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1.
Cell ; 149(1): 188-201, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22365813

RESUMO

Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion.


Assuntos
Envelhecimento , Giro Denteado/citologia , Giro Denteado/fisiologia , Animais , Pareamento Cromossômico , Giro Denteado/crescimento & desenvolvimento , Proteínas de Fluorescência Verde/genética , Hipocampo/fisiologia , Memória , Camundongos , Camundongos Transgênicos
2.
Immunity ; 47(3): 421-434.e3, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930658

RESUMO

Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.


Assuntos
Regulação da Expressão Gênica/efeitos da radiação , Inflamação/genética , Inflamação/metabolismo , Radiação Ionizante , Transdução de Sinais , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Análise por Conglomerados , Proteína Quinase Ativada por DNA/metabolismo , Relação Dose-Resposta à Radiação , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Interferons/metabolismo , Interferons/farmacologia , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Proteínas de Membrana/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Transcrição Gênica/efeitos da radiação , Ativação Transcricional , Regulador Transcricional ERG/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
ArXiv ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38855547

RESUMO

Image-guided mouse irradiation is essential to understand interventions involving radiation prior to human studies. Our objective is to employ Swin UNEt Transformers (Swin UNETR) to segment native micro-CT and contrast-enhanced micro-CT scans and benchmark the results against 3D no-new-Net (nnU-Net). Swin UNETR reformulates mouse organ segmentation as a sequence-to-sequence prediction task, using a hierarchical Swin Transformer encoder to extract features at 5 resolution levels, and connects to a Fully Convolutional Neural Network (FCNN)-based decoder via skip connections. The models were trained and evaluated on open datasets, with data separation based on individual mice. Further evaluation on an external mouse dataset acquired on a different micro-CT with lower kVp and higher imaging noise was also employed to assess model robustness and generalizability. Results indicate that Swin UNETR consistently outperforms nnU-Net and AIMOS in terms of average dice similarity coefficient (DSC) and Hausdorff distance (HD95p), except in two mice of intestine contouring. This superior performance is especially evident in the external dataset, confirming the model's robustness to variations in imaging conditions, including noise and quality, thereby positioning Swin UNETR as a highly generalizable and efficient tool for automated contouring in pre-clinical workflows.

4.
Cell Rep ; 43(6): 114289, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38833371

RESUMO

Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.


Assuntos
Fator Regulador 1 de Interferon , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Imunidade , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Fator de Transcrição STAT1/metabolismo , Masculino , Feminino
5.
Antioxidants (Basel) ; 11(9)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36139722

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is recognized as a master transcription factor that regulates expression of numerous detoxifying and antioxidant cytoprotective genes. In fact, models of NRF2 deficiency indicate roles not only in redox regulation, but also in metabolism, inflammatory/autoimmune disease, cancer, and radioresistancy. Since ionizing radiation (IR) generates reactive oxygen species (ROS), it is not surprising it activates NRF2 pathways. However, unexpectedly, activation is often delayed for many days after the initial ROS burst. Here, we demonstrate that, as assayed by γ-H2AX staining, rapid DNA double strand break (DSB) formation by IR in primary mouse Nrf2-/- MEFs was not affected by loss of NRF2, and neither was DSB repair to any great extent. In spite of this, basal and IR-induced transformation was greatly enhanced, suggesting that NRF2 protects against late IR-induced genomic instability, at least in murine MEFs. Another possible IR- and NRF2-related event that could be altered is inflammation and NRF2 deficiency increased IR-induced NF-κB pro-inflammatory responses mostly late after exposure. The proclivity of NRF2 to restrain inflammation is also reflected in the reprogramming of tumor antigen-specific lymphocyte responses in mice where Nrf2 k.o. switches Th2 responses to Th1 polarity. Delayed NRF2 responses to IR may be critical for the immune transition from prooxidant inflammation to antioxidant healing as well as in driving cellular radioresistance and survival. Targeting NRF2 to reprogram immunity could be of considerable therapeutic benefit in radiation and immunotherapy.

6.
Adv Radiat Oncol ; 6(3): 100645, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748547

RESUMO

PURPOSE: The clinical efficacy of radiation therapy is mechanistically linked to ionization-induced free radicals that cause cell and tissue injury through direct and indirect mechanisms. Free radical reaction dynamics are influenced by many factors and can be manipulated by static weak magnetic fields (WMF) that perturb singlet-triplet state interconversion. Our study exploits this phenomenon to directly increase ionizing radiation (IR) dose absorption in tumors by combining WMF with radiation therapy as a new and effective method to improve treatment. METHODS AND MATERIALS: Coils were custom made to produce both homogeneous and gradient magnetic fields. The gradient coil enabled simultaneous in vitro assessment of free radical/reactive oxygen species reactivity across multiple field strengths from 6 to 66 G. First, increases in IR-induced free radical concentrations using oxidant-sensitive fluorescent dyes in a cell-free system were measured and verified. Next, human and murine cancer cell lines were evaluated in in vitro and in vivo models after exposure to clinically relevant doses of IR in combination with WMF. RESULTS: Cellular responses to IR and WMF were field strength and cell line dependent. WMF was able to enhance IR effects on reactive oxygen species formation, DNA double-strand break formation, cell death, and tumor growth. CONCLUSIONS: We demonstrate that the external presence of a magnetic field enhances radiation-induced cancer cell injury and death in vitro and in vivo. The effect extends beyond the timeframe when free radicals are induced in the presence of radiation into the window when endogenous free radicals are produced and therefore extends the applicability of this novel adjunct to cancer therapy in the context of radiation treatment.

7.
Front Pharmacol ; 12: 666776, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084139

RESUMO

We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits." Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

8.
Health Phys ; 118(2): 209-214, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31869317

RESUMO

The University of California possesses a large number of Cs irradiators that are used in a wide variety of medical and research applications. The university president made a system-wide decision to reduce the potential threat of malevolent use of Cs by switching wherever feasible to x-ray irradiators over a 3-y period of time. A Radioactive Source Replacement Working Group of involved faculty was formed to study the topic and to make recommendations as to when alternative technologies could offer equivalency. The Working Group concluded that x-ray irradiators could replace Cs irradiators in most applications, with some likely exceptions. They found that the depth dose curve for the 320 kVp x-ray irradiator was found to be nearly identical to that of Cs down to a depth in tissue of 4 cm. It was concluded that x rays (energies ≤320 keV) are more biologically effective than Cs gamma rays, suggesting that lower doses of x rays will be required to achieve the same biological endpoint as Cs gamma rays. A simple conversion factor for equating x-ray effects to Cs effects was not recommended because relative biological effectiveness depends on multiple factors. They concluded that each experiment should be individually calibrated when converting from Cs irradiators to x-ray irradiators. The lessons learned from implementing the project to date have shown the importance of having senior management buy-in, involving the research community in the decision making process and allowing for exceptions where equivalency of Cs to x ray cannot be established.


Assuntos
Radioisótopos de Césio/administração & dosagem , Geradores de Radionuclídeos/instrumentação , Humanos , Eficiência Biológica Relativa , Raios X
9.
PLoS One ; 15(5): e0232411, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392259

RESUMO

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-ß/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.


Assuntos
MicroRNAs/genética , Lesões Experimentais por Radiação/genética , Pneumonite por Radiação/genética , Animais , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Feminino , Coração/efeitos da radiação , Humanos , Pulmão/metabolismo , Pulmão/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/metabolismo , Miocárdio/metabolismo , Modelos de Riscos Proporcionais , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/metabolismo , Pneumonite por Radiação/sangue , Pneumonite por Radiação/metabolismo , Especificidade da Espécie , Distribuição Tecidual
10.
Immunology ; 128(1 Suppl): e797-804, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19740341

RESUMO

Radiation therapy affects the immune system. In addition to killing radiosensitive immune cells, it can induce functional changes in those cells that survive. Our recent studies showed that the exposure of dendritic cells (DCs) to radiation in vitro influences their ability to present tumour antigen in vivo. Here we show that local radiation therapy of B16 melanoma tumours inhibits the development of systemic immunity to the melanoma antigen MART-1. This inhibition could not be overcome by intratumoral injection of DCs expressing human MART-1 after radiation therapy, suggesting that a form of immune suppression might have developed. On the other hand, injection of MART-expressing DCs prior to tumour irradiation was able to prevent inhibition from developing. These results suggest that local radiation therapy may block the generation of immunity under some circumstances and that strategies may be required to prevent this and allow radiation-induced cell death to translate fully into the development of systemic immunity.


Assuntos
Apresentação de Antígeno/efeitos da radiação , Antígenos de Neoplasias/imunologia , Células Dendríticas/efeitos da radiação , Melanoma Experimental/radioterapia , Proteínas de Neoplasias/imunologia , Neoplasias Cutâneas/radioterapia , Evasão Tumoral/efeitos dos fármacos , Animais , Células Dendríticas/imunologia , Antígeno MART-1 , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Doses de Radiação , Neoplasias Cutâneas/imunologia
11.
Mol Cancer Res ; 6(3): 426-34, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18337449

RESUMO

Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28alpha and beta) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established.


Assuntos
Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Inibidores de Proteassoma , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Primers do DNA , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/genética , Humanos , Microscopia Confocal , Complexo de Endopeptidases do Proteassoma/efeitos da radiação , Proteínas Recombinantes de Fusão/biossíntese , Retroviridae , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Int J Radiat Biol ; 85(6): 483-94, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19401903

RESUMO

PURPOSE: The classical radiobiological paradigm is that DNA is the target for cell damage caused by ionising radiation. However, evidence is accumulating that other constituents, such as the membrane, organelles, and proteins, are also important targets. We have shown that the isolated 26S proteasome is one such target and here we wish to substantiate it within the cell, in situ. MATERIALS AND METHODS: We used confocal microscopy to quantitatively detect and subcellularly localise radiation-induced 26S proteasome inhibition in cells expressing an ornithine decarboxylase degron that targets a fused Zoanthus species green (ZsGreen) fluorescent protein reporter specifically to the 26S proteasome. RESULTS: Exposure of cells to a range of radiation doses, even as low as 0.05 Gy inhibited 26S activity within minutes. Initially, punctate nuclear ZsGreen fluorescence was observed that became cytoplasmic after seven hours -- a pattern distinct from the diffuse homogeneous fluorescence of cells incubated in the conventional proteasome inhibitor MG-132. CONCLUSIONS: Our study clearly indicates that the 26S proteasome is a radiation target with physiological consequences and introduces a new perspective in mechanistic investigations of cellular responses to stresses.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Ciclo Celular/efeitos da radiação , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Ornitina Descarboxilase/genética , Radiação Ionizante , Estresse Fisiológico/efeitos da radiação , Ubiquitina/metabolismo
13.
Adv Radiat Oncol ; 4(4): 738-747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673667

RESUMO

PURPOSE: Second malignancies (SMs) after radiation therapy are rare but serious sequelae of treatment. This study investigates whether radiation therapy use is associated with changes in baseline SM risk. METHODS AND MATERIALS: We extracted all patients with cancer, with or without SM, in the Surveillance, Epidemiology, and End Results database from 1973 to 2014. Cumulative incidence of SM for patients stratified by radiation therapy status was calculated using a competing risk model, both for the entire cohort and for subgroups based on the primary tumor's anatomic location. RESULTS: We identified 2,872,063 patients with cancer, including 761,289 patients who received radiation therapy and 2,110,774 who did not. The SM rate at 20 years for patients receiving radiation therapy versus no radiation therapy was 21.4% versus 18.8%. The relative risk for SM associated with radiation therapy for the overall group was 1.138 at 20 years. The relative risks for SM associated with radiation therapy to malignancies arising from central nervous system and orbits, head and neck, thorax, abdomen, and pelvis at 20 years were 0.704, 1.011, 0.559, 0.646, and 1.106 for men and 0.792, 1.298, 1.265, 0.780, and 0.988 for women, respectively. CONCLUSIONS: The association between SM and radiation therapy varies with both sex and disease anatomic location, with the largest increase in SM seen in females irradiated to the head and neck region. Overall, the absolute change in SM rates associated with radiation therapy remains small, with differences in various clinical contexts.

14.
Radiat Res ; 191(4): 323-334, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30730284

RESUMO

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.


Assuntos
Síndrome Aguda da Radiação/imunologia , Síndrome Aguda da Radiação/prevenção & controle , Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/efeitos da radiação , Protetores contra Radiação/farmacologia , Síndrome Aguda da Radiação/microbiologia , Síndrome Aguda da Radiação/mortalidade , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos da radiação , Coração/efeitos dos fármacos , Coração/efeitos da radiação , Masculino , Camundongos , Neoplasias Induzidas por Radiação/imunologia , Neoplasias Induzidas por Radiação/microbiologia , Neoplasias Induzidas por Radiação/mortalidade , Neoplasias Induzidas por Radiação/prevenção & controle , Sulfonamidas/farmacologia , Análise de Sobrevida
15.
Radiother Oncol ; 86(1): 14-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18158194

RESUMO

Antiprotons are interesting as a possible future modality in radiation therapy for the following reasons: When fast antiprotons penetrate matter, protons and antiprotons have near identical stopping powers and exhibit equal radiobiology well before the Bragg-peak. But when the antiprotons come to rest at the Bragg-peak, they annihilate, releasing almost 2 GeV per antiproton-proton annihilation. Most of this energy is carried away by energetic pions, but the Bragg-peak of the antiprotons is still locally augmented with approximately 20-30 MeV per antiproton. Apart from the gain in physical dose, an increased relative biological effect also has been observed, which can be explained by the fact that some of the secondary particles from the antiproton annihilation exhibit high-LET properties. Finally, the weakly interacting energetic pions, which are leaving the target volume, may provide a real time feedback on the exact location of the annihilation peak. We have performed dosimetry experiments and investigated the radiobiological properties using the antiproton beam available at CERN, Geneva. Dosimetry experiments were carried out with ionization chambers, alanine pellets and radiochromic film. Radiobiological experiments were done with V79 WNRE Chinese hamster cells. The radiobiological experiments were repeated with protons and carbon ions at TRIUMF and GSI, respectively, for comparison. Several Monte Carlo particle transport codes were investigated and compared with our experimental data obtained at CERN. The code that matched our data best was used to generate a set of depth dose data at several energies, including secondary particle-energy spectra. This can be used as base data for a treatment planning software such as TRiP. Our findings from the CERN experiments indicate that the biological effect of antiprotons in the plateau region may be reduced by a factor of 4 for the same biological target dose in a spread-out Bragg-peak, when comparing with protons. The extension of TRiP to handle antiproton beams is currently in progress. This will enable us to perform planning studies, where the potential clinical consequences can be examined, and compared to those of other beam modalities such as protons, carbon ions, or IMRT photons.


Assuntos
Partículas Elementares/uso terapêutico , Radioterapia de Alta Energia , Animais , Humanos , Transferência Linear de Energia , Modelos Biológicos , Prótons , Dosagem Radioterapêutica , Eficiência Biológica Relativa
16.
Radiat Res ; 169(4): 460-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18363435

RESUMO

Reactive oxygen species (ROS) have been implicated in many ionizing radiation-related phenomena, including bystander effects. The oxidation of 2'7'-dichlorofluorescin (DCFH) to fluorescent 2'7'-dichlorofluorescein (DCF) is commonly used for the detection of radiation-induced ROS. The DCF assay was adapted for efficient, systematic flow cytometry quantification of low-linear energy transfer (LET) gamma-radiation-induced ROS in vitro in Chinese hamster ovary (CHO) cells. This method is optimized for increased sensitivity to radiation-induced ROS and to discriminate against measurement of extracellular ROS. This method can detect a significant increase in ROS in cells exposed to gamma radiation at doses as low as 10 cGy. The antioxidants N-acetyl-cysteine and ascorbic acid (vitamin C) significantly reduced the amount of ROS measured in cells exposed to 5 Gy ionizing radiation. This method was used to measure the intracellular ROS in unirradiated CHO bystander cells co-cultured with low-LET-irradiated cells. No increase in ROS was measured in bystander cell populations co-cultured with the irradiated cells beginning 9 s after radiation exposure.


Assuntos
Efeito Espectador , Citometria de Fluxo/métodos , Fluoresceínas/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/efeitos da radiação , Acetilcisteína/farmacologia , Animais , Ácido Ascórbico/farmacologia , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta à Radiação
17.
Cancer Res ; 66(13): 6756-62, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16818651

RESUMO

Resistance of glioblastoma multiforme to radiotherapy poses a major clinical challenge. Farnesyltransferase inhibitors (FTI), such as R115777, have potential to increase radiotherapeutic benefit in this disease, although their mechanism of action is unclear. In our study with eight glioblastoma multiforme cell lines, the most sensitive ones underwent cell cycle arrest in response to FTI treatment. Radiosensitization by FTIs, however, seemed to involve other pathways. If R115777 treatment was initiated < 6 hours before irradiation, all eight glioblastoma multiforme lines were radiosensitized. However, if the time between drug and radiation was extended to 24 hours, cells harboring wild type but not mutated p53 were able to counteract drug-induced radiosensitization. The involvement of the p53/p21 pathway in the development of resistance was confirmed by showing that U87 cells transfected with human papillomavirus E6 to block p53 or interfering RNA to inhibit p21 stayed radiosensitive for 24 hours after drug treatment. The time dependency of R115777-induced radiosensitization suggested that the initial FTI target for early radiosensitization was short-lived, and that a p21-directed pathway restored resistance. Consideration of prenylated molecules that could potentially be involved led us to consider HDJ-2, a co-chaperone of heat shock protein 70. This hypothesis was strengthened by finding that cellular radiosensitivity was increased by genetic inhibition of HDJ-2, whereas overexpression conferred radioresistance. Importantly, irradiation of cells caused HDJ-2 to migrate from the cytoplasm to the nucleus, and this migration was inhibited by prior FTI treatment. These results have clinical relevance in that they help explain the variability in responses to FTIs that occurs following radiotherapy and elucidate some of the reasons for the complexity underlying FTI-induced radiosensitization.


Assuntos
Farnesiltranstransferase/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Proteínas de Choque Térmico HSP40/fisiologia , Quinolonas/farmacologia , Radiossensibilizantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidores Enzimáticos/farmacologia , Glioblastoma/enzimologia , Glioblastoma/patologia , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Proteína Supressora de Tumor p53/metabolismo
18.
Radiat Res ; 168(2): 168-74, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17638404

RESUMO

Cells preconditioned with low doses of low-linear energy transfer (LET) ionizing radiation become more resistant to later challenges of radiation. The mechanism(s) by which cells adaptively respond to radiation remains unclear, although it has been suggested that DNA repair induced by low doses of radiation increases cellular radioresistance. Recent gene expression profiles have consistently indicated that proteins involved in the nucleotide excision repair pathway are up-regulated after exposure to ionizing radiation. Here we test the role of the nucleotide excision repair pathway for adaptive response to gamma radiation in vitro. Wild-type CHO cells exhibited both greater survival and fewer HPRT mutations when preconditioned with a low dose of gamma rays before exposure to a later challenging dose. Cells mutated for ERCC1, ERCC3, ERCC4 or ERCC5 did not express either adaptive response to radiation; cells mutated for ERCC2 expressed a survival adaptive response but no mutation adaptive response. These results suggest that some components of the nucleotide excision repair pathway are required for phenotypic low-dose induction of resistance to gamma radiation in mammalian cells.


Assuntos
Adaptação Fisiológica , Sobrevivência Celular/efeitos da radiação , Reparo do DNA , Mutação , Animais , Células CHO , Ciclo Celular/efeitos da radiação , Cricetinae , Cricetulus , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Raios gama , Tolerância a Radiação , Proteína Grupo D do Xeroderma Pigmentoso/genética
19.
Radiother Oncol ; 123(1): 133-138, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28187996

RESUMO

BACKGROUND AND PURPOSE: Second malignancies (SM) after external beam radiotherapy (EBRT) or brachytherapy (BT) for prostate cancer (PCa) are rare but serious sequelae. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify men diagnosed with cT1-2N0M0 PCa between 1999 and 2005, who underwent EBRT, BT or radical prostatectomy (RP). Patients with time interval to second malignancy or follow-up shorter than five and two years were excluded for solid and hematopoietic SM analyses respectively. Risks for solid and hematopoietic SM were evaluated via the multivariate Fine and Gray proportional hazards model. RESULTS: EBRT and BT resulted in similar increases in solid and hematopoietic SM compared to RP. In subgroup analysis stratified by treatment modality, only the EBRT cohort demonstrated significantly decreased solid and hematopoietic SM in years 2002-2005 compared to years 1999-2001, with adjusted-hazard ratios of 0.752 (p=0.001) and 0.815 (p=0.018) respectively. CONCLUSIONS: EBRT and BT resulted in statistically equivalent increase in both solid and hematopoietic SM compared to RP. EBRT in more recent years resulted in significantly decreased solid and hematopoietic SM, coinciding with increased utilization of IMRT.


Assuntos
Braquiterapia/efeitos adversos , Segunda Neoplasia Primária/epidemiologia , Neoplasias da Próstata/radioterapia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Prostatectomia , Neoplasias da Próstata/cirurgia
20.
PLoS One ; 12(7): e0181577, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28732024

RESUMO

Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Piperazinas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/efeitos da radiação
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