BACKGROUND: Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. METHODS: Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. RESULTS: S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. CONCLUSIONS: The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. Prostate © 2012 Wiley Periodicals, Inc.

This report presents the extremely rare case of an adult patient who presented with peritonitis caused by the perforation of an ileal duplication, associated with a gastrointestinal stromal tumor (GIST) arising within the duplication. A 70-year-old female was admitted to the hospital with lower abdominal pain. Abdominal computed tomography showed free air in the peritoneal cavity. An emergency laparotomy was performed, presuming diffuse peritonitis caused by a perforation of the gastrointestinal tract. The surgical findings showed that the peritonitis was caused by the perforation of an ileal duplication, 90 cm proximal to the ileocecal valve, with an extrinsic tumor protruding from the duplication. A segmental resection of the ileum-including the tumor and ileal duplication-was performed. Histopathology showed that the tumor was composed of spindle-shaped and epithelioid cells. The tumor was immunohistochemically positive for KIT, with a deletion mutation spanning the intron 10-exon 11 boundary. Accordingly, a diagnosis was made of a GIST arising within a duplication of the ileum. Duplications of the alimentary tract are encountered only occasionally in adults. Although quite rare, malignant change should therefore be considered as a possible complication when a solid portion is observed within a duplication of the alimentary tract.

We identified the prevalence of depression and quality of life (QOL) of Japanese children with childhood cancer after discharge using the Birleson Depression Self-rating Scale for Children (DSRS-C) and the Pediatric Quality of Life Inventory (PedsQL). Subjects were 118 caregivers who raised children ages 2-18 with childhood cancer; subjects resided in suburban districts of Japan and completed instruments after their children were discharged. Multiple regression analysis of data collected from 105 respondents revealed that lower PedsQL scores correlated with more problems in life at school and at home, an increased frequency of hospital visits, less cooperation within the family, and higher DSRS-C scores. To ensure the QOL of children with childhood cancer, outpatient nurses need to encourage children to psychosocially adapt after discharge, periodically screen children during outpatient treatment using instruments such as the DSRS-C, and conduct preventive interventions for children who meet screening criteria and their families before they suffer from adaptation disorders and offer multilateral psychosocial assistance in cooperation with a multidisciplinary care team.

We report on the mapping of quantum-Hall edge states by quasiresonant photovoltage measurements using a near-field scanning optical microscope. We have observed fine structures near sample edges that shift inward with an increase in magnetic field in accordance with the shift of the positions of the quantum-Hall edge states. We have found a transition from the weak disorder regime where compressible-incompressble strips are visible to the strong disorder regime where fluctuations smear out incompressible strips.

Synthetic polymer nanoparticles (NPs) that bind venomous molecules and neutralize their function in vivo are of significant interest as "plastic antidotes." Recently, procedures to synthesize polymer NPs with affinity for target peptides have been reported. However, the performance of synthetic materials in vivo is a far greater challenge. Particle size, surface charge, and hydrophobicity affect not only the binding affinity and capacity to the target toxin but also the toxicity of NPs and the creation of a "corona" of proteins around NPs that can alter and or suppress the intended performance. Here, we report the design rationale of a plastic antidote for in vivo applications. Optimizing the choice and ratio of functional monomers incorporated in the NP maximized the binding affinity and capacity toward a target peptide. Biocompatibility tests of the NPs in vitro and in vivo revealed the importance of tuning surface charge and hydrophobicity to minimize NP toxicity and prevent aggregation induced by nonspecific interactions with plasma proteins. The toxin neutralization capacity of NPs in vivo showed a strong correlation with binding affinity and capacity in vitro. Furthermore, in vivo imaging experiments established the NPs accelerate clearance of the toxic peptide and eventually accumulate in macrophages in the liver. These results provide a platform to design plastic antidotes and reveal the potential and possible limitations of using synthetic polymer nanoparticles as plastic antidotes.

In the developed countries, especially Japan, elderly population is rapidly increasing, but outcomes of elderly patients with the age of 80 years and older suffering from subarachnoid hemorrhage (SAH) remain still unclear. We retrospectively reviewed the medical records of nontraumatic SAH patients aged 80 years and older, who were hospitalized in a single center between 1998 and 2009. There were 28 patients (80-90 years old and 75% female), representing 5.9% of all non-traumatic SAHs (n = 474). Of those, 16 patients received an intervention (ten clipping and six endovascular coiling) and the remaining 12 patients were managed conservatively. The median survival time of intervention group was 110 days and that of conservative group 49 days (p = 0.12, log rank analysis). Cox's proportional hazards model yielded two variables, the Japan Coma Scale (JCS) grade on admission ( hazard ratio: 2.93 [p = 0.009]) and conservative treatment (hazard ratio: 2.14 [p = 0.054]). In the outcome of the modified Rankin Scale between these two groups, logistic regression analysis had significant variable; the JCS grade on admission (odds ratio: 280,[p = 0.020]). In the elderly patients with good initial clinical condition, an acute intervention may have good outcome.

Mutations in IDH1 and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q codeletion also had an IDH mutation, and these alterations were significantly correlated (p< 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (p= 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 gliomas (p< 0.001) and grade 3 (p= 0.02) gliomas. IDH mutation and 1p/19q codeletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q codeletion, IDH mutation was strongly associated with increased progression-free survival (p< 0.0001) and overall survival (p< 0.0001), while such marked correlation was not observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most such grade 3 gliomas. © 2011 Japanese Cancer Association.

A hepatic tumor was found in a 57-year-old man with glycogen storage disease type 1a (GSD1a) with a mutation in exon 5 of the glucose-6-phosphatase gene (G727T). Partial hepatectomy was performed, and the tumor was histologically diagnosed as moderately differentiated hepatocellular carcinoma (HCC). On contrast-enhanced ultrasonography, the tumor had a late phase defect. Abdominal imaging with other modalities was also performed. More studies are needed to clarify the differences in imaging findings between GSD1a-associated HCC and other tumors such as adenomas.

A rationally designed tetrahydroquinoline (1) for nonsteroidal selective androgen receptor modulators was modified for the exploration of promising compounds by Grieco three-component condensation using various dienophiles. Based on the in vitro effects and physicochemical properties of the synthesized compounds, compound 4c was selected for further study. Compound 4c increased the femoral bone mineral density as much as DHT, but it reduced the uterus effect compared with DHT in ovariectomized rats. Thus, compound 4c has desirable osteoanabolic effects with weak undesirable effects on the uterus in a female osteoporosis model.