by means of sophisticated wordsmithing. At the time his academic department head George Beadle came to chair the BEAR Genetics Panel in the summer of 1956, the Beadle-inspired-Lewis LNT activity acquired an urgency when a study of 70,000 offspring from survivors of the A-bombs failed to show genetic damage after a decade of careful study, undercutting Panel recommendations. With Beadle's guidance, the Lewis effort redirected the Panel's focus from the atomic bomb genetic damage study, which had acrimoniously disrupted Panel relationships and priorities, to more immediate disciplinary/professional opportunities with concerns about fallout, leukemia risks and a new cancer causation role for mutation. The serious limitations of the Lewis paper affected neither its publication in Science nor its receiving an editorial endorsement, possibly due to influence by powerful Panel members, such as Bentley Glass, one of only six senior editors for Science. The Science publication restored, even though improperly, the scientific and moral initiatives of the Panel and led directly to multiple high level LNT recommendations for cancer risk assessment based on the Precautionary Principle, which Lewis asserted, and which remains in place today in essentially all countries. The present paper explores how such a scientific long-shot and quasi-stalking horse, who was unsupported by BEAR Panel members during the withering criticism prompted by his Science article, nevertheless endured in the pursuit of his LNT goal, becoming strikingly successful in achieving a global cancer risk assessment revolution which remains in place.


Assuntos
Neoplasias Induzidas por Radiação , Animais , Relação Dose-Resposta à Radiação , Cavalos , Mutação , Medição de Risco
20.
J Econ Entomol ; 114(3): 1345-1352, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33909080

RESUMO

The median lethal dose (LD50) is commonly used to indicate acute toxicity of an insecticide to an insect species. Approximate confidence intervals for LD50s are often calculated using the Fieller and delta methods. It is often necessary to compare the relative potencies of several insecticides with a population or of one insecticide with different populations. Comparing the LD50s using probit/logit-log(dose) regressions with parallel slopes can be implemented in many software packages, but for the cases with arbitrary slopes are not generally available. We used the glm function in R to calculate and compare lethal doses without assuming equal slopes. Bioassay datasets from the literature fitted using the logit model gave the 95% confidence limits (95% CLs) for the lethal doses using Fieller's theorem and incorporating a heterogeneity factor identical to the 95% CLs determined using the PoloPlus software. The delta method gave 95% CLs identical to the 95% CLs determined using the R drc package. The same datasets fitted using the probit model gave 95% CLs similar to the 95% CLs determined using PoloPlus and the drc package. The natural response rates for the control group were included using Abbott's equation. When the potency ratio method and the z-test were used to identify differences between two lethal doses, and when the χ2 and log likelihood ratio tests were used to determine whether the regression lines were parallel, the conclusions were the same as those gave by PoloPlus and the drc package.


Assuntos
Inseticidas , Animais , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Dose Letal Mediana , Funções Verossimilhança
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