Prognostic significance of serum osteoprotegerin levels in patients with bladder carcinoma

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in the process of lymphocyte-mediated cytotoxicity against malignant cells. Osteoprotegerin (OPG) is a soluble decoy receptor for TRAIL, and circulating OPG has been implicated in the protection of cells from TRAIL-mediated apoptosis. Thus, OPG may protect tumor cells from lymphocyte-mediated cytotoxicity and, as a result, contribute to tumor progression. In the current study, the authors investigated this hypothesis in patients with bladder carcinoma. METHODS: Serum OPG levels for 185 patients with bladder carcinoma were determined using an enzyme-linked immunosorbent assay. These levels then were assessed for potential correlations with various disease characteristics and outcome measures. RESULTS: The mean serum OPG concentration in patients with bladder carcinoma was approximately 3 times greater than the mean concentration in healthy individuals, and among patients with bladder carcinoma, higher tumor stage and grade were found to be associated with increased serum OPG levels. Within the subpopulation of patients with superficial bladder carcinoma, after a follow-up period of 5 years, those who had low serum OPG levels tended to have a longer postoperative tumor-free interval compared with those who had high serum OPG levels. Furthermore, among patients with muscle-invasive bladder carcinoma, the 5-year disease-specific survival rate was greater for those who had low serum OPG levels than for those who had high serum OPG levels. CONCLUSIONS: To the authors' knowledge, the current study is the first to demonstrate that serum OPG concentration is correlated with both tumor stage and tumor grade and that elevated serum OPG levels are predictive of early recurrence in patients with bladder carcinoma. These findings suggest that serum OPG concentration may have utility as a prognostic parameter in this setting.     

Evidence for the involvement of double-strand breaks in heat-induced cell killing

To identify critical events associated with heat-induced cell killing, we examined foci formation of gammaH2AX (histone H2AX phosphorylated at serine 139) in heat-treated cells. This assay is known to be quite sensitive and a specific indicator for the presence of double-strand breaks. We found that the number of gammaH2AX foci increased rapidly and reached a maximum 30 minutes after heat treatment, as well as after X-ray irradiation. When cells were heated at 41.5 degrees C to 45.5 degrees C, we observed a linear increase with time in the number of gammaH2AX foci. An inflection point at 42.5 degrees C and the thermal activation energies above and below the inflection point were almost the same for cell killing and foci formation according to Arrhenius plot analysis. From these results, it is suggested that the number of gammaH2AX foci is correlated with the temperature dependence of cell killing. During periods when cells were exposed to heat, the cell cycle-dependent pattern of cell killing was the same as the cell cycle pattern of gammaH2AX foci formation. We also found that thermotolerance was due to a depression in the number of gammaH2AX foci formed after heating when the cells were pre-treated by heat. These findings suggest that cell killing might be associated with double-strand break formation via protein denaturation.     

Complete response in a case of advanced esophageal cancer treated by combined chemotherapy of TS-1 and CDDP with radiotherapy

A 70-year-old patient with advanced esophageal cancer with invasion to the aorta was treated by combined chemotherapy of TS-1 and CDDP with radiotherapy. TS-1 (80 mg/m2) was administered for 14 days followed by 14 days rest, CDDP (70 mg/m2) was administered by 24 h continuous intravenous infusion at day 8 after the start of TS-1. Radiotherapy (5 days/week) at 2 Gy/day was concurrently started from the beginning of chemotherapy for 3 weeks. After the end of the first course, leukocytopenia of grade 2 and thrombocytopenia of grade 2 were observed. The second course of chemoradiotherapy was suspended for 1 week. After recovery from the toxicity, the second course was started. After the 2 courses of chemoradiotherapy, endoscopic examination with biopsy revealed the disappearance of the esophageal cancer. Combined chemotherapy of TS-1 and CDDP was administered 2 times after chemoradiotherapy. After this therapy, endoscopy and a CT showed a complete clinical response. No severe adverse effects were observed during this therapy. Combined chemotherapy of TS-1 and CDDP with radiotherapy can be effective for advanced esophageal cancer.     

Ganglioside complexes as new target antigens in Guillain-Barré syndrome

Antibodies specific for a complex of gangliosides GD1a and GD1b (GD1a/GD1b) were found in sera from eight of 100 patients with Guillain-Barre syndrome (GBS) by the use of enzyme-linked immunosorbent assay and thin-layer chromatogram immunostaining. Those sera also had antibody activities to such ganglioside complexes as GD1a/GM1, GD1b/GT1b, and GM1/GT1b but had little or no reactivity to the each isolated antigen. Clustered epitopes of the ganglioside complex in the plasma membrane may be targeted by such an antibody, and interaction between the antibody and ganglioside complex may induce the neuropathy.     

Afferent connections of the corpus cerebelli in holocentrid teleosts

The holocentrid corpus cerebelli (CC) is composed of the dorsal (CCd) and ventral (CCv) lobes. In the present study, afferent connections of the CCd and CCv in holocentrid teleosts (Sargocentron rubrum and S. diadema) were examined by means of tract-tracing methods. Tracer injections into either lobe of the CC labeled neurons in the ipsilateral area pretectalis pars anterior et posterior, nucleus paracommissuralis (NPC), nucleus accessorius opticus and nucleus tegmentocerebellaris. Labeled neurons were also present in the bilateral nucleus lateralis valvulae (NLV), nucleus raphes, nucleus reticularis lateralis and inferior reticular formation, and in the contralateral inferior olive. Injections into the CCd labeled only a few neurons in the area pretectalis pars anterior et posterior, nucleus accessorius opticus and nucleus tegmentocerebellaris, whereas many labeled cells were seen in these nuclei after CCv injections. Injections into the CCv also revealed afferent connections that were not observed after CCd injections. The CCv injections labeled additional neurons in the ipsilateral torus longitudinalis and nucleus subeminentialis and in the bilateral nucleus subvalvularis and nucleus of the commissure of Wallenberg. These differences in afferent connections suggest functional differences between the CCd and CCv. After injections into the CCd, labeled neurons in the NPC were restricted to a medial portion of the nucleus. On the other hand, after injections into the CCv, labeled neurons were found throughout the NPC. Labeled neurons in the NLV were mainly located in its rostral portion following CCd injections, whereas labeled neurons were mainly distributed in the medial portion following CCv injections. These observations suggest topographical organizations of the NPC-CC and NLV-CC projections.     

Fiber connections of the lateral valvular nucleus in a percomorph teleost, tilapia (Oreochromis niloticus)

Fiber connections of the lateral valvular nucleus were investigated in a percomorph teleost, the tilapia (Oreochromis niloticus), by tract-tracing methods. Following tracer injections into the lateral valvular nucleus, neurons were labeled in the ipsilateral dorsal part of dorsal telencephalic area, corpus glomerulosum pars anterior, dorsomedial thalamic nucleus, central nucleus of the inferior lobe, mammillary body, semicircular torus, valvular and cerebellar corpus, in the bilateral rostral regions of the central part of dorsal telencephalic area, dorsal region of the medial part of dorsal telencephalic area, habenula, anterior tuberal nucleus, posterior tuberal nucleus, and spinal cord, and in the contralateral lateral funicular nucleus. Labeled fibers and terminals were found in the ipsilateral cerebellar corpus and bilateral valvula of the cerebellum. Tracers were injected into portions of the telencephalon, pretectum, inferior lobe, and cerebellum to confirm reciprocally connections with the lateral valvular nucleus and to determine afferent terminal morphology in the lateral valvular nucleus. Telencephalic fibers terminated mainly in a dorsolateral portion of the lateral valvular nucleus. Terminals from the corpus glomerulosum pars anterior, central nucleus of the inferior lobe, and mammillary body showed more diffuse distributions and were not confined to particular portions of the lateral valvular nucleus. Labeled terminals in the lateral valvular nucleus were cup-shaped or of beaded morphology. These results indicate that the lateral valvular nucleus receives projections from various sources including the telencephalon, pretectum, and inferior lobe to relay information to the valvular and cerebellar corpus. In addition, the corpus glomerulosum pars anterior in tilapia is considered to be homologous to the magnocellular part of superficial pretectal nucleus in cyprinids.     

Anti-GQ1b antibody as a factor predictive of mechanical ventilation in Guillain-Barré syndrome

Compared with 87 unventilated patients with Guillain-Barré syndrome (GBS), 44 ventilated patients with GBS more frequently had multiple cranial nerve involvement (91 vs 50%; p < 0.001) and IgG anti-GQ1b antibody (27 vs 8%; p = 0.006). In GBS patients without ophthalmoparesis, the presence of IgG anti-GQ1b antibody was associated with respiratory failure (12 [3/25] vs 0% [0/67]; p = 0.04). The presence of the antibody may be a factor predictive of respiratory failure in GBS.     

Optical bioimaging: from living tissue to a single molecule: single-molecule visualization of cell signaling processes of epidermal growth factor receptor

Single-molecule imaging is an ideal technology to study molecular mechanisms of biological reactions in vitro. Recently, this technology has been extended to real-time observation of fluorescent dye-labeled molecules in living cells. Total internal reflection fluorescence microscopy is the major technique for this purpose. Using this technique, we have studied the process of early signal transduction of epidermal growth factor (EGF) in single molecules: binding of EGF to its receptor (EGFR) on the cell surface, dimerization of EGFR induced by binding of EGF, fluctuation of the structure of EGFR clusters, activation of EGFR through tyrosine phosphorylations on its cytoplasmic domain, and recognition of activated EGFR by a cytoplasmic adaptor protein, Grb2. EGF induces intracellular calcium response, sometimes caused by less than one hundred EGF molecules. Single-molecule studies suggested that this highly sensitive response to EGF was due to the amplification of the EGFR signal using dynamic clustering, reorganization of the dimers, and lateral mobility of EGFR on the cell surface. Through these studies, single-molecule analysis has proven to be a powerful technology to analyze intracellular protein systems.     

Undifferentiated spindle and giant cell carcinoma of the common bile duct

Undifferentiated spindle and giant cell carcinoma of the common bile duct has not been reported previously. We present here a case of 71-year-old man with the undifferentiated spindle and giant cell carcinoma of the common bile duct, including immunohistochemical findings. A nodular infiltrating tumor was located at the lower portion of the extrahepatic bile duct, and measured 1.2 x 0.6 cm in size. Histologically, the tumor was composed of proliferated sarcomatoid spindle tumor cells. Numerous multinucleated giant cells were intermingled with the sarcomatoid spindle tumor cells. Immunohistochemically, the tumor cells were positive for both cytokeratin and vimentin. We speculated that the tumor originated from epithelial cells, and showed sarcomatoid neplastic changes.