Other than hamartomatous enlargement of the cerebellum as in Lhermitte-Duclos syndrome, diffuse enlargement of the cerebellum is not clearly described. We report four patients (ages 9 months to 2 years) with diffusely enlarged cerebelli as identified by measurement of the cerebellum and comparison to age appropriate normal values. The cerebellar measurements were determined in absolute numbers and expressed as ratios of cerebellum to whole brain and supratentorial brain. The clinical features of these four children (3 boys, 1 girl) consistently include global developmental delay, tone abnormalities, preserved reflexes, delayed or abnormal maturation of the visual system (oculomotor apraxia), and deficient or delayed myelination of cerebral white matter. The etiology of the macrocerebellum is unknown but we propose that the cerebellum is responding to the elaboration of growth factors intended to augment the slow development of cerebral structures. Regardless of the etiology, the finding of a macrocerebellum appears to allow the clinician to predict the clinical features of the patient and probably represents a marker for disturbed cerebral development. (J Child Neurol 1997;12:365-368 5-year period (1990-1994
The pro-apoptotic death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received significant attention as a novel cancer therapeutic, since it selectively induces apoptosis in malignant and not normal cells. Unfortunately, prostate cancer cells display little if any susceptibility to TRAIL-induced apoptosis. However, sensitivity to TRAIL is enhanced by doxorubicin, which correlated with a decrease in expression of the caspase-8 inhibitor cFLIP (Kelly et al., Cancer Biol Ther 1:520). In this study we show that doxorubicin induces a time-and dose-dependent loss of cFLIP protein, but does not affect steady-state mRNA levels. Proteasome inhibition stabilized cFLIP L in the presence of doxorubicin. Although proteasome inhibitors increased basal levels of short cFLIP isoforms, cFLIP S declined at a similar rate in the absense or presence of proteasome inhibition during doxorubicin treatment. Ectopic expression of a cFLIP S GFP fusion protein protected PC3 cells from TRAIL-induced apoptosis in the absence or presence of doxorubicin, whereas downregulation of cFLIP S by RNA interference resulted in sensitization to TRAIL-induced apoptosis. We conclude that doxorubicin-mediated downregulation of cFLIP S , which occurs at the post-transcriptional level independent of proteasome-mediated pathways, is sufficient to enhance TRAIL sensitivity in PC3 prostate carcinoma cells.
To develop animal models that represent the broad spectrum of human prostate cancer, we created transgenic mice with targeted prostate-specific expression of two genes (EcoRI and c-fos) implicated in the induction of genomic instability. Expression of the transgenes was restricted to prostate epithelial cells by coupling them to the tissuespecific, hormonally regulated probasin promoter (PB). The effects of transgene expression were examined histologically in prostate sections at time points taken from 4 to 24 months of age. The progressive presence of regions of mild-to-severe hyperplasia, low-and high-grade prostatic intra-epithelial neoplasia, and well-differentiated adenocarcinoma was observed in both PBEcoRI lines but no significant pathology was detected in the PBfos line. Prostate tissue of PBEcoRI mice was examined for expression of p53, proliferating cell nuclear antigen (PCNA) and Ki67 at multiple time points. Although p53 does not appear to be mutated, levels of PCNA and Ki67 are elevated and correlate with the severity of the prostatic lesions. Overall, pre-neoplastic and neoplastic stages represented in the PBEcoRI model showed similarity to corresponding early stages of the human disease. This genomic instability-based model will be used to study the mechanisms involved in the early stages of prostate carcinogenesis and to investigate the nature of subsequent events necessary for the progression to advanced disease.Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer death in American men but its etiology is poorly understood. One in five American males will eventually develop the disease but the high rate of clinical incidence is exceeded by the prevalence of prostate carcinomas undetected until autopsy (1,2). Although several Abbreviations: PB, probasin promoter; PCNA, proliferating cell nuclear antigen; PIN, prostatic intra-epithelial neoplasia; TRAMP, transgenic adenocarcinoma mouse prostate.© Oxford University Press 1623 genetic alterations have been documented (3), critical early molecular events involved in neoplastic initiation and progression from latent prostate cancer to the aggressive form of clinical disease remain poorly understood. Therefore, animal models that faithfully represent the broad spectrum of the human disease are required. A number of animal models for prostate cancer have been developed (4) but many lack a natural environment and characterization of early and late stages is not possible. The most successful mouse models to date utilize targeted expression of the SV40 early genes (T/t antigens) that function as oncoproteins, in part, by binding to and interfering with the p53 and/or Rb tumor suppressor proteins or by interfering with protein phosphatase 2A activity (5).In an attempt to create a model for early prostate cancer, we generated transgenic mice in which the restriction enzyme EcoRI or the proto-oncogene c-fos were expressed from a truncated rat probasin promoter. This promoter has been shown to express the SV40 early ...
It has been suggested that the size of the corpus callosum may have diagnostic significance in cerebral palsy, although this relationship is incompletely defined. Ninety-one patients with cerebral palsy had been studied by magnetic resonance imaging in the 5-year period from 1990 to 1994. Fifty-seven of these 91 patients had a technically appropriate midsagittal magnetic resonance image for quantitative morphometric analysis. The ratio of the area of the corpus callosum to the area of the supratentorial brain was compared to published age- and gender-specific norms. Imaging findings were correlated with clinical history and cause of cerebral palsy. The corpus callosum was of normal size in 43 patients and more than 2 standard deviations below the mean in 14 patients. The causes for cerebral palsy included hypoxic ischemic encephalopathy (32), cerebral dysgenesis (8), and porencephalic strokes (6); the etiology could not be established in 11 patients. The size of the corpus callosum was highly correlated with the cause of cerebral palsy, such that all patients with cerebral dysgenesis had hypoplasia of the corpus callosum (one-sided z test, p < 0.0001). Conversely, the callosum was of normal size in 32 of 38 patients with hypoxic ischemic encephalopathy and porencephalic strokes. The presence of a hypoplastic corpus callosum is highly associated with cerebral dysgenesis as a cause for cerebral palsy.
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