Free and N-(2-hydroxypropyl)methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells

The effects of geldanamycin (GA), 17-(3-aminopropylamino)-17-demethoxygeldanamycin (AP-GA), and N-(2-hydroxypropyl)methacrylamide copolymer-AP-GA conjugate [P(AP-GA)] on A2780 human ovarian carcinoma cells at an equitoxic dose (2x IC(50)) were compared by the gene expression array analysis. All treatments resulted in similar gene expression profiles up to 12 h (e.g., down-regulation of CDK4 and up-regulation of APAF-1), although P(AP-GA)-treated cells showed delayed gene expression because of time-dependent internalization of the conjugate and intracellular drug release from P(AP-GA). However, AP-GA-treated cells showed elevated expression of HSP70 and HSP27 after 6 h compared with that observed by GA and P(AP-GA) treatments. Depletion of C-Raf, an HSP90 client protein, was observed in all treatments up to 12 h. Confocal microscopy using mesochlorin e(6) as a model drug revealed that drug release caused by the lysosomal cleavage of glycylphenylalanylleucylglycine oligopeptide spacer, used as GA derivative copolymer attachment/release point, was moderately fast. These results suggested that AP-GA treatment may activate stress-response pathways, whereas P(AP-GA) treatment may suppress them and trigger signaling pathways essential to cell growth arrest and death by inducing an HSP90-active factor. Although GA and P(AP-GA) treatments induced a time-dependent increase in HSP70 and HSP27 protein expression (detected by Western blotting analysis), AP-GA treatment resulted in more rapid and more intense expression of both proteins. Our results suggest that conjugation of AP-GA to N-(2-hydroxypropyl)methacrylamide copolymer may be able to modulate the cell stress responses induced by AP-GA because of differences in its internalization mechanism, subcellular localization, and intracellular concentration gradients.     

Beta-adrenergic-mediated inhibition of feeding by mercaptoacetate in food-deprived rats

This study investigated the effect of intraperitoneal (IP) injections of the fatty acid oxidation (FAO) inhibitor mercaptoacetate (MA, 45.6 mg/kg) on feeding in food-deprived rats. As previously, MA significantly stimulated feeding in ad libitum-fed rats. MA, however, reduced feeding in 18 and 36 h-fasted rats despite apparently antagonizing the fasting-induced increase in hepatic FAO. To test whether this anorectic effect involves beta-adrenergic stimulation, 36 h-fasted rats were IP injected with the nonspecific beta-adrenergic receptor antagonist propranolol (PROP, 0.5 mg/kg) just before MA injection. PROP attenuated MA's feeding-inhibitory effect, suggesting that MA anorexia is at least partially mediated by beta-adrenergic stimulation. Finally, we evaluated the role of subdiaphragmatic vagal afferent fibers in MA's feeding-inhibitory effect by testing the ability of MA to inhibit food intake in fasted rats after subdiaphragmatic vagal deafferentation (SDA). MA inhibited feeding similarly in SDA rats and sham-operated rats. These data demonstrate that subdiaphragmatic vagal afferents are not necessary for the feeding-inhibitory effect of peripheral MA. These results suggest that the FAO inhibitor MA elicits a feeding-inhibitory effect in fasted rats that is mediated by a different mechanism than its feeding-stimulatory effect.     

Endocrine-disrupting chemicals and testicular cancer: a case-control study

Environmental factors appear to be important in the etiology of testicular cancer. In this study, the authors identified some risk factors for testicular cancer, paying particular attention to prenatal and early life exposure to endocrine-disrupting chemicals (EDCs). Using a questionnaire, the authors obtained information on male participants' environmental and occupational exposures during adolescence and adulthood. A multivariate logistic regression analysis of 103 cases and 215 controls showed an association between seminoma and nonseminoma and hobby activities that potentially involved the use of EDCs (eg, paints, glues, or solvents). Rural residence during adolescence was associated with all histological types of testicular cancer and with seminoma. No association was found with occupational exposures of the subjects. This study's findings also confirm previously identified risk factors, such as history of cryptorchidism and undescended testicle, high educational level, and low birth weight, and it gives some support to the hypothesis of a possible association between EDC exposures and testicular cancer.     

A transient lesion in splenium of the corpus callosum in a patient with childhood-onset anorexia nervosa

OBJECTIVE: Although a transient lesion in the splenium of the corpus callosum (SCC) has been reported predominantly regarding patients with epilepsia, it is of rare occurrence, and its underlying biological basis remains unknown. This is a report of an SCC lesion in a patient with anorexia nervosa (AN). METHOD: The patient was a 15-year-old girl with childhood-onset (11 years) and a protracted course of AN. On admission, the patient showed no apparent neurological abnormalities. Magnetic resonance imaging (MRI) scans revealed a circumscribed lesion in the SCC. We treated her with nutritional rehabilitation supplemented with B vitamins. RESULTS: One month later, the lesion completely disappeared, but her weight was not restored. CONCLUSION: Treatment with B-vitamin supplementation may be beneficial for the treatment of patients with AN, in cases in which the disorder develops at an early age before brain maturation (i.e., childhood-onset cases), along with an enduring course of malnutrition.     

Transposon-mediated insertional mutagenesis revealed the functions of animal cellulose synthase in the ascidian Ciona intestinalis

Tunicates are the only animals that perform cellulose biosynthesis. The tunicate gene for cellulose synthase, Ci-CesA, was likely acquired by horizontal transfer from bacteria and was a key innovation in the evolution of tunicates. Transposon-based mutagenesis in an ascidian, Ciona intestinalis, has generated a mutant, swimming juvenile (sj). Ci-CesA is the gene responsible for the sj mutant, in which a drastic reduction in cellulose was observed in the tunic. Furthermore, during metamorphosis, which in ascidians convert the vertebrate-like larva into a sessile filter feeder, sj showed abnormalities in the order of metamorphic events. In normal larvae, the metamorphic events in the trunk region are initiated after tail resorption. In contrast, sj mutant larvae initiated the metamorphic events in the trunk without tail resorption. Thus, sj larvae show a "swimming juvenile" phenotype, the juvenile-like trunk structure with a complete tail and the ability to swim. It is likely that ascidian cellulose synthase is required for the coordination of the metamorphic events in the trunk and tail in addition to cellulose biosynthesis.     

Testicular tumors in Italy: historical trends,geographic differences,and etiological hypotheses

Testicular cancer is a rare tumour. Its incidence has been increasing in many parts of the world during the last decades. This cancer has an unusual age distribution with one peak in incidence in young adults (aged 20-39) and a second peak in over 60. On the basis of the Italian Bureau of Statistics, mortality rate was higher in northern regions of the country compared to southern ones, up to the beginning of the 1980's. However, the progressive decline in mortality in all regions eliminated the geographical differences in recent years. Incidence rates obtained from the existing cancer Registries, confirm a strong geographical gradient, with higher rates in the North (ex. 5.1/100,000 in Parma in 1988-92) than in the South (ex. 1.1/100,000 in Ragusa in 1988-92). The comparison between incidence rates of two recent periods (1983-87 and 1988-92), showed an increase in most of the provinces for which data were available. The age distribution curve showed that testicular cancer occurs after puberty, with a peak in incidence among 30-34 year olds, and after the age of 60. These observations suggest the possible causative role of some environmental exposures. Epidemiological studies have found an association between some occupational exposures in industrial and agricultural settings and testicular cancer. Moreover some studies have found an association between parental occupation and testicular cancer in the offspring. However, the aetiology of testicular cancer is still poorly understood.