[Inhibitors of the key enzymes of androgen synthesis: potential agents as targets for prostate cancer].
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17-Hydroxysteroid Dehydrogenases↗
Biomedical subjects
M Hosaka
Publications and source records attributed to M Hosaka.
[Rebound of prostate specific antigen after discontinuation of antiandrogen therapy for benign prostatic hyperplasia].
We compared the prostate specific antigen (PSA) levels in benign prostatic hyperplasia (BPH) patients with antiandrogen chlormadinone acetate (CMA) or allylestrenol (AE) before and during the treatment. We also investigated the serial change of PSA levels before, during and after discontinuation of antiandrogen therapy. Fifty-one BPH patients with normal PSA levels were treated with CMA or AE for 16 weeks. The mean serum PSA level significantly decreased after the treatment from 1.9 +/- 1.0 ng/ml to 1.1 +/- 0.7 ng/ml (M +/- SD). We discontinued medication with informed consent and the patients were carefully monitored for another 16 weeks. Nineteen patients were followed for 32 weeks. The mean serum PSA level decreased significantly from 2.0 +/- 1.0 ng/ml to 1.1 +/- 0.5 ng/ml (M +/- SD) and recovered approximately to the pretreatment level (1.7 +/- 1.1 ng/ml) at the end of this study. We found only one patient whose PSA was slightly elevated to a subnormal range (4.3 ng/ml) after discontinuation of therapy. The other BPH patients with normal PSA levels showed no excessive increase in PSA levels beyond the normal limit after discontinuation of antiandrogen therapy compared with the pretreatment baseline. In conclusion, BPH patients with a marked increase in PSA after discontinuation of antiandrogen therapy should be checked for prostate cancer.
Aged↗
[In vitro antibacterial activity of prulifloxacin, a new oral quinolone, and comparative susceptibility rate at clinical breakpoint MIC].
In vitro drug sensitivity of clinically isolated bacteria against prulifloxacin (PUFX), which is a new quinolone, was investigated, and the antibacterial activity and susceptibility rate at clinical breakpoint were compared with those of norfloxacin, ofloxacin (OFLX), ciprofloxacin, tosufloxacin, fleroxacin, sparfloxacin and levofloxacin (LVFX). The following results were obtained. 1) PUFX showed a broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. 2) MIC80 of PUFX was 0.25 and 1 microgram/ml, against methicillin susceptible Staphylococcus aureus and Streptococcus pneumoniae, respectively and below 0.125 microgram/ml against Gram-negative Enterobacteriaceae. MIC90 of PUFX against Pseudomonas aeruginosa, which has MIC not exceeding 4 micrograms/ml to OFLX, was 0.5 microgram/ml. 3) PUFX was judged as active against the bacteria under the criteria proposed presented by "the Sensitivity Determination Committee for Antibiotics, Japan Society of Chemotherapy: Break Point for Respiratory Infectious Diseases and Sepsis". It is suggested that the sensitivity of each bacterial species to PUFX was high. 4) From the correlation analysis of MIC, PUFX was shown to have two to eight times higher antibacterial acitivity than LVFX for Citrobacter freundii, Serratia marcescens and Pseudomonas aeruginosa. 5) PUFX showed potent short-time bactericidal activity against S. aureus and P. aeruginosa.
Anti-Infective Agents↗
DNA polymerase beta gene mutation in human breast cancer.
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Adult↗
A conformational switch in syntaxin during exocytosis: role of munc18.
Syntaxin 1, an essential protein in synaptic membrane fusion, contains a helical autonomously folded N-terminal domain, a C-terminal SNARE motif and a transmembrane region. The SNARE motif binds to synaptobrevin and SNAP-25 to assemble the core complex, whereas almost the entire cytoplasmic sequence participates in a complex with munc18-1, a neuronal Sec1 homolog. We now demonstrate by NMR spectroscopy that, in isolation, syntaxin adopts a 'closed' conformation. This default conformation of syntaxin is incompatible with core complex assembly which requires an 'open' syntaxin conformation. Using site-directed mutagenesis, we find that disruption of the closed conformation abolishes the ability of syntaxin to bind to munc18-1 and to inhibit secretion in PC12 cells. These results indicate that syntaxin binds to munc18-1 in a closed conformation and suggest that this conformation represents an essential intermediate in exocytosis. Our data suggest a model whereby, during exocytosis, syntaxin undergoes a large conformational switch that mediates the transition between the syntaxin-munc18-1 complex and the core complex.
Animals↗
Homo- and heterodimerization of synapsins.
In vertebrates, synapsins constitute a family of synaptic vesicle proteins encoded by three genes. Synapsins contain a central ATP-binding domain, the C-domain, that is highly homologous between synapsins and evolutionarily conserved in invertebrates. The crystal structure of the C-domain from synapsin I revealed that it constitutes a large (>300 amino acids), independently folded domain that forms a tight dimer with or without bound ATP. We now show that the C-domains of all synapsins form homodimers, and that in addition, C-domains from different synapsins associate into heterodimers. This conclusion is based on four findings: 1) in yeast two-hybrid screens with full-length synapsin IIa as a bait, the most frequently isolated prey cDNAs encoded the C-domain of synapsins; 2) quantitative yeast two-hybrid protein-protein binding assays demonstrated pairwise strong interactions between all synapsins; 3) immunoprecipitations from transfected COS cells confirmed that synapsin II heteromultimerizes with synapsins I and III in intact cells, and similar results were obtained with bacterial expression systems; and 4) quantification of the synapsin III level in synapsin I/II double knockout mice showed that the level of synapsin III is decreased by 50%, indicating that heteromultimerization of synapsin III with synapsins I or II occurs in vivo and is required for protein stabilization. These data suggest that synapsins coat the surface of synaptic vesicles as homo- and heterodimers in which the C-domains of the various subunits have distinct regulatory properties and are flanked by variable C-terminal sequences. The data also imply that synapsin III does not compensate for the loss of synapsins I and II in the double knockout mice.
Animals↗
A phospho-switch controls the dynamic association of synapsins with synaptic vesicles.
Synapsins constitute a family of synaptic vesicle proteins essential for regulating neurotransmitter release. Only two domains are conserved in all synapsins: a short N-terminal A domain with a single phosphorylation site for cAMP-dependent protein kinase (PKA) and CaM Kinase I, and a large central C domain that binds ATP and may be enzymatic. We now demonstrate that synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles. Furthermore, we show that the A domain binds phospholipids and is inhibited by phosphorylation. Our results suggest a novel mechanism by which proteins reversibly bind to membranes using a phosphorylation-dependent phospholipid-binding domain. The dynamic association of synapsins with synaptic vesicles correlates with their role in activity-dependent plasticity.
Amino Acid Sequence↗
Telomerase activity in oral cancer.
Telomerase activity can be detected in most human cancers. This is consistent with the telomere hypothesis, which predicts upregulation of telomerase expression after a number of mitotic divisions to prevent the progressive and catastrophic loss of telomeres. However, telomerase has not been fully analyzed in oral cancers. In this report, telomerase activity was analyzed in 31 human oral malignant tumors, 11 leukoplakias, three pleomorphic adenomas, and 40 samples taken from normal tissues of the oral cavity, using a polymerase chain reaction (PCR)-based telomeric repeat amplification protocol assay. Telomerase activity was detected in most oral cancers [squamous cell carcinoma (SCC), non-Hodgkin's lymphoma, adenoid cystic carcinomas, mucoepidermoid carcinoma, osteosarcoma, acinic cell carcinoma, rhabdomyosarcoma]. None of the normal tissues or pleomorphic adenomas displayed telomerase activity. In leukoplakia, telomerase activity was seen in moderate or severe dysplastic tissue and carcinoma in situ. Mild dysplasia did not reveal telomerase activity. In SCC, there was no clear association between relative telomerase activity and grade or stage. These results suggest that detection of telomerase activity in oral tissues could be used to differentiate malignant from benign or normal tissues.
Aged↗
Effects of extracellular ions on the reactivation of human spermatozoa preserved in electrolyte-free solution.
It has previously been reported that human spermatozoa preserved in an electrolyte-free solution can survive for several weeks at 4 degrees C. However, the motility of spermatozoa after preservation cannot be restored when incubated at 37 degrees C, unless reactivated by extracellular alkalisation. Under weak acidic conditions, the reactivation is induced by > or = 10 mmol l-1 Na+ and inhibited by a Na(+)-H+ antiporter inhibitor. The addition of > or = 0.1 mmol l-1 K+ also induces the reactivation. In the present study, the reactivation was induced by > or = 0.1 mmol l-1 Rb+ or > or = 1 mmol l-1 Cs+ at an acidic pH. The maximum motility rate with K+, Rb+ or Cs+ was obtained at 10-20 mmol l-1 and inhibited by 10(-5)-10(-2) mol l-1 ouabain in a dose-dependent manner, while ouabain had no effect on the Na(+)-induced reactivation. The addition of K+ further increased sperm motility reactivated by Na+, which was also inhibited by ouabain. The addition of Ca2+ did not induce the reactivation or increase sperm motility reactivated by Na+ or K+. It was concluded that activation of the ouabain-sensitive Na(+)-K(+)-ATPase and Na(+)-H+ exchange mechanism has an important role in sperm motility.
Calcium↗
Direct and indirect effects of electrical stimulation on the motility of human sperm.
BACKGROUND: Electroejaculation is a technique that is becoming more frequently available for obtaining sperm from men with spinal cord injury or psychogenic anejaculation. However, the effect of electrical stimulation on the movement of human sperm has not been clarified. METHODS: Electrical stimulation was applied to ejaculated semen or washed sperm via a pair of electrodes in the sperm-counting chamber while sperm motility was recorded using a computer-assisted semen analyzer. RESULTS: When monopolar pulse stimulation was applied to sperm, the motility rate and velocity of sperm near both electrodes decreased according to the number of pulses and current despite low electrical voltages. However, motility of sperm in the center between electrodes did not change. When extremely high-voltage electrical stimulation with more than 80 V/2 mm (distance between electrodes) was applied to sperm, sperm stopped moving regardless of their location between the electrodes, despite a low electrical current and low energy. Replicating clinical rectal probe electroejaculation, continuous sinusoidal alternating current at 50 V/10 mm was applied to a untreated ejaculated semen. The motility of sperm, except for those adjacent to both electrodes, did not change after stimulation for 60s, despite a high electrical energy. CONCLUSIONS: The motility of sperm near electrodes was decreased when high electric current flowed, despite low electrical voltages. In addition, sperm lost their motility when extremely high-voltage electrical stimulation was applied. However, electrical stimulation during clinical rectal probe electroejaculation seems to have no effect on sperm motility.
Ejaculation↗
Primary hepatic amyloidosis well delineated by Tc-99m DTPA galactosyl HSA liver SPECT.
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Aged↗
Use of Tc-99m DTPA galactosyl human serum albumin to predict postoperative residual liver function.
PURPOSE: Residual liver uptake at 15 minutes (RLU15), a new index for predicting residual liver function after excision of hepatocellular carcinoma, was evaluated using dynamic liver images and SPECT by Tc-99m DTPA galactosyl human serum albumin. MATERIALS AND METHODS: In 13 cases of hepatectomy, RLU15 was compared with postoperative serum prothrombin levels, serum bilirubin levels, and ascites. RESULTS: RLU15 showed good correlation with both the prothrombin activity and the serum bilirubin, with correlation coefficients of r = 0.829 and r = -0.757. CONCLUSION: This new index appears useful for predicting residual liver function after hepatectomy.
Ascites↗
The worst histologic elements predict prognosis in moderately-differentiated prostate cancer patients with androgen-withdrawal endocrine therapy.
OBJECTIVES: We evaluated the prognostic value of the worst histologic elements in 155 patients with moderately-differentiated prostate cancer (Gleason sum 5-7) treated with androgen-withdrawal endocrine therapy. METHODS: In individual cases, the proportion (%) of medullary/solid combined with columns-and-cords/trabecular (MED & C-C), regarded as the worst histologic elements, determined according to WHO-Mostofi's classification of histologic patterns, within the total adenocarcinoma area obtained from needle specimens was estimated. RESULTS: Patients with proportion of MED & C-C >5% had a significantly poorer prognosis than those with <5% (p < 0.05). A significant difference was also found in the survival curves of patients grouped by stage (p < 0.01). There was no significant difference among the patients with Gleason sum of 5, 6 and 7. Multivariate analysis showed that stage and MED & C-C had independent prognostic value. CONCLUSIONS: Proportion of MED & C-C may provide useful prognostic information about patients with moderately-differentiated, Gleason sum 5-7, prostate cancer treated with androgen-withdrawal endocrine therapy.
Adenocarcinoma↗
Fibrous dysplasia arising from the calcaneus.
A case of an 18-year-old woman with fibrous dysplasia arising in the calcaneus, which is extremely rare, is reported, with the emphasis placed on differential diagnosis from low-grade central osteosarcoma. She had a severe pain in her left ankle after sprain. Plain radiographs showed a radiolucent lesion measuring 6.3 x 2.5 cm with a sclerotic margin in the left calcaneus. CT scans showed a well-defined lytic lesion with disruption of the lateral cortex and an ossification or calcification in its center. On MR imaging, the lesion had isointensities and high intensities on T1 and T2 weighted images, respectively, but its central portions showed lower intensities both on T1 and T2 weighted images. The lesion was enhanced with gadolinium except for the central portions. The specimen obtained by open biopsy consisted of fibrous tissue and foci of irregular woven bone. None of the nuclear atypia, mitoses, longitudinal stream of bone or invasive nature of growth was detected. The diagnosis of fibrous dysplasia was histologically made. The lesion was curetted and packed with autogenous bone chips. No evidence of recurrence was noted postoperatively.
Adolescent↗
Identification of a 5-cM region of common allelic loss on 8p12-p21 in human breast cancer and genomic analysis of the hEXT1L/EXTR1/EXTL3 gene in this locus.
The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer, suggesting the presence of a tumor suppressor gene(s) in this region. We identified a gene termed hEXT1L/EXTR1/EXTL3 (hEXT1L hereinafter) that was mapped to chromosome bands 8p12-p21 where frequent LOHs of this region was reported in breast cancer. The existence of the third breast cancer susceptibility gene was also suggested in this region by linkage analysis. We further performed LOH analysis in 8p12-p21 in 34 breast cancers and identified a 5-cM region of common allelic loss that overlapped with the locus for positive lod score in familial breast cancer. We further analyzed genomic alterations of hEXT1L in tumors in which frequent LOHs of 8p were reported. A total of 327 cancers (313 primary tumors and 14 cancer cell lines) including 22 primary breast cancers were analyzed, but none of the tumors had somatic mutations: only one thyroid cancer patient without any family history of cancer had a 9-bp insertion in the constitutional DNA. These results suggest that mutations of hEXT1L do not play a major role in the development of sporadic cancers including breast cancer, and that other tumor suppressor gene(s) exists in the 5-cM region identified in this study.
Alleles↗
Expression and prognostic value of CD44 isoforms in transitional cell carcinoma of renal pelvis and ureter.
PURPOSE: We retrospectively evaluated the expression and prognostic value of CD44 isoforms in transitional cell carcinoma of the renal pelvis and ureter. MATERIALS AND METHODS: Using a labeled streptavidin-biotin-peroxidase method we performed immunohistochemical staining of archival tissue specimens from 62 men and 26 women with a mean age of 66.5 years who had transitional cell carcinoma of the renal pelvis and ureter. RESULTS: The expression of CD44 standard (CD44s) and splice variant 6 (CD44v6) proteins was significantly decreased in relation to histological grade and pathological stage, while expression of the CD44 splice variant 3 (CD44v3) protein was decreased in relation to histological grade. The prognosis was more favorable in patients with greater versus less than 25% CD44s positive cells. CD44v3 and CD44v6 proteins had no prognostic value. Multivariate analysis indicated that only pathological stage has an independent prognostic value. CONCLUSIONS: The expression of CD44 isoforms is closely associated with tumor differentiation and progression. However, it is not an independent marker and has no statistical significance greater than that of stage.
Adult↗
Computerized tomography nephroscopic images of renal pelvic carcinoma.
PURPOSE: Computerized tomography (CT) endoscopy is an interactive 3-dimensional image acquired by helical CT. We assess the usefulness of CT nephroscopy in the diagnosis of renal pelvic cancers. MATERIALS AND METHODS: Surface rendering CT nephroscopy was performed after intravenous administration of contrast agent and furosemide in 32 patients with suspected renal pelvic carcinoma. Retrospective review revealed that 23 patients later underwent nephroureterectomy. Two observers blinded to the pathology results independently reviewed the CT nephroscopic and axial CT images of the 23 patients to localize pelvic tumors and to determine the extent of the disease. The CT nephroscopic and axial CT images were correlated with the pathological findings. RESULTS: Pathological examination revealed 4 polypoid, 6 pedunculated, 7 sessile, 1 sessile with ulceration and 6 infiltrating renal pelvic carcinomas in the 23 patients. CT nephroscopy revealed 22 carcinomas (92%) and CT demonstrated 20 (83%). CT nephroscopy was superior to axial CT in detecting 4 pedunculated and 3 infiltrating carcinomas but failed to detect 1 sessile carcinoma which completely replaced the upper portion of a double renal pelvis and 1 polypoid tumor associated with infiltrating carcinoma. The CT nephroscopic images correlated well with pathological findings. CONCLUSIONS: CT nephroscopy is useful to visualize the complex morphology of renal pelvic carcinomas noninvasively and is superior to axial CT for the detection of infiltrating and pedunculated carcinomas.
Adult↗
Desmoplastic small round-cell tumor of the paratesticular region: report of an adult case with demonstration of EWS and WT1 gene fusion using paraffin-embedded tissue.
Desmoplastic small round-cell tumor typically occurs in the abdomen of young men, but it can also develop at other anatomic sites and in older people, presenting greater diagnostic difficulties. We report a case of this tumor arising from the paratesticular region in a 43-year-old man. The tumor showed histologic, immunohistochemical, and ultrastructural evidence of multilineage differentiation, including epithelial, mesenchymal, and neuronal features. In addition, the presence of an EWS and WT1 chimeric messenger RNA was demonstrated by the reverse transcriptase-polymerase chain reaction using an EWS exon 7 primer and WT1 exon 8 and exon 9 primers, which revealed single polymerase chain reaction products with a junction of EWS exon 7 to WT1 exon 8. Our study demonstrates that desmoplastic small round-cell tumors of the paratesticular region share not only morphologic but also molecular genetic features with those of the abdomen and that reverse transcriptase-polymerase chain reaction analysis using paraffin sections is useful for a conclusive diagnosis.
Abdominal Neoplasms↗