Carcinogenicity of 1,2-dimethylhydrazine dihydrochloride in BALB/c mice

Summary The carcinogenicity of 1,2-dimethylhydrazine dihydrochloride (DMH) by oral, intragastric and subcutaneous administration was examined in 339 BALB/c mice. Subcutaneous injection of DMH induced intestinal tumors in the lower colon of all mice. After oral administration it induced a high incidence of vascular tumors in the liver and soft tissues, but colon tumors were found in only 2 mice when given at a high dosage. On intragastric administration, it induced a fairly high incidence both of colon and vascular tumors. The sites and incidences of vascular tumors and squamous cell carcinomas of the perianal glands were also described.This work was supported in part by a Grant-in Aid for Cancer Research from the Ministry of Education, Japan.     

The effectors of killer activity induced by interferon-alpha and gamma in peripheral blood mononuclear cells

The nature of effectors of interferon (IFN)-alpha or IFN-gamma-induced killer cell activity remains unclear. The aim of this study was to examine killer cell activity induced by IFN-alpha alone, IFN-gamma alone or a combination of both in patients with renal cell carcinoma (RCC) and to determine the phenotypic patterns of these effectors. The study group included 14 patients (12 men and 2 women, median age 64 years, range 36-77) with confirmed RCC. Peripheral blood mononuclear cells (PBMC) from RCC patients or normal volunteers were cultured with IFN-alpha alone, IFN-gamma alone or a combination of both. Cytotoxic activity was assayed against ACHN cells. Subpopulations of effector cells in IFN-induced killer cell activity were characterized by cell sorting. The most effective type of IFN and the optimal concentration of IFN necessary to induce the maximal killer cell activity varied among RCC patients. The killer activity induced by a combination of IFN-alpha and IFN-gamma was significantly greater than that induced by IFN-alpha or IFN-gamma alone. The greatly increased killer activity induced by IFN-alpha and IFN-gamma was seen in the subpopulations CD3(-) CD16(+), CD3(-) CD56(+) and subpopulation CD3(+)CD4(-), CD3(-)CD16(+), CD3(-)CD56(+), CD57(+)CD16(-), respectively. An optimal type of IFN and optimal concentration of IFN seem to increase the effective rate of treatment of RCC. In addition, the role of IFN-alpha seems to be different from that of IFN-gamma in host defense against RCC. A combination treatment with IFN-alpha and IFN-gamma seems to be suitable to increase the effective rate if we could reduce the side effects of IFNs.     

Evolutionary changes in the structures of the cox2 and atp6 loci in the mitochondrial genome of soybean involving recombination across small interspersed sequences

Mitochondrial DNA (mtDNA) fragments that contained cox2 or atp6 loci were cloned from three accessions of wild soybean (Glycine soja) in order to understand the evolutionary changes of mitochondrial genomes in the genus Glycine subgenus Soja. Cox2 was cloned as a single configuration, while atp6 was cloned as either one or two configurations from each accession. Structural variations were detected in the 5′ upstream region of cox2 and in both the 5′ upstream and 3′ downstream regions of atp6. These variations appeared to be the results of recombination events. A comparison of the mtDNA fragments previously cloned from a cultivated soybean (G. max) and a wild soybean revealed various sites of recombination, as well as various combinations of the 5′ and 3′ regions, at the cox2 and atp6 loci. Some of the cloned fragments were found to contain a set of repeated sequences, namely 299-bp and 23-bp repeats in the 5′ region of cox2 or atp6, which were interspersed in the mitochondrial genome in the subgenus Soja. Recombination events involving the 299-bp or 23-bp repeated sequences were shown to account for the generation of structural variations in the 5′ regions of these loci. Received: 21 March / 4 August 1998     

Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma

This study concerns the significance of aberrant (nuclear/cytoplasmic) expression of beta-catenin in pancreatoblastoma (PBL). On immunohistochemistry, all seven PBLs examined showed nuclear/cytoplasmic expression of beta-catenin, predominantly in the squamoid corpuscles (SCs). In areas with acinar/ductular differentiation, few tumour cells displayed nuclear/cytoplasmic expression of beta-catenin and more than half of the tumour cells showed membranous expression. Two out of five (40%) tumours examined showed missense mutations in codons 33 and 37 of exon 3 of the beta-catenin gene. No mutation of the adenomatous polyposis coli (APC) gene was detected in two of the remaining three tumours. Amplifiable DNA for APC analysis was not obtained from the one other tumour. Immunoreactivity for cyclin D1, one of the nuclear targets of beta-catenin, was found predominantly in the SCs of the seven tumours. In contrast, the Ki-67 labelling index was 2-4% (median 3%) in the SCs and 8-18% (median 12%) in the other areas, indicating a negative correlation with nuclear cyclin D1 reactivity. These results imply that in PBLs, nuclear/cytoplasmic accumulation of beta-catenin and overexpression of its target gene cyclin D1 are not associated with the induction of tumour cell proliferation. Nuclear/cytoplasmic accumulation of beta-catenin may be related to the morphogenesis of the SCs that are considered most characteristic for PBL.     

Membrane potential changes in vocal cord tensor motoneurons during breathing, vocalization, coughing and swallowing in decerebrate cats

We studied the patterns of membrane potential changes in vocal cord tensor motoneurons, i.e. cricothyroid muscle motoneurons (CTMs), during fictive breathing, vocalization, coughing, and swallowing in decerebrate paralyzed cats to determine the nature of central drives to CTMs during these behaviors. CTMs were identified by antidromic activation from the superior laryngeal nerve. During breathing, CTMs always depolarized during the inspiratory phase, and sometimes depolarized during the expiratory phase as well. During vocalization, CTMs strongly depolarized. During coughing, CTMs exhibited depolarizations during both inspiratory and expiratory phases, but it was interrupted by a transient repolarization between the last part of the inspiratory phase and the first part of the abdominal burst during which chloride-dependent inhibitory postsynaptic potentials were revealed. During swallowing, most CTMs hyperpolarized, and this hyperpolarization was sometimes followed by a weak depolarization. We conclude that the main role of the cricothyroid muscle is vocalization but the functional roles in coughing and swallowing are minor, and that the CTM activity during resting breathing and vocalization are primarily controlled by excitatory inputs, while during coughing and swallowing, inhibitory inputs play roles in shaping membrane potential trajectories.     

Correlation between clinical pathologic factors and activity of 5-FU-metabolizing enzymes in colorectal cancer.

INTRODUCTION: Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthase (TS) are initial key enzymes in the 5-fluorouracil (5-FU) metabolic pathway. The expression levels and activities of these three enzymes play important roles in the response of cancer patients to 5-FU-based chemotherapy. PURPOSE: The purpose of this study was to investigate the relationship between the activities of 5-FU metabolic enzymes and clinicopathologic factors in colorectal cancer. METHODS: We measured the activities of OPRT, DPD, and TS in colorectal cancer tissues. We also investigated the correlations between the activities of these three enzymes and clinicopathologic factors (histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, and vascular invasion). We examined 100 patients with surgically resected colorectal cancer. RESULTS: Poorly differentiated adenocarcinoma showed significantly higher DPD activities than did moderately differentiated or well-differentiated adenocarcinoma. In patients with lymph-node metastasis, OPRT activity was significantly lower than in patients without lymph-node metastasis. No significant relation was found between TS activity and histological type, depth of tumor invasion, extent of lymph node metastasis, Dukes' stage, lymphatic invasion, or vascular invasion. CONCLUSION: The response to 5-FU may be poor in patients with lymph-node metastasis, because of low OPRT activity, and in patients with poorly differentiated adenocarcinoma, because of high DPD activity.