Lafoensia pacari alleviates intestinal damage by modulating cyclooxygenase-2: In silico and in vivo evaluation in a colitis model.

BACKGROUND: Inflammatory bowel diseases (IBD) are a worldwide health problem and mainly affect young people, consequently affecting the workforce. Available treatments are often associated with side effects, and new therapeutic options are needed. For centuries, plants have represented important substrates in the field of drug development. Lafoensia pacari (L. pacari) is a plant whose pharmaceutical potential has been described, and may have biological activity relevant to the treatment of IBD symptoms. AIM: To investigate the activity of keto-alcoholic extracts of L. pacari with respect to ameliorating the inflammatory and nociceptive symptoms of acute experimental colitis in mice. METHODS: Keto-alcoholic extracts of L. pacari leaves and bark were administered to male and female Swiss mice weighing 25 g to 30 g (n = 8 male mice and n = 8 female mice). The effect of these extracts was observed in an acetic acid-induced acute experimental model of colitis with regard to antinociception/analgesia and inflammatory tissue damage. Recorded macroscopic indices included the Wallace score and the colon weight obtained using a precision scale. Mechanical hyperalgesia was determined using an electronic analgesimeter. Behavior related to overt pain was determined by quantifying the number of writhing instances within 20 min of administration of acetic acid. Molecular docking was performed using human and murine cyclooxygenase-2 (COX-2) with 3 flavonoids (ellagic acid, kaempferol, and quercetin) on the AutoDock Vina software. Analysis of variance followed by Tukey's posttest was used with P < 0.05 indicating significance. RESULTS: In this murine model of colitis, administration of extracts from L. pacari ameliorated acetic acid-induced writhing and colitis-associated inflammatory pain. These improvements may be attributable to the reduction in edema, inflammation (e.g., ulcers, hyperemia, and bowel wall damage), and the intensity of abdominal hyperalgesia. The keto-alcoholic extracts of L. pacari leaves and bark administered at a dose of either 100 mg/kg or 300 mg/kg significantly reduced the number of writhing events when compared to the negative control (P < 0.05). Additionally, extracts of L. pacari bark also performed better than Dipyrone. Leaf extracts administered at 10 mg/kg, 30 mg/kg, and 100 mg/kg and bark extracts administered at 30 mg/kg significantly reduced or prevented the development of edema in the colon of treated mice, while mesalazine did not. Moreover, using molecular docking, we observed that the flavonoids present in L. pacari extracts bind to COX-2, an event not unique to ellagic acid. CONCLUSION: The results of this study demonstrate a potential novel application of L. pacari extracts for the reduction of inflammation and promotion of antinociception/analgesia as demonstrated by our findings in a murine model of colitis. These findings were also corroborated by in silico analyses, and suggest that L. pacari extracts may be a promising therapeutic agent in the treatment of IBD.

SF-1 overexpression in childhood adrenocortical tumours.

The steroidogenic factor 1 (SF-1) gene encodes a transcription factor playing a pivotal role in the regulation of adrenogenital development. We have recently shown that SF-1 is amplified in childhood adrenocortical tumours (ACT). This study was aimed to assess if an increase in SF-1 gene copy number was associated with increased protein levels and to study the correlation between SF-1 expression and ACT clinical parameters. An increased SF-1 copy number was detected in eight of the 10 ACT cases studied. Conversely, the SF-1 protein was found to be overexpressed in all cases, compared to normal age-matched adrenal glands. No significant correlation was found between SF-1 protein levels and its gene copy number. Furthermore, no significant correlation existed with histological grade or with the clinical manifestation or evolution of disease. This data show that SF-1 overexpression is widespread in childhood ACT and is likely to play a role in its pathogenesis.

Childhood adrenocortical tumours: a review.

Childhood adrenocortical tumour (ACT) is not a common disease, but in southern Brazil the prevalence is 15 times higher than in other parts of the world. One hundred and thirty-seven patients have been identified and followed by our group over the past four decades. Affected children are predominantly girls, with a female-to-male ratio of 3.5:1 in patients below 4 years of age. Virilization alone (51.6%) or mixed with Cushing's syndrome (42.0%) was the predominant clinical picture observed in these patients. Tumours are unilateral, affecting both glands equally. TP53 R337H germline mutations underlie most childhood ACTs in southern Brazil. Epidemiological data from our casuistic studies revealed that this mutation has ~10% penetrance for ACT. Surgery is the definitive treatment, and a complete resection should always be attempted. Although adjuvant chemotherapy has shown some encouraging results, its influence on overall outcome is small. The survival rate is directly correlated to tumour size; patients with small, completely excised tumours have survival rates close to 90%, whereas in those patients with inoperable tumours and/or metastatic disease it is less than 10%. In the group of patients with large, excisable tumours, half of them have an intermediate outcome. Recent molecular biology techniques and genomic approaches may help us to better understand the pathogenesis of ACT, the risk of developing a tumour when TP53 R337H is present, and to predict its outcome. An ongoing pilot study consisting of close monitoring of healthy carriers of the TP53 R337H mutation - siblings and first-degree relatives of known affected cases - aims at the early detection of ACTs and an improvement of the cure rate.

Tratamento do tumor do córtex adrenal na infância / Treatment of childhood adrenocortical tumor

O tumor do córtex adrenal (TCA) na infância é raro. Entretanto, no Paraná sua incidência é 15 vezes maior do que a observada em outros países. A mutação germinativa R337H TP53, presente em mais de 95 por cento dos nossos pacientes, provavelmente está relacionada à maior incidência. Cento e vinte e cinco pacientes foram tratados no período de 1966 a 2003. A cirurgia é o único tratamento curativo. Em nossa experiência, tumores no estádio I, ausência de spillage durante a cirurgia e ausência de trombo são parâmetros relacionados à maior sobrevida. Dados preliminares mostram que a associação de etoposídeo, doxorrubicina, cisplatina e mitotano produziu remissão completa do tumor e/ou das metástases em alguns pacientes. Os efeitos colaterais destas drogas são comuns e pode ocorrer insuficiência adrenocortical. As doses de reposição de glicocorticóides e mineralocorticóides devem ser 2 a 3 vezes maiores que as doses fisiológicas.

[Treatment of childhood adrenocortical tumor]. / Tratamento do tumor do córtex adrenal na infância.

Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Paraná is 15 times higher than that worldwide. A germline mutation, R337H TP53, present in more than 95% of our patients, is probably the reason for the higher incidence in our state. A hundred twenty-five patients were treated in the period of 1966 to 2003. Surgery is the only curative treatment. In our experience, disease stage I, absence of spillage during surgery and absence of intravenous thrombus are associated with better survival rates. Preliminary data with the combination of etoposide, doxorubicin, cisplatin, and mitotane have shown that in some patients a complete remission is observed both of the tumor and metastasis. Side effects due to these drugs are common and adrenal insufficiency may occur. Glucocorticoid and mineralocorticoid reposition should be done with 2 to 3 times the physiological doses.

Tumores do córtex adrenal na infância / Childhood adrenocortical tumors

O tumor do córtex adrenal (TCA) na infância é raro. Entretanto, no Paraná sua incidência é 15 vezes maior do que a observada em outros países. Descrevemos as características clínicas, laboratoriais, tratamento e evolução de 125 pacientes atendidos em uma única instituição no Paraná. A média de idade ao diagnóstico foi de 4,3 anos, com uma relação feminino:masculino de 2,6:1. As formas clínicas mais comuns foram virilização isolada (51,2 por cento) e virilização e síndrome de Cushing (42 por cento). Em 4,8 por cento dos casos, os tumores foram não-funcionantes. Dois pacientes (1,6 por cento) apresentaram síndrome de Cushing isolado e 1 (0,8 por cento) síndrome de Conn. Hipertensão arterial ocorreu em 56 por cento dos pacientes. O único tratamento curativo é a cirurgia. Os dados da nossa casuística mostram que estádio clínico 1 do TCA, ausência de trombo intra-venoso e ausência de spillage durante a cirurgia estão associados a uma maior sobrevida.

A constrained-syntax genetic programming system for discovering classification rules: application to medical data sets.

This paper proposes a new constrained-syntax genetic programming (GP) algorithm for discovering classification rules in medical data sets. The proposed GP contains several syntactic constraints to be enforced by the system using a disjunctive normal form representation, so that individuals represent valid rule sets that are easy to interpret. The GP is compared with C4.5, a well-known decision-tree-building algorithm, and with another GP that uses Boolean inputs (BGP), in five medical data sets: chest pain, Ljubljana breast cancer, dermatology, Wisconsin breast cancer, and pediatric adrenocortical tumor. For this last data set a new preprocessing step was devised for survival prediction. Computational experiments show that, overall, the GP algorithm obtained good results with respect to predictive accuracy and rule comprehensibility, by comparison with C4.5 and BGP.

[Childhood adrenocortical tumors]. / Tumores do córtex adrenal na infância.

Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Paraná, Brazil, is 15 times higher than that worldwide. We describe the clinical, laboratory and treatment characteristics and outcome of 125 patients treated in a single institution in the State of Paraná. The median age at diagnosis was 4.3 years, with a female:male ratio of 2.6:1. The most common forms of presentation were isolated virilization (51.2%) and virilization and Cushing's syndrome (42%). Nonfunctioning tumors comprised 4.8% of the cases. Two patients (1.6%) had isolated Cushing's syndrome and 1 (0.8%) had Conn's syndrome. Fifty-six percent presented hypertension. Surgery is the only curative treatment. Our data show that disease stage 1, absence of spillage during surgery and absence of intravenous thrombus were associated with better survival rates.

Tratamento conservador do câncer de mama / Conservative treatment of cancer of the breast

Ha muito tempo vem-se tantando encontrar uma alternativa para o tratamento do cancer de mama diferente da cirurgia radical proposta por Halsted em 1890. Muitas formas de cirurgia conservadora foram desenvolvidas com esta finalidade. A eficacia de seu emprego ainda tem sido muito discutida,porem ha estudos que demonstram inexistir diferenca de sobrevida entre as pacientes com tratamento conservador e radical. Parece haver, contudo, maior incidencia de recidiva local nas pacientes tratadas conservadoramente