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1.
Clin Immunol ; 214: 108375, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135275

RESUMO

Up to 80% of juvenile-onset systemic lupus erythematosus (jSLE) patients develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably diagnose LN, leaving kidney biopsies as the gold-standard. Calcium-binding S100 proteins are expressed by innate immune cells and epithelia and may act as biomarkers in systemic inflammatory conditions. We quantified S100 proteins in the serum and urine of jSLE patients, matched healthy and inflammatory (IgA vasculitis) controls. Serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients when compared to controls. Furthermore, serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients with active as compared to patients with inactive/no LN. No differences in S100A4 levels were seen between groups. This study demonstrates potential promise for S100A8/A9 and S100A12 as biomarkers for jSLE and active LN. Findings require to be confirmed and tested prospectively in independent and larger multi-ethnic cohorts.


Assuntos
Calgranulina A/sangue , Calgranulina B/sangue , Calgranulina B/urina , Nefrite Lúpica/sangue , Nefrite Lúpica/urina , Proteína S100A12/sangue , Proteína S100A12/urina , Adolescente , Idade de Início , Biomarcadores/sangue , Biomarcadores/urina , Calgranulina A/análise , Estudos de Casos e Controles , Criança , Pré-Escolar , Creatinina/sangue , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/urina , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Prognóstico , Índice de Gravidade de Doença , Adulto Jovem
2.
Leukemia ; 22(1): 66-77, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17851551

RESUMO

Human leukemias harboring chromosomal translocations involving the mixed lineage leukemia (MLL, HRX, ALL-1) gene possess high-level expression, and frequent activating mutations of the receptor tyrosine kinase FLT3. We used a murine bone marrow transplant model to assess cooperation between MLL translocation and FLT3 activation. We demonstrate that MLL-AF9 expression induces acute myelogenous leukemia (AML) in approximately 70 days, whereas the combination of MLL-AF9 and FLT3-ITD does so in less than 30 days. Secondary transplantation of splenic cells from diseased mice established that leukemia stem cells are present at a very high frequency of approximately 1:100 in both diseases. Importantly, prospectively isolated granulocyte macrophage progenitors (GMPs) coinfected with MLL-AF9 and FLT3-ITD give rise to a similar AML, with shorter latency than from GMP transduced with MLL-AF9 alone. Cooperation between MLL-AF9 and FLT3-ITD was further verified by real-time assessment of leukemogenesis using noninvasive bioluminescence imaging. We used this model to demonstrate that MLL-AF9/FLT3-ITD-induced leukemias are sensitive to FLT3 inhibition in a 2-3 week in vivo assay. These data show that activated FLT3 cooperates with MLL-AF9 to accelerate onset of an AML from whole bone marrow as well as a committed hematopoietic progenitor, and provide a new genetically defined model system that should prove useful for rapid assessment of potential therapeutics in vivo.


Assuntos
Modelos Animais de Doenças , Leucemia Mieloide Aguda/etiologia , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Southern Blotting , Western Blotting , Transplante de Medula Óssea , Proliferação de Células , Feminino , Granulócitos/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Imunoprecipitação , Leucemia Mieloide Aguda/patologia , Luciferases/metabolismo , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sequências de Repetição em Tandem , Transfecção , Células Tumorais Cultivadas , Tirosina Quinase 3 Semelhante a fms/metabolismo
3.
Nat Med ; 6(8): 904-9, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10932228

RESUMO

The facilitating cell is a rare CD8+ bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3epsilon-associated complex on the facilitating cell surface that consists of the T-cell receptor beta-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor beta. Expression of this CD3-T-cell receptor beta-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Complexo CD3/química , Complexo CD3/metabolismo , Linfócitos T CD8-Positivos/transplante , Proteínas de Transporte/genética , Dimerização , Dissulfetos/química , Facilitação Imunológica de Enxerto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Quaternária de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transplante Homólogo
4.
Cell Tissue Res ; 291(2): 175-89, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9426306

RESUMO

As an alternative to primary fetal tissue, immortalized central nervous system (CNS)-derived cell lines are useful for in vitro CNS model systems and for gene manipulation with potential clinical use in neural transplantation. However, obtaining immortalized cells with a desired phenotype is unpredictable, because the molecular mechanisms of growth and differentiation of CNS cells are poorly understood. The SV40 large T antigen is commonly used to immortalize mammalian cells, but it interferes with multiple cell-cycle components, including p53, p300, and retinoblastoma protein, and usually produces cells with undifferentiated phenotypes. In order to increase the phenotypic repertoire of immortalized CNS cells and to address the molecular mechanisms underlying immortalization and differentiation, we constructed an expression vector containing a truncated SV40 large T gene that encodes only the amino-terminal 155 amino acids (T155), which lacks the p53-binding domain. Constructs were first transfected into a p53-temperature-sensitive cell line, T64-7B. Colonies expressing T155 proliferated at the growth-restrictive temperature. T155 was then transfected into primary cultures from embryonic day-14 rat mesencephalon. Two clonal cell lines were derived, AF-5 and AC-10, which co-expressed T155 and mature neuronal and astrocytic markers. Thus, the amino-terminal portion of SV40 large T is sufficient to: (1) overcome p53-mediated growth arrest despite the absence of a p53-binding region, and (2) immortalize primary CNS cells expressing mature markers while actively dividing. T155 and T155-transfectants may be useful for further studies of cell-cycle mechanisms and phenotyic expression in CNS cells or for further gene manipulation to produce cells with specific properties.


Assuntos
Antígenos Transformantes de Poliomavirus/metabolismo , Transformação Celular Viral , Mesencéfalo/citologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antígenos Transformantes de Poliomavirus/química , Sítios de Ligação , Ciclo Celular , Linhagem Celular Transformada , Fibroblastos/citologia , Neurônios/citologia , Nervo Óptico/citologia , Fenótipo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Transfecção , Proteína Supressora de Tumor p53/antagonistas & inibidores
5.
Clin Exp Pharmacol Physiol ; 18(7): 469-74, 1991 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1680587

RESUMO

1. The proposition that stimulation of the secretomotor nerve to the ovine parotid gland might involve co-release of vasoactive intestinal peptide (VIP) was tested by studying responses to infusion of VIP directly into the gland's arterial blood supply and by assay of VIP in parotid venous blood. 2. In unstimulated glands, an arterial blood concentration of 1.5 - 2.5 X 10(-9) mol/L VIP did not evoke fluid secretion but it increased K+ and phosphate secretion and glandular blood flow. The same blood concentration of VIP potentiated the stimulation of salivary flow rate caused by intraarterial infusion of bethanechol but nerve stimulation was not potentiated. VIP increased glandular blood flow in both conditions of stimulation. 3. Atropine blocked neurally stimulated salivary secretion but an increase in glandular blood flow was still detectable. There was therefore no evidence for a non-cholinergic neural mechanism for salivary secretion. 4. Furthermore, VIP concentrations in glandular venous blood were not increased by nerve stimulation. 5. The results indicate that exogenous VIP can affect the flow and composition of ovine parotid secretion but was not involved in the response to secretomotor nerve stimulation.


Assuntos
Glândula Parótida/metabolismo , Peptídeo Intestinal Vasoativo/fisiologia , Animais , Atropina/farmacologia , Betanecol , Compostos de Betanecol/farmacologia , Estimulação Elétrica , Infusões Intra-Arteriais , Glândula Parótida/irrigação sanguínea , Glândula Parótida/inervação , Fosfatos/metabolismo , Potássio/metabolismo , Saliva/efeitos dos fármacos , Saliva/metabolismo , Salivação/efeitos dos fármacos , Ovinos , Estimulação Química , Peptídeo Intestinal Vasoativo/sangue , Peptídeo Intestinal Vasoativo/farmacologia
6.
Biochemistry ; 30(2): 569-75, 1991 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-1899030

RESUMO

Complementary DNA clones coding for the human secreted carbonic anhydrase isozyme (CA VI) have been isolated and their nucleotide sequences determined. These clones identify a 1.45-kb mRNA that is present in high levels in parotid submandibular salivary glands but absent in other tissues such as the sublingual gland, kidney, liver, and prostate gland. Hybridization histochemistry of human salivary glands shows mRNA for CA VI located in the acinar cells of these glands. The cDNA clones encode a protein of 308 amino acids that includes a 17 amino acid leader sequence typical of secreted proteins. The mature protein has 291 amino acids compared to 259 or 260 for the cytoplasmic isozymes, with most of the extra amino acids present as a carboxyl terminal extension. In comparison, sheep CA VI has a 45 amino acid extension [Fernley, R. T., Wright, R. D., & Coghlan, J. P. (1988b) Biochemistry 27, 2815]. Overall the human CA VI protein has a sequence identity of 35% with human CA II, while residues involved in the active site of the enzymes have been conserved. The human sheep secreted carbonic anhydrases have a sequence identity of 72%. This includes the two cysteine residues that are known to be involved in an intramolecular disulfide bond in the sheep CA VI. The enzyme is known to be glycosylated and three potential N-glycosylation sites (Asn-X-Thr/Ser) have been identified. Two of these are known to be glycosylated in sheep CA VI. Southern analysis of human DNA indicates that there is only one gene coding for CA VI.


Assuntos
Anidrases Carbônicas/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Southern Blotting , Clonagem Molecular , DNA/genética , Expressão Gênica , Genes , Humanos , Dados de Sequência Molecular , RNA Mensageiro/genética , Ovinos/genética
7.
Am J Clin Pathol ; 92(5): 659-61, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2816818

RESUMO

A technique for measuring the absorption of 260-nm ultraviolet light by cell nuclei is described. The results of such measurements of normal thyroid epithelial cells and benign and malignant thyroid neoplastic cells demonstrate a progressive increase in absorbance that correlates with the histologic appearance of neoplasia. The possible theoretic basis for this phenomenon is explored. The increased nuclear absorbance observed in neoplastic cells is hypothesized to result from the disruption of hydrogen bonds between the DNA base pairs, which allows unwinding of the double helix and loss of the normal control of mitosis.


Assuntos
Núcleo Celular/fisiologia , Glândula Tireoide/ultraestrutura , Neoplasias da Glândula Tireoide/fisiopatologia , Raios Ultravioleta , Absorção , Adenocarcinoma/fisiopatologia , Adenoma/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fotometria
8.
Biochemistry ; 27(8): 2815-20, 1988 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-3135834

RESUMO

The primary structure of the secreted carbonic anhydrase from ovine salivary glands has been determined by automated Edman sequence analysis of peptides generated by cyanogen bromide and tryptic cleavage of the protein and Staphylococcus aureus V8 protease, trypsin, and alpha-chymotrypsin subdigests of the large cyanogen bromide peptides. The enzyme is a single polypeptide chain comprising 307 amino acids and contains two apparent sites of carbohydrate attachment at Asn-50 and Asn-239. The protein contains two half-cystine residues at 25 and 207 which appear to form an intramolecular disulfide bond. Salivary carbonic anhydrase shows 33% sequence identity with the ovine cytoplasmic carbonic anhydrase II enzyme, with residues involved in the active site highly conserved. Compared to the cytoplasmic carbonic anhydrases, the secreted enzyme has a carboxyl-terminal extension of 45 amino acids. This is the first report of the complete amino acid sequence of a secreted carbonic anhydrase (CA VI).


Assuntos
Anidrases Carbônicas , Saliva/enzimologia , Sequência de Aminoácidos , Animais , Brometo de Cianogênio , Isoenzimas , Dados de Sequência Molecular , Fragmentos de Peptídeos/análise , Homologia de Sequência do Ácido Nucleico , Serina Endopeptidases , Ovinos , Tripsina
11.
Aust N Z J Surg ; 36(1): 1-2, 1966 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-5334316
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