In the year after successful H. pylori eradication, precancerous lesions improved in most patients.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.

Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIPchip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and lossof-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgendependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer. [Cancer Res 2009;69(1):137-42]

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T 1 versusT 2 -T 4 ; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.