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1.
Nat Commun ; 12(1): 1333, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637761

RESUMO

T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m6A-miCLIP-seq shows the 3' UTR of Tcf7 mRNA is subjected to METTL3-dependent m6A modification. Loss of METTL3 or mutation of the Tcf7 3' UTR m6A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Metiltransferases/genética , Metiltransferases/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animais , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Centro Germinativo/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Ativação Linfocitária , Linfócitos Nulos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA Mensageiro/metabolismo , Receptores CXCR5/metabolismo
2.
Cell Death Differ ; 27(11): 3131-3145, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32494025

RESUMO

Estrogen receptor α (ERα) is the crucial factor in ERα-positive breast cancer progression. Endocrine therapies targeting ERα signaling is one of the widely used therapeutic strategies for breast cancer. However, a large number of the patients become refractory to therapy. Abnormal expression of ERα co-regulator facilitates breast cancer development and tendency of endocrine resistance. Thus, it is necessary to discover the novel co-regulators modulating ERα action. Here, we demonstrate that histone deubiquitinase USP22 is highly expressed in breast cancer samples compared with that in the benign tissue, and high expression of USP22 was significantly associated with poorer overall survival in BCa samples. Moreover, USP22 associates with ERα to be involved in maintenance of ERα stability. USP22 enhances ERα-induced transactivation. We further provide the evidence that USP22 is recruited together with ERα to cis-regulatory elements of ERα target gene. USP22 promotes cell growth even under hypoxia condition and with the treatment of ERα antagonist in breast cancer cells. Importantly, the deubiquitination activity of USP22 is required for its functions on maintenance of ERα stability, thereby enhancing ERα action and conferring endocrine resistance in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Histonas/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos Nulos , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Ubiquitina Tiolesterase/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Neurosurg Focus ; 48(6): E13, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32480370

RESUMO

OBJECTIVE: Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs. METHODS: The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected. RESULTS: Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p < 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07-12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04-15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09-4.59; p = 0.030). CONCLUSIONS: This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.


Assuntos
Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Gonadotrofos/patologia , Linfócitos Nulos/patologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral/fisiologia , Adulto Jovem
4.
Rheumatology (Oxford) ; 59(11): 3340-3349, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32306043

RESUMO

OBJECTIVES: SLE is an autoimmune disease characterized by aberrant autoantibody production and immune dysfunctions. Whether the anti-CMV immunity is impaired in SLE patients is poorly understood. We investigated the specific anti-viral T-cell response in SLE patients with CMV infection and its possible impacts on clinical manifestations in lupus. METHODS: CD28 null T-cell percentages were measured by flow cytometry in 89 SLE patients and 58 healthy controls. A specific anti-CMV CD8 T-cell response was assessed ex vivo by the production of intracellular cytokines in response to CMV phosphoprotein 65 (pp65) by flow cytometry. Clinical manifestations and immune parameters were analysed in SLE patients according to their CMV serostatus. RESULTS: CD28 null T cells were significantly expanded in SLE patients. When the anti-CMV pp65 CD8 polyfunctional T cell response was analysed, as defined by production of at least three of four functional cytokines or effectors (intracellular IFN-γ, IL-2, TNF-α and surface CD107a), the results demonstrated that it was not impaired in SLE patients. In contrast, when comparing clinical manifestations, there were lower anti-ds-DNA levels and decreased SLEDAI in SLE patients with CMV infection. Furthermore, the expansion of CD4+CD28 null T cells was negatively associated with anti-ds-DNA levels and SLEDAI in these lupus patients. CONCLUSION: In SLE patients with CMV infection, the specific anti-CMV CD8 T-cell response is preserved but is associated with decreased disease activity and lower anti-DNA levels among these patients, suggesting CMV infection may mitigate lupus activity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas da Matriz Viral/imunologia , Adulto , Anticorpos Antivirais/sangue , Especificidade de Anticorpos , Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , DNA/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunidade Celular , Imunoglobulina G/sangue , Interferon gama/biossíntese , Interleucina-2/biossíntese , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Ativação Linfocitária , Linfócitos Nulos/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/biossíntese
5.
BMC Endocr Disord ; 19(1): 90, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455321

RESUMO

BACKGROUND: Endothelial cell-specific molecule-1 (ESM-1) is a biomarker associated with tumor progression in pituitary adenoma. We specifically focused on one type of pituitary adenoma, namely null cell adenoma (NCA) and evaluated the relationship between invasion and ESM-1 expression in both vascular endothelial and adenoma tissues. METHODS: Tissue samples from 94 patients with pituitary NCA were obtained through microscopic transsphenoidal resection. Tumor size and invasion were determined through preoperative magnetic resonance imaging. Immunohistochemical staining was performed to detect ESM-1 expression. ESM-1 index of ≥3 was defined as high expression. RESULTS: Signs of invasion were observed in 46 (47.9%) of the 94 patients. Significant differences were observed in the invasion state and maximum tumor diameter between high and low expression of ESM-1 in vascular endothelial tissues (both P < 0.05). Significant positive associations were noted between ESM-1 expression in vascular endothelial tissues and tumor invasion (P = 0.002) and tumor size (P = 0.020). However, only tumor size was associated with ESM-1 expression in adenoma tissues (P = 0.016). CONCLUSION: In NCA, a significant positive association between tumor invasion and ESM-1 expression was observed only in vascular endothelial tissues, suggesting that tumor progression occurs mainly through ESM-1-associated mechanism.


Assuntos
Adenoma/patologia , Biomarcadores/metabolismo , Linfócitos Nulos/patologia , Proteínas de Neoplasias/metabolismo , Neoplasias Hipofisárias/patologia , Proteoglicanas/metabolismo , Adenoma/metabolismo , Adenoma/cirurgia , Feminino , Seguimentos , Humanos , Linfócitos Nulos/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/cirurgia , Prognóstico
6.
Pituitary ; 22(5): 514-519, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401793

RESUMO

PURPOSE: The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). METHODS: Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. RESULTS: Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). CONCLUSIONS: Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.


Assuntos
Hipófise/diagnóstico por imagem , Hipófise/patologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos Nulos/patologia , Masculino , Doenças da Hipófise/diagnóstico por imagem , Doenças da Hipófise/mortalidade , Doenças da Hipófise/patologia , Neoplasias Hipofisárias/mortalidade , Intervalo Livre de Progressão , Estudos Retrospectivos , Organização Mundial da Saúde
8.
Hum Immunol ; 80(9): 748-754, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30853362

RESUMO

End-stage renal disease (ESRD) patients, including those on hemodialysis, possess a high risk for cardiovascular diseases, as the first leading cause of death among them. Traditional risk factors do not utterly elucidate this. Throughout the last two decades, CD4+CD28null T cells; an unusual subset of T lymphocytes, was detected high with excess cardiovascular (CV) mortality. We aimed to investigate the circulating CD4+CD28null T cells frequency in ESRD patients on hemodialysis and to evaluate their relationship with atherosclerotic changes. High-resolution carotid ultrasonography was done to assess the common carotid artery intima media thickness in a number of ESRD patients, accordingly patients were selected and subdivided into two groups; 30 with atherosclerosis (mean [SD] age, 51.6 [6.3] years) and 30 without (mean [SD] age, 48.9 [5.5] years). Another 30 healthy individuals (mean [SD] age, 48.5 [6.8] years) were enrolled. Analysis of CD4+CD28null T-cells frequency by flow-cytometry was performed in all studied subjects. CD4+CD28null T cell percentage was significantly higher in ESRD patients, (mean [SD], 7.3 [2.7] %) compared to healthy individuals (mean [SD], 3.0 [0.8] %), (p < 0.001). Additionally, the expansion of these unusual T lymphocytes was significantly higher in ESRD patients with atherosclerotic changes (mean [SD], 9.47 [0.75] %) compared to those without atherosclerosis (mean [SD], 5.22 [2.14] %), (p < 0.001). In conclusion circulating CD4+CD28null T lymphocyte population showed expansion in ESRD patients, and of interest in correlation to preclinical atherosclerotic changes.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Falência Renal Crônica/complicações , Linfócitos Nulos/metabolismo , Diálise Renal , Adulto , Área Sob a Curva , Aterosclerose/patologia , Proteína C-Reativa/análise , Espessura Intima-Media Carotídea , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunossenescência/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC
9.
JCI Insight ; 4(5)2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30843874

RESUMO

Treg differentiation, maintenance, and function are controlled by the transcription factor FoxP3, which can be destabilized under inflammatory or other pathological conditions. Tregs can be destabilized under inflammatory or other pathological conditions, but the underlying mechanisms are not fully defined. Herein, we show that inflammatory cytokines induce ER stress response, which destabilizes Tregs by suppressing FoxP3 expression, suggesting a critical role of the ER stress response in maintaining Treg stability. Indeed, genetic deletion of Hrd1, an E3 ligase critical in suppressing the ER stress response, leads to elevated expression of ER stress-responsive genes in Treg and largely diminishes Treg suppressive functions under inflammatory condition. Mice with Treg-specific ablation of Hrd1 displayed massive multiorgan lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. At the molecular level, the deletion of Hrd1 led to the activation of both the ER stress sensor IRE1α and its downstream MAPK p38. Pharmacological suppression of IRE1α kinase, but not its endoribonuclease activity, diminished the elevated p38 activation and fully rescued the stability of Hrd1-null Tregs. Taken together, our studies reveal ER stress response as a previously unappreciated mechanism underlying Treg instability and that Hrd1 is crucial for maintaining Treg stability and functions through suppressing the IRE1α-mediated ER stress response.


Assuntos
Citocinas/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Colite/imunologia , Colite/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Homeostase , Inflamação/imunologia , Inflamação/patologia , Linfócitos Nulos , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Transcriptoma , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética
11.
Nat Cell Biol ; 20(8): 862-863, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30050117
12.
Endocrinol. diabetes nutr. (Ed. impr.) ; 64(7): 384-395, ago.-sept. 2017. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-171797

RESUMO

Clinically non-functioning pituitary adenomas (NFPAs) are among the most common tumors in the sellar region. These lesions do not cause a hormonal hypersecretion syndrome, and are therefore found incidentally (particularly microadenomas) or diagnosed based on compressive symptoms such as headache and visual field defects, as well as clinical signs of pituitary hormone deficiencies. Immunohistochemically, more than 45% of these adenomas stain for gonadotropins or their subunits and are therefore called gonadotropinomas, while 30% of them show no immunostaining for any hormone and are known as null cell adenomas. The diagnostic approach to NFPAs should include visual field examination, an assessment of the integrity of all anterior pituitary hormone systems, and magnetic resonance imaging of the sellar region to define tumor size and extension. The treatment of choice is transsphenoidal resection of the adenoma, which in many instances cannot be completely accomplished. The recurrence rate after surgery may be up to 30%. Persistent or recurrent adenomas are usually treated with radiation therapy. In a small proportion of these cases, drug treatment with dopamine agonists and, to a lesser extent, somatostatin analogs may achieve reduction or at least stabilization of the tumor (AU)


Los adenomas hipofisarios clínicamente no funcionantes son los tumores más frecuentes de la región selar. Dado que estas lesiones no resultan en un síndrome de hipersecreción hormonal, se manifiestan por síntomas compresivos como cefalea y alteraciones campimétricas, así como por manifestaciones clínicas de hipopituitarismo, o bien son descubiertos de forma incidental (en particular los microadenomas). Inmunohistoquímicamente, más del 45% de estos adenomas inmunotiñen para gonadotropinas o sus subunidades, por lo que se los conoce como gonadotropinomas; mientras que el 30% de los casos no inmunotiñe para ninguna hormona y se los denomina adenomas de células nulas. El abordaje diagnóstico de los adenomas hipofisarios clínicamente no funcionantes debe incluir la evaluación de los campos visuales y la medición de las hormonas de la hipófisis anterior, así como una resonancia magnética nuclear para establecer el tamaño y la extensión del tumor. El tratamiento de elección es la resección transesfenoidal del adenoma, que en ocasiones no se logra completamente. La tasa de recurrencia después de la cirugía puede ser de hasta el 30%. Los adenomas persistentes o recurrentes suelen ser tratados con radioterapia. Una proproción pequeña de estos pacientes puede responder de forma favorable a agonistas dopaminérgicos y, en menor medida, a análogos de la somatostatina (AU)


Assuntos
Humanos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/terapia , Hipopituitarismo/complicações , Hormônio Foliculoestimulante/análise , Neoplasias Hipofisárias/patologia , Linfócitos Nulos/patologia , Carcinogênese/patologia , Imuno-Histoquímica/métodos
13.
Oncol Rep ; 38(2): 1140-1148, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656268

RESUMO

Pituitary null cell adenoma is a challenging clinical condition, and its pathogenesis remains to be elucidated. We performed this study to determine the roles of C5orf66-AS1, NORAD, and TINCR in the pathogenesis and invasion of pituitary null cell adenomas. Expression of the three long non-coding RNAs in pituitary null cell adenoma tissues of 11 patients and normal pituitary tissues from four donors was examined by performing quantitative reverse transcription-polymerase chain reaction. We found that C5orf66-AS1 expression was lower in pituitary null cell adenoma tissues than in normal pituitary tissues. Moreover, C5orf66-AS1 expression level was significantly lower in invasive pituitary null cell adenomas than in non-invasive ones. After transfection of C5orf66-AS1 into pituitary adenoma cells, assessment of cell viability and invasion suggested that overexpressed C5orf66-AS1 inhibited cell viability and cell invasion. In silico algorithms predicted several cis- and trans-acting target genes of C5orf66-AS1, including PITX1 and SCGB3A1. In addition, expression of some of the predicted target genes was determined using microarray data of another cohort with pituitary null cell adenomas. It showed that some of these target genes were differentially expressed between pituitary null cell adenoma tissues and normal pituitary tissues as well as between invasive and non-invasive tumors. Co-expression analysis in RNA sequencing data showed that PAQR7 was the most correlated gene of C5orf66-AS1 and that several predicted trans-acting target genes, including SCGB3A1, were highly correlated with C5orf66-AS1. NORAD and TINCR expression was not statistically significant in the complete cohort; however, a negative correlation was observed between NORAD expression and maximum tumor diameter in some subgroups. These results indicate that C5orf66-AS1 suppresses the development and invasion of pituitary null cell adenomas. However, our results do not provide enough statistical evidence to support the roles of NORAD and TINCR in the development and invasion of pituitary null cell adenomas.


Assuntos
Biomarcadores Tumorais/genética , Linfócitos Nulos/patologia , Neoplasias Hipofisárias/patologia , RNA Longo não Codificante/genética , Adulto , Idoso , Apoptose , Proliferação de Células , Feminino , Seguimentos , Humanos , Linfócitos Nulos/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Hipofisárias/genética , Prognóstico , Células Tumorais Cultivadas
14.
Endocr Pathol ; 26(1): 63-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25403448

RESUMO

The aim of the study was to establish if the null cell adenoma (NCA) forms a distinct subgroup with unique clinicopathological characteristics within the nonfunctioning pituitary adenoma group particularly in relation to the silent gonadotroph adenomas (SGAs). We identified 31 patients with the pathological diagnosis of NCA verified by routine histology and immunohistochemistry with distinct differentiation from SGAs by an established negative testing for SF-1 at the Toronto Western Hospital between December 2004 and August 2010. We reviewed their demographic data, clinical features, magnetic resonance imaging, and the histologic variables: MIB-1, FGFR4, and P27. We compared these to 63 SGAs identified within the same period. All the NCAs were macroadenomas with diameter ranging from 15-57 mm and tumor volumes between 1.95-53.5 mm(3). Preoperative cavernous sinus tumor growth was able to predict the presence of a residual after surgery (p = 0.023). Furthermore, preoperative cavernous sinus extension (p = 0.002) and negative P27 expression (p = 0.035) were able to independently predict the subsequent growth of the postoperative tumor residual. Comparing the NCA to SGA, we found that MIB-1 was higher in NCA (mean ± SD = 3.43 ± 2.76 %) compared to SGAs (mean ± SD = 2.49 ± 1.41 %) (p = 0.044). The preoperative and postoperative tumor volume doubling times (TVDTs) displayed a negative correlation in the SGA (r = -0.855, p = 0.002) while in the NCA, a positive correlation was evident (r = 0.718, p = 0.029). Our study suggests that the NCAs are a distinct group with differing behavioral characteristics from the SGAs. It also appears that the finding of cavernous sinus extension on preoperative imaging and a negative P27 expression on immunohistochemistry in NCAs may be valuable tools in predicting residual tumor growth which may impact on postoperative care.


Assuntos
Adenoma/patologia , Linfócitos Nulos/patologia , Neoplasias Hipofisárias/patologia , Adenoma/diagnóstico , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
15.
Angiogenesis ; 18(1): 69-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25298070

RESUMO

Targeted ultrasound contrast imaging has the potential to become a reliable molecular imaging tool. A better understanding of the quantitative aspects of molecular ultrasound technology could facilitate the translation of this technique to the clinic for the purposes of assessing vascular pathology and detecting individual response to treatment. The objective of this study was to evaluate whether targeted ultrasound contrast-enhanced imaging can provide a quantitative measure of endogenous biomarkers. Endoglin, an endothelial biomarker involved in the processes of development, vascular homeostasis, and altered in diseases, including hereditary hemorrhagic telangiectasia type 1 and tumor angiogenesis, was the selected target. We used a parallel plate perfusion chamber in which endoglin-targeted (MBE), rat isotype IgG2 control and untargeted microbubbles were perfused across endoglin wild-type (Eng+/+), heterozygous (Eng+/-) and null (Eng-/-) embryonic mouse endothelial cells and their adhesion quantified. Microbubble binding was also assessed in late-gestation, isolated living transgenic Eng+/- and Eng+/+ embryos. Nonlinear contrast-specific ultrasound imaging performed at 21 MHz was used to collect contrast mean power ratios for all bubble types. Statistically significant differences in microbubble binding were found across genotypes for both in vitro (p<0.05) and embryonic studies (p<0.001); MBE binding was approximately twofold higher in Eng+/+ cells and embryos compared with their Eng+/- counterparts. These results suggest that molecular ultrasound is capable of reliably differentiating between molecular genotypes and relating receptor densities to quantifiable molecular ultrasound levels.


Assuntos
Embrião de Mamíferos/diagnóstico por imagem , Células Endoteliais/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Western Blotting , Adesão Celular/fisiologia , Endoglina , Células Endoteliais/diagnóstico por imagem , Genótipo , Linfócitos Nulos , Camundongos , Camundongos Knockout , Microbolhas , Imagem Molecular , Ratos , Ultrassonografia
17.
Eur J Immunol ; 43(2): 521-32, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23172374

RESUMO

Ikaros is important in the development and maintenance of the lymphoid system, functioning in part by associating with chromatin-remodeling complexes. We have studied the functions of Ikaros in the transition from pre-T cell to the CD4(+) CD8(+) thymocyte using an Ikaros null CD4(-) CD8(-) mouse thymoma cell line (JE131). We demonstrate that this cell line carries a single functional TCR ß gene rearrangement and expresses a surface pre-TCR. JE131 cells also carry nonfunctional rearrangements on both alleles of their TCR α loci. Retroviral reintroduction of Ikaros dramatically increased the rate of transcription in the α locus and TCR Vα/Jα recombination resulting in the appearance of many new αßTCR(+) cells. The process is RAG dependent, requires switch/sucrose nonfermentable chromatin-remodeling complexes and is coincident with the binding of Ikaros to the TCR α enhancer. Furthermore, knockdown of Mi2/nucleosome remodeling and deacetylase complexes increased the frequency of TCR α rearrangement. Our data suggest that Ikaros controls Vα/Jα recombination in T cells by controlling access of the transcription and recombination machinery to the TCR α loci. The JE131 cell line should prove to be a very useful tool for studying the molecular details of this and other processes involved in the pre-T cell to αßTCR(+) CD4(+) CD8(+) thymocyte transition.


Assuntos
Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Linfócitos Nulos/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Timoma/genética , Alelos , Animais , Linhagem Celular , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Linfócitos Nulos/metabolismo , Linfócitos Nulos/patologia , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Timoma/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética
18.
Thromb Haemost ; 108(5): 812-23, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22955940

RESUMO

Intraluminal thrombus formation in aortic abdominal aneurysms (AAA) is associated with adverse clinical prognosis. Interplay between coagulation and inflammation, characterised by leukocyte infiltration and cytokine production, has been implicated in AAA thrombus formation. We studied leukocyte (CD45+) content by flow cytometry in AAA thrombi from 27 patients undergoing surgical repair. Luminal parts of thrombi were leukocyte-rich, while abluminal segments showed low leukocyte content. CD66b+ granulocytes were the most prevalent, but their content was similar to blood. Monocytes (CD14+) and T cells (CD3+) were also abundant, while content of B lymphocytes (CD19+) and NK cells (CD56+CD16+) were low. Thrombi showed comparable content of CD14highCD16- monocytes and lower CD14highCD16+ and CD14dimCD16+, than blood. Monocytes were activated with high CD11b, CD11c and HLA-DR expression. Total T cell content was decreased in AAA thrombus compared to peripheral blood but CD8 and CD3+CD4-CD8- (double negative T cell) contents were increased in thrombi. CD4+ cells were lower but highly activated (high CD69, CD25 and HLA-DR). No differences in T regulatory (CD4+CD25+FoxP3+) cell or pro-atherogenic CD4+CD28null lymphocyte content were observed between thrombi and blood. Thrombus T cells expressed high levels of CCR5 receptor for chemokine RANTES, commonly released from activated platelets. Leukocyte or T cell content in thrombi was not correlated with aneurysm size. However, CD3+ content was significantly associated with smoking in multivariate analysis taking into account major risk factors for atherosclerosis. In conclusion, intraluminal AAA thrombi are highly inflamed, predominantly with granulocytes, CD14highCD16- monocytes and activated T lymphocytes. Smoking is associated with T cell infiltration in AAA intraluminal thrombi.


Assuntos
Aneurisma da Aorta Abdominal/complicações , Trombose/etiologia , Idoso , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Aortite/sangue , Aortite/complicações , Aortite/imunologia , Aortite/patologia , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Leucócitos/classificação , Leucócitos/imunologia , Leucócitos/patologia , Ativação Linfocitária , Linfócitos Nulos/imunologia , Linfócitos Nulos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Receptores CCR5/metabolismo , Fatores de Risco , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Trombose/sangue , Trombose/imunologia , Trombose/patologia
19.
Neurol Med Chir (Tokyo) ; 52(8): 591-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22976143

RESUMO

Coexistence of brain tumors of different pathologies is rare, and the majority of the cases were related to genetic disorders or secondary tumors occurring after radiotherapy. A 73-year-old man was introduced to the outpatient department suffering from severe nausea and vertigo. Magnetic resonance imaging showed a cystic tumor in the left cerebellar hemisphere and another lesion in the sella turcica. There was no evident family history of von Hippel-Lindau (VHL) disease, and the systemic investigation failed to detect any other tumors or signs of VHL disease. Treatment was performed in two stages, and he was discharged with remaining slight ataxic gait. The diagnoses were cerebellar hemangioblastoma and pituitary null cell adenoma. Additional immunohistochemical investigation using VHL disease gene-related protein in both tumors showed minute granular positive staining in the cytoplasm of stromal cells in the former, and diffuse and strong granular cytoplasmic positive staining in the latter. Further analysis is required to confirm the true implication of the VHL gene mutation, and the possible involvement of VHL gene-related protein in the pathogenesis of these coexisting tumors.


Assuntos
Adenoma/complicações , Neoplasias Cerebelares/complicações , Hemangioblastoma/complicações , Neoplasias Primárias Múltiplas/complicações , Neoplasias Hipofisárias/complicações , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Adenoma/metabolismo , Adenoma/patologia , Adenoma/cirurgia , Idoso , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/cirurgia , Hemangioblastoma/metabolismo , Hemangioblastoma/patologia , Hemangioblastoma/cirurgia , Humanos , Imuno-Histoquímica , Linfócitos Nulos , Masculino , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Resultado do Tratamento
20.
Endocr Pathol ; 23(3): 151-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22569896

RESUMO

Clinically nonfunctioning pituitary adenomas (CNFPAs) consist of several histological subtypes, including null cell adenoma (NCA), silent gonadotroph cell adenoma (SGA), silent corticotroph adenoma (SCA), and other silent adenomas (OSA) (i.e., GH, TSH, and prolactin adenomas). To detect possible correlations between MRI findings and the subtypes, we retrospectively studied 390 consecutive patients with CNFPA who underwent surgery between 2008 and 2010. They were classified into three groups: NCA/SGA (313 cases), SCA (39 cases), and OSA (36 cases); in addition there were two unusual cases of plurihormonal adenoma. Three MRI findings were less common in NCA/SGA than in the other groups (P < 0.0001): giant adenoma (>40 mm), marked cavernous sinus invasion (Knosp grade 4), and lobulated configuration of the suprasellar tumor. When these MRI findings were negative in patients older than 40 years old, 91.0% (212/233) were NCA/SGA. These MRI findings were frequently noted despite a low MIB-1 index in SCA. OSA showed a high MIB-1 index and a preponderance in younger patients. In conclusion, although SCA and OSA consisted of only 20% of CNFPAs, their frequency significantly increased when the tumor was large, invasive, and lobulated, and the patient was younger than 40 years old.


Assuntos
Adenoma/classificação , Adenoma/patologia , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Linfócitos Nulos/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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