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1.
J Endocrinol Invest ; 46(5): 1009-1016, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36459368

RESUMO

PURPOSE: To evaluate: (1) clinical and epidemiological characteristics of outpatients transitioned from Pediatrics Endocrine (PED) to Adult Endocrine Department (AED) in a tertiary center; (2) transition process features, and predictors of drop-out. METHODS: Demographic, clinical, and transition features of 170 consecutive patients with pediatric onset of chronic endocrine or metabolic disease (excluded type 1 diabetes) who transitioned from PED to AED (2007-2020) were retrospective evaluated. RESULTS: The age at transition was 18.4 ± 4 years (F:M = 1.2: 1), and mean follow-up 2.8 years. The population was heterogeneous; the most (69.4%) was affected by one, 24.1% by two or more endocrine diseases, 6.5% were followed as part of a cancer survivor's surveillance protocol. The comorbidity burden was high (37, 20.6, and 11.2% of patients had 2, 3, 4, or more diseases). The number of visits was associated with the number of endocrine diseases and the type of them. Adherent subjects had a higher number of comorbidities. Thyroid disorders and more than one comorbidity predicted the adherence to follow-up. Having performed one visit only was predictive of drop-out, regardless of the pathology at diagnosis. CONCLUSION: This is the first study that analyzed a specific transition plan for chronic endocrine diseases on long-term follow-up. The proposed "one-size-fits-all model" is inadequate in responding to the needs of patients. A structured transition plan is an emerging cornerstone.


Assuntos
Doenças do Sistema Endócrino , Endocrinologia , Neoplasias , Adulto , Humanos , Criança , Adolescente , Adulto Jovem , Seguimentos , Estudos Retrospectivos , Doenças do Sistema Endócrino/epidemiologia
3.
J Endocrinol Invest ; 41(8): 977-983, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29423542

RESUMO

PURPOSE: To describe the course of growth hormone response to growth hormone releasing hormone (GHRH) plus arginine provocative test in children with idiopathic short stature (ISS) and to evaluate the role of peak time. METHODS: A retrospective study was performed analyzing 344 GHRH plus arginine provocative tests performed in children and adolescents with short stature. Serum GH levels were measured at four-time points (T0', T30', T45' and T60') and GH peak was defined as the maximum value at any time point. Mean (T30'-T60') GH value and area under the curve (AUC) were calculated. RESULTS: When analyzing the time of peak at the provocative test, the most frequent peak time was T45' (53.8%) in the ISS group, with no differences in gender, age, and pubertal stage. Analyzing GHD subjects, the most frequent time of peak was T30 (50%). Analyzing the whole population, the GH T0' levels were significantly lower in subjects with the GH peak at T45' than those with the GH peak at T30' (1.7 ± 2.0 vs. 3.2 ± 4.0, p < 0.001). In subjects with GH peak at T45', the value of GH peak, AUC and mean GH were significantly higher than in those with GH peak at T30' and T60'. A direct correlation was found between the value of GH peak and growth velocity SDS (r = 0.127, p = 0.04) and a negative one between GH peak and GH level at T0' (r = - 0.111, p = 0.04), even when adjusted for gender, age, pubertal stage and BMI Z score. CONCLUSIONS: The time peak at 45 min seems to be associated with a better response to the test considering GH peak, mean and AUC. Patients with a GH peak at 30 min more probably could have a derangement in GH secretion showing worst growth pattern and/or a GH deficiency and should be carefully observed.


Assuntos
Arginina/administração & dosagem , Nanismo/sangue , Nanismo/tratamento farmacológico , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento Humano/sangue , Imunoensaio/métodos , Adolescente , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos
5.
Oncogene ; 34(23): 3076-84, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-25088204

RESUMO

The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including Hmga2, c-Myc and Igf2bp3. This H19/let-7-dependent regulation is recapitulated in vivo where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19 via DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.


Assuntos
Neoplasias do Endométrio/patologia , Metformina/farmacologia , MicroRNAs/metabolismo , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA/efeitos dos fármacos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , MicroRNAs/genética , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Transdução de Sinais
6.
Br J Cancer ; 111(9): 1750-6, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25268372

RESUMO

BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Técnicas In Vitro , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Endocrinol Invest ; 37(9): 805-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24923900

RESUMO

BACKGROUND: Vitamin D exerts pleiotropic effects and few studies are available in the Italian population. AIM: Aim of our study was to evaluate vitamin D status in children living in Northern Italy. METHODS: We studied vitamin D levels in a population of 113 normal weight (NW) and 444 obese (OB) children, prepubertal and pubertal. We considered vitamin D levels >20 ng/ml as normal, but also measured percentage of children with vitamin D levels higher than a cutoff of 30 ng/ml. RESULTS: 68.2 % of NW children showed normal levels of vitamin D, while 31.8 % showed a clear vitamin D deficiency. Only 28.3 % showed vitamin D levels higher than 30 ng/ml. Obese children showed 55.6 % of subjects with normal levels of vitamin D and 44.4 % of subjects a status of vitamin D deficiency. Only the 18.9 % showed vitamin D levels higher than 30 ng/ml. Mean vitamin D levels in NW children (27.3 ± 1.2 ng/ml) were higher than in OB children (21.8 ± 0.6 ng/ml). No differences have been found between prepubertal and pubertal children in terms of vitamin D levels. CONCLUSIONS: Our paediatric population demonstrates a low percentage of vitamin D sufficiency. In particular, obese children show only 19 % of subjects with normal levels while almost half of this population shows a clear deficiency. Further studies are needed to support these results and to evaluate the possible metabolic consequences.


Assuntos
Peso Corporal , Obesidade Infantil/sangue , Puberdade/sangue , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Adolescente , Criança , Feminino , Humanos , Itália/epidemiologia , Masculino , Obesidade Infantil/epidemiologia , Deficiência de Vitamina D/epidemiologia
8.
Minerva Pediatr ; 65(6): 673-6, 2013 Dec.
Artigo em Italiano | MEDLINE | ID: mdl-24217636

RESUMO

The craniopharyngioma is a benign intracranial nonglial tumor derived from a malformation of the embryonic tissue. Represents approximately 6-9% of brain tumors in children. It grows close to the optic nerve, hypothalamus and pituitary. The most frequent histological variety in children is adamantinomatous. The initial symptoms of intracranial hypertension is headache and nausea, followed by visual disturbances, impaired hormonal changes such as the secretion of GH, gonadotropins, TSH and ACTH and central diabetes insipidus. We present the clinical case of MD, 5yrs at age, which shows signs of intracranial hypertension syndrome: neuroradiological findings raise the diagnosis of adamantinomatous craniopharyngioma for which the child underwent to sub-total surgical removal of the lesion and radiosurgery treatment. During the disease develops visual impairment, and secondary diabetes insipidus, hypothyroidism hipocotisolism that takes therapy with desmopressin (Minirin), Cortone acetate and L-tiroxine. For the failure of previous therapies, the child has performed chemotherapy with cisplatin (30 mg/sqm/day) and Etoposide (150 mg/mq/day). A year after the end of the last cycle of chemotherapy was detected new progression of the lesion with the appearance of worsening headache and vomiting in the upright position. TC notes the expansion of the third ventricle and the patient undergoes surgery craniotomy. This clinical case underlines the difficulties in treatment of recurrent craniopharyngioma in situations where the anatomical location do not permit aggressive radical surgery. Anyway, new studies are needed to evaluate the effectiveness of systemic chemotherapy as a method of experimental treatment that could reduce the progression of disease.


Assuntos
Craniofaringioma/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias Hipofisárias/terapia , Pré-Escolar , Humanos , Masculino , Equipe de Assistência ao Paciente
9.
Br J Cancer ; 109(2): 462-71, 2013 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-23807163

RESUMO

BACKGROUND: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. METHODS: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. RESULTS: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs. CONCLUSION: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Mamoglobina B/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Mamoglobina B/genética , Análise em Microsséries , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Transcriptoma , Estudos de Validação como Assunto
10.
J Endocrinol Invest ; 36(9): 716-21, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23563316

RESUMO

BACKGROUND: TSHR is a G-protein-coupled seven transmembrane domain receptor that activates the two major signal transduction pathways: the Gαs/adenylate cyclase and the Gαq/11/phospholipase C pathways. Inactivating mutations in the TSHR gene have been demonstrated to be responsible for subclinical hypothyroidism, a disorder characterized by elevated serum TSH concentrations despite normal thyroid hormones levels. AIM: We identified in a child a nonsense mutation (W520X) in the third transmembrane domain of the TSHR that causes the lack of the C-terminus portion of the receptor. The functional significance of this variation was assessed in vitro. MATERIAL/SUBJECT AND METHODS: The W520X mutation was introduced into the pSVL vector containing the wild-type sequence of TSHR gene. Wild-type and mutated vectors were expressed in Chinese Hamster Ovary (CHO) cells, and cAMP, inositol phosphate (IP), immunofluorescence and FACS analyses were performed. RESULTS: Transfection with pSVL-TSHR vector induced basal cAMP and IP production in the absence of TSH stimulation, indicating a constitutive activity for the TSHR. An impairment of receptor function was demonstrated by the observation that cells expressing the mutant TSHR exhibited a lower second messenger production with respect to the wild-type, despite a normal expression of the receptor at the cell surface. CONCLUSIONS: The mechanism through which the W520X mutation exerts its effect is more likely haploinsufficiency rather than a dominant-negative effect. This could explain the phenotype of our patient, who has a hormonal pattern in the range of a mild subclinical hypothyroidism, without an overt disease phenotype.


Assuntos
Hipotireoidismo/genética , Receptores da Tireotropina/genética , Animais , Células CHO , Criança , Cricetinae , Cricetulus , Feminino , Haploinsuficiência , Humanos , Masculino , Receptores da Tireotropina/fisiologia
11.
Pituitary ; 16(4): 499-506, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23179963

RESUMO

To assess the incidence of abnormal neuroendocrine function post-traumatic brain injuriy (TBI) in a large group of paediatric patients and its correlations with clinical parameters (Glasgow coma scale-GCS, Glasgow outcome scale-GOS, TC marshall scale, height velocity). We evaluated 70 patients [58 M, 12 F; age at the time of TBI (mean ± SEM) 8.12 ± 4.23 years] previously hospitalized for TBI at the "Regina Margherita" Hospital, in Turin and "Maggiore della Carità Hospital" in Novara, Italy, between 1998 and 2008. All patients included underwent: auxological, clinical, hormonal and biochemical assessments at recall (after at least 1 year from TBI to T0); auxological visit after 6 months (T6) and hormonal assessments at 12 months (T12) in patients with height velocity (HV) below the 25th centile. At T0, 4 cases of hypothalamus-pituitary dysfunction had been diagnosed; At T6 20/70 patients had an HV <25th centile, but no one had HV < the 3rd centile limit. At T12, among the 20 patients with HV <25th centile, in 13 patients the HV was below the 25th centile and GHRH + Arginine test has been performed. Four subjects demonstrated an impaired GH peak and were classified as GH deficiency (GHD). Of these 4 subjects, 3 subjects showed isolated GHD, while one patient showed multiple hypopituitarism presenting also secondary hypocortisolism and hypothyroidism. The GCS at admission and GOS do not correlate with the onset of hypopituitarism. A simple measurement of the height velocity at least 1 year after the TBI, is enough to recognize patients with a pituitary impairment related to GH deficiency. We suggest to follow-up paediatric population who had TBI with auxological evaluations every 6 months, limiting hormonal evaluation in patients with a reduction of height velocity below the 25th centile limit.


Assuntos
Estatura/fisiologia , Lesões Encefálicas/fisiopatologia , Hipófise/fisiopatologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/metabolismo , Humanos , Masculino , Hipófise/metabolismo , Hipófise/patologia , Estudos Prospectivos
12.
J Endocrinol Invest ; 36(7): 466-73, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23211535

RESUMO

BACKGROUND: To establish the rate of agreement in predicting metabolic syndrome (MS) in different pediatric classifications using percentiles or fixed cut-offs, as well as exploring the influence of cholesterol. SUBJECTS AND METHODS: Cross-sectional study in a tertiary care center. Nine hundred and twenty-three obese children and adolescents were evaluated for metabolic characteristics, cholesterol levels, the agreement rate and prevalence of MS across age subgroups with pediatric National Cholesterol Education Program/ Adult Treatment Panel III (NCEP-ATP III) and International Diabetes Federation (IDF) classifications. RESULTS: The overall prevalence of MS was 36.2% and 56.7% with NCEPATP III and IDF. The overall concordance was fair (k: 0.269), with substantial values observed only in children older than 10 (k: 0.708) and 16 yr (0.694). Concordant subjects for both classifications, ≤6 yr, had higher triglycerides, blood pressure (p<0.05) and lower HDL-cholesterol (p<0.0001), with respect to those found to be discordant. Concordant subjects ranging 6-10 yr had all parameters higher than those discordant for IDF (p<0.01) and insulin resistance (p<0.05) than those discordant for NCEP-ATP III. Concordant subjects ≥10 yr presented more altered parameters than those included only in NCEP-ATP III (p<0.05). Overt glucose alterations were uncommon (7.4%; confidence interval 95% 0.1-14.9%), although glucose was modestly higher in MS subjects (p<0.01). Total and LDL-cholesterol was lower in subjects with MS than in those without (p<0.05), and in concordant rather than discordant subjects (p<0.05). CONCLUSIONS: Classifications of MS do not identify the same pediatric population. Subjects who satisfied any classification were the most compromised. Lipid alterations were precocious in the youngest. Obese youths with MS presented lower total and LDL-cholesterol.


Assuntos
Colesterol/sangue , Síndrome Metabólica/classificação , Adolescente , Criança , Pré-Escolar , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Lipídeos/sangue , Masculino , Síndrome Metabólica/epidemiologia , Prevalência , Triglicerídeos/sangue
13.
Panminerva Med ; 54(4): 323-31, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23123585

RESUMO

An increased prevalence of depression, emotional lability, decreased energy levels, and poor quality of life have been reported in adults with GH deficiency (GHD). The impairment of psychological parameters depends on the aetiology of GHD and the presence of other pituitary hormone deficiencies because of hormonal effects on neural cell metabolism. Cognitive dysfunctions appear to be specifically related to GHD itself, whereas the lower emotional well-being and reduced motor performance are attributed to other pituitary hormone deficiencies. Traumatic Brain Injury causes very often hypopituitarism and GHD as well as other many psychological symptoms: cognitive impairment, sleeping disorders, and depression. Many neurobehavioral symptoms of postconcussion syndrome (PCS) are the same suffered by adult GHD and hypopituitaric patients but there are no data about the occurrence of hypopituitarism in PCS. In some studies treatment with rhGH is reported to have a beneficial effect and GHD could contribute itself to the global impairment of psychological dysfunctions. The link between psychosocial impairments and GHD is not fully understood. The effects of long-term rhGH therapy on cognitive functions are largely unknown. Thus, long-term placebo-controlled double-blind studies are required to investigate whether psychological dysfunctions are reversible on GH substitution.


Assuntos
Afeto , Transtornos do Crescimento/psicologia , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/psicologia , Saúde Mental , Qualidade de Vida , Adulto , Biomarcadores/sangue , Cognição , Transtornos do Crescimento/sangue , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento Humano/sangue , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/epidemiologia , Prognóstico , Fatores de Risco
14.
Br J Cancer ; 106(9): 1543-50, 2012 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-22531721

RESUMO

BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos CD55/química , Antígenos CD55/genética , Antígenos CD59/química , Antígenos CD59/genética , Ativação do Complemento , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Citotoxicidade Imunológica , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Trastuzumab , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia
15.
J Endocrinol Invest ; 35(2): 191-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21623149

RESUMO

BACKGROUND: Ghrelin circulates in blood as acylated (AG) and unacylated (UAG) ghrelin. The physiological role of the two forms is poorly understood, in particular in childhood. Aim of the study was to evaluate the AG and UAG levels in obese and normal weight (NW) children, pre-pubertal and pubertal, and their relationship with insulin, leptin and adiponectin levels. SUBJECTS AND METHODS: A population based study in which AG, UAG, leptin, adiponectin, glucose, insulin, testosterone or estradiol levels, insulinemic indexes were evaluated in 82 NW and 58 obese (OB) children. RESULTS: Both ghrelin forms in NW were higher (AG, p<0.02; UAG, p<0.0001) than in OB subjects, with similar ratio AG/UAG . While no differences were observed for gender, puberty AG (p<0.01) and UAG (p<0.0001) levels were higher in pre-pubertal than pubertal NW and OB subjects. Adiponectin levels in NW subjects were higher (p<0.001), while leptin and insulin levels were lower (p<0.0001) than in OB subjects. NW children showed homeostasis model assessment (HOMA) and HOMAß indices lower than OB children (p<0.0001) with a higher a quantitative insulin sensitivity check index (p<0.0001). AG and UAG levels correlated to each other (p<0.0001), each showing a negative correlation to age, height, weight and body mass index. Both forms, but more strongly UAG, correlated with adiponectin, leptin, and insulin. CONCLUSIONS: OB children show lower levels of both AG and UAG when compared to NW subjects, with lower levels during puberty. These results demonstrate a peculiar strong relationship between UAG levels and metabolic parameters in the pediatric population, suggesting a role for UAG in metabolic functions.


Assuntos
Adiponectina/sangue , Grelina/sangue , Peso Corporal Ideal/fisiologia , Insulina/sangue , Leptina/sangue , Obesidade/sangue , Puberdade/fisiologia , Acilação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Grelina/metabolismo , Humanos , Masculino , Obesidade/metabolismo , Processamento de Proteína Pós-Traducional , Puberdade/sangue , Puberdade/metabolismo
16.
J Endocrinol Invest ; 35(2): 160-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21623150

RESUMO

AIM: To evaluate if nutritional intakes and lipid profile fulfill international guidelines and recommendations before and after a structured dietician training to a Mediterranean- style diet in an Italian pediatric population with Type 1 diabetes. METHODS: A 6-month prospective cohort study. Baseline and after-intervention nutritional intakes, lipid profile, glycated hemoglobin (HbA(1c)), and clinical parameters of 96 children and adolescents with Type 1 diabetes were assessed. A comparative computerized system which was approved and validated by the Italian Diabetologist Association was used to define the amounts of nutrients. RESULTS: At baseline mean daily dietary intakes of carbohydrates, proteins, and lipids were respectively (mean ± SEM) 51.8 ± 0.5, 15.9 ± 0.2, 33.8 ± 0.6%, with a contribution of cholesterol of 248.7 ± 12.5 mg/day. Fiber assumption was 18.0 ± 0.4 g/day. The 64.5% and 29.1% (p<0.0001) of subjects had at least one lipid parameter higher than 75(th) and 95(th) percentiles, respectively, of selected cut points (American Diabetes Association guidelines for total and LDL-cholesterol and American Academy of Pediatrics standards for HDL-cholesterol and triglycerides). Six months after the dietician intervention, dietary lipids and cholesterol decreased (p<0.0001) while fibers (p<0.0001) increased. LDL-cholesterol, non-HDL-cholesterol, and total cholesterol:HDL-cholesterol ratios significantly decreased (p<0.001) with a reduction of rate of subjects with at least one pathological lipid parameter (p<0.01) independently by weight and glucose control. CONCLUSIONS: Italian pediatric subjects with Type 1 diabetes present a balanced diet with exception of lipids intake and a suboptimal lipid profile. A structured dietician training to a Mediterranean-style diet improves the quality of nutrient intakes being followed by a reduction of LDL-cholesterol, non- HDL-cholesterol, and total cholesterol:HDL-cholesterol ratios.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/dietoterapia , Dieta Mediterrânea , Lipídeos/sangue , Educação de Pacientes como Assunto , Adolescente , Fenômenos Fisiológicos da Nutrição do Adolescente/efeitos dos fármacos , Criança , Fenômenos Fisiológicos da Nutrição Infantil/efeitos dos fármacos , Estudos de Coortes , Diabetes Mellitus Tipo 1/metabolismo , Gorduras na Dieta/farmacologia , Fibras na Dieta/farmacologia , Comportamento Alimentar , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/análise , Masculino , Educação de Pacientes como Assunto/métodos , Comportamento de Redução do Risco , Adulto Jovem
17.
Eur J Endocrinol ; 166(1): 115-20, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22004908

RESUMO

CONTEXT: Ghrelin is a peptide with multiple functions that circulates in acylated (AG) and unacylated (UAG) forms. However, the role of ghrelin in neonates (NN) remains to be clarified. OBJECTIVE: The aim of this study was to determine ghrelin concentrations of the two forms in NN to clarify their biological roles. As such, ghrelin levels at birth were compared with those in later life. SETTING AND DESIGN: Tertiary Care Center. In this cross-sectional study, we evaluated AG, UAG, AG/UAG ratio, and insulin levels in venous cord blood from NN and in fasted normal weight (NW) and obese (OB) children, both prepubertal and pubertal. SUBJECTS: We studied 82 NN, 82 NW, and 58 OB children. RESULTS: AG levels were lower in NN than in NW and OB children (P<0.0001), more specifically the prepubertal NW and OB children (P<0.0001). UAG levels were higher in NN than in NW and OB children (P<0.0001). Therefore, the AG/UAG ratio was lower in NN than in NW and OB children (P<0.0001). NN showed insulin levels similar to NW and lower than OB children (P<0.0001). At birth UAG was positively correlated with AG (Pearson: 0.425; P<0.0001) and negatively with insulin (-0.253; P<0.02). In NW and OB, UAG and AG were positively correlated to each other and negatively correlated with insulin and body mass index (-0.566; P<0.0001). CONCLUSIONS: NN compared with children, showed higher UAG and lower AG levels. The AG/UAG ratio showed a very different profile in NN, being lower than in NW and OB children, thus suggesting a different metabolic function for the two forms in NN. Further studies are needed to clarify the exact role of the different ghrelin forms in NN.


Assuntos
Sangue Fetal/metabolismo , Grelina/sangue , Antropometria , Índice de Massa Corporal , Feminino , Humanos , Recém-Nascido , Insulina/metabolismo , Masculino , Obesidade/sangue
18.
Oncogene ; 31(42): 4559-66, 2012 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-22139083

RESUMO

Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Regiões 3' não Traduzidas/genética , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Interferência de RNA , Resultado do Tratamento , Proteínas ras/metabolismo
19.
Minerva Pediatr ; 63(6): 527-31, 2011 Dec.
Artigo em Italiano | MEDLINE | ID: mdl-22075807

RESUMO

The 22q11.2 microdeletion produces many syndromes, characterized by similar phenotypical features. The most known syndromes are: the DiGeorge syndrome, the velocardiofacial syndrome, the conotruncal anomaly face syndrome. The hallmark features are represented by cardiac anomalies, palate defects, immune and cognitive deficiencies, facial dysmorphisms. Less common disorders include: genito-urinary abnormalities, visual defects, autoimmune disorders and pituitary anomalies, being the last represented by growth hormone and/or insulin growth factor-I deficiency. We present the case of a 8 years old male admitted to our Division for failure to thrive. We found growth hormone deficiency and pituitary hypoplasia associated with some of the anomalies shown above, thus we suspected and confirmed the 22q11.2 deletion syndrome. In literature few cases of associated 22q11.2 deletion syndrome with growth hormone deficiency are described, while short stature between children with and children without cleft palate is reported to be more frequent in the first ones, suggesting that the 22q11.2 deletion syndrome remains undetected in many affected children and that the growth hormone deficiency prevalence in affected children has to be investigated. The wide phenotypical presentation of 22q11.2 deletion syndrome requires a multidisciplinary approach to the affected subject and, from the auxologic point of view, is good to monitoring the growing trend and, if short stature is present, check for the growth hormone deficiency.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de DiGeorge/genética , Nanismo Hipofisário/genética , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Criança , Perda Auditiva/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgia , Humanos , Deficiência Intelectual/genética , Masculino , Monitorização Fisiológica , Fatores de Risco , Transtornos da Visão/genética
20.
Minerva Pediatr ; 63(4): 335-9, 2011 Aug.
Artigo em Italiano | MEDLINE | ID: mdl-21909069

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by cafe-au-lait spots, axillary and inguinal freckling, cutaneous neurofibromas with a variable clinical expression, iris Lisch nodules, and multiple tumors, in particular optic nerve and other central nervous system gliomas. About 6% of patients develop hypertension due to renovascular diseases, mid-aortic syndrome, or pheochromocytoma. We present a case of a 8 year old girl with primary diagnosis of NF1suffering of skin and encefalic neurofibromas, inguinal freckling, café-au-lait spots, optic nerve glioma, headache, facial flushing. The 24-h ambulatory blood pressure revealed hypertension without paroximal attacks. Urinary metanephrines, serum aldosteron, renin and kalemia were constantly normal. Magnetic resonance imaging (MRI) and angioMRI excluded stenoses of the renal arteries or adrenal masses. Standard 2D echocardiography was normal. The antihypertensive medication controlled pressure values. We concluded for hypertension due to a low-grade vasculopathy. The periodic monitoring of blood pressure in NF1 patients, accompanied by appropriate diagnostic modalities and physical examination, is essential to precociously diagnose hypertension and avoid life-threatening organ damages and increased mortality.


Assuntos
Hipertensão/diagnóstico , Hipertensão/etiologia , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Anti-Hipertensivos/uso terapêutico , Axila , Monitorização Ambulatorial da Pressão Arterial , Neoplasias Encefálicas/diagnóstico , Manchas Café com Leite/etiologia , Criança , Diagnóstico Diferencial , Oftalmopatias/diagnóstico , Feminino , Seguimentos , Cefaleia/etiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Neurofibroma/diagnóstico , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/genética , Glioma do Nervo Óptico/diagnóstico , Neoplasias Cutâneas/diagnóstico , Resultado do Tratamento
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