Molecular modeling approaches in the discovery of new drugs for anti-cancer therapy: the investigation of p53-MDM2 interaction and its inhibition by small molecules.

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53-MDM2 interaction and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.

Psychosocial outcome in growth hormone deficient patients diagnosed during childhood.

Social disabilities have been described in GHD patients. The aim of this study was to evaluate the social outcome of a group of adult hypopituitary patients diagnosed and treated during childhood. Seventy patients were interviewed at a mean age of 25.6 years (range 18-50 yr). They answered a semistructured questionnaire and the Beck Depression Inventory test. Patients were compared for academic achievement, marital status and employment with the nearest age sibling. We found high levels of school repeaters, school was often not completed, and around 50% were overprotected by teachers and teased by peers. 32% were unemployed, while 58% of those employed work with their families. 80% still live with their parents; only 16% are married and 9% have children. 44% had no dating experience and 52% had never had sexual intercourse. Depression was common, especially in hypogonadic subjects. Juvenilization was the most common complaint. We did not found differences in maximal educational achievements and levels of employment between patients and siblings, but significantly more married siblings were found. Depression, social isolation and dependent life style were found in GHD patients. Appropriate medical and psychological counseling should be included for patients and their families as part of treatment.

[Nutritional studies in a commune of Lazio. Anthropometric data and food consumption in childhood]. / Indagine nutrizionale in un comune del Lazio. Dati antropometrici e consumi alimentari in età scolare.

The present study concerns with anthropometric and nutritional data collected in the school population of a small rural town in Lazio. We studied 368 school-children of both sexes, belonging to the following age groups: from 7 to 8 years, 9 to 10 years, 11 to 12 years, 13 to 14 years. The technique of evaluation of obesity used in this paper is: weight 20% higher than the height-adjusted figure according to NCHS's curves and triceps skinfold higher than 90 degrees centile according to Tanner's curves. Dietary intake was assessed by a "24 hour-recall" on three consecutive days one of which of holiday. The prevalence of obesity is 17.7%. In all the age groups daily caloric intake is adjusted to that recommended by Italian 1987 Larn. On the other hand the single nutrient's assumption shows important differences from Larn. Particularly in all the age groups daily protein intake is high (14.6%-15.8% of the energy in a day), with an increased animal-vegetable protein ratio (1.5-2.1). Dietary lipids are higher than 35.9% of day's energy (35.9%-39.5%); the polyunsaturated/saturated fatty acids ratio is low (0.3-0.5). Cholesterol in the diet (231-347 mg/day) exceeds the level recommended. The daily intake of total carbohydrates (45.3%-48.5%) is low. Crude fiber intake increases with age from 2.8 g to 4.5 g/day. There is no statistical difference between obese and not obese subjects for what concerns energy intake or single nutrient's assumption.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adolescents and breast feeding]. / Adolescenti ed allattamento al seno.

The attitudes and future decisions of teenage girls towards infant feeding methods, breast-feeding or bottle feeding have been investigated. A self-conducted questionnaire was completed by 146 secondary school girls ranging in age from 16 to 18 years. Economic convenience, better nutritional value, deeper emotional link with the infant, own and friends past experience nearly always in favour of breast-feeding, represent for the girls the main advantages of breast-feeding. On the other hand, many girls apprehend breast-feeding for various possible physical, psychological and social implications. Some aspects of the problem studied in this paper show a significant correlation with the future choice of infant feeding. The girls would be interested in receiving information at school. Suitable information during school health lessons may positively influence teenage girls to adopt breast-feeding as the infant feeding method of choice.

[Risk factors present in the recreation areas of nursery schools]. / Indagine sui fattori di rischio presenti nelle aree ricreative delle scuole materne.

In order to evaluate the playground risk factors, 45 nursery schools of a USL were investigated. The results show that the risk factors depend mostly on inadequacy of the playground equipment and of its installation and maintenance. Moreover the playground surfaces are frequently nonelastic and the first-aid kits insufficient. Pediatricians have a key position in scholastic accident prevention.

[Congenital pseudoarthrosis of the clavicle]. / Pseudoartrosi congenita della clavicola.

A case of congenital pseudarthrosis of the clavicle is presented. Congenital pseudarthrosis of the clavicle is a rare entity that has poorly been documented in the pediatric literature. The etiology and pathogenesis still remain obscure. The clinical and radiological appearances are characteristic. Differential diagnosis lies between postpartum fracture, posttraumatic pseudarthrosis, cleidocranial dysostosis and neurofibromatosis.

Differentiation of neurologic and pseudo-neurologic patients with combined MMPI mini-mult and pseudo-neurologic scale.

Patients who were complaining of neurologic symptomagology completed the MMPI Mini-Mult plus the Shaw and Matthews Pseudo-Neurologic Scale to determine whether Pseudo-Neurologic and Neurologic patients could be separated. This was done with statistical significance, but not with clinical utility. There were no significant differences among the mean Mini-Mult profiles for the neurologic subcategory groups. Mean profiles for the Neurologic, Pseudo-Neurologic, and Mixed groups also were not significantly different, but analyses of the individual profiles in the Neurologic and Pseudo-Neurologic groups produced statistical and clinical significance. Presenting complaints of all Ss were investigated to see whether the Scale could predict differentially for patients in each of these groups. Only the complaint of weakness predicted with statistical significance and clinical utility. Attempts to create a new, more effective scale were disappointing despite statistical significance as misclassification decreased clinical utility.