Active Cyclin A-CDK2 Complex, a Possible Critical Factor for Cell Proliferation in Human Primary Lung Carcinomas

Expression of cyclins A and E and cyclin-dependent kinase 2 (CDK2) was examined immunohistochemically in 190 cases of human lung carcinoma. Cyclin A and CDK2 were expressed in the majority of squamous cell carcinomas, small cell carcinomas, and large cell carcinomas, but in significantly fewer cases of adenocarcinomas. Cyclin E was expressed in a minority of all subtypes. In particular, well differentiated cells in squamous cell carcinoma stained positively for cyclin E; in contrast, cyclin A was expressed in the nonkeratinized proliferating areas of the tumor nests. Immunoblotting revealed that all these proteins were expressed at higher levels in tumor tissues than in adjacent normal tissues. Immunoprecipitation also revealed higher levels of cyclin A and cyclin E associated with CDK2 in tumor tissues. Furthermore, tumor tissues which exhibited higher cyclin A and CDK2 expression also had higher CDK2 kinase activity. However, cyclin E-associated kinase activity was barely detectable even in tumor samples exhibiting higher cyclin E expression. Consistent with these data, elevated expression of cyclin A correlated to shorter survival periods in contrast to expression of cyclin E, which correlated to longer survival periods. These results suggest that in human lung carcinomas, elevated expression of active cyclin A-CDK2 complexes with associated higher CDK2 kinase activity is critical for promoting cell cycle progression and unrestrained proliferation of tumor cells and can be a predictive marker for patients’ prognosis. On the other hand, immunohistochemical detection of cyclin E-CDK2 reflects accumulation of inactive forms of protein complexes, implying differentiation or senescence of the tumor and the better prognosis.     

Specific effect of antimony(V) containing initiators on the cationic copolymerization of 1,3-dioxolane with 5-methyl-2,3-dihydro-2-furanone

The copolymerization of 1,3-dioxolane ( 1 ) with 5-methyl-2,3-dihydro-2-furanone ( 2 ) was carried out in dichloromethane and nitrobenzene by use of triethyloxonium hexachloroantimonate, triethyloxonium hexafluoroantimonate, antimony pentachloride, antimony trichloride, and tin tetrachloride as initiators. The microstructures of the copolymers were analysed by means of ¹H-NMR, showing that monomer 2 was incorporated into the copolymer chain by the ring-opening reaction as well as by the ?normal”? vinyl addition, when triethyloxonium hexachloroantimonate, triethyloxonium hexafluoroantimonate, and antimony pentachloride were used. On the basis of NMR and IR studies on the complexation of Lewis acids with γ-lactones, it was concluded that the prominent effect of the initiators observed in the copolymerization of 1 with 2 was mainly attributable to the coordination between the initiator and the γ-lactone ring of monomer 2 .     

2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment induces c-Fos expression in the forebrain of the Long-Evans rat

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants. In the present study, we examined c-Fos expression in the central nervous system (CNS) after administration of a lethal dose of TCDD to the adult Long-Evans rat to clarify if the CNS participates in TCDD-induced intoxication. A single dose of TCDD (dissolved in olive oil, 50 microg/kg) or olive oil alone was administered to the rats by gavage. Animals were allowed to survive for 1 day to 5 weeks. Three days after the administration, a significantly large number of Fos-immunopositive cells were found in the hypothalamus (i.e. dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, medial preoptic nucleus), central amygdaloid nucleus and bed nucleus of the stria terminalis. These results suggest that some TCDD toxicity may be induced by its direct action on the CNS.     

The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma

Recently, there has been increasing interest in treating intraocular retinoblastoma with systemic chemotherapy combined with focal laser therapy and cryotherapy instead of radiotherapy. We developed a system of selective ophthalmic arterial infusion (SOAI) therapy, administering melphalan, the agent which had the greatest effect on retinoblastoma in a clonogenic assay. The SOAI system consists of a combination of a micro-balloon, a guiding catheter, and a flushing hub. After selective catheterization to the cervical segment of the internal carotid artery by the guiding catheter, the micro-balloon was propelled to the portion just distal to the orifice of the ophthalmic artery. During temporary occlusion of the internal carotid artery, melphalan was infused from the introduced catheter tip. We treated 187 patients with intraocular retinoblastoma with SOAI; 563 SOAIs were performed for 610 eyes. The technical success rate was 97.51%. Fourteen examinations failed. No significant complication due to catheterization (including brain infarction) was detected. SOAI, using the balloon occlusion technique, is safe, and its use will prevent the side effects that occur with systemic chemotherapy, and eliminate the need for irradiation and enucleation.     

Actin mutations are one cause of congenital fibre type disproportion

We report three heterozygous missense mutations of the skeletal muscle alpha actin gene (ACTA1) in three unrelated cases of congenital fiber type disproportion (CFTD) from Japan and Australia. This represents the first genetic cause of CFTD to be identified and confirms that CFTD is genetically heterogeneous. The three mutations we have identified Leucine221Proline, Aspartate292Valine, and Proline332Serine are novel. They have not been found previously in any cases of nemaline, actin, intranuclear rod, or rod-core myopathy caused by mutations in ACTA1. It remains unclear why these mutations cause type 1 fiber hypotrophy but no nemaline bodies. The three mutations all lie on one face of the actin monomer on the surface swept by tropomyosin during muscle activity, which may suggest a common pathological mechanism. All three CFTD cases with ACTA1 mutations had severe congenital weakness and respiratory failure without ophthalmoplegia. There were no clinical features specific to CFTD cases with ACTA1 mutations, but the presence of normal eye movements in a severe CFTD patient may be an important clue for the presence of a mutation in ACTA1.