Homotypic Adhesion through Carcinoembryonic Antigen Plays a Role in Hepatic Metastasis Development

We established a cell line with high metastatic potential to the liver (LS-LM4) after four successive repetitions of splenic injection of liver-metastatic cells in SCID mice. This cell line strongly expressed CEA and showed increased homotypic adhesion as compared with the parent cell line (LS174T). To examine the role of CEA in the increased homotypic adhesion, LS-LM4 cells were treated with anti-CEA antibody and subjected to an in vitro adhesion and aggregation assay. Further, to study the role of CEA in the hepatic metastasis of cells with high metastatic potential, LS-LM4 cells were treated with anti-CEA antibody, and the inhibition of hepatic metastasis after splenic injection in vivo was examined. There was a 62% decrease in the homotypic adhesion of anti-CEA antibody-treated (100 μg/ml) LS-LM4 cells under a Ca²⁺-free condition as compared with the control ( P <0.01). Anti-CEA antibody (100 μg/ml) inhibited cell aggregation under a Ca²⁺-free condition ( P <0.05). Treatment with anti-E-cadherin antibody (60 μ/ml) plus anti-CEA antibody (100 μg/ml) inhibited cell aggregation more potently than anti-E-cadherin antibody treatment alone in the presence of Ca²⁺. In vivo , there was a 75% decrease in the number of hepatic metastatic nodules in the G125 anti-CEA antibody-treated group as compared with the control group ( P <0.01). Similarly, there was a 40% decrease in the diameter of metastatic nodules and there was a 90% decrease in total tumor volume of hepatic metastasis in the G125 anti-CEA antibody-treated group as compared with the control ( P <0.01). These results suggest that increased metastatic potential to the liver is at least partly due to increased homotypic binding mediated by CEA.     

Absence of p53 Overexpression and Favorable Response to Cisplatin-based Neoadjuvant Chemotherapy in Urothelial Carcinomas

It has been controversial whether cancer cells harboring loss or inactivation of the tumor suppressor p53 are resistant or sensitive to DNA-damaging agents including cisplatin and doxorubicin. Overexpression of mdm2 oncoprotein, a negative regulator of p53, is assumed to be an alternative to p53 dysfunction. Archival urothelial carcinoma specimens obtained from 60 patients prior to cisplatin-based chemotherapy were immunohistochemically studied for overexpression of p53 and mdm2. Thirty-two patients (group I) were treated with chemotherapy in the neoadjuvant setting, while 28 patients (group II) underwent chemotherapy for distant metastases or inoperable locoregional tumors. In group I, the responsiveness was correlated with staining status of p53 ( P =0.0225) and the combination of p53 and mdm2 ( P =0.0497). Negative staining of p53 and negative for both p53 and mdm2 could have predicted favorable response to chemotherapy in 16 of 18 (88.9%) and in 12 of 13 (92.3%) tumors, respectively. On the other hand, p53-positive and p53 and/or mdm2-positive staining could have predicted poor response only in 7 of 14 (50.0%) and 8 of 19 (42.1%) tumors, respectively. Disease-specific survival of the p53-negative group was significantly superior to that of the p53-positive group ( P =0.0086). Difference in survival did not become more significant when overexpression of mdm2 was taken into consideration ( P =0.0456). In contrast, in group II, there was no correlation of responsiveness to chemotherapy or survival with p53- or p53/mdm2-staining status. The patients with urothelial carcinomas negative for overexpression of p53 will benefit from neoadjuvant chemotherapy. From clinical viewpoint, however, p53 status alone or the combination of p53 and mdm2 status is not enough to identify those patients who will not benefit from the treatment.     

Plasticity of central monoaminergic systems during aging]

The locus coeruleus (LC), located within the caudal pontine central gray, is composed of noradrenaline-containing neurons. The axons of these neurons form extensive collateral branches that project widely to many brain sites. The function of the LC is still unclear at present, however, LC neurons are known to exhibit marked axonal regeneration and sprouting in response to brain damage. We investigated the age-related changes in noradrenergic innervations of the frontal cortex, using in vivo electrophysiological techniques and immunohistochemistry. While noradrenergic innervations gradually decreased with age in the frontal cortex, a high degree of sprouting occurred in the LC axon terminals in middle age. Neither the electrophysiological properties of LC neurons nor NA levels in the frontal cortex changed with age. These findings suggested that the LC neurons preserve a strong capacity to remodel their axon terminals even in the aging brain. Exogenous brain-derived neurotrophic factor (BDNF) infusion caused a marked increase in the density of noradrenergic axon in the aged brain, but no trophic action of BDNF was observed in the young or middle-aged brain. The result suggests that BDNF is necessary for the maintenance of noradrenergic innervations in the aged brain.     

Visual event-related potentials in progressive supranuclear palsy, corticobasal degeneration, striatonigral degeneration, and Parkinson's disease

To determine whether there are characteristic changes in event-related potentials (ERPs) in parkinsonian syndromes we studied 8 patients with progressive supranuclear palsy (PSP), 10 patients with corticobasal degeneration (CBD), 9 patients with striatonigral degeneration (SND), and 16 patients with idiopathic Parkinson's disease (PD) with a mean duration of illness shorter than 5 years in each group. A visual oddball paradigm was employed to elicit P300. P300 to the rare target and rare nontarget stimuli and reaction time (RT) to rare target stimuli in each group were compared with those in the corresponding age-matched normal control group and to each other after age correction. The correlation of P300 and RT to motor disability score was also studied. In PSP P300 amplitude was markedly reduced while in CBD P300 latency was prolonged. P300 amplitude to rare nontargets in SND and PD was attenuated. The mean RT in the PSP and the CBD group was significantly longer than in the other two groups. The mean RT in PD and P300 amplitude to rare nontargets in both CBD and PD showed significant correlation with the severity of motor disability. Simultaneous measurement of P300 and RT may yield useful supplementary information in facilitating diagnosis of parkinsonian syndromes in addition to clinical criteria. Received: 6 April 1999, Received in revised form: 5 August 1999, Accepted: 12 January 2000     

Serine protease inhibitors prevent alcoholic liver injury]

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially characterized. It now appears that Kupffer cell derived TNF-alpha participates in several aspects of alcoholic liver injury. On the other hand, protease inhibitors have been used successfully for treatment of intractable diseases in which TNF-alpha is involved in the pathogenesis, including ulcerative colitis and Crohn's disease. Here, we will review new evidence for the proposal that serine protease inhibitors prevents alcoholic liver injury via mechanisms dependent on Kupffer cell derived TNF-alpha.     

Gender difference in alcoholic liver injury]

Gender differences of alcoholic liver injury have been described previously, but mechanisms have only partially characterized. For example, it is known that females develop alcoholic liver injury more rapidly and to a greater extent than males. It now appears that estrogen participates in several aspects of this phenomenon. On the other hand, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxins via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cell and alcohol-induced liver injury.     

Study of the distribution by age group of serum cross-linked C-terminal telopeptide of type I collagen and procollagen type I N-propeptide in healthy Japanese women to establish reference values

Osteoporosis prevention is an important public health goal. Bone turnover markers are clinically measured to assess bone strength. C-terminal telopeptide of type I collagen (CTX) is released when collagens degrade and serves as an indicator of bone resorption. Simple CTX immunoassays are now available. However, serum CTX (sCTX) reference ranges for Japanese women are lacking. Procollagen type I N-propeptide (intact P1NP) reflects osteoblast activity, serving as a marker of bone formation. Because sCTX and intact P1NP are clinically applied as bone turnover markers, we determined reference ranges for both sCTX and intact P1NP in healthy Japanese women. We collected 228 blood samples from healthy Japanese women aged 19–83 years, grouped by age and menopausal status. We measured sCTX and intact P1NP and examined their correlation. sCTX values differed significantly between the two consecutive decade groups encompassing 19–39 years of age, intact P1NP values between 20 and 30 s, between post-menopausal 50 and 60 s, and between pre-and post-menopausal women in their 50 s. The mean sCTX of 91 healthy pre-menopausal women was 0.255 (0.100–0.653) ng/mL, the intact P1NP in 90 women 33.2 (17.1–64.7) μg/L. Corresponding values for post-menopausal women were 0.345 (0.115–1.030) ng/mL and 41.6 (21.9–79.1) μg/L. sCTX correlated with intact P1NP. Bone resorption markers are measured to assess anti-resorption agents, bone formation markers to assess the effects of bone-forming agents. The sCTX and intact P1NP reference values determined herein, in healthy Japanese women, are expected to be useful for osteoporosis treatment, assessment of fracture risk, and other clinical applications.