Carcinogenicity of triethanolamine in mice and its mutagenicity after reaction with sodium nitrite in bacteria.
Mice fed a diet containing 0.3 or 0.03% triethanolamine developed malignant tumors. Females showed a high incidence of tumors in lymphoid tissues, while this type was absent in males. Tumors in other tissues were produced at a considerable rate in both sexes, but no hepatoma was found. Triethanolamine was not mutagenic to Bacillus subtilis by itself, but it became mutagenic after reacting with sodium nitrite under acidic conditions or when the mixture was heated. Although N-nitrosodiethanolamine, a known carcinogen and mutagen, was detected in the reaction mixture by thin-layer chromatography, it may not be the main mutagenic product, because the product was a stable and direct mutagen and its mutagenic activity was destroyed by liver enzymes, unlike N-nitrosodiethanolamine. The lethal and mutagenic DNA damages produced by this unidentified product were susceptible to some extent to the repair functions of the bacteria. (+info)
Immune responses to all ErbB family receptors detectable in serum of cancer patients.
Employing NIH3T3 transfectants with individual human ErbB receptor coding sequences as recombinant antigen sources, we detected by immunoblot analysis specific immunoreactivity against all four ErbB receptors among 13 of 41 sera obtained from patients with different types of epithelial malignancies. Overall, serum positivity was most frequently directed against ErbB2 followed by EGFR, ErbB3 and ErbB4. Specificity patterns comprised tumor patients with unique serum reactivity against ErbB2 or ErbB4. Moreover, approximately half of the positive sera exhibited concomitant reactivity with multiple ErbB receptors including EGFR and ErbB2, EGFR and ErbB4, ErbB2 and ErbB3 or EGFR, ErbB2 and ErbB3. Serum reactivity was confirmed for the respective ErbB receptors expressed by human tumor cells and corroborated on receptor-specific immunoprecipitates. Positive sera contained ErbB-specific antibodies of the IgG isotype. Representative immunohistochemical analysis of tumor tissues suggested overexpression of ErbB receptors for which serum antibodies were detectable in five of six patients. These findings implicate multiple ErbB receptors including ErbB3 and ErbB4 in addition to EGFR and ErbB2 in primary human cancer. Heterogeneity of natural ErbB-specific responses in cancer patients warrants their evaluation in light of immunotherapeutic approaches targeting these receptors. (+info)
ATF-2-binding regulatory element is responsible for the Ly49A expression in murine T lymphoid line, EL-4.
To understand the mechanism of Ly49A-expression and its significance in T-cell differentiation, we analyzed the 5'-flanking region of the Ly49A gene in a search for the Ly49A-regulatory element. Since very few known regulatory elements have been found in this region, presumably a novel regulatory sequence(s) could exist. Accordingly, we defined the 13-bp regulatory element, 5'-ATGACGAGGAGGA-3', restricted to Ly49A-expression in EL-4 cells in comparison with two other representative cell lines tested. This element, designated as EL13, proved to be previously undiscovered by homology search and is highly homologous with several virus DNAs. Using EL13 as a probe we have cloned a cDNA encoding a binding protein to EL13. Its deduced nucleotide sequence revealed that EL13-binding protein is almost identical with rat ATF-2. Although ATF-2 is known to bind to cyclic AMP responsive element (CRE), EL13 shares five out of eight nucleotides with this consensus sequence. Our results suggested that ATF-2 may play an important role via binding to EL13 for the expression of Ly49A. These data will provide useful information for understanding T-cell and NK-cell differentiation in murine immune system. (+info)
Incidence and occupational pattern of leukaemias, lymphomas, and testicular tumours in western Ireland over an 11 year period.
STUDY OBJECTIVE: To determine incidence of the following malignancies, testicular tumours, all leukaemias and all lymphomas in the West of Ireland in an 11 year period. Secondly, to examine the relation between disease patterns and available occupational data in male subjects of working age. DESIGN: A census survey of all cases occurring in the three counties in the Western Health Board (WHB) area, Galway, Mayo and Roscommon, for the 11 year period 1980 to 1990 inclusive. Average annual age standardised incidence rates for the period were calculated using the 1986 census data. Rates for the area are compared with rates from the southern region of Ireland, which had a tumour registry. Trends over the time period are evaluated. All male subjects for whom occupational data were available were categorised using the Irish socioeconomic group classification and incidence rates by occupation were compared using the standardised incidence ratio method. In one of the counties, Galway, a detailed occupational history of selected cases and an age matched control group was also elicited through patients' general practitioners. SETTING: All available case records in the West of Ireland. RESULTS: There are no national incidence records for the period. Compared with data from the Southern Tumour Registry, the number of cases of women with myeloid leukaemias was significantly lower. Male leukaemia rates were significantly lower as a group (SIR 84 (95% CI 74, 95) but not when considered as individual categories. Regression analysis revealed an increasing trend in the number of new cases of non-Hodgkin's lymphoma among both men (r = 0.47, p = 0.02) and women (r = 0.90, p = 0.0001) and of chronic lymphocytic leukaemia in men (r = 0.77, p = 0.005) and women (r = 0.68 p = 0.02) in the WHB region over the last decade. Four hundred and fifty six male cases over the age of 15 years were identified and adequate occupational information was available for 74% of these. Standardised incidence ratios of testicular tumours 100, 938) and agriworkers other than farmers (SIR 377, 95% CI 103, 967). There were also significantly increased incidence ratios for both non-Hodgkin's lymphoma (SIR 169, 95% CI 124, 266) and three categories of leukaemias among farmers. Hodgkin's disease and acute myeloid leukaemias were significantly increased among semi-skilled people. Interview data with 90 cases and 54 controls of both sexes revealed that among farmers, cases (n = 31) were significantly less likely than controls (n = 20) to use tractor mounted spraying techniques (OR = 0.19 (95% CI 0.04, 0.80)) and less likely to wear protective masks (OR 0.22 (95% CI 0.05, 0.84)). CONCLUSIONS: Trends of increase in non-Hodgkin's lymphoma and some leukaemias are consistent with studies elsewhere. The study provides further evidence of the relation between agricultural work and certain lymphoproliferative cancers. The possible carcinogenic role of chemicals used in agricultural industries must be considered as an explanation. (+info)
A case of primary lymphoma of the liver.
A case of primary malignant lymphoma of the liver is described. Presenting with epistaxis, he died in hepatic encephalopathy with an intractable bleeding post-bulbar duodenal ulcer. (+info)
Ovine MHC class II DRB1 alleles associated with resistance or susceptibility to development of bovine leukemia virus-induced ovine lymphoma.
For the further characterization of bovine leukemia virus (BLV)-induced leukemogenesis, we investigated the association between polymorphism of ovine leukocyte antigen (OLA)-DRB1 gene and tumor development after infection of sheep with BLV. We infected 28 sheep with BLV and cloned exon 2 of the OLA-DRB1 gene from asymptomatic animals and from animals with lymphoma Sequence analysis revealed that, among 12 healthy sheep without any evidence of tumor, ten (83.3%) carried DRB1 alleles encoding Arg-Lys (RK) at positions beta70/71 as compared with only 6 (37.5%) of the 16 sheep with lymphoma, which suggested that alleles encoding the RK motif might protect against development of tumors after infection by BLV. By contrast, alleles encoding Ser-Arg (SR) at positions beta70/71 were present at a significantly elevated frequency in sheep with lymphoma as compared with the healthy carriers, which indicated that OLA-DRB1 alleles encoding the SR motif might be positively related to susceptibility to tumor development. The two amino acids in these motifs line a pocket that accommodates the side chain of a bound peptide according to a model of the crystal structure of human leukocyte antigen (HLA)-DR1. To analyze immunoreactions of sheep with alleles that encoded RK or SR at beta70/71, we selected sheep with either the RK/SR genotypes or the SR/SR genotypes and immunized them with a mixture of multiple synthetic antigenic peptides that corresponded to T-helper, T-cytotoxic, and B-cell epitopes of the BLV envelope glycoprotein gp51. Two weeks after the last immunization, all of the sheep were challenged with BLV. Sheep with the RK/SR genotype produced neutralizing antibodies against BLV; they eliminated BLV completely within 28 weeks of the BLV challenge, and they gave strong lymphocyte-proliferative responses to the peptides used for immunization. Moreover, such animals did not develop lymphoma. By contrast, sheep with the SR/SR genotype continued to produce BLV throughout the experimental period and developed terminal disease. Our results indicate that the differences in immunoresponse were due to differences in major histocompatibility complex class II alleles and reflected the risk of BLV-induced leukemogenesis. In addition, it appears that susceptibility to tumor development may be determined to some extent by polymorphic residues binding to antigenic peptides directly within the binding cleft of the OLA-DR molecule. (+info)
Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas.
CYP1B1-null mice, created by targeted gene disruption in embryonic stem cells, were born at the expected frequency from heterozygous matings with no observable phenotype, thus establishing that CYP1B1 is not required for mouse development. CYP1B1 was not detectable in cultured embryonic fibroblast (EF) or in different tissues, such as lung, of the CYP1B1-null mouse treated with the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin whereas the equivalent wild-type EF cells express basal and substantial inducible CYP1B1 and lung expresses inducible CYP1B1. CYP1A1 is induced to far higher levels than CYP1B1 in liver, kidney, and lung in wild-type mice and is induced to a similar extent in CYP1B1-null mice. 7,12-dimethylbenz[a]anthracene (DMBA) was toxic in wild-type EFs that express CYP1B1 but not CYP1A1. These cells effectively metabolized DMBA, consistent with CYP1B1 involvement in producing the procarcinogenic 3,4-dihydrodiol as a major metabolite, whereas CYP1B1-null EF showed no significant metabolism and were resistant to DMBA-mediated toxicity. When wild-type mice were administered high levels of DMBA intragastrically, 70% developed highly malignant lymphomas whereas only 7.5% of CYP1B1-null mice had lymphomas. Skin hyperplasia and tumors were also more frequent in wild-type mice. These results establish that CYP1B1, located exclusively at extrahepatic sites, mediates the carcinogenicity of DMBA. Surprisingly, CYP1A1, which has a high rate of DMBA metabolism in vitro, is not sufficient for this carcinogenesis, which demonstrates the importance of extrahepatic P450s in determining susceptibility to chemical carcinogens and validates the search for associations between P450 expression and cancer risk in humans. (+info)
Can we cure indolent lymphomas?
The current consensus is that indolent lymphomas are incurable disorders. There are some indications that these malignancies are potentially curable. Indeed, not all indolent lymphomas are currently incurable. For example, patients with Ann Arbor stage I-II indolent lymphomas can experience long-term disease-free survival and probable cure. Also, from the available literature data, it seems that the achievement of a molecular complete remission is a desirable objective. Patients who achieve a persistently negative PCR state seldom relapse, whereas the opposite is true for persistently positive cases. In view of its excellent correlation with disease-free survival when examined serially in multiple blood or marrow samples, the PCR technique has the potential of providing a tumor marker that can be used as an early end point for clinical trials. By serving as an early surrogate end point, PCR could play an important role in expediting the development of new treatment strategies. Whether IFN is capable of increasing the molecular complete remission rate as measured by PCR is not known. However, it is clear that from the clinical standpoint, IFN has been able to increase 2-fold the length of remission in patients with advanced indolent lymphomas. In at least two studies, this has been associated with prolongation of survival. More intensive regimens such as alternating triple therapy, when used in combination with IFN, seem to have improved the quality of remissions as judged by the PCR assay. Finally, the site where the bcl-2 breakpoint occurs seems to have clinical significance. Those follicular lymphomas with germ-line bcl-2, in our experience, have behaved more aggressively than the others, and their failure-free survival seems different from the usual indolent lymphomas and more closely resembles the large cell lymphomas. Although the biological significance of this observation is not yet understood, this group might actually constitute a prognostically different subset with a more aggressive and perhaps more curable lymphoma. Whether the plateau observed in their failure-free survival curve will be maintained with more follow-up and whether they might be a curable subset remain to be determined. (+info)