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1.
Int J Radiat Biol ; 95(7): 892-899, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30652952

RESUMO

Studies of the responses of hematopoietic stem and progenitor cells (HSPCs) to low doses of ionizing radiation formed an important aspect of the RISK-IR project ( www.risk-ir.eu ). A brief overview of these studies is presented here. The findings confirm the sensitivity of HSPCs to radiation even at low doses, and illustrate the substantial impact that differentiation state has upon cell sensitivity. The work provides mechanistic support for epidemiological findings of leukemia risk at dose levels used in diagnostic CT imaging, and further suggests that low-dose irradiation may facilitate bone marrow transplantation, a finding that could lead to refinements in clinical practice.


Assuntos
Células-Tronco Hematopoéticas/citologia , Leucemia/etiologia , Leucemia/radioterapia , Doses de Radiação , Radiação Ionizante , Células-Tronco/citologia , Animais , Diferenciação Celular/efeitos da radiação , Células Cultivadas , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Neoplasias Induzidas por Radiação , Tolerância a Radiação , Tomografia Computadorizada por Raios X
2.
Leukemia ; 32(6): 1435-1444, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29556020

RESUMO

Epidemiological studies have demonstrated an increased leukemia incidence following ionizing radiation exposure, but to date, the target cells and underlying mechanisms of radiation leukemogenesis remain largely unidentified. We engineered a mouse model carrying a different fluorescent marker on each chromosome 2, located inside the minimum deleted region occurring after radiation exposure and recognized as the first leukemogenic event. Using this tailored model, we report that following radiation exposure, more than half of asymptomatic CBA Sfpi1 GFP/mCh mice presented with expanding clones of preleukemic hematopoietic cells harboring a hemizygous interstitial deletion of chromosome 2. Moreover, following isolation of preleukemic hematopoietic stem and progenitor cells irradiated in their native microenvironment, we identified the presence of Sfpi1 point mutations within a subpopulation of these preleukemic cells expanding rapidly (increasing from 6% to 55% in 21 days in peripheral blood in one case), hence identifying for the first time the presence of such cells within a living animal. Importantly, we also report a previously undescribed gender difference in the phenotype of the preleukemic cells and leukemia, suggesting a gender imbalance in the radiation-induced leukemic target cell. In conclusion, we provide novel insights into the sequence of molecular events occurring during the (radiation-induced) leukemic clonal evolution.


Assuntos
Leucemia Induzida por Radiação/etiologia , Pré-Leucemia/etiologia , Animais , Evolução Clonal , Progressão da Doença , Feminino , Células-Tronco Hematopoéticas/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos CBA , Mutação Puntual , Proteínas Proto-Oncogênicas/genética , Caracteres Sexuais , Transativadores/genética
3.
Oncotarget ; 9(98): 37078-37079, 2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30647845
4.
Cell Mol Life Sci ; 74(23): 4339-4351, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28667356

RESUMO

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces "aging-like" effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.


Assuntos
Expressão Gênica/efeitos da radiação , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos da radiação , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/efeitos da radiação , Animais , Senescência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Raios gama , Expressão Gênica/imunologia , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos NOD , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Quimeras de Transplante , Transplante Homólogo , Recombinação V(D)J/imunologia
5.
Int J Mol Sci ; 17(11)2016 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-27827995

RESUMO

Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning. We transplanted allogeneic HSCs constitutively expressing the mCherry fluorescent marker into age-matched NSG mice and assessed donor chimerism 6 months post-transplantation. All transplanted NSG mice showed long-term myeloid and lymphoid cell chimerism. Also, in vivo irradiated HSCs showed long-term engraftment, although overall white blood cell (WBC) donor chimerism was lower compared with non-irradiated HSCs. Using this novel NSG transplantation model, we will be able to study the effects of low dose in vivo X-ray exposure on the long-term fate of HSCs, without the requirement of prior radio-ablation of the recipient, and thus leaving the recipient's BM microenvironment uncompromised. In conclusion, we demonstrated for the first time that allogeneic HSCs from a different inbred strain can compete for niches in the BM compartment of NSG mice.


Assuntos
Medula Óssea/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Nicho de Células-Tronco/efeitos da radiação , Quimeras de Transplante/imunologia , Animais , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Relação Dose-Resposta à Radiação , Expressão Gênica , Genes Reporter , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/efeitos da radiação , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Nicho de Células-Tronco/imunologia , Transplante Homólogo , Raios X , Proteína Vermelha Fluorescente
6.
Int J Radiat Oncol Biol Phys ; 95(2): 772-81, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27020103

RESUMO

PURPOSE: Poly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiation therapy in preclinical models of human non-small cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models. METHODS AND MATERIALS: NSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth. RESULTS: In vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors. CONCLUSIONS: Our data suggest that hypoxia potentiates the radiation-sensitizing effects of olaparib by contextual synthetic killing, and that tumor hypoxia may be a potential biomarker for selecting patients who may get the greatest benefit from the addition of olaparib to radiation therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos da radiação , Carcinoma Pulmonar de Células não Pequenas/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Dano ao DNA , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rad51 Recombinase/análise , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Carcinogenesis ; 36(4): 413-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25750172

RESUMO

The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the -14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Induzida por Radiação/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Animais , Modelos Animais de Doenças , Regulação para Baixo , Raios gama/efeitos adversos , Deleção de Genes , Humanos , Camundongos , Proteínas Proto-Oncogênicas/biossíntese , Transativadores/biossíntese , Translocação Genética , Proteína Supressora de Tumor p53/genética , Raios X/efeitos adversos , Tirosina Quinase 3 Semelhante a fms/genética
8.
Res Vet Sci ; 94(3): 446-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23178045

RESUMO

This study determines the influence of general anesthesia on serum cardiac troponin I (cTnI) concentrations in dogs. All dogs showed no abnormalities on clinical and echocardiographic examination. Venous blood samples were drawn within 12 h of induction and 12 h after discontinuation of anesthesia. Each dog was premedicated with methadone i.v. and induced with diazepam i.v. and propofol i.v.. Anesthesia was maintained using isoflurane in oxygen in combination with a continuous rate infusion of fentanyl. The cTnI concentrations were measured using a third generation chemiluminescent microparticle immunoassay with a detection limit of 0.01 ng/mL (below this level '<0.01 ng/mL'). Ten dogs (55%) had a post-anesthetic increase of cTnI concentration relative to their pre-anesthetic cTnI concentration, whereas a decrease was observed in two dogs (11%). This study shows that cTnI can increase in healthy dogs undergoing general anesthesia.


Assuntos
Período Perioperatório/veterinária , Troponina I/sangue , Anestesia Geral/efeitos adversos , Anestesia Geral/veterinária , Animais , Diazepam/farmacologia , Cães/sangue , Cães/cirurgia , Feminino , Fentanila/farmacologia , Infusões Intravenosas/veterinária , Isoflurano/farmacologia , Masculino , Metadona/farmacologia , Propofol/farmacologia
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