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1.
Am J Med Genet A ; 194(4): e63476, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37974505

RESUMO

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.


Assuntos
Aneuploidia , Transtornos Cromossômicos , Cromossomos Humanos Par 22 , Anormalidades do Olho , Cardiopatias Congênitas , Humanos , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/genética
2.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33558238

RESUMO

Propranolol, a nonselective ß-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Aquaporina 1/metabolismo , Hemangioma Capilar/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Neovascularização Patológica/metabolismo , Propranolol/farmacologia , Telócitos/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Hemangioma Capilar/tratamento farmacológico , Humanos , Camundongos , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Propranolol/uso terapêutico , Proteoma/genética , Proteoma/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Telócitos/efeitos dos fármacos , Telócitos/fisiologia
3.
NMR Biomed ; 36(3): e4858, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36285719

RESUMO

Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (St O2 -MRI) to the fluorine-18 fluoromisonidazole ([18 F]FMISO) positron emission tomography (PET) volume for hypoxia imaging validation, and to analyze the ability of St O2 -MRI to depict the different hypoxic tissue types in the acute phase of stroke. In a pertinent model of stroke in the rat, the volume of tissue with decreased St O2 -MRI signal and that with increased uptake of [18 F]FMISO were equivalent and correlated (r = 0.706; p = 0.015). The values of St O2 in the tissue at risk were significantly greater than those quantified in the core of the lesion, and were less than those for healthy tissue (52.3% ± 2.0%; 43.3% ± 1.9%, and 67.9 ± 1.4%, respectively). A threshold value for St O2 of ≈60% as the cut-off for the identification of the tissue at risk was calculated. Tissue volumes with reduced St O2 -MRI correlated with the final lesion (r = 0.964, p < 0.0001). The findings show that the St O2 -MRI approach is sensitive for the detection of hypoxia and for the prediction of the final lesion after stroke. Once validated in acute clinical settings, this approach might be used to enhance the stratification of patients for potential therapeutic interventions.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , Tomografia por Emissão de Pósitrons , Acidente Vascular Cerebral/diagnóstico por imagem , Misonidazol , Hipóxia/diagnóstico por imagem , Imageamento por Ressonância Magnética , Compostos Radiofarmacêuticos
4.
Nucleic Acids Res ; 49(19): 11241-11256, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34634812

RESUMO

The stable insertion of the retroviral genome into the host chromosomes requires the association between integration complexes and cellular chromatin via the interaction between retroviral integrase and the nucleosomal target DNA. This final association may involve the chromatin-binding properties of both the retroviral integrase and its cellular cofactor LEDGF/p75. To investigate this and better understand the LEDGF/p75-mediated chromatin tethering of HIV-1 integrase, we used a combination of biochemical and chromosome-binding assays. Our study revealed that retroviral integrase has an intrinsic ability to bind and recognize specific chromatin regions in metaphase even in the absence of its cofactor. Furthermore, this integrase chromatin-binding property was modulated by the interaction with its cofactor LEDGF/p75, which redirected the enzyme to alternative chromosome regions. We also better determined the chromatin features recognized by each partner alone or within the functional intasome, as well as the chronology of efficient LEDGF/p75-mediated targeting of HIV-1 integrase to chromatin. Our data support a new chromatin-binding function of integrase acting in concert with LEDGF/p75 for the optimal association with the nucleosomal substrate. This work also provides additional information about the behavior of retroviral integration complexes in metaphase chromatin and the mechanism of action of LEDGF/p75 in this specific context.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromatina/metabolismo , Integrase de HIV/genética , Histonas/genética , Interações Hospedeiro-Patógeno/genética , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cromatina/química , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Integrase de HIV/metabolismo , Histonas/metabolismo , Humanos , Células K562 , Cultura Primária de Células , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/virologia , Fatores de Transcrição/metabolismo
5.
Clin Genet ; 95(3): 420-426, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.


Assuntos
Proteína de Ligação a CREB/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Fenótipo , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Autopsia , Feminino , Morte Fetal , Dosagem de Genes , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Sequenciamento do Exoma
6.
Prenat Diagn ; 38(13): 1111-1119, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30328630

RESUMO

OBJECTIVE: The aim of this study is to evaluate the diagnostic utility of prenatal diagnosis using the chromosomal microarray analysis (CMA) for fetuses presenting with isolated or associated intrauterine growth restriction (IUGR). METHOD: We retrospectively included all fetuses with IUGR referred for prenatal testing and studied by rapid fluorescence in situ hybridization (FISH), karyotype, and CMA. RESULTS: Among the 162 IUGR fetuses (78 associated and 84 isolated IUGR) included, 15 had an abnormal FISH result: 10 associated and five isolated fetal IUGRs. Among the 143 fetuses studied by CMA, 10 (7%) presented pathogenic copy number variations (CNVs). All 10 were in the associated fetal IUGR group (10/65 or 15.4%; 95% confidence interval [CI]: 8.4%-26.2%) versus 0/78 in the isolated fetal IUGR group (95% CI: 0%-5.6%). Six fetuses (4.2%) carried variants of unknown significance (VOUS) (three associated and three isolated fetal IUGRs). CONCLUSION: Our study highlights the added value of CMA in the case of associated fetal IUGR with an incremental yield of 6.1% (4/65) over karyotyping. No pathogenic CNVs were reported in the isolated fetal IUGR group. More studies must be conducted to determine when and whether CMA would be wisely indicated in this population.


Assuntos
Hibridização Genômica Comparativa/métodos , Retardo do Crescimento Fetal/genética , Hibridização in Situ Fluorescente , Cariotipagem , Análise em Microsséries/métodos , Adulto , Variações do Número de Cópias de DNA , Feminino , Humanos , Cariótipo , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Adulto Jovem
7.
Eur J Nucl Med Mol Imaging ; 43(4): 682-94, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26537287

RESUMO

PURPOSE: The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. METHODS: MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([(18)F]FDG and [(18)F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. RESULTS: Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [(18)F]FLT uptake, cerebral blood volume and oedema. [(18)F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [(18)F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. CONCLUSION: The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [(18)F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Didesoxinucleosídeos , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Compostos Radiofarmacêuticos , Ratos
8.
Gynecol Obstet Invest ; 81(1): 54-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25998012

RESUMO

BACKGROUND: Reduced telomere length in placental mesenchymal core cells has been reported during pregnancies complicated by intrauterine growth restriction. To estimate telomere length, a precise, accurate and reproducible technique must be used. OBJECTIVE: We evaluated the characteristics of a quantitative fluorescence in situ hybridization (Q-FISH) technique for measuring relative telomere length in placental mesenchymal core cells. METHODS: From late chorionic villus samplings, telomere length in placental mesenchymal core cells was estimated by a Q-FISH technique using peptide nucleic acid telomere probes. The main characteristics of the Q-FISH technique, such as precision and reproducibility, were evaluated. RESULTS: The telomere length of the cultured placental mesenchymal cells did not follow a normal distribution. When the Q-FISH technique was performed on interphase nuclei of uncultured mesenchymal core cells, normal telomere length distribution was observed. The precision of the technique when applied to cultured placental mesenchymal core cells was estimated to be <6%, and its reproducibility ranged from to 92.9 to 104.7%. CONCLUSION: Our results showed that cell culture of placental villi produced a non-normal telomere length distribution, probably related to telomere DNA replication during the cell cycle. Despite the influence of cell culture, the Q-FISH technique reported herein showed good precision and reproducibility.


Assuntos
Hibridização in Situ Fluorescente/normas , Placenta/citologia , Telômero/química , Adulto , Amostra da Vilosidade Coriônica , Feminino , Humanos , Gravidez
9.
Stroke ; 46(6): 1673-80, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25953371

RESUMO

BACKGROUND AND PURPOSE: Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia. METHODS: Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways). RESULTS: Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated. CONCLUSIONS: Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy.


Assuntos
Isquemia Encefálica/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Transdução de Sinais , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia
11.
Prenat Diagn ; 35(1): 35-43, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25118001

RESUMO

OBJECTIVE: Microduplication 22q11.2 is primarily characterized by a highly variable clinical phenotype, which ranges from apparently normal or slightly dysmorphic features (in the presence or absence of learning disorders) to severe malformations with profound mental retardation. Hence, genetic counseling is particularly challenging when microduplication 22q11.2 is identified in a prenatal diagnosis. Here, we report on 24 prenatal cases of microduplication 22q11.2. METHODS: Seventeen of the cases were also reanalyzed by microarray analysis, in order to determine copy number variations (CNVs, which are thought to influence expressivity). We also searched for possible correlations between fetal phenotypes, indications for invasive prenatal diagnosis, inheritance, and pregnancy outcomes. RESULTS: Of the 24 cases, 15 were inherited, six occurred de novo, and three were of unknown origin. Termination of pregnancy occurred in seven cases and was mainly decided on the basis of ultrasound findings. Moreover, additional CNVs were found in some patients and we try to make a genotype-phenotype correlation. CONCLUSION: We discuss the complexity of genetic counseling for microduplication 22q11.2 and comment on possible explanations for the clinical heterogeneity of this syndrome. In particular, we assessed the co-existence of additional CNVs and their contribution to phenotypic variations in chromosome 22q11.2 microduplication syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Síndrome de DiGeorge/diagnóstico , Estudos de Associação Genética , Diagnóstico Pré-Natal/métodos , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Análise Citogenética , Síndrome de DiGeorge/epidemiologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia
12.
Am J Med Genet A ; 164A(8): 1965-75, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24782328

RESUMO

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).


Assuntos
Obesidade/diagnóstico , Obesidade/genética , Fenótipo , Locos de Características Quantitativas , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Lactente , Masculino , Síndrome
13.
Int J Radiat Oncol Biol Phys ; 118(4): 1081-1093, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-37866760

RESUMO

PURPOSE: Radiation therapy for brain tumors increases patient survival. Nonetheless, side effects are increasingly reported such as cognitive deficits and fatigue. The etiology of fatigue remains poorly described. Our hypothesis is that the abscopal effects of radiation therapy on skeletal muscle may be involved in fatigue. The present study aims to assess the effect of brain irradiation on skeletal muscles and its relationship with fatigue and to analyze whether physical activity could counteract brain radiation-induced side effects. METHODS AND MATERIALS: Adult Wistar rats were randomly distributed between 4 groups: control (CTL), irradiated (IR), nonirradiated with physical activity (PA), and irradiated with physical activity (IR+PA). IR rats were exposed to a whole-brain irradiation (WBI) of 30 Gy (3 × 10 Gy). Rats subjected to PA underwent sessions of running on a treadmill, 3 times/week for 6 months. The effects of WBI on muscles were evaluated by complementary approaches: behavioral tests (fatigue, locomotion activity), magnetic resonance imaging, and histologic analyses. RESULTS: IR rats displayed a significant fatigue and a reduced locomotor activity at short term compared with the CTL group, which were attenuated with PA at 6 months after WBI. The IR rat's gastrocnemius mass decreased compared with CTL rats, which was reversed by physical activity at 14 days after WBI. Multiparametric magnetic resonance imaging of the skeletal muscle highlighted an alteration of the fiber organization in IR rats as demonstrated by a significant decrease of the mean diffusivity in the gastrocnemius at short term. Alteration of fibers was confirmed by histologic analyses: the number of type I fibers was decreased, whereas that of type IIa fibers was increased in IR animals but not in the IR+PA group. CONCLUSIONS: The data show that WBI induces skeletal muscle damage, which is attenuated by PA. This muscle damage may explain, at least in part, the fatigue of patients treated with radiation therapy.


Assuntos
Lesões por Radiação , Corrida , Humanos , Ratos , Animais , Ratos Wistar , Encéfalo/efeitos da radiação , Lesões por Radiação/etiologia , Músculo Esquelético
14.
Cancer Imaging ; 24(1): 95, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39026377

RESUMO

BACKGROUND: Radiotherapy is a major therapeutic approach in patients with brain tumors. However, it leads to cognitive impairments. To improve the management of radiation-induced brain sequalae, deformation-based morphometry (DBM) could be relevant. Here, we analyzed the significance of DBM using Jacobian determinants (JD) obtained by non-linear registration of MRI images to detect local vulnerability of healthy cerebral tissue in an animal model of brain irradiation. METHODS: Rats were exposed to fractionated whole-brain irradiation (WBI, 30 Gy). A multiparametric MRI (anatomical, diffusion and vascular) study was conducted longitudinally from 1 month up to 6 months after WBI. From the registration of MRI images, macroscopic changes were analyzed by DBM and microscopic changes at the cellular and vascular levels were evaluated by quantification of cerebral blood volume (CBV) and diffusion metrics including mean diffusivity (MD). Voxel-wise comparisons were performed on the entire brain and in specific brain areas identified by DBM. Immunohistology analyses were undertaken to visualize the vessels and astrocytes. RESULTS: DBM analysis evidenced time-course of local macrostructural changes; some of which were transient and some were long lasting after WBI. DBM revealed two vulnerable brain areas, namely the corpus callosum and the cortex. DBM changes were spatially associated to microstructural alterations as revealed by both diffusion metrics and CBV changes, and confirmed by immunohistology analyses. Finally, matrix correlations demonstrated correlations between JD/MD in the early phase after WBI and JD/CBV in the late phase both in the corpus callosum and the cortex. CONCLUSIONS: Brain irradiation induces local macrostructural changes detected by DBM which could be relevant to identify brain structures prone to radiation-induced tissue changes. The translation of these data in patients could represent an added value in imaging studies on brain radiotoxicity.


Assuntos
Lesões Encefálicas , Animais , Ratos , Masculino , Lesões Encefálicas/etiologia , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/patologia , Lesões por Radiação/etiologia , Encéfalo/efeitos da radiação , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/etiologia , Imageamento por Ressonância Magnética Multiparamétrica/métodos
15.
Nanoscale ; 16(25): 11959-11968, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38874227

RESUMO

Nanoparticles have emerged as promising theranostic tools for biomedical applications, notably in the treatment of cancers. However, to fully exploit their potential, a thorough understanding of their biodistribution is imperative. In this context, we prepared radioactive [64Cu]-exchanged faujasite nanosized zeolite ([64Cu]-FAU) to conduct positron emission tomography (PET) imaging tracking in preclinical glioblastoma models. In vivo results revealed a rapid and gradual accumulation over time of intravenously injected [64Cu]-FAU zeolite nanocrystals within the brain tumor, while no uptake in the healthy brain was observed. Although a specific tumor targeting was observed in the brain, the kinetics of uptake into tumor tissue was found to be dependent on the glioblastoma model. Indeed, our results showed a rapid uptake in U87-MG model while in U251-MG glioblastoma model tumor uptake was gradual over the time. Interestingly, a [64Cu] activity, decreasing over time, was also observed in organs of elimination such as kidney and liver without showing a difference in activity between both glioblastoma models. Ex vivo analyses confirmed the presence of zeolite nanocrystals in brain tumor with detection of both Si and Al elements originated from them. This radiolabelling strategy, performed for the first time using nanozeolites, enables precise tracking through PET imaging and confirms their accumulation within the glioblastoma. These findings further bolster the potential use of zeolite nanocrystals as valuable theranostic tools.


Assuntos
Neoplasias Encefálicas , Radioisótopos de Cobre , Glioblastoma , Nanopartículas , Tomografia por Emissão de Pósitrons , Zeolitas , Animais , Zeolitas/química , Radioisótopos de Cobre/química , Humanos , Distribuição Tecidual , Camundongos , Linhagem Celular Tumoral , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Glioblastoma/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Nanopartículas/química , Camundongos Nus
16.
Int J Radiat Biol ; 100(5): 744-755, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38466699

RESUMO

PURPOSES: Lymphopenia is extensively studied, but not circulating leucocyte subpopulations, which however have distinct roles in tumor tolerance. Proton therapy has been shown to have a lesser impact on the immune system than conventional X-ray radiotherapy through lower dose exposure to healthy tissues. We explored the differential effects of brain X-ray and proton irradiation on circulating leucocyte subpopulations. MATERIALS AND METHODS: Leucocyte subpopulation counts from tumor-free mice were obtained 12 hours after 4 fractions of 2.5 Gy. The relationships between irradiation type (X-rays or protons), irradiated volume (whole-brain/hemi-brain) and dose rate (1 or 2 Gy/min) with circulating leucocyte subpopulations (T-CD4+, T-CD8+, B, and NK-cells, neutrophils, and monocytes) were investigated using linear regression and tree-based modeling approaches. Relationships between dose maps (brain, vessels, lymph nodes (LNs)) and leucocyte subpopulations were analyzed and applied to construct the blood dose model, assessing the hypothesis of a direct lymphocyte-killing effect in radiation-induced lymphopenia. RESULTS: Radiation-induced lymphopenia occurred after X-ray but not proton brain irradiation in lymphoid subpopulations (T-CD4+, T-CD8+, B, and NK-cells). There was an increase in neutrophil counts following protons but not X-rays. Monocytes remained unchanged under both X-rays and protons. Besides irradiation type, irradiated volume and dose rate had a significant impact on NK-cell, neutrophil and monocyte levels but not T-CD4+, T-CD8+, and B-cells. The dose to the blood had a heterogeneous impact on leucocyte subpopulations: neutrophil counts remained stable with increasing dose to the blood, while lymphocyte counts decreased with increasing dose (T-CD8+-cells > T-CD4+-cells > B-cells > NK-cells). Direct cell-killing effect of the dose to the blood mildly contributed to radiation-induced lymphopenia. LN exposure significantly contributed to lymphopenia and partially explained the distinct impact of irradiation type on circulating lymphocytes. CONCLUSIONS: Leucocyte subpopulations reacted differently to X-ray or proton brain irradiation. This difference could be partly explained by LN exposure to radiation dose. Further researches and analyses on other biological processes and interactions between leucocyte subpopulations are ongoing. The various mechanisms underlying leucocyte subpopulation changes under different irradiation modalities may have implications for the choice of radiotherapy modalities and their combination with immunotherapy in brain cancer treatment.


Assuntos
Encéfalo , Leucócitos , Animais , Camundongos , Encéfalo/efeitos da radiação , Leucócitos/efeitos da radiação , Linfopenia/etiologia , Relação Dose-Resposta à Radiação , Masculino , Raios X , Terapia com Prótons/efeitos adversos , Camundongos Endogâmicos C57BL
17.
Biol Chem ; 394(4): 529-39, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23399636

RESUMO

Despite multiple advances in cancer therapies, patients with glioblastoma (GBM) still have a poor prognosis. Numerous glioma models are used not only for the development of innovative therapies but also to optimize conventional ones. Given the significance of hypoxia in drug and radiation resistance and that hypoxia is widely observed among GBM, the establishment of a reliable method to map hypoxia in preclinical human models may contribute to the discovery and translation of future and more targeted therapies. The aim of this study was to compare the hypoxic status of two commonly used human orthotopic glioma models (U87 and U251) developed in rats and studied by noninvasive hypoxia imaging with 3-[18F]fluoro-1-(2-nitro-1-imidazolyl)-2-propanol-micro-positron emission tomography ([18F]-FMISO-µPET). In parallel, because of the relationships between angiogenesis and hypoxia, we used magnetic resonance imaging (MRI), histology, and immunohistochemistry to characterize the tumoral vasculature. Although all tumors were detectable in T2-weighted MRI and 2-deoxy-2-[18F]fluoro-d-glucose-µPET, only the U251 model exhibited [18F]-FMISO uptake. Additionally, the U251 tumors were less densely vascularized than U87 tumors. Our study demonstrates the benefits of noninvasive imaging of hypoxia in preclinical models to define the most reliable one for translation of future therapies to clinic based on the importance of intratumoral oxygen tension for the efficacy of chemotherapy and radiotherapy.


Assuntos
Glioma/patologia , Hipóxia/diagnóstico , Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética
18.
Mol Genet Metab ; 110(1-2): 90-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23920044

RESUMO

Congenital deletions at the 3q13.31 locus have been recently described as a novel microdeletion syndrome characterized by developmental delay, postnatal overgrowth, hypoplastic male genitalia and characteristic facial features. A common critical region of overlapping of 580kb was delineated including two strong candidate genes for developmental delay: DRD3 and ZBTB20. In this report, we describe a new case of 3q13.31 microdeletion identified by array-CGH in a 16year-old girl sharing clinical features commonly observed in the 3q13.31 microdeletion syndrome. This girl had a microdeletion of 7.39Mb spanning the common critical region of overlapping. More interestingly, we report for the first time the existence of a microduplication reciprocal to the microdeletion syndrome. This familial 2.76Mb microduplication identified by array-CGH was carried by two brothers and their father. The phenotype shared by the brothers resembled the phenotype related to the 3q13.31 microdeletion syndrome including especially severe intellectual disability, developmental delay, behavioral abnormalities and obesity. This microduplication involves three strong candidate genes for the developmental delay ZBTB20, LSAMP and GAP43. Further molecular characterization showed that DRD3, another strong candidate gene for developmental delay, was not included in the duplicated region. However, a dosage alteration of this gene cannot be completely excluded as the duplication was inverted at proximity of this gene, as revealed by FISH analysis. Finally, we hypothesized that the phenotype shared by the two brothers could be related to a gene dosage imbalance even if gene expression could not be measured in relevant tissues such as brain or adipocytes.


Assuntos
Deficiências do Desenvolvimento/genética , Deleção de Genes , Genes Duplicados , Obesidade/genética , Adolescente , Moléculas de Adesão Celular Neuronais/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Feminino , Proteína GAP-43/genética , Proteínas Ligadas por GPI/genética , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas do Tecido Nervoso/genética , Obesidade/patologia , Receptores de Dopamina D3/genética , Fatores de Transcrição/genética
19.
Cell Death Dis ; 14(12): 823, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-38092743

RESUMO

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/patologia
20.
EJNMMI Res ; 13(1): 102, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38006431

RESUMO

BACKGROUND: Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. RESULTS: First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p < 0.01), while no uptake is observed in striatal BM 23 days after tumor implantation. Pimonidazole, HIF-1α, HIF-2α, CA-IX as well as GFAP, CTR1 and DMT1 immunostainings are positive in both BM. CONCLUSION: Overall, [64Cu][Cu(ATSM)] imaging and proteomic results showed the presence of hypoxia and protein expression changes linked to hypoxia and oxidative stress in BM, which are more pronounced in cortical BM compared to striatal BM. Moreover, it emphasized the interest of [64Cu][Cu(ATSM)] PET to characterize TME of BM and depict inter-metastasis heterogeneity that could be useful to guide treatments.

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