Expression of p53 and glutathione S-transferase-pi relates to clinical drug resistance in non-small cell lung cancer

To determine the predictive value of the expression of p53 and glutathione S-transferase-pi (GST-pi) with respect to chemotherapy response, immunostaining was performed on transbronchial biopsy specimens from previously untreated patients with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37 patients (69%) were positive for p53 and GST-pi, respectively. The response rates in the p53-positive and p53-negative group were 15 and 45%, and those in GST-pi-positive and GST-pi-negative groups were 16 and 47%, respectively. A multiple logistic regression analysis revealed that positive immunostaining for GST-pi was a significant risk factor for clinical chemotherapy resistance. The combination of these two markers was the most important independent factor in predicting a response to chemotherapy in multiple logistic regression analysis. Immunohistochemical expression of p53 and GST-pi was independently related to clinical chemoresistance in patients with non-small cell lung cancer. Combined use of these two biomarkers may be a useful predictor of clinical chemoresistance. Copyright Copyright 1999 S. Karger AG, Basel     

Dietary prevention of azoxymethane-induced colon carcinogenesis with rice-germ in F344 rats.

The modifying effect of dietary administration of defatted rice-germ and gamma-aminobutyric acid (GABA)-enriched defatted rice-germ on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with male F344 rats. In the first experiment (the pilot study), the effects of the defatted rice-germ, the GABA-enriched defatted rice-germ and rice-germ on AOM-induced (15 mg/kg body wt once a week for 3 weeks) formation of aberrant crypt foci (ACF) were examined. The latter two preparations (2.5% in the diet) significantly inhibited ACF formation (P < 0.005). In the second experiment, a long-term study of the effects of rice-germ was done. One group was treated with AOM alone, four groups received the carcinogen and were fed the diets containing 2.5% rice-germ or 2.5% GABA-enriched defatted rice-germ for 5 (initiation phase) or 30 weeks (post-initiation phase), two groups were treated with rice-germ or GABA-enriched defatted rice-germ alone and one group was kept on the basal diet. At the termination of the study, dietary exposure to rice-germ during the initiation phase significantly reduced the incidence of colonic adenocarcinoma (71 versus 29%, P < 0.01). GABA-enriched defatted rice-germ or rice-germ during the post-initiation phase also decreased the frequency of colonic adenocarcinoma (71 versus 20%, GABA-enriched defatted rice-germ feeding, P < 0.01; 27%, rice-germ feeding, P < 0.01). These data suggest that constituents of rice-germ are possible dietary preventatives for human colon cancers.     

Modifying effects of a flavonoid morin on azoxymethane-induced large bowel tumorigenesis in rats.

The modifying effect of dietary exposure to a flavonoid morin during the initiation and post-initiation phases of azoxymethane (AOM)-initiated colorectal carcinogenesis was investigated in male F344 rats. A total of 55 animals were initiated with AOM by weekly s. c. injections of 15 mg/kg body wt for 3 weeks to induce colorectal neoplasms. Rats were fed a diet containing 500 p.p.m. morin for 5 ('initiation feeding') or 28 ('post-initiation feeding') weeks. Other groups contained rats treated with morin alone (500 p.p.m. in diet) and untreated rats. At the end of the study (32 weeks), the incidence of adenocarcinoma in the large intestine of rats initiated with AOM together with (43%) or followed by (29%) a diet containing morin was smaller than that of rats given AOM alone (75%). A significant difference was found between 'post-initiation feeding' and untreated groups (P = 0.023). Although both 'initiation feeding' and 'post-initiation feeding' of morin reduced polyamine levels in colorectal mucosa and blood, 'post-initiation feeding' of morin significantly decreased the proliferating cell nuclear antigen-positive index in aberrant crypt foci. 'Post-initiation feeding' of morin significantly elevated glutathione S-transferase and quinone reductase activities in the liver and large bowel, but 'initiation feeding' caused a significant elevation of these enzymes activities only in the large bowel. These results indicate that morin could exert a weak chemopreventive effect on large bowel tumorigenesis induced by AOM when fed during the post-initiation phase.     

Pituitary adenylate cyclase activating peptide mediates inhibitory nonadrenergic noncholinergic relaxation

We investigated the contribution of pituitary adenylate cyclase activating peptide (PACAP) to inhibitory nonadrenergic noncholinergic (inhibitory-NANC) relaxation of tracheal smooth muscle in cats. We also investigated the roles of vasoactive intestinal peptide (VIP) and nitric oxide (NO) on this function. Smooth muscle strips prepared from feline trachea were precontracted with 1 microM serotonin, and inhibitory-NANC relaxation was induced by electrical-field stimulation in the presence of atropine and propranolol. PACAP-(6-38) (a selective antagonist of PACAP; 1, 3 and 10 microM), VIP-(10-28) (a selective antagonist of VIP; 1, 3 and 10 microM) and N(omega)-nitro-L-arginine methyl ester (L-NAME, a selective NO synthase inhibitor; 3, 10 and 30 microM) each partially but significantly attenuated the amplitude of inhibitory-NANC relaxation. The effects of PACAP-(6-38) and VIP-(10-28) were additive. Addition of PACAP-(6-38) and/or VIP-(10-28) further attenuated relaxation in the presence of L-NAME. These results suggest that PACAP, VIP and NO contribute to the relaxation induced by inhibitory-NANC in tracheal smooth muscle in cats, and that they mediate this relaxation via different pathways.     

Paralytic poliomyelitis in a child with agammaglobulinemia

This paper gives the clinical, immunological and virological data on a patient with agammaglobulinemia who developed paralytic poliomyelitis. The patient was a 3 year-old boy who had a typical B-cell defect without a T-cell defect. He had profound hypogammaglobulinemia and defective plasma cells and had repeated pyogenic infections which were controlled by gammaglobulin replacement therapy. At 3 years of age, he was admitted to our hospital with suspected meningitis. He had fever, tremor and neck stiffness for 3 days and subsequently developed paralysis in his left arm and right leg. There was lymphocytosis in the cerebrospinal fluid. A non vaccine-like strain of poliovirus type 2 was isolated from the stool.     

Intranuclear inclusions of meningioma associated with abnormal cytoskeletal protein expression

We describe a case of meningothelial meningioma with a large number of intranuclear inclusions. Morphologically, these are divided into cytoplasmic inclusions and nuclear vacuoles. The cytoplasmic inclusion has a limiting membrane with cell organelles and filaments. Inclusions of this type are generally eosinophilic, like the cytoplasm. However, there are many inclusions that are more eosinophilic than the cytoplasm or that have a ground-glass appearance. Some of them may contain fine or coarse granules. On the other hand, the nuclear vacuole lacks a limiting membrane and appears empty. In most of the inclusions of this type, there is a faintly basophilic substance in the margin. Generally, the cytoplasmic inclusions are as immunopositive as cytoplasm with vimentin, but some of these cytoplasmic inclusions are more reactive. Under the electron microscope, abnormal aggregation of intermediate filaments is recognized in the cytoplasmic inclusions. It is considered that a strong reaction of cytoplasmic inclusions with vimentin immunostaining is due to abnormal aggregation of intermediate filaments. The present study distinctly demonstrates abnormal localization of intermediate filaments in the cytoplasmic inclusions, and it is suggested that the cytoskeleton participates in the evolution of the cytoplasmic inclusions.     

Laparoscopic total gastrectomy with distal pancreatosplenectomy and D2 lymphadenectomy for advanced gastric cancer

Received on Aug. 31, 1999; accepted on Jan. 27, 2000     

Inhibitory effects of clozapine and other antipsychotic drugs on noradrenaline transporter in cultured bovine adrenal medullary cells

The effects of clozapine and other antipsychotic drugs on noradrenaline (NA) transport were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NA transporter. Incubation of adrenal medullary cells with clozapine (30–1000 ng/ml) inhibited desipramine (DMI)-sensitive uptake of [³H]NA in a concentration-dependent manner (IC₅₀=110 ng/ml or 336 nM). Other antipsychotic drugs such as haloperidol, chlorpromazine, and risperidone also decreased [³H]NA uptake (IC₅₀= 144, 220, and 210 ng/ml or 383, 690, and 512 nM, respectively). Eadie-Hofstee analysis showed that clozapine reduced V_max of uptake of [³H]NA and increased K_m. Furthermore, clozapine inhibited specific binding of [³H]DMI to plasma membranes isolated from bovine adrenal medulla (IC₅₀=48 ng/ml or 146 nM). Scatchard plot analysis of [³H]DMI binding revealed that clozapine decreased both B_max and K_d. Other antipsychotic drugs, including haloperidol, chlorpromazine, and risperidone, also reduced [³H]DMI binding to the membranes. In transfected Xenopus oocytes expressing the bovine NA transporter, clozapine inhibited [³H]NA uptake in a concentration-dependent manner similar to that observed in adrenal medullary cells. These results suggest that clozapine and haloperidol directly inhibit transport of NA by acting on the site of an NA transporter that influences both substrate transport and binding of tricyclic antidepressants. Received: 13 April 1999 / Final version: 2 November 1999