Protein p21 (Waf1/Cip1) plays a critical role in controlling the cell cycle especially as a check point of G1 and is intimately associated with important cellular activities including differentiation, senescence, tumorigenesis, and apoptosis. In the present study, we examined the expression of p21 in multiple myeloma (MM) cells for prognostic evaluation. The immunocytochemical localization of p21 could be categorized into nuclear and cytoplasmic types. The nuclear-type p21 localization was correlated with the severity of MM and the expression of proliferating cell nuclear antigen and p53. Patients with the nuclear-type p21 localization survived significantly shorter than those with the cytoplasmic-type localization. Thus, the present study suggests that p21-immunolocalization can be a useful prognostic marker of MM.

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The liver is one of the major organs that remove exogenous substances and waste products from the blood circulation. Hepatic macrophages (Kupffer cells) and sinusoidal endothelial cells are responsible for the scavenger function of the liver. The sinusoidal endothelial cells, called scavenger endothelial cells, are believed to take up only soluble substances and nanometer-sized particles under normal conditions, while Kupffer cells can ingest larger particles and whole cells. However, the sinusoidal endothelial cells may have the potential to take up considerably large particles under special conditions. In this morphological study, we compared the uptake ability between sinusoidal endothelial cells and Kupffer cells after intravenous injections of latex beads (20 nm, 100 nm and 500 nm in diameter), bovine serum albumin (BSA) and dextran. Under normal conditions, the sinusoidal endothelial cells vigorously took up 100-nm-sized latex beads as well as 20-nm latex beads. BSA and dextran were ingested by the endothelial cells but not the Kupffer cells. The administration of lipopolysaccharide (LPS), which mimics inflammation, stimulated the uptake by endothelial cells. The uptake of latex beads by Kupffer cells was also elevated under LPS-stimulated conditions, but the uptake of BSA and dextran by them was not. These findings suggest that the sinusoidal endothelial cells can ingest not only soluble substances but also larger particles than those expected, and their uptake ability is strengthened under inflammatory conditions.

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Mutations in human BRCA2 confer an increased risk of female breast cancer. In this study, we found a novel insertion/deletion polymorphism (10204insAAA causing amino acid change M3332IK) in canine BRCA2, which is located in the putative second nuclear localization signal (NLS2) and C-terminal Rad51-binding region. The nuclear localization of the insAAA C-terminus was more efficient than localization of the delAAA sequence when NLS1 was mutated. Strong, comparable Rad51 binding was observed for both the insAAA and delAAA C-termini. Dogs with the insertion/deletion polymorphism will provide a new model for studying the function of BRCA2.

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Our recent studies have demonstrated that the middle domain of N-acetyl-D-glucosamine (GlcNAc) 2-epimerase participates in the specificity for and binding of nucleotides. To identify the residue conferring nucleotide binding, amino acid substitutions were introduced in the human and rat GlcNAc 2-epimerases. The mutational analyses indicate that residue 171 of GlcNAc 2-epimerase is critical for the nucleotide binding of GlcNAc 2-epimerase.

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Abnormal spontaneous firing of primary sensory neurons is considered to be a cause of neuropathic pain. However, pathogenic mechanisms of hyperexcitable sensory neurons in neuropathic model animals are unclear. We examined effects of chronic treatment of nerve growth factor (NGF), one of candidate mediators for the pathogenesis, on excitability of sensory neurons by voltage-clamped recording in a cell-attached configuration. From rat dorsal root ganglion (DRG) neurons cultured without NGF, only stable holding currents without spontaneous firing activity were recorded. On the other hand, more than 20% neurons cultured in the presence of NGF for more than 3 days showed spontaneous current spikes at frequencies between 0.1 and 5 Hz. Each spikes had an initial inward phase followed by the outward phase, resulted from spontaneous transient depolarization followed by transient hyperpolarization. These spontaneous spikes were abolished by tetrodotoxin, lidocaine and reduction of extracellular concentration of Na⁺ from 154 mM to 100 mM, in all-or-none fashion, suggesting that spontaneous current spikes reflected spontaneous action potentials. From these results, it became evident that DRG neurons of adult rats had a nature to respond to NGF and obtained the abnormal hyperexcitability to fire spontaneously.

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2-Methoxyestradiol (2ME), an endogenous metabolite of 17β-estradiol, has been reported to play an active role in the induction of apoptosis in both proliferating endothelial and cancer cells. Since it has been indicated that an increased ratio of pro-apoptotic Bax protein to anti-apoptotic Bcl-2 protein expression can be associated with apoptosis, and since the exact action mechanism of 2ME is still not clearly defined and appears to vary according to cell type, the influence of 1 μM 2ME was investigated on Bax and Bcl-2 expression levels in squamous esophageal carcinoma cells. 2ME exposure led to statistically significant decreases (0.69 over DMSO controls) in Bcl-2 expression levels. In contrast, no statistically significant effects were observed on Bax expression levels after exposure to 2ME. The Bax/Bcl-2 ratio for 2ME-exposed cells was 1.45, normalised against Bcl-2 levels. Although the exact mechanisms of apoptosis induction in squamous esophageal cancer cells require further invest gation, the present study suggests that this altered ratio in favor of Bax could lead to the induction of apoptosis in these cells.

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A 49-year-old man with pulmonary metastasis from renal cell carcinoma (RCC) was treated with recombinant IFN-α2b (Intron A®). A complete response was achieved within 4 months and thereafter persisted for 5 years until he developed another lung lesion. Interleukin-2 (Imunace®) was administered without any response. Finally, he was treated by natural IFN-α (OIF®). The pulmonary lesion achieved a partial response after 11 months of treatment. Because IFN-α preparations include different subtypes, changing the use of IFN-α preparations may thus be a potentially useful option for the successful immunotherapy of RCC.

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