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1.
J Neonatal Perinatal Med ; 9(1): 41-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27002269

RESUMO

BACKGROUND: Preeclampsia affects up to 10% of pregnancies worldwide and is one of the main causes of fetal morbidity and mortality. Although it has been linked to developmental delay, its long-term effects on neurologic development in children have yet to be sufficiently quantified. OBJECTIVES: To evaluate whether preeclampsia's severity and its obstetric management correlate to the degree of disability in these infants. MATERIALS AND METHOD: This is an observational and descriptive study performed on a population of 96 women who were diagnosed with preeclampsia at Hospital General Universitario Gregorio Marañón between 2007 and 2014, and their 111 children. To evaluate the mother, we gathered data pertaining to her medical history, renal function markers, and medical management of the preeclampsia. To assess the children, we collected fetal growth measurements, acute fetal distress markers and main diagnoses at birth. We used the Pediatric Evaluation of Disability Inventory in its computerized adaptive test version (PEDI-CAT) to study performance in the relevant areas, and the TNO-AZL Preschool children Quality of Life (TAPQOL) to estimate health-related quality of life. RESULTS: PEDI-CAT percentiles were consistently lower in the social/cognitive domain than in other areas. Lower social/cognitive percentiles were associated to both lower maternal IgG levels and presence of necrotizing enterocolitis during the neonatal period. CONCLUSIONS: A connection between preeclampsia and poor social/cognitive outcomes exists that warrants further research.


Assuntos
Deficiências do Desenvolvimento/etiologia , Crianças com Deficiência , Pré-Eclâmpsia/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Avaliação da Deficiência , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Psicometria , Estudos Retrospectivos
2.
Eur J Med Chem ; 66: 56-68, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23792316

RESUMO

A series of new histone deacetylase inhibitors were designed and synthesized based on hybridization between SAHA or oxamflatin and 5-phenyl-1,4-benzodiazepines. The compounds were tested for their enzyme inhibitory activity on HeLa nuclear extracts, and on human recombinant HDAC1 and HDAC6. Antiproliferative activity was tested on different cancer cells types, while proapoptotic activity was primarily tested on NB4 cells. The compounds showed IC50 values similar to those of SAHA. Compound (S)-8 displayed interesting activity against hematological and solid malignancies.


Assuntos
Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodiazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Inibidores de Histona Desacetilases/química , Humanos , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade
3.
Br J Pharmacol ; 169(1): 156-66, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23347136

RESUMO

BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinazolinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Glioma/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Quinazolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Leukemia ; 26(7): 1630-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22333881

RESUMO

Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.


Assuntos
Anticonvulsivantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Ácido Valproico/farmacologia , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Recidiva Local de Neoplasia , Proteínas de Fusão Oncogênica/metabolismo , Transdução de Sinais , Tretinoína/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Immunopathol Pharmacol ; 20(1): 103-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17346433

RESUMO

Rheumatoid arthritis (RA) is currently believed to have originated in America, and after the discovery of this continent in 1492, to have been exported to the Old World. We evaluated the genetic predisposition to RA in the "Braids Lady" from Arezzo (Italy), a partially mummified woman's body dating back to the end of 1500 AD which presents the anatomical and pathological features of this disease. The study of the polymorphic HLA-DRB1 locus, which includes alleles strongly associated with RA onset, has received much attention over recent years, especially the loci codifying for the DR1 and DR4 antigens, widely represented in the Mediterranean population, and for DR14, widespread among Native Americans. Molecular analysis was performed on extracts of DNA from the mummy, firstly from histological bone sections and then from the whole bone. Two different HLA typing techniques, PCR-sequence-specific oligonucleotides (PCR-SSO) and PCR-sequence-specific primers (PCR-SSP), were employed to identify HLA-DRB alleles. Both genotyping methods showed that the "Braids Lady" carried the DRB1*0101 allele, the serological equivalent of the DR1 antigen. Although the possession of RA risk factor genes cannot be considered a diagnostic marker, the positive result of the Italian mummy for DRB1*0101 and the RA features present, support the idea that this pathology was present in the Old World from at least the mid-16th century. A pathogenetic hypothesis of RA which might well explain its worldwide diffusion is the "molecular mimicry", resulting from a cross-reactive antibody response between certain microbial antigens and shared epitopes of specific HLA-DR1, DR4 and DR14 susceptibility alleles, the frequency of which varies among different ethnic groups.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Artrite Reumatoide/patologia , Osso e Ossos/patologia , DNA/genética , DNA/isolamento & purificação , Sondas de DNA de HLA , Feminino , Dedos/patologia , Teste de Histocompatibilidade , Humanos , Úmero/patologia , Itália , Pessoa de Meia-Idade , Paleontologia , Inclusão em Parafina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Dedos do Pé/patologia
6.
EMBO J ; 21(12): 3171-81, 2002 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-12065429

RESUMO

Studies in model organisms have contributed to elucidate multiple levels at which regulation of eukaryotic DNA replication occurs. Cdc7, an evolutionarily conserved serine-threonine kinase, plays a pivotal role in linking cell cycle regulation to genome duplication, being essential for the firing of DNA replication origins. Binding of the cell cycle-regulated subunit Dbf4 to Cdc7 is necessary for in vitro kinase activity. This binding is also thought to be the key regulatory event that controls Cdc7 activity in cells. Here, we describe a novel human protein, Drf1, related to both human and yeast Dbf4. Drf1 is a nuclear cell cycle-regulated protein, it binds to Cdc7 and activates the kinase. Therefore, human Cdc7, like cyclin-dependent kinases, can be activated by alternative regulatory subunits. Since the Drf1 gene is either absent or not yet identified in the genome of model organisms such as yeast and Drosophila, these findings introduce a new level of complexity in the regulation of DNA replication of the human genome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ciclo Celular/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Linhagem Celular , Forminas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/química , Proteínas Nucleares/genética , Filogenia , Ligação Proteica , Proteínas Serina-Treonina Quinases/química , Subunidades Proteicas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
7.
Ann Ital Chir ; 73(4): 377-9, 2002.
Artigo em Italiano | MEDLINE | ID: mdl-12661225

RESUMO

Female breast carcinoma with neuroendocrine differentiation is a lesion which can enhance of conventional therapy added with tamoxifene-octreotide association. The Authors report a case completely responsive after two years therapy, which grading was: pT4, N1biii, Mx, G2 staging III.


Assuntos
Neoplasias da Mama/patologia , Tumores Neuroendócrinos/patologia , Idoso , Feminino , Humanos
8.
EMBO Rep ; 1(1): 71-9, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11256629

RESUMO

The Cdc25 A phosphatase is required for the G1-S transition of the cell cycle and is overexpressed in human cancers. We found that it is ubiquitylated and rapidly degraded by the proteasome and that its levels increase from G1 until mitosis. By treating cells with the DNA synthesis inhibitor hydroxyurea, Cdc25 A rapidly decreased in abundance, and this was accompanied by an increase in Cdk2 phosphotyrosine content and a decrease in Cdk2 kinase activity. Cdc25 A overexpression altered the ability of cells to arrest in the presence of hydroxyurea, and caused them to undergo premature chromosome condensation. Cdc25 A overexpression could render tumor cells less sensitive to DNA replication checkpoints, thereby contributing to their genomic instability.


Assuntos
Fase S/fisiologia , Fosfatases cdc25/metabolismo , Bromodesoxiuridina/metabolismo , Cicloeximida/farmacologia , Fase G1/fisiologia , Células HeLa , Humanos , Hidroxiureia/farmacologia , Immunoblotting , Microscopia de Fluorescência , Mitose/fisiologia , Nocodazol/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Plasmídeos/genética , Plasmídeos/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Fase S/efeitos dos fármacos , Transfecção , Ubiquitinas/metabolismo
10.
Biochem Biophys Res Commun ; 233(3): 673-7, 1997 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-9168912

RESUMO

Butyrate, a dietary fiber derivative, is a well-known differentiating agent in cultured cell lines. In addition, its antineoplastic activity toward colon-rectum cancers has been documented both in vivo and in vitro. Despite the large amount of information on the potential clinical efficacy of butyrate, its mechanism of action at the molecular level has only been partially investigated. Here, we show that serine/threonine protein kinase CKII is a target of butyrate activity. In the human adenocarcinoma cell line, HT29, treated with 2 mM sodium butyrate, CKII activity decreases 50% at 24 and 48 hours after drug addition. The enzyme down-regulation is not due to changes in protein amount since the levels of the different CKII subunits remain constant during butyrate treatment. The data reported provide the first evidence that CKII down-regulation is involved in the signal transduction pathway started by butyrate.


Assuntos
Butiratos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Adenocarcinoma/enzimologia , Sequência de Aminoácidos , Ácido Butírico , Caseína Quinase II , Diferenciação Celular/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Oligopeptídeos/química , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Células Tumorais Cultivadas
11.
J Biol Chem ; 271(27): 15942-9, 1996 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-8663131

RESUMO

The regulation of the D-type cyclin-dependent kinase (CDK4 and CDK6) activity appears to be the key step in the progression of eukaryotic cells through the G1 cell cycle phase. One of the mechanisms involved in this process is the binding of some small proteic inhibitors, with a molecular mass ranging between 14 and 20 kDa, to these CDKs. We have evaluated the amount of two such inhibitors, namely p16(INK4) and p18, in normal and transformed cells, as well as the biochemical features of the macromolecular complexes containing these proteins. The results obtained indicated that (i) p18 gene expression, unlike p16(INK4) gene, is not regulated by pRb status, (ii) no evident relationship exists between the expression of p16(INK4) and p18 genes, (iii) significant amounts of the two proteins are not bound to CDKs but occur as free molecules, (iv) each inhibitor forms a complex with the CDK protein with a 1:1 stoichiometry, and (v) a competition exists between cyclin D and the inhibitor protein toward the CDK protein resulting in the absence of detectable cellular free kinase. Moreover, employing the human native partially purified p16(INK4)or the pure recombinant protein, we have been able to demonstrate in vitro the dissociation of CDK4-cyclin D1 complex and the formation of CDK4-p16(INK4) bimolecular complex. Our findings suggest that during the cell division cycle the members of the p16(INK4) protein family and cyclin Ds compete for binding to CDK4/CDK6 and that their quantitative ratio is essential for G1 --> S transition.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Inibidores Enzimáticos , Proteínas Proto-Oncogênicas , Proteína do Retinoblastoma/metabolismo , Proteínas Supressoras de Tumor , Proteínas de Transporte/biossíntese , Proteínas de Transporte/isolamento & purificação , Linhagem Celular , Linhagem Celular Transformada , Cromatografia em Gel , Ciclina D1 , Quinase 4 Dependente de Ciclina , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18 , Quinases Ciclina-Dependentes/isolamento & purificação , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/isolamento & purificação , Ciclinas/metabolismo , Escherichia coli , Expressão Gênica , Genes Supressores de Tumor , Humanos , Immunoblotting , Cinética , Peso Molecular , Proteínas Oncogênicas/isolamento & purificação , Proteínas Oncogênicas/metabolismo , Ligação Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Células Tumorais Cultivadas
12.
Biochem Biophys Res Commun ; 223(3): 514-9, 1996 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-8687427

RESUMO

5'-Methylthioadenosine phosphorylase gene maps on the 9p21 chromosome, strictly linked to the important tumor suppressor gene p16INK4A. Chromosomal deletions encompassing both the phosphorylase and p16INK4A genes cause the complete absence of the enzymatic activity in a large number of tumors, thus resulting in well-defined metabolic differences between malignant and normal cells. Recently, the cloning of the phosphorylase gene has been reported on the basis of indirect evidence. In order to demonstrate definitely the identification of 5'-methylthioadenosine phosphorylase gene, we have cloned the putative enzyme coding sequence in a prokaryotic expression vector and expressed the protein in bacteria. The recombinant phosphorylase has been purified to homogeneity and its physicochemical, immunological and kinetic features have been characterized. The results obtained allowed the conclusive demonstration of 5'-methylthioadenosine phosphorylase gene cloning and the use of recombinant protein for further characterization.


Assuntos
Purina-Núcleosídeo Fosforilase/isolamento & purificação , Purina-Núcleosídeo Fosforilase/metabolismo , Cromatografia em Gel , Cromatografia por Troca Iônica , Mapeamento Cromossômico , Cromossomos Humanos Par 9 , Clonagem Molecular , DNA Complementar , Inibidores Enzimáticos/farmacologia , Escherichia coli , Ligação Genética , Humanos , Isopropiltiogalactosídeo/farmacologia , Peso Molecular , Fosfatos/farmacologia , Purina-Núcleosídeo Fosforilase/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
13.
Haematologica ; 80(6): 557-68, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8647524

RESUMO

Recent advances in cancer biology have clearly demonstrated that the development of neoplasms as well as their progression are strictly linked to the alteration of molecular mechanisms controlling the cell division cycle. Among these mechanisms the functional inactivation of two important tumor suppressor genes, namely RB1 and p53, has been widely recognized as a pivotal step in human cancerogenesis. In addition to such well-known genes, a new tumor suppressor gene, mapping on chromosome 9p21, has recently been identified and cloned. Several findings suggest that its loss of function is involved in the initiation and/or progression of an enormous number of different malignancies. This gene, named p16INK4, codifies for a small protein capable of binding to, and thus of inhibiting, some specific cyclin-dependent threonine-serine kinases that represent key enzymatic activities essential for the G1-S transition in mammalian cells. This review will summarize some aspects of the cell cycle control mechanisms, with major emphasis devoted to the role played by this recently characterized inhibitor and to the possible linkage between its inactivation and cancer formation. In particular, we will discuss these aspects in the light of the role of p16INK4 gene inactivation in the development of human acute lymphoblastic leukemias. Indeed this gene seems to be the first, and so far the only tumor suppressor gene consistently altered in specific acute hematological malignancies. Finally, future trends in the investigation of cell cycle control and leukemogenesis will be analyzed.


Assuntos
Genes Supressores de Tumor , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Ciclo Celular/genética , Humanos
15.
J Esthet Dent ; 4(5): 159-63, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1288601

RESUMO

A microleakage and scanning electron microscope (SEM) study was conducted in order to investigate the effects of acidic primers on prepared dentin surfaces. The microleakage study revealed that no significant differences were noted between the five materials tested in regard to leakage at enamel and dentin margins. SEM analyses revealed that the smear layers of all specimens were altered in some manner. Further long-term clinical studies should be conducted to evaluate acidic treatment of dentin.


Assuntos
Adesivos Dentinários/farmacologia , Dentina/efeitos dos fármacos , Ácido Nítrico , Cimentos de Resina , Resinas Compostas/farmacologia , Forramento da Cavidade Dentária , Infiltração Dentária , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Nitratos/farmacologia , Oxalatos/farmacologia , Camada de Esfregaço
16.
Clin Orthop Relat Res ; (158): 129-6, 1981.
Artigo em Inglês | MEDLINE | ID: mdl-7023772

RESUMO

Four cases of osteochondritis dissecans, three of the knee and one of the talus in situ (prior to loosening of the fragment from its host bone) were successfully treated with modified drilling and bone grafting procedure. The procedure consists of retrograde insertion of a small guide pin through the radiolucent zone and osteochondral fragment to the subchondral bone, retrograde reaming of bone across the radiolucent zone into the osteochondral fragment with a bone biopsy needle, and cancellous bone grafting between the osteochondral fragment and the host bone. All lesions were found to be healed after more than six months' follow-up. Three patients had complete relief and the fourth had significant improvement of symptoms.


Assuntos
Parafusos Ósseos , Transplante Ósseo , Artropatias/cirurgia , Osteocondrite/cirurgia , Adolescente , Adulto , Articulação do Tornozelo/cirurgia , Criança , Seguimentos , Humanos , Artropatias/diagnóstico por imagem , Articulação do Joelho/cirurgia , Masculino , Osteocondrite/diagnóstico por imagem , Radiografia
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