Yasuko Kobayashi

Common Structural and Epigenetic Changes in the Genome of Castration-Resistant Prostate Cancer

Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge.

A sequence-based survey of the complex structural organization of tumor genomes

BackgroundThe genomes of many epithelial tumors exhibit extensive chromosomal rearrangements. All classes of genome rearrangements can be identified using end sequencing profiling, which relies on paired-end sequencing of cloned tumor genomes.ResultsIn the present study brain, breast, ovary, and prostate tumors, along with three breast cancer cell lines, were surveyed using end sequencing profiling, yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent. Sequencing and fluorescence in situ hybridization confirmed translocations and complex tumor genome structures that include co-amplification and packaging of disparate genomic loci with associated molecular heterogeneity. Comparison of the tumor genomes suggests recurrent rearrangements. Some are likely to be novel structural polymorphisms, whereas others may be bona fide somatic rearrangements. A recurrent fusion transcript in breast tumors and a constitutional fusion transcript resulting from a segmental duplication were identified. Analysis of end sequences for single nucleotide polymorphisms revealed candidate somatic mutations and an elevated rate of novel single nucleotide polymorphisms in an ovarian tumor.ConclusionThese results suggest that the genomes of many epithelial tumors may be far more dynamic and complex than was previously appreciated and that genomic fusions, including fusion transcripts and proteins, may be common, possibly yielding tumor-specific biomarkers and therapeutic targets.

Effects of valproate on biogenesis and function of liver mitochondria

The mitochondrial protein content of liver increased, and mitochondria enlarged after prolonged administration of valproic acid (VPA: N-dipropylacetic acid) to rats. The mitochondria showed low specific activities of membrane-bound enzymes, decreased content of cytochrome aa3, and decreased respiration in states 3 and 4. In vitro studies of amino acid incorporation suggested a decrease in protein synthesis in liver mitochondria from VPA-treated rats. Prolonged administration of VPA seems to impair mitochondrial structure and function.

Brain magnetic resonance imaging and motor and intellectual functioning in 86 patients born at term with spastic diplegia.

Aim  To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia.

Familial intrahepatic cholestasis associated with progressive neuromuscular disease and vitamin E deficiency.

Three Japanese patients with familial progressive intrahepatic cholestasis developed complications involving neurologic abnormalities characterized by ataxia and pigmentary retinopathy. Serum vitamin E concentrations were extremely low in all patients, suggesting a long-term vitamin E deficiency. High dose oral supplementation of alpha-tocopherol produced normal serum vitamin E levels in two patients. Parenteral administration of vitamin E resulted in no clinical improvement in one patient who first received the treatment at 14 years of age. In the other two patients, the progression of neurological abnormalities was slowed by vitamin E supplementation. Cholestyramine treatment resulted in an apparent decrease in serum vitamin E levels despite oral alpha-tocopherol supplementation.

An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer

Prostate cancer is the second leading cause of cancer related deaths in US men, largely because of metastasis, which is ultimately fatal. A better understanding of metastasis biology will lead to improved prognostication and therapeutics. We previously reported 11q13.1 gain was independently predictive of recurrence after radical prostatectomy. Multiple endocrine neoplasia I (MEN1) maps to this region of copy number gain in aggressive prostate tumors and was shown to be the only gene at this locus at increased expression in prostate cancer. Here, we demonstrate an oncogenic role for MEN1 in prostate cancer using a variety of independent assays.

The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study

We report on metabolic changes in the brain of a boy with Menkes disease. He was treated with parenteral copper (Cu)-histidine supplementation, from 5 months of age, and assessed with proton magnetic resonance spectroscopy ((1)H-MRS). The single-voxel (1)H-MRS before treatment revealed an accumulation of lactate and a reduced N-acetyl aspartate (NAA)/total creatine (tCr) ratio with a z-score of -3.0. During treatment, the lactate signal faded away, whereas the NAA signal gradually increased to a z-score of -1.5 at 120 days of treatment. The choline/tCr ratio did not deviate much initially (z-score +0.5), but the ratio increased markedly during treatment (z-score +4.8). Consequently, the Cu-histidine therapy initiated after the critical period still improved the neuronal metabolism, suggesting that some Cu was delivered to neurons. Nevertheless, the brain atrophy, impaired myelination, and severe neurological symptoms were not ameliorated.

The neurological outcomes of cerebellar injury in premature infants

AIM Cerebellar injury is a characteristic injury associated with preterm infants. However, the impact of cerebellar injury on the development of preterm infants is unclear. METHOD We reviewed magnetic resonance image studies of preterm infants with cerebral palsy retrospectively and evaluated the developmental outcomes. RESULTS Cerebellar injury was recognized in 9 (2.4%) of 381 patients with cerebral palsy who were born preterm. The median gestational age was 26 (range 23-32) weeks and the median birth weight was 938 (range 492-1450) g. Seven of the nine patients had severe symmetric injuries to the inferior cerebellar hemispheres, resulting in a pancake-like appearance of the residual upper cerebellum. Supratentorial lesions were also recognized: periventricular leukomalacia in seven; atrophy of the basal ganglia in two; and intraventricular hemorrhage in two. Importantly, the motor dysfunction was related to the reduction in the white matter volume and severity of basal ganglia atrophy, but not to the cerebellar injury. Four of the nine patients could walk without limitations despite extensive cerebellar disruption. Only four patients could speak meaningful words during the study and only one spoke two-word sentences. INTERPRETATION The patients with cerebellar injury might have a communication handicap, rather than altered motor function. Prematurity-related cerebellar complications require more attention in terms of cognitive and speech function, in addition to neuromotor development.