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1.
Neurobiol Dis ; 134: 104705, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830525

RESUMO

Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

2.
Oper Neurosurg (Hagerstown) ; 18(3): E82, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173153

RESUMO

A 54-yr-old man presented with the radiological recurrence of a glioblastoma at the level of the left anterior cingulate gyrus, 46 mo after first surgery, which had been complicated by bone flap infection. Due to the relatively small recurrence, the long survival, and the good neurological status, surgery was warranted. A new, high-definition (4 K) and 3-dimensional exoscope (ORBEYE; Sony Olympus Medical Solutions Inc, Tokyo, Japan) was used during the surgical approach and throughout tumor removal, which was aided by five-aminolevulinic acid (5-ALA) derived fluorescence. The postoperative course was characterized by supplementary motor area syndrome, which quickly improved, leading to a discharge home 1 wk after surgery. Histological examination confirmed a wild-type (WT) IDH1/2, MGMT (DNA repair enzyme O6-methylguanine-DNA methyltransferase) methylated glioblastoma with a proliferative index focally as high as 20%. He is now being considered for a second-line treatment. As recently reported for spinal surgery,1 we believe this technology has significant potential for its small dimension (which can provide optimal positioning even in ergonomically challenging positions), ease of movement, and image quality, including 5-ALA fluorescence. The patient's consent was obtained for publication.

3.
Cancer Lett ; 469: 447-455, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31733287

RESUMO

The need of reliable syngeneic animal models for gliomas has been addressed in the last decades by reproducing genetic alterations typical of human glioblastoma in the mouse. Since different alterations underlie different molecular glioblastoma subtypes it is commonly expected that tumors induced by specific alterations represent models of the corresponding subtypes. We tested this assumption by a multilevel analysis ranging from a detailed histopathological analysis to a genome-wide expression profiling by microarray and RNA-seq on gliomas induced by two distinct molecular alterations: the overstimulation of the PDGF- and the EGF- pathways. These alterations are landmarks of proneural and classical glioblastoma subtypes respectively. However, our results consistently showed a strong similarity between the two glioma models. The expression profiles of both models converged toward a signature typical of oligodendrocyte progenitor cells, regardless the wide differentiative potential of the cell of origin. A classification based on similarity with human gliomas profiles revealed that both models belong to the proneural subtype. Our results highlight that reproducing a molecular alteration specific of a glioblastoma subtype not necessarily generates a tumor model recapitulating such subtype.

4.
Cancers (Basel) ; 11(12)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817110

RESUMO

Invasiveness in pituitary adenomas has been defined and investigated from multiple perspectives, with varying results when its predictive value is considered. A systematic literature review, following PRISMA guidelines, was performed, searching PubMed and Scopus databases with terms that included molecular markers, histological, radiological, anatomical and surgical data on invasiveness of pituitary adenomas. The results showed that differing views are still present for anatomical aspects of the sellar region that are relevant to the concept of invasiveness; radiological and histological diagnoses are still limited, but might improve in the future, especially if they are related to surgical findings, which have become more accurate thanks to the introduction of the endoscope. The aim is to achieve a correct distinction between truly invasive pituitary adenomas from those that, in contrast, present with extension in the parasellar area through natural pathways. At present, diagnosis of invasiveness should be based on a comprehensive analysis of radiological, intra-operative and histological findings.

5.
Mol Cell Endocrinol ; 498: 110585, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536779

RESUMO

Adrenocortical cancer (ACC) is a rare and aggressive malignancy with a poor prognosis. The overall 5-year survival rate of patients with ENS@T stage IV ACC is less than 15%. Systemic antineoplastic therapies have a limited efficacy and new drugs are urgently needed. Human ACC primary cultures and cell lines were used to assess the cytotoxic effect of cabazitaxel, and the role of P-glycoprotein in mediating this effect. Cabazitaxel reduced ACC cell viability, both in ACC cell lines and in ACC primary cell cultures. Molecular and pharmacological targeting of ABCB1/P-gp did not modify its cytotoxic effect in NCI-H295R cells, while it increased the paclitaxel-induced toxicity. Cabazitaxel modified the expression of proteins involved in cellular physiology, such as apoptosis and cell cycle regulation. The drug combination cabazitaxel/mitotane exerted an additive/moderate synergism in different ACC cell experimental models. These results provide a rationale for testing cabazitaxel in a clinical study.

7.
Front Immunol ; 10: 447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949166

RESUMO

The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

9.
Int J Cancer ; 144(10): 2539-2554, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30418668

RESUMO

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate-aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST-expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST-depleted glioma. Despite their GLAST expression, GBM stem-like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+-ATPase. Overexpression of Na+/K+-ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH-101. In glioma-bearing mice, a single intratumoral injection of UCPH-101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Glioblastoma/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Ácido Aspártico/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Feminino , Glioma/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo
10.
J Neuroinflammation ; 15(1): 33, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402285

RESUMO

BACKGROUND: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in combination with magnetic resonance imaging (MRI). METHODS: MOG35-55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. RESULTS: In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels.


Assuntos
Radioisótopos de Flúor/metabolismo , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Quinolinas/metabolismo , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL
11.
Brain Pathol ; 28(6): 875-888, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29330884

RESUMO

Lewy bodies (LB) and Lewy neurites (LN), which are primarily composed of α-synuclein (α-syn), are neuropathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We recently found that the neuronal phosphoprotein synapsin III (syn III) controls dopamine release via cooperation with α-syn and modulates α-syn aggregation. Here, we observed that LB and LN, in the substantia nigra of PD patients and hippocampus of one subject with DLB, displayed a marked immunopositivity for syn III. The in situ proximity ligation assay revealed the accumulation of numerous proteinase K-resistant neuropathological inclusions that contained both α-syn and syn III in tight association in the brain of affected subjects. Most strikingly, syn III was identified as a component of α-syn-positive fibrils in LB-enriched protein extracts from PD brains. Finally, a positive correlation between syn III and α-syn levels was detected in the caudate putamen of PD subjects. Collectively, these findings indicate that syn III is a crucial α-syn interactant and a key component of LB fibrils in the brain of patients affected by PD.


Assuntos
Corpos de Lewy/metabolismo , Corpos de Lewy/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Sinapsinas/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Dopamina/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Putamen/metabolismo , Putamen/patologia , Substância Negra/metabolismo , Substância Negra/patologia
12.
Biochem Biophys Res Commun ; 493(1): 660-665, 2017 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-28865960

RESUMO

Caveolae are cholesterol enriched invaginations of the plasma membrane involved in a variety of processes, including glucose and fatty acids absorption, cell transduction and mechanoprotection. The biogenesis and function of caveolae depend on the activity of Caveolin (Cav-1, -2 and -3) and Cavin (Cavin-1, -2, -3 and -4) protein families. Since the membrane Cavin-2 protein was reported to play a key role in caveolae formation of adipocytes, in this work we have used a multidisciplinary approach to investigate its expression in liposarcoma (LPS), an adipocytic soft tissue sarcoma affecting adults. Data obtained through an in silico and immunohistochemical analysis suggest that Cavin-2, along with Cavin-1, Cav-1 and Cav-2, is mostly expressed in the least aggressive LPS subtype, namely well-differentiated LPS, while is almost undetectable in the more aggressive myxoid, pleomorphic and dedifferentiated LPS tumors. Accordingly, in vitro analysis confirmed that Cavin-2 expression increases in LPS tumor cell lines during differentiation as compared to proliferation, as detected by immunoblotting and immunofluorescence analysis. Overall, these data suggest that Cavin-2 represents a useful marker for discriminating the degree of differentiation in LPS tumors.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Fosfato , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Especificidade da Espécie
13.
Neurol Neuroimmunol Neuroinflamm ; 4(3): e342, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28616446

RESUMO

OBJECTIVE: To investigate the effects of targeting the high-affinity receptor for immunoglobulin E (FcεRI), that plays a central role in allergic responses and is constitutively expressed on mast cells and basophils, in clinical disease and autoimmune T-cell response in experimental MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein 35-55. Anti-FcεRI α-chain antibody was administered intraperitoneally. CNS immunohistochemistry, flow cytometry analysis of immune cell populations, IgE and histamine serum concentration, immune cell proliferation, and cytokine measurement were performed. In BALB/c mice, EAE was induced by immunization with myelin proteolipid protein 185-206. RESULTS: Treatment with anti-FcεRIα antibody resulted in exacerbation of EAE and increased CNS inflammation in C57BL/6 mice. Treated mice displayed long-lasting complete depletion of basophils in the blood stream and peripheral lymphoid organs and increased antigen-induced immune cell proliferation and production of interferon-γ, interleukin (IL)-17, IL-6, and granulocyte-macrophage colony-stimulating factor. In BALB/c mice, which are T-helper (Th) 2 prone and resistant to EAE, treatment with anti-FcεRIα antibody restored susceptibility to EAE. CONCLUSION: Our observations that anti-FcεRIα antibody increases Th1 and Th17 responses against myelin antigen and exacerbates EAE suggest that FcεRI, basophils, and possibly other FcεRI-bearing cells that might be affected by this antibody play important roles in influencing the severity of CNS autoimmunity.

14.
J Exp Med ; 214(3): 623-637, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28148688

RESUMO

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.


Assuntos
Doenças do Desenvolvimento Ósseo/etiologia , Deficiências do Desenvolvimento/etiologia , Síndromes de Imunodeficiência/etiologia , Mutação , N-Acetilglucosaminiltransferases/genética , Animais , Pré-Escolar , Feminino , Heparitina Sulfato/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Lactente , Linfócitos/fisiologia , Peixe-Zebra
15.
Dis Model Mech ; 10(1): 15-28, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27935819

RESUMO

Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p)-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.


Assuntos
Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transativadores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Aminoacil-tRNA Sintetases/genética , Animais , Neoplasias Encefálicas/genética , Carcinogênese/genética , Carcinogênese/patologia , Proliferação de Células , Sobrevivência Celular , Células Clonais , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Genes ras , Glioblastoma/genética , Glioblastoma/patologia , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Mesoderma/patologia , Células-Tronco Neurais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Telencéfalo/patologia , Proteínas de Peixe-Zebra/genética
16.
Eur J Cell Biol ; 95(8): 252-64, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27168348

RESUMO

Caveolins (Cav-1, -2 and -3) and Cavins (Cavin-1, -2, -3 and -4) are two protein families controlling the biogenesis and function of caveolae, plasma membrane omega-like invaginations representing the primary site of important cellular processes like endocytosis, cholesterol homeostasis and signal transduction. Caveolae are especially abundant in fat tissue, playing a consistent role in a number of processes, such as the insulin-dependent glucose uptake and transmembrane transport of lipids underlying differentiation, maintenance and adaptive hypertrophy of adipocytes. Based on this premise, in this work we have investigated the expression of caveolar protein components in liposarcoma (LPS), an adipocytic soft tissue sarcoma affecting adults categorized in well-differentiated, dedifferentiated, myxoid and pleomorphic histotypes. By performing an extensive microarray data analysis followed by immunohistochemistry on human LPS tumors, we demonstrated that Cav-1, Cav-2 and Cavin-1 always cluster in all the histotypes, reaching the highest expression in well-differentiated LPS, the least aggressive of the malignant forms composed by tumor cells with a morphology resembling mature adipocytes. In vitro experiments carried out using two human LPS cell lines showed that the expression levels of Cav-1, Cav-2 and Cavin-1 proteins were faintly detectable during cell growth, becoming consistently increased during the accumulation of intracellular lipid droplets characterizing the adipogenic differentiation. Moreover, in differentiated LPS cells the three proteins were also found to co-localize and form molecular aggregates at the plasma membrane, as shown via immunofluorescence and immunoprecipitation analysis. Overall, these data indicate that Cav-1, Cav-2 and Cavin-1 may be considered as reliable markers for identification of LPS tumors characterized by consistent adipogenic differentiation.


Assuntos
Adipogenia , Caveolina 1/metabolismo , Caveolina 2/metabolismo , Lipossarcoma/genética , Caveolina 1/genética , Caveolina 2/genética , Diferenciação Celular , Linhagem Celular Tumoral , Humanos
17.
J Exp Med ; 213(3): 355-75, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26926994

RESUMO

Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2(R229Q) knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2(R229Q) mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2(R229Q) microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad-spectrum antibiotics (ABXs) in Rag2(R229Q) mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut-tropic CCR9(+) Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS.


Assuntos
Autoimunidade , Proteínas de Ligação a DNA/metabolismo , Microbioma Gastrointestinal , Inflamação/imunologia , Inflamação/patologia , Transferência Adotiva , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Autoimunidade/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Carga Bacteriana/efeitos dos fármacos , Translocação Bacteriana/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Proteínas de Ligação a DNA/deficiência , Microbioma Gastrointestinal/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Imunoglobulina E/metabolismo , Imunofenotipagem , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Tropismo/efeitos dos fármacos
18.
J Neurooncol ; 128(2): 303-12, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27025858

RESUMO

To analyse the pattern of recurrence of patients treated with Stupp protocol in relation to technique, to compare in silico plans with reduced margin (1 cm) with the original ones and to analyse toxicity. 105 patients were treated: 85 had local recurrence and 68 of them were analysed. Recurrence was considered in field, marginal and distant if >80 %, 20-80 % or <20 % of the relapse volume was included in the 95 %-isodose. In silico plans were retrospectively recalculated using the same technique, fields angles and treatment planning system of the original ones. The pattern of recurrence was in field, marginal and distant in 88, 10 and 2 % respectively and was similar in in silico plans. The margin reduction appears to spare 100 cc of healthy brain by 57 Gy-volume (p = 0.02). The target coverage was worse in standard plans (pt student < 0.001), especially if the tumour was near to organs at risk (pχ2 < 0.001). PTV coverage was better with IMRT and helical-IMRT, than conformal-3D (pAnova test = 0.038). This difference was no more significant with in silico planning. A higher incidence of asthenia and leuko-encephalopathy was observed in patients with greater percentage of healthy brain included in 57 Gy-volume. No differences in the pattern of recurrence according to margins were found. The margin reduction determines sparing of healthy brain and could possibly reduce the incidence of late toxicity. Margin reduction could allow to use less sophisticated techniques, ensuring appropriate target coverage, and the choice of more costly techniques could be reserved to selected cases.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Radioterapia Conformacional , Idoso , Neoplasias Encefálicas/epidemiologia , Quimiorradioterapia/efeitos adversos , Feminino , Glioblastoma/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Órgãos em Risco , Radioterapia Conformacional/efeitos adversos , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral
19.
J Leukoc Biol ; 99(6): 1027-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26744451

RESUMO

Chemokine (CC motif) receptor-like 2 is a 7-transmembrane protein related to the family of the atypical chemokine receptors, which are proteins devoid of chemotactic activity and involved in the control of inflammation. Experimental autoimmune encephalitis is an autoimmune disorder that replicates the inflammatory aspects of multiple sclerosis. Chemokine (CC motif) receptor-like 2-deficient mice developed exacerbated, nonresolving disease with protracted inflammatory response and increased demyelination. The increased severity of the disease was associated with higher levels of microglia/macrophage activation markers and imbalanced M1/M2 polarization. Thus, chemokine (CC motif) receptor-like 2 is involved in the downregulation of central nervous system-associated experimental autoimmune encephalitis inflammation in the recovery phase of the disease. Therefore chemokine (CC motif) receptor-like 2 should be considered to be a molecule involved in the regulation of the inflammatory response associated with multiple sclerosis.


Assuntos
Polaridade Celular , Encefalomielite Autoimune Experimental/patologia , Macrófagos/patologia , Receptores de Quimiocinas/metabolismo , Animais , Antígenos/imunologia , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Apresentação Cruzada/imunologia , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Feminino , Imunização , Inflamação/patologia , Interferon gama/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/metabolismo , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
20.
PLoS One ; 10(6): e0130287, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26086601

RESUMO

The purpose of this study was to investigate whether MURC/cavin-4, a plasma membrane and Z-line associated protein exhibiting an overlapping distribution with Caveolin-3 (Cav-3) in heart and muscle tissues, may be expressed and play a role in rhabdomyosarcoma (RMS), an aggressive myogenic tumor affecting childhood. We found MURC/cavin-4 to be expressed, often concurrently with Cav-3, in mouse and human RMS, as demonstrated through in silico analysis of gene datasets and immunohistochemical analysis of tumor samples. In vitro expression studies carried out using human cell lines and primary mouse tumor cultures showed that expression levels of both MURC/cavin-4 and Cav-3, while being low or undetectable during cell proliferation, became robustly increased during myogenic differentiation, as detected via semi-quantitative RT-PCR and immunoblotting analysis. Furthermore, confocal microscopy analysis performed on human RD and RH30 cell lines confirmed that MURC/cavin-4 mostly marks differentiated cell elements, colocalizing at the cell surface with Cav-3 and labeling myosin heavy chain (MHC) expressing cells. Finally, MURC/cavin-4 silencing prevented the differentiation in the RD cell line, leading to morphological cell impairment characterized by depletion of myogenin, Cav-3 and MHC protein levels. Overall, our data suggest that MURC/cavin-4, especially in combination with Cav-3, may play a consistent role in the differentiation process of RMS.


Assuntos
Caveolina 3/metabolismo , Neoplasias Musculares/metabolismo , Proteínas Musculares/metabolismo , Rabdomiossarcoma/metabolismo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Camundongos , Neoplasias Musculares/mortalidade , Neoplasias Musculares/patologia , Proteínas Musculares/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Proteínas de Transporte Vesicular
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