Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis.

The androgen receptor (AR) plays a key role as a transcriptional factor in prostate development and carcinogenesis. Identification of androgen-regulated genes is essential to elucidate the AR pathophysiology in prostate cancer. Here, we identified androgen target genes that are directly regulated by AR in LNCaP cells, by combining chromatin immunoprecipitation (ChIP) with tiling microarrays (ChIP-chip). ChIP-enriched or control DNAs from the cells treated with R1881 were hybridized with the ENCODE array, in which a set of regions representing approximately 1% of the whole genome. We chose 10 bona fide AR-binding sites (ARBSs) (P<1e-5) and validated their significant AR recruitment ligand dependently. Eight upregulated genes by R1881 were identified in the vicinity of the ARBSs. Among the upregulated genes, we focused on UGT1A and CDH2 as AR target genes, because the ARBSs close to these genes (in UGT1A distal promoter and CDH2 intron 1) were most significantly associated with acetylated histone H3/H4, RNA polymerase II and p160 family co-activators. Luciferase reporter constructs including those two ARBSs exhibited ligand-dependent transcriptional regulator/enhancer activities. The present study would be powerful to extend our knowledge of the diversity of androgen genetic network and steroid action in prostate cancer cells.

In vivo induction of human immunodeficiency virus type 1 entry into nucleus-free cells by CD4 gene transfer to hematopoietic stem cells: a hypothetical possible strategy for therapeutic intervention.

As a useful alternative to employing soluble CD4 to inhibit binding of human immunodeficiency virus type 1 (HIV-1) to target cells, the introduction of CD4-bearing erythrocyte has been proposed by two study groups (see Refs. (5,6)). Prominently, Nicolau and colleagues demonstrated that the electroinserted CD4 molecules in the membranes of erythrocytes are capable of mediating HIV-1 entry. The implications of the studies are that inactivation of the integration-dependent retrovirus by the facilitation of entry into the nucleus-free cells, referred to as 'fake host trap' or 'host cell decoy', may be a possible therapeutic approach. Here we expand this concept to include genetic modification of autologous hematopoietic stem cells and review the relevant theoretical basis. Effective application of molecular technologies to induce partial replacement of hematopoiesis may be critical for this strategy.

Minor form of trigonocephaly is an autistic skull shape? A suggestion based on homeobox gene variants and MECP2 mutations.

A possible role for Hoxa1 genotype in susceptibility to autism spectrum disorders was recently proposed. Furthermore, it has been demonstrated that Rett syndrome, which is categorized into pervasive developmental disorders the same as the autism spectrum disorders are, is associated with mutations in MECP2 gene. These findings suggest that the genetic backgrounds of these behavioral conditions may involve genes which also have an important role in the development of skull, because Hoxa1 is a key gene for skull development as well as for brain development and one of the clinical characteristics of Rett syndrome is deceleration in head growth. Together with this evolving knowledge, a series of ethical arguments concerning the indication of surgical treatment in patients with minor forms of trigonocephaly with autistic behaviors and/or hyperactivity leads us to hypothesize the presence of an autism subtype which may frequently be accompanied by specific morphological skull characteristics (autistic skull shape).

Heat transfer and flow characteristics on a gas turbine shroud.

The work described in this paper is an experimental investigation of the heat transfer from the main flow to a turbine shroud surface, which may be applicable to ceramic gas turbines. Three kinds of turbine shrouds are considered with a flat surface, a taper surface and a spiral groove surface opposite to the blades in an axial flow turbine of actual turbo-charger. Heat transfer measurements were performed for the experimental conditions of a uniform heat flux or a uniform wall temperature. The effects of the inlet flow angle, rotational speed, and tip clearance on the heat transfer coefficient were clarified under on- and off-design flow conditions. The mean heat transfer coefficient was correlated to the blade Reynolds number and tip clearance, and compared with an experimental correlation and measurements of a flat surface. A comparison was also made for the measurement of static pressure distributions.

Reflux of HTLV-I infected lymphocytes from the privileged compartment(s) to peripheral blood flow in patients with HTLV-I-associated myelopathy.

To understand the mechanisms involved in the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), three in vivo phenomena which have been observed in the peripheral blood of patients and differing from that in asymptomatic HTLV-I carriers must be taken into consideration: (a) the presence of increased HTLV-I viral load, (b) a higher immune responsiveness against HTLV-I antigens, and (c) biased nucleotide substitutions in the HTLV-I pX region which indicate a decreased selection pressure for viral amino acid changes. We now propose a hypothesis which focuses on the in vivo dynamics of HTLV-I infected lymphocyte migration and which incorporates these features. In addition, the hypothesis assumes the existence of a deviation in immune surveillance for HTLV-I in the central nervous system (CNS) in spite of the presence of frequent specific immune effectors. We suggest that in the active phase of HAM/TSP, accompanied with or following autoaggressive interactions between infected lymphocytes and immunocompetent cells in the CNS, there is a consequential reflux of the infected lymphocytes to the peripheral blood. The reflux of infected cells would be expected to provide peripheral blood with tissue-derived HTLV-I proviruses which have been indulged and propagated in an immune-privileged site. This process would result in and account for the observed increase in viral load and the substitution bias in HTLV-I sequences in the peripheral blood.

[HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP)].

Human T lymphotropic virus type I(HTLV-I) is associated with the nonfatal neurologic disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Many clinical signs of involvement outside the central nervous system (CNS) have been described in some patients with HAM/TSP and have triggered the discovery of some HTLV-I-associated concepts in the infected individuals without signs of CNS involvement. Most of these HTLV-I-associated diseases exhibit common possible viroimmunologic characteristics that include a distributional bias of HTLV-I activation between the blood flow and the affected lesions and accumulated cellular immune responses in the lesions. This review summarizes the recent perspectives of the molecular pathogenesis of HAM/TSP and other HTLV-I-associated diseases. Furthermore, the feasible pathogenic involvement of cellular interactions between infected cells and responding immunocompetent cells in the affected tissues is emphasized (bystander auto-aggressiveness).

Angiographic morphology of the posterior communicating artery and basilar in patients with ICA-PComA aneurysm.

The relationships between the angiographic morphology of the posterior communicating artery (PComA) and the basilar artery (BA) and saccular aneurysms at the internal carotid artery (ICA)-PComA junction were evaluated in 23 patients with ICA-PComA aneurysm and 46 controls. No significant differences were found in the height of the basilar top, the dislocation and inner diameter of the BA, and the distance between the basilar top and the ICA-PComA junction. However, the angle between the PComA and C2 portion of the ICA was larger and the PComA straighter in ICA-PComA aneurysm patients. Tension in the PComA and mechanical damage to the divergent angle of the PComA are probably important factors in the development of ICA-PComA aneurysms.

[Efficacy of leukocytapheresis and low-dose prednisolone treatment in a patient with HTLV-I-associated myelopathy (HAM)].

The patient, a 66-year-old woman, was admitted because of a two year history of slowly progressive gait disturbance. A diagnosis of HTLV-I-associated myelopathy (HAM) was made on the basis of the clinical and serological criteria. Although the ordinary dose of oral prednisolone (PSL) is more than 30 mg in the treatment of HAM, we treated this patient by low-dose (5-10 mg) oral PSL administration. A series of leukocytapheresis performed before the PSL treatment halted the progression of symptoms transiently. Alterations in peripheral blood lymphocyte (PBL) subpopulations and augmented autologous proliferative response of PBLs improved concurrently with the resolution of neurological symptoms after the low-dose PSL treatment. The result suggests that some cases with HAM may respond with PSL treatment in low doses.

Type IIa hyperlipoproteinemia masquerading as cerebrotendinous xanthomatosis.

We describe an adult patient with type IIa hyperlipoproteinemia, presenting with Achilles tendon xanthomas, cataracts, dementia, ataxia, pyramidal tract signs, and peripheral neuropathy, which are commonly seen in cerebrotendinous xanthomatosis (CTX). However, the diagnosis of CTX was excluded on the basis of the cholestanol level and the normal cholestanol/cholesterol ratio in his serum and tendon. The pathomechanism for some of the clinical manifestations in type IIa hyperlipoproteinemia and CTX might be caused by a common biochemical disturbance.

Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells.

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.