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1.
Phys Med Biol ; 66(17)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34352743

RESUMO

Quantifying parenchymal tissue changes in the lungs is imperative in furthering the study of radiation induced lung damage (RILD). Registering lung images from different time-points is a key step of this process. Traditional intensity-based registration approaches fail this task due to the considerable anatomical changes that occur between timepoints. This work proposes a novel method to successfully register longitudinal pre- and post-radiotherapy (RT) lung computed tomography (CT) scans that exhibit large changes due to RILD, by extracting consistent anatomical features from CT (lung boundaries, main airways, vessels) and using these features to optimise the registrations. Pre-RT and 12 month post-RT CT pairs from fifteen lung cancer patients were used for this study, all with varying degrees of RILD, ranging from mild parenchymal change to extensive consolidation and collapse. For each CT, signed distance transforms from segmentations of the lungs and main airways were generated, and the Frangi vesselness map was calculated. These were concatenated into multi-channel images and diffeomorphic multichannel registration was performed for each image pair using NiftyReg. Traditional intensity-based registrations were also performed for comparison purposes. For the evaluation, the pre- and post-registration landmark distance was calculated for all patients, using an average of 44 manually identified landmark pairs per patient. The mean (standard deviation) distance for all datasets decreased from 15.95 (8.09) mm pre-registration to 4.56 (5.70) mm post-registration, compared to 7.90 (8.97) mm for the intensity-based registrations. Qualitative improvements in image alignment were observed for all patient datasets. For four representative subjects, registrations were performed for three additional follow-up timepoints up to 48 months post-RT and similar accuracy was achieved. We have demonstrated that our novel multichannel registration method can successfully align longitudinal scans from RILD patients in the presence of large anatomical changes such as consolidation and atelectasis, outperforming the traditional registration approach both quantitatively and through thorough visual inspection.


Assuntos
Anormalidades Induzidas por Radiação , Neoplasias Pulmonares , Algoritmos , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Tomografia Computadorizada por Raios X
2.
Radiat Res ; 196(2): 156-174, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019667

RESUMO

Coagulopathies are well documented after acute radiation exposure at hematopoietic doses, and radiation-induced bleeding is notably one of the two main causes of mortality in the hematopoietic acute radiation syndrome. Despite this, understanding of the mechanisms by which radiation alters hemostasis and induces bleeding is still lacking. Here, male Göttingen minipigs received hematopoietic doses of 60Co gamma irradiation (total body) and coagulopathies were characterized by assessing bleeding, blood cytopenia, fibrin deposition, changes in hemostatic properties, coagulant/anticoagulant enzyme levels, and markers of inflammation, endothelial dysfunction, and barrier integrity to understand if a relationship exists between bleeding, hemostatic defects, bone marrow aplasia, inflammation, endothelial dysfunction and loss of barrier integrity. Acute radiation exposure induced coagulopathies in the Göttingen minipig model of hematopoietic acute radiation syndrome; instances of bleeding were not dependent upon thrombocytopenia. Neutropenia, alterations in hemostatic parameters and damage to the glycocalyx occurred in all animals irrespective of occurrence of bleeding. Radiation-induced bleeding was concurrent with simultaneous thrombocytopenia, anemia, neutropenia, inflammation, increased heart rate, decreased nitric oxide bioavailability and endothelial dysfunction; bleeding was not observed with the sole occurrence of a single aforementioned parameter in the absence of the others. Alteration of barrier function or clotting proteins was not observed in all cases of bleeding. Additionally, fibrin deposition was observed in the heart and lungs of decedent animals but no evidence of DIC was noted, suggesting a unique pathophysiology of radiation-induced coagulopathies. These findings suggest radiation-induced coagulopathies are the result of simultaneous damage to several key organs and biological functions, including the immune system, the inflammatory response, the bone marrow and the cardiovasculature.


Assuntos
Síndrome Aguda da Radiação/patologia , Hematopoese/genética , Hemorragia/patologia , Inflamação/patologia , Anormalidades Induzidas por Radiação , Síndrome Aguda da Radiação/sangue , Síndrome Aguda da Radiação/etiologia , Animais , Transtornos de Proteínas de Coagulação/sangue , Transtornos de Proteínas de Coagulação/etiologia , Transtornos de Proteínas de Coagulação/patologia , Modelos Animais de Doenças , Hematopoese/efeitos da radiação , Hemorragia/sangue , Hemorragia/etiologia , Humanos , Inflamação/sangue , Inflamação/etiologia , Suínos , Porco Miniatura
3.
PLoS One ; 16(2): e0247748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33635906

RESUMO

PURPOSE: To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children. METHODS AND MATERIALS: Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients' brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations. RESULTS: The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p<0.05). In 5/10 ROIs, RT dose and cognitive tests were associated with p<0.01 and preliminary RT threshold dose values, implying a possible cognitive or neuropsychological damage, were calculated. The analysis of domains showed that the most involved one was the "school-related activities". CONCLUSION: This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.


Assuntos
Anormalidades Induzidas por Radiação/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos da radiação , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos da radiação , Criança , Imagem de Tensor de Difusão/métodos , Feminino , Seguimentos , Humanos , Masculino , Testes de Estado Mental e Demência , Transtornos Neurocognitivos , Estudos Retrospectivos
4.
PLoS One ; 16(1): e0239639, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33471803

RESUMO

The phenomenon of a massive vertebral deformity was recorded in the radiating Labeobarbus assemblage from the middle reaches of the Genale River (south-eastern Ethiopia, East Africa). Within this sympatric assemblage, five trophic morphs-generalized, lipped, piscivorous and two scraping feeders-were reported between 1993 and 2019. In 2009, a new morph with prevalence of ~10% was discovered. The new morph, termed 'short', had an abnormally shortened vertebral column and a significantly deeper body. This type of deformity is common in farmed Atlantic salmon and other artificially reared fish, but is rare in nature. In the Genale Labeobarbus assemblage, the deformity was present exclusively within the generalized and lipped morphs. The short morph had between seven and 36 deformed (compressed and/or fused) vertebrae. Their body depth was positively correlated with number of deformed vertebrae. In another collection in 2019, the short morph was still present at a frequency of 11%. Various environmental and genetic factors could contribute to the development of this deformity in the Genale Labeobarbus, but based on the available data, it is impossible to confidently identify the key factor(s). Whether the result of genetics, the environment, or both, this deep-bodied phenotype is assumed to be an anti-predator adaptation, as there is evidence of its selective advantage in the generalized morph. The Genale monstrosity is the first reported case of a massive deformity of the vertebral column in a natural population of African fishes.


Assuntos
Cyprinidae/anormalidades , Cyprinidae/genética , Coluna Vertebral/efeitos da radiação , Anormalidades Induzidas por Radiação/epidemiologia , Adaptação Fisiológica/genética , Adaptação Fisiológica/efeitos da radiação , África Oriental , Animais , Etiópia , Rios , Coluna Vertebral/metabolismo
5.
Radiat Res ; 195(2): 173-190, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33045079

RESUMO

Radiation-induced skin injury remains a serious concern for cancer radiotherapy, radiation accidents and occupational exposure, and the damage mainly occurs due to apoptosis and reactive oxygen species (ROS) generation. There is currently no effective treatment for this disorder. The ß-catenin signaling pathway is involved in the repair and regeneration of injured tissues. However, the role of the ß-catenin signaling pathway in radiation-induced skin injury has not been reported. In this study, we demonstrated that the ß-catenin signaling pathway was activated in response to radiation and that its activation by Wnt3a, a ligand-protein involved in the ß-catenin signaling pathway, inhibited apoptosis and the production of ROS in irradiated human keratinocyte HaCaT cells and skin fibroblast WS1 cells. Additionally, Wnt3a promoted cell migration after irradiation. In a mouse model of full-thickness skin wounds combined with total-body irradiation, Wnt3a was shown to facilitate skin wound healing. The results from RNA-Seq revealed that 24 genes were upregulated and 154 were downregulated in Wnt3a-treated irradiated skin cells, and these dysregulated genes were mainly enriched in the tight junction pathway. Among them, Marvel D3 showed the most obvious difference. We further found that the activated ß-catenin signaling pathway stimulated the phosphorylation of JNK by silencing Marvel D3. Treatment of irradiated cells with SP600125, a JNK inhibitor, augmented ROS production and impeded cell migration. Furthermore, treatment with Wnt3a or transfection with Marvel D3-specific siRNAs could reverse the above effects. Taken together, these findings illustrate that activated ß-catenin signaling stimulates the activation of JNK by negatively regulating Marvel D3 to ameliorate radiation-induced skin injury.


Assuntos
Anormalidades Induzidas por Radiação/genética , MAP Quinase Quinase 4/genética , Via de Sinalização Wnt/genética , Proteína Wnt3A/genética , beta Catenina/genética , Anormalidades Induzidas por Radiação/tratamento farmacológico , Anormalidades Induzidas por Radiação/patologia , Animais , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Camundongos , Fosforilação/genética , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio , Via de Sinalização Wnt/efeitos da radiação , Cicatrização/genética
6.
Int J Radiat Oncol Biol Phys ; 109(5): 1521-1532, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232771

RESUMO

PURPOSE: Computed tomographic (CT) scans in adolescents have increased dramatically in recent years. However, the effects of cumulative low-dose exposures on the development of radiation sensitive organs, such as the mammary gland, is unknown. The purpose of this work was to define the effects of dose rate on mammary organ formation during puberty, an especially sensitive window in mammary development. We used a fractionated low-dose x-ray exposure to mimic multiple higher dose CT scans, and we hypothesized that fractionated exposure would have less of an effect on the number of mammary gland defects compared with an acute exposure. METHODS AND MATERIALS: Female mice were subjected to fractionated low-dose x-ray exposure (10 cGy/d for 5 days), acute x-ray exposure (1 × 50 cGy), or sham exposure. As the wide genetic diversity in humans can play a role in a person's response to irradiation, 2 genetically diverse mouse strains differing in radiation sensitivity (BALB/c-sensitive; C57BL/6-resistant) were used to investigate the role of genetic background on the magnitude of the effect. RESULTS: Unexpectedly, our data reveal that multiple low-dose exposures produce greater immune and mammary defects for weeks after exposure compared with controls. The most pronounced defects being increased ductal branching in both strains and a greater percentage of terminal end buds in the BALB/c strain of mice exposed to fractionated radiation compared with sham. Radiation-induced defects near the terminal end bud were also increased in both strains. CONCLUSIONS: The findings suggest that fractionated low-dose exposures are potentially more damaging to organ development compared with an equivalent, single acute exposure and that genetic background is an important parameter modifying the severity of these effects.


Assuntos
Fracionamento da Dose de Radiação , Glândulas Mamárias Animais/efeitos da radiação , Maturidade Sexual , Anormalidades Induzidas por Radiação/etiologia , Fatores Etários , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos da radiação , Feminino , Imunidade Celular/efeitos da radiação , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C/genética , Camundongos Endogâmicos C57BL/genética , Morfogênese/efeitos da radiação , Exposição à Radiação/efeitos adversos , Lesões Experimentais por Radiação/etiologia , Tolerância a Radiação/genética , Tomografia Computadorizada por Raios X/efeitos adversos
7.
Int J Mol Sci ; 21(22)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238631

RESUMO

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS-STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS-STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer-highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS-STING signaling, deleterious effects associated with cGAS-STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS-STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.


Assuntos
Anormalidades Induzidas por Radiação/genética , Imunidade/genética , Proteínas de Membrana/genética , Neoplasias/genética , Nucleotidiltransferases/genética , Anormalidades Induzidas por Radiação/imunologia , Anormalidades Induzidas por Radiação/patologia , Dano ao DNA/imunologia , Dano ao DNA/efeitos da radiação , Humanos , Imunidade/imunologia , Imunidade/efeitos da radiação , Imunidade Inata/efeitos da radiação , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia , Nucleotidiltransferases/imunologia , Transdução de Sinais/efeitos da radiação
9.
Cancer ; 126(15): 3552-3559, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32412661

RESUMO

BACKGROUND: The role and impact of radiation therapy (RT) on the development of herpes zoster (HZ) has not been well studied. The objective of this study was to investigate the association between RT and HZ. METHODS: A propensity score-matched, retrospective cohort study was conducted using institutional cancer registry data and medical records from 2011 to 2015. The risk of developing HZ in the RT and non-RT groups was compared using a Cox proportional hazards model. Associations also were explored between the RT field and the anatomic location of HZ in patients who developed HZ after RT. The expected number of HZ events within the radiation field was calculated according to the RT received by each patient; then, this number was compared with the observed number of in-field events. RESULTS: Of 17,655 patients, propensity score matching yielded 4350 pairs; of these, 3891 pairs were eligible for comparison. The cumulative incidence of HZ in the RT group (vs the non-RT group) during the first 5 years after the index date was 2.1% (vs 0.7%) at 1 year, 3.0% (vs 1.0%) at 2 years, 3.4% (vs 1.3%) at 3 years, 4.1% vs 1.7% at 4 years, and 4.4% vs 1.8% at 5 years. The RT group showed a significantly higher risk of HZ than the non-RT group (hazard ratio, 2.59, 95% CI, 1.84-3.66). In the 120 patients who developed HZ after RT, HZ events were observed significantly more frequently within the RT field than expected (74 vs 43.8 events; P < .001). CONCLUSIONS: Patients with cancer who received RT showed a significantly higher risk of HZ, which was commonly observed within the radiation field.


Assuntos
Anormalidades Induzidas por Radiação/diagnóstico , Herpes Zoster/diagnóstico , Neoplasias/radioterapia , Anormalidades Induzidas por Radiação/epidemiologia , Anormalidades Induzidas por Radiação/patologia , Anormalidades Induzidas por Radiação/virologia , Idoso , Feminino , Herpes Zoster/epidemiologia , Herpes Zoster/etiologia , Herpes Zoster/virologia , Herpesvirus Humano 3/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco
10.
Cancer ; 126(15): 3560-3568, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32426866

RESUMO

BACKGROUND: The comparative risks of a second cancer diagnosis are uncertain after primary cancer treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam radiotherapy (PBRT). METHODS: Pediatric and adult patients with a first cancer diagnosis between 2004 and 2015 who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database from 9 tumor types: head and neck, gastrointestinal, gynecologic, lymphoma, lung, prostate, breast, bone/soft tissue, and brain/central nervous system. The diagnosis of second cancer was modeled using multivariable logistic regression adjusting for age, follow-up duration, radiotherapy (RT) dose, chemotherapy, sociodemographic variables, and other factors. Propensity score matching also was used to balance baseline characteristics. RESULTS: In total, 450,373 patients were identified (33.5% received 3DCRT, 65.2% received IMRT, and 1.3% received PBRT) with median follow-up of 5.1 years after RT completion and a cumulative follow-up period of 2.54 million person-years. Overall, the incidence of second cancer diagnosis was 1.55 per 100 patient-years. In a comparison between IMRT versus 3DCRT, there was no overall difference in the risk of second cancer (adjusted odds ratio [OR], 1.00; 95% CI, 0.97-1.02; P = .75). By comparison, PBRT had an overall lower risk of second cancer versus IMRT (adjusted OR, 0.31; 95% CI, 0.26-0.36; P < .0001). Results within each tumor type generally were consistent in the pooled analyses and also were maintained in propensity score-matched analyses. CONCLUSIONS: The risk of a second cancer diagnosis was similar after IMRT versus 3DCRT, whereas PBRT was associated with a lower risk of second cancer risk. Future work is warranted to determine the cost-effectiveness of PBRT and to identify the population best suited for this treatment.


Assuntos
Anormalidades Induzidas por Radiação/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Terapia com Prótons/efeitos adversos , Radioterapia Conformacional/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Anormalidades Induzidas por Radiação/epidemiologia , Anormalidades Induzidas por Radiação/patologia , Idoso , Feminino , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/radioterapia , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/radioterapia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Linfoma/complicações , Linfoma/epidemiologia , Linfoma/radioterapia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/patologia , Fatores de Risco
11.
J Cell Mol Med ; 24(7): 3917-3930, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135028

RESUMO

Radiation protection on male testis is an important task for ionizing radiation-related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll-like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low-toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage-derived exosomes protein expression. We proved that after MPLA treatment, macrophage-derived exosomes played an important role in testis radiation protection, and specially, G-CSF and MIP-2 in exosomes are the core molecules in this protection effect.


Assuntos
Anormalidades Induzidas por Radiação/genética , Lipídeo A/análogos & derivados , Testículo/lesões , Receptor 4 Toll-Like/genética , Anormalidades Induzidas por Radiação/tratamento farmacológico , Anormalidades Induzidas por Radiação/patologia , Animais , Modelos Animais de Doenças , Exossomos/efeitos dos fármacos , Humanos , Lipídeo A/química , Lipídeo A/genética , Lipídeo A/farmacologia , Masculino , Camundongos , Proteção Radiológica , Testículo/efeitos dos fármacos , Testículo/patologia , Testículo/efeitos da radiação , Receptor 4 Toll-Like/agonistas
12.
Diagn. tratamento ; 25(1): 32-35, jan.-mar. 2020. tab
Artigo em Português | LILACS | ID: biblio-1099971

RESUMO

Contexto: Os telefones celulares emitem radiações eletromagnéticas que são classificadas como possivelmente cancerígenas para os seres humanos. A hipótese de que o uso de telefones celulares pode estar relacionado ao risco de desenvolvimento de tumor cerebral, tem sido motivo de muita controvérsia e de grande debate na comunidade científica. Objetivos: O objetivo foi avaliar as evidências na literatura, relativas à exposição à radiação de telefones celulares e o risco de desenvolvimento de tumores cerebrais. Desenho de estudo: Trata-se de scoping review. Métodos: Procedeu-se à busca por estudos no MEDLINE/PubMed e na Cochrane Library. Foram utilizados descritores do DeCS (Descritores em Ciências da Saúde) e não houve restrição geográfica e temporal das publicações. O critério de inclusão consistia em estudos em humanos abrangendo a exposição a telefones celulares e o desenvolvimento de neoplasias cerebrais. Resultados: A estratégia de busca recuperou 77 citações e, destas, 8 estudos foram incluídos nessa revisão. A grande maioria dos estudos são do tipo caso-controle e há resultados divergentes entre eles. A maioria não demonstra risco entre a exposição habitual ao celular e o desenvolvimento de tumores cerebrais. Entretanto, alguns estudos correlacionam um possível risco associado à exposição intensa à radiação do telefone celular. Conclusão: Os estudos realizados até o momento não permitem concluir sobre o risco da exposição ao telefone celular e o desenvolvimento de tumores cerebrais, sendo recomendada a realização de novos estudos para elucidação da questão.


Assuntos
Anormalidades Induzidas por Radiação , Fatores de Risco , Telefone Celular , Prática Clínica Baseada em Evidências , Neoplasias , Sistema Nervoso
13.
Radiat Res ; 193(4): 383-393, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32097101

RESUMO

The functions and molecular mechanism of circRNAs in the development of radiation-induced liver disease (RILD) remain largely unknown. The goal of this study was to explore the expression and potential role of a new circular RNA, named circTUBD1, in irradiated and lipopolysaccharide (LPS)-stimulated human hepatic stellate cell (HSC) line LX-2 cells. The expression of circTUBD1 was significantly upregulated in irradiated and LPS-stimulated LX-2 cells compared to non-treated LX-2 cells. To explore the functions of circTUBD1, small interfering RNAs targeting circTUBD1 were designed. Silencing circTUBD1 inhibited proliferation, promoted apoptosis of LX-2 cells, and significantly decreased the expression level of pro-inflammatory cytokines, including IL-1ß, IL-6 and TNF-α in irradiated and LPS-stimulated LX-2 cells. Mechanistic analysis suggested that circTUBD1 acted as the miR-146a-5p sponge to affect pro-inflammatory cytokine production through regulating expression of Toll-like receptor 4 (TLR4), interleukin receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor-6 (TRAF6), and phosphorylation of nuclear factor-kappa B (pNF-κB) in irradiated and LPS-stimulated LX-2 cells. To our knowledge, this is the first study to show that circTUBD1 acts as a miR-146a-5p sponge to affect the viability and pro-inflammatory cytokine production of LX-2 cells through the TLR4 pathway, suggesting that circTUBD1 is a potential target for RILD therapy.


Assuntos
Anormalidades Induzidas por Radiação/genética , MicroRNAs/genética , RNA Circular/genética , Receptor 4 Toll-Like/genética , Sobrevivência Celular/efeitos da radiação , Citocinas/biossíntese , Citocinas/genética , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/efeitos da radiação , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos da radiação , Hepatopatias/etiologia , Transdução de Sinais/efeitos da radiação , Tubulina (Proteína)/genética
14.
Hong Kong Med J ; 25(6): 460-467, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31796645

RESUMO

INTRODUCTION: This study assessed the incidence of late rectal toxicities and evaluated potential predictive factors for late proctitis in patients treated with prostate-specific intensity-modulated radiotherapy in Hong Kong. METHODS: This retrospective longitudinal observational study included patients with localised prostate cancer who were treated with intensity-modulated radiation therapy in an oncology unit in Hong Kong between January 2007 and December 2011, and who had >1 year of follow-up. Clinical, pharmacological, and radiation parameters were recorded. Toxicities were measured by Common Terminology Criteria for Adverse Events version 4. RESULTS: In total, 232 patients were included in this analysis. The mean follow-up time was 7.3 ± 2.1 years and 46.5% of the patients had late rectal toxicities. Late proctitis occurred in 30.5% of patients; 25% of the patients with late proctitis exhibited grade ≥2 toxicity. Median onset times for late proctitis and rectal bleeding were 15 and 18.4 months, respectively. Multivariable regression showed increased odds for the occurrence of late proctitis in patients with older age (odds ratio [OR]=1.11, 95% confidence interval [CI]=1.04-1.19, P=0.003), higher V70 (OR=1.08, 95% CI=1.01-1.15, P=0.027), and presence of acute rectal toxicities (OR=4.47, 95% CI=2.37-8.43, P<0.001). Antiplatelet use was not significantly associated with the occurrence of late proctitis (OR=1.98, 95% CI=0.95-4.14, P=0.07). CONCLUSIONS: The incidence of late rectal toxicities was considerable among patients in this study. Clinicians should consider the possibility of late proctitis for patients with older age, acute rectal toxicities, and higher V70. High doses to rectal volumes should be limited because of the significant association with V70.


Assuntos
Anormalidades Induzidas por Radiação/epidemiologia , Neoplasias da Próstata/radioterapia , Doenças Retais/epidemiologia , Reto/efeitos da radiação , Anormalidades Induzidas por Radiação/etiologia , Idoso , Hong Kong/epidemiologia , Humanos , Incidência , Estudos Longitudinais , Masculino , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada , Doenças Retais/etiologia , Estudos Retrospectivos
15.
Cell Death Dis ; 10(12): 957, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862870

RESUMO

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.


Assuntos
Anormalidades Induzidas por Radiação/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Diterpenos/farmacologia , Lesão Pulmonar/tratamento farmacológico , Anormalidades Induzidas por Radiação/genética , Anormalidades Induzidas por Radiação/patologia , Animais , Modelos Animais de Doenças , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/genética , Inflamação/patologia , Pulmão/anormalidades , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Camundongos , Piroptose/efeitos dos fármacos , Piroptose/genética , Protetores contra Radiação/farmacologia
16.
Cir. Esp. (Ed. impr.) ; 97(9): 517-522, nov. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-187628

RESUMO

Introducción: Las técnicas de radioterapia asociadas a la cirugía conservadora del cáncer de mama precoz han evolucionado gracias a un mayor conocimiento de la radiobiología tumoral, destacando entre ellas la radioterapia intraoperatoria (RIO). Sin embargo, se han documentado complicaciones con dicha técnica, principalmente la fibrosis. El factor de crecimiento transformante beta (TGF-β) es una citocina relacionada con la fibrosis inducida después de la radiación que podría servir como marcador temprano del riesgo de desarrollo de la misma. Métodos: Estudio prospectivo multicéntrico de 60 pacientes a las que se les ha sometido a cirugía conservadora por cáncer de mama, asociada a RIO en 30 de ellas. Se evalúan los valores de TGF-β en muestras de suero preoperatorio y a las 24 h desde la cirugía, y de muestras de drenaje a las 6 y 24 h desde la cirugía. Resultados: Los valores de TGF-β objetivados en el suero y en el débito de drenaje a las 24 h desde la cirugía de las pacientes que recibieron RIO fueron significativamente mayores que los de aquellas que no la recibieron (p < 0,0001). De entre ellas, 8 pacientes presentaron valores superiores a 1.000 pg/ml. Estas diferencias entre los grupos no se modifican por el tipo de muestra utilizada, bien sea suero, bien débito de drenaje (p = 0,5881). Conclusiones: Aunque deben realizarse más estudios, valores elevados de TGF-β en las pacientes con cáncer de mama a las que se les realiza cirugía conservadora asociada a RIO pueden predecir el riesgo de fibrosis


Introduction: Radiotherapy techniques associated with breast-conserving surgery have evolved in early breast cancer thanks to a better knowledge of tumor radiobiology, highlighting intraoperative radiotherapy (IORT). However, complications have been documented with this procedure, mainly fibrosis. Transforming growth factor beta (TGF-β) is a cytokine with an active role in radiation-induced fibrosis, which could be used as an early biomarker for the development of fibrosis. Methods: Multicentric prospective analysis of 60 patients with breast cancer who underwent breast-conserving surgery, 30 of whom had received additional IORT. TGF-β values were evaluated in serum pre-surgery and in serum collected 24 h after surgery. In addition, we evaluated surgical wound fluids collected 6 h and 24 h following surgery. Results: Serum and surgical wound fluids TGF-β values collected over 24 h following surgery were significantly higher in patients who received additional IORT (P < .0001). Notably, 8 of these patients showed values above 1,000 pg/ml. There were no differences between the samples (serum or surgical wound fluids) (P = .5881). Conclusions: Although further investigation is needed, higher TGF-β values in IORT during breast-conserving surgery can be used as an early biomarker for the development of fibrosis


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Radioterapia/efeitos adversos , Fator de Crescimento Transformador beta/sangue , Anormalidades Induzidas por Radiação/patologia , Mama/patologia , Fibrose/epidemiologia , Cuidados Intraoperatórios/métodos , Estudos Prospectivos
17.
Sci Rep ; 9(1): 14134, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575959

RESUMO

Radiation-induced intestinal injury (RIII) constitutes a crucial clinical element of acute radiation syndrome with life-threatening implications posing challenges in devising effective medical countermeasures. Herein, we report the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to mitigate RIII following total-body irradiation (TBI) in C57BL/6 mice and underlying mechanisms. Administration of DAMTC 24 hours post TBI facilitated structural reconstitution and restoration of functional absorption linked to alleviation of radiation-induced apoptotic death of intestinal crypt progenitor/stem (ICPS) and villus stromal cells through induction of Bcl-2 family-mediated anti-apoptotic signalling. Reduction in TBI-induced DNA damage accumulation coupled with inhibition of cell cycle arrest through stimulation of anti-p53- and anti-p21-dependent synergistic signalling protected ICPS cells from radiation injury. Enhanced proliferation of crypt stem cells, induction of anti-oxidant defence, subjugation of TBI-induced lipid peroxidation and phenotypic polarization of intestinal macrophages to anti-inflammatory M2 class underlie amelioration of RIII. Stimulation of multiple mitigative signalling processes by DAMTC appeared to be associated with enhanced protein acetylation, an important regulator of cellular responses to radiation damage. Our findings establish the mitigative potential of DAMTC against RIII by hyper-acetylation-mediated epigenetic regulation, which triggers axes of anti-apoptotic and pro-survival pathways, enabling proliferation and maintenance of ICPS cells leading to epithelial regeneration.


Assuntos
Anormalidades Induzidas por Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/tratamento farmacológico , Cumarínicos/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos da radiação , Anormalidades Induzidas por Radiação/metabolismo , Síndrome Aguda da Radiação/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Trato Gastrointestinal/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/efeitos da radiação , Irradiação Corporal Total/efeitos adversos
18.
Free Radic Biol Med ; 145: 161-174, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31550530

RESUMO

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn2+ in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)2Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)2Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)2Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ±â€¯0.14) compared to radiation alone group (1.60 ±â€¯0.07) was observed. DT(GS)2Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)2Mn(II) with an average of 1546 ±â€¯61 µm versus 763 ±â€¯154 µm for radiation alone group. The present findings suggested DT(GS)2Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.


Assuntos
Anormalidades Induzidas por Radiação/tratamento farmacológico , Glutationa/farmacologia , Peptidomiméticos/farmacologia , Protetores contra Radiação/farmacologia , Anormalidades Induzidas por Radiação/metabolismo , Anormalidades Induzidas por Radiação/patologia , Acetilcisteína/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Glutationa/química , Humanos , Manganês/química , Manganês/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Peptidomiméticos/química , Radiação Ionizante , Protetores contra Radiação/química
19.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382644

RESUMO

Radiation-induced oral mucositis represents an influential factor in cancer patients' accepted radiation therapy, especially in head and neck cancer. This research investigates the treatment effect of Ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) and Paeonol (a compound derived from Cortex Moutan) on radiation-induced oral mucositis and possible underlying mechanisms. Concisely, 20 Gy of X-rays (single-dose) irradiated the cranial localization in rats for the modeling of oral mucositis. The therapeutic effects of Ecdysterone-Paeonol oral cavity directly administered on radiation-induced oral mucositis were investigated by weight changes, direct observations, visual scoring methods, ulcer area/total area, and basic recovery days. Assessments of tumor necrosis factor α and interleukin-6 were performed to evaluate the inflammatory cytokines secretion in the damaged areas of tongues harvested post-treatment, and changes in signaling pathways were investigated by Western blotting. System Drug Target (SysDT) methods revealed the targets of Ecdysterone-Paeonol in order to support compound-target network construction. Four representative targets with different functions were chosen. The binding interactions between the compound and receptor were evaluated by molecular docking to investigate the binding affinity of the ligand to their protein targets. Ecdysterone-Paeonol, administered orally, effectively improved radiation-induced oral mucositis in rats, and the therapeutic effect was better than Ecdysterone administered orally on its own. In this study, calculational chemistry revealed that Ecdysterone-Paeonol affected 19 function targets associated with radiation-induced oral mucositis, including apoptosis, proliferation, inflammation, and wound healing. These findings position Ecdysterone-Paeonol as a potential treatment candidate for oral mucositis acting on multiple targets in the clinic.


Assuntos
Anormalidades Induzidas por Radiação/tratamento farmacológico , Acetofenonas/farmacologia , Ecdisterona/farmacologia , Lesões por Radiação/tratamento farmacológico , Estomatite/tratamento farmacológico , Anormalidades Induzidas por Radiação/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Boca/efeitos dos fármacos , Boca/patologia , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Estomatite/etiologia , Estomatite/patologia
20.
Cir Esp (Engl Ed) ; 97(9): 517-522, 2019 Nov.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31320114

RESUMO

INTRODUCTION: Radiotherapy techniques associated with breast-conserving surgery have evolved in early breast cancer thanks to a better knowledge of tumor radiobiology, highlighting intraoperative radiotherapy (IORT). However, complications have been documented with this procedure, mainly fibrosis. Transforming growth factor beta (TGF-ß) is a cytokine with an active role in radiation-induced fibrosis, which could be used as an early biomarker for the development of fibrosis. METHODS: Multicentric prospective analysis of 60 patients with breast cancer who underwent breast-conserving surgery, 30 of whom had received additional IORT. TGF-ß values were evaluated in serum pre-surgery and in serum collected 24h after surgery. In addition, we evaluated surgical wound fluids collected 6h and 24h following surgery. RESULTS: Serum and surgical wound fluids TGF-ß values collected over 24h following surgery were significantly higher in patients who received additional IORT (P<.0001). Notably, 8 of these patients showed values above 1,000pg/ml. There were no differences between the samples (serum or surgical wound fluids) (P=.5881). CONCLUSIONS: Although further investigation is needed, higher TGF-ß values in IORT during breast-conserving surgery can be used as an early biomarker for the development of fibrosis.


Assuntos
Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Radioterapia/efeitos adversos , Fator de Crescimento Transformador beta/sangue , Anormalidades Induzidas por Radiação/patologia , Idoso , Mama/patologia , Feminino , Fibrose/epidemiologia , Humanos , Cuidados Intraoperatórios/métodos , Pessoa de Meia-Idade , Estudos Prospectivos
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