Biomedical subjects

V M Kosma

Publications and source records attributed to V M Kosma.

At least 19 recordsLinked to original sources

PubMed2002

Supraglottic and glottic carcinomas. clinically and biologically distinct entities?

This study aimed to examine the clinical and biological differences in 198 patients with either T1-T2 local glottic or supraglottic squamous cell carcinomas. The patients with supraglottic cancer had a poorer prognosis, as well as more advanced and histologically aggressive tumours than the patients with glottic tumours. They also had lower levels of haemoglobin and a poorer nutritional and performance status. Expression of alpha-catenin, hyaluronan, CD44, p53, p21/WAF1 and bcl-2 in the primary tumour were not associated with the site of the laryngeal carcinoma. In supraglottic tumours, the rate of spontaneous apoptosis and mitotic indices were significantly higher than in glottic tumours. The results suggest that clinical parameters including the haemoglobin level of the patient together with the tumour cell kinetics (mitotic and apoptotic rates) may contribute to the aggressive nature of supraglottic carcinoma.

Adult↗

PubMed2001

Inflammatory responses in mice after intratracheal instillation of spores of Streptomyces californicus isolated from indoor air of a moldy building.

Microbial growth in buildings is associated with respiratory symptoms in the occupants. However, the specific effects of the microbes and the way they provoke clinical manifestations are poorly understood. In the current study, mice were exposed via intratracheal instillation to single doses of the spores of Streptomyces californicus, isolated from indoor air of a moisture-damaged building (2.2 x 10(7), 1.1 x 10(8), and 3.3 x 10(8) spores), or lipopolysaccharide (50 microg). Inflammation and toxicity in lungs were evaluated 24 h later. The time course of the effects was explored with the dose of 1.1 x 10(8) spores for up to 7 days. The microbial spores elevated proinflammatory cytokine (i.e., TNFalpha and IL-6) levels in bronchoalveolar lavage fluid (BALF) and in serum in a dose- and time-dependent manner and evoked expression of inducible nitric oxide synthase in BAL cells. Both TNFalpha and IL-6 responses peaked at 6 h after instillation, but TNFalpha leveled off more quickly than IL-6. The cytokine surge was followed by inflammatory cell recruitment into airways. Moreover, the spores increased dose- and time-dependently total protein, albumin, hemoglobin, and lactate dehydrogenase concentrations in BALF during the first 24 h. Histopathological examination of lungs confirmed the inflammatory changes. With the exception of macrophage and lymphocyte numbers, all parameters returned to control level at 7 days. In summary, these observations indicate that the spores of S. californicus are capable of provoking an acute inflammation in mouse lungs and can cause cytotoxicity. Thus, S. californicus can be considered as a species with potential to cause adverse health effects in occupants of moisture-damaged buildings.

Air Microbiology↗

PubMed2001

Prognostic value of hyaluronan expression in non-small-cell lung cancer: Increased stromal expression indicates unfavorable outcome in patients with adenocarcinoma.

The prognostic value of hyaluronan (HA) was analyzed in a large number of patients (n = 261) with non-small-cell lung cancer (NSCLC) by staining archived tumor samples with a biotinylated HA-specific probe. The level of HA in the tumor cells and surrounding stroma was scored and compared with parallel CD44 stainings, clinicopathological factors and survival data. Adenocarcinomas were characterized by a low percentage of HA-positive cells with low staining intensity compared with squamous-cell and large-cell/anaplastic carcinomas. The HA signal in the peri-tumoral stroma was often higher than that in the uninvolved stroma in all subgroups of NSCLC. CD44 and HA associated with the cancer cells showed a strong positive correlation with each other. In the whole tumor material, dominated by squamous-cell carcinomas (n = 168), recurrences were more often found in cases showing a low percentage of cancer cell-associated HA. However, within the adenocarcinoma subgroup (n = 68), a high percentage of cell-associated HA was correlated with poor tumor differentiation. Also specific for the adenocarcinoma subgroup was the increased number of recurrences in cases with a strong stromal HA signal. In survival analysis of the whole material (n = 189), a low percentage of HA-positive cancer cells was associated with a shortened disease-free survival (DFS) together with stage and tumor type. However, in the subgroup of patients with adenocarcinoma (n = 49), a strong stromal signal for HA predicted poor DFS. The level of HA in the stroma of adenocarcinomas retained its prognostic value in Cox's multivariate analysis. These results indicate that the frequency and intensity of HA has a significant prognostic value in NSCLC, particularly when the histological subtypes are analyzed as separate entities.

Adenocarcinoma↗

PubMed2001

High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer.

Several epithelial tumours accumulate hyaluronan (HA) which promotes cancer cell invasion and metastasis. We analysed the expression of HA and its receptor CD44 and their prognostic value in 166 prostate cancer patients followed up for a mean of 13 years; standard deviation (S.D.) 2.7; range 8.7-21.4 years. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognising all forms of CD44. The peri- and intratumoral stroma from half of the patients strongly expressed immunohistochemically detectable HA in < or = 15% of the stromal area; the tumours in the remaining half expressed HA in > 15% of the area. The staining of cancer cells for HA was scored positive or negative, and for CD44 the median value of 80% of positive tumour cells was used as a cut-off point. The expression of HA in cancer cells was weakly associated with perineural infiltration of the tumour (P = 0.03) and high Gleason score (P = 0.002). There was also a significant inverse relationship between the expression of HA and CD44 in cancer cells (P < 0.001). The high level of HA in the peri-and intratumoral stroma was related to metastasis, high T-category, high Gleason score, perineural infiltration and high mitotic activity of the tumour (for all P < 0.001). There was a significant inverse relationship between the expression of CD44 in cancer cells and high level of strong expression of HA in the tumour stroma (P < 0.001). A low fraction of CD44-positive cells was related to a high TM-category, high Gleason score and rapid cell proliferation (for all P < 0.0001; M/V P value = 0.0013). In the univariate survival analysis, the high level of strong expression of HA in tumour stroma predicted an unfavourable outcome in the entire series (P = 0.003) and also in the M0 tumours (P = 0.07), while in T1-2 M0 tumours the prognostic value did not reach the level of statistical significance (P = 0.1). A low fraction of CD44-positive cells predicted a poor outcome in the entire series (P < 0.001) and also in M0 tumours (P = 0.003). Cancer cell-associated HA expression had no prognostic value in any tumour categories. In the multivariate analysis of prognostic factors, HA expression in the cancer cells or in the tumour stroma had no additional value to the standard prognostic factors TM-classification, Gleason score and CD44 expression. Our results show that stromal HA accumulation is related to several malignant features and adverse clinical outcome in prostate cancer. However, further studies based on uniformly treated patient cohorts are needed to establish the clinical significance of these findings in current clinical practice.

Adult↗

PubMed2001

Angiographically guided utero-placental gene transfer in rabbits with adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine complexes.

We examined the feasibility of gene transfer to rabbit placenta using adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine (PEI) complexes. Pregnant New Zealand White rabbits (n = 17) were anesthetized and local gene transfer was done via a catheter inserted in uterine arteries under direct angiographic control. Either nuclear targeted LacZ adenoviruses (1.0 x 10(10) p.f.u.), nuclear targeted LacZ plasmid (500 microg)/liposome (DOTMA:DOPE 1:1) complexes or nuclear targeted LacZ plasmid (250 microg)/PEI (25 kDa) complexes (charge ratio +/-4) were used. Animals were killed 3 days later and detection of the transgene expression was done by X-gal staining and RT-PCR. Adenovirus-mediated gene transfer resulted in a high transfection efficiency (34 +/- 10%) in placental trophoplastic cells. Very little, if any, transfection was seen in fetal membranes. Plasmid/liposomes and plasmid/PEI complexes led to a very low (<0.01%) transfection efficiency in trophoblastic cells, but some transfection was seen in fetal membranes. A total of 25 fetuses were analyzed for the presence of transgene at the time of death. In most fetuses expression of the LacZ gene was below the sensitivity of the X-gal staining, but expression was detected by PCR in 50%, 50% and 42% of the analyzed fetuses after adenoviral, plasmid/PEI and plasmid/liposome gene transfer, respectively. No major inflammatory changes were present in the transfected placentas as analyzed by general histology and macrophage- and T cell-specific immunostainings. We conclude that catheter-mediated intravascular gene transfer with adenoviruses can be used for the transfection of placental trophoplastic cells, but plasmid complexes are inefficient for this purpose. However, selective angiographically guided gene transfer also led to leakage of the vector to fetuses. Therefore, if gene therapy is developed for the treatment of placental disorders, the gene-vector combination should not be harmful to the fetus and the expression of the transgene should only occur in placenta.

Adenoviridae↗

PubMed2001

Expression of CD44 and its variant isoform v3 has no prognostic value in gastric cancer.

AIMS: To study the controversial role of transmembrane glycoprotein CD44 as a moderator of tumour spread and as a prognostic factor in gastric cancer. METHODS AND RESULTS: The expression of all CD44 forms and that with exon v3 was assessed in 198 stage I-IV gastric adenocarcinomas using immunohistochemistry. CD44 expression was found in 72% and CD44v3 in 55% of the cases. The intensity of CD44 expression was associated with the level of invasion and with hyaluronan expression, while the frequency of CD44 positive cells was not significantly related to any of the clinical or histological features of the tumours. CD44v3 expression failed to show any association with the clinical or histological variables examined. Neither total CD44 nor CD44v3 expression affected survival. The most important prognostic factors in this cohort were the level of invasion, lymph node status, tumour size and vascular or perineural invasion. CONCLUSIONS: Changes in CD44 or CD44v3 expression level do not predict tumour spread or patient survival in gastric cancer.

Adenocarcinoma↗

PubMed2001

Effects of 50 Hz magnetic fields on cancer induced by ionizing radiation in mice.

PURPOSE: To evaluate the effects of 50 Hz magnetic fields (MF) on the development of cancer induced by ionizing radiation. MATERIALS AND METHODS: A total of 150 female CBA/S mice were randomized into three equal groups at the age of 3-5 weeks. One of the groups served as a 'cage-control group'. The two other groups were exposed to ionizing radiation in the beginning of the study. One of these two groups was exposed 24 h per day, for 1.5 years, to a 50Hz vertical MF, the intensity of which varied regularly between 1.3, 13 and 130 muT. The other served as a control group and was sham-exposed to MF in similar, but unenergized, exposure racks. Body weights, clinical signs, and food and water consumption were recorded regularly. Haematological examination, and the histopathological analysis of all lesions and major tissues were performed on all animals. RESULTS: MF exposure did not increase the incidence of any primary neoplasms. However, the incidence of basophilic liver foci, a probable pre-neoplastic change in liver, was increased. The incidence of hepatocellular adenomas was unchanged, whereas the incidence of hepatocellular carcinomas was slightly, but not statistically significantly, elevated. CONCLUSIONS: It is concluded that overall the results of this study do not support a role for MF as a tumour promoter.

Animals↗

PubMed2001

Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk.

Superoxide dismutases play a key role in the detoxification of superoxide radicals and thus protect cells from damage induced by free radicals. Within mitochondria manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species. Polymorphism in the mitochondrial targeting sequence of MnSOD has recently been associated with risk of breast cancer. We examined this in a study population consisting of 483 breast cancer cases and 482 controls, all of Finnish Caucasian origin. Odds ratios (OR) and 95% confidence intervals (95% CIs) were estimated by unconditional logistic regression. MnSOD genotypes containing the variant A allele were found to be associated with a 1.5-fold (95% CI 1.1-2.0) increased risk of breast cancer compared with those with the homozygous wild-type genotype (MnSOD VV). This finding supports the proposal that MnSOD genotypes may modify individual breast cancer risk.

Base Sequence↗

PubMed2001

Decline after immobilisation and recovery after remobilisation of synovial fluid IL1, TIMP, and chondroitin sulphate levels in young beagle dogs.

OBJECTIVE: To monitor the concentration of markers of cartilage and synovium metabolism in the knee (stifle) joint synovial fluid of young beagles subjected to immobilisation and subsequent remobilisation. METHODS: The right hind limb of 17 dogs was immobilised in flexion for 11 weeks. Simultaneously, the contralateral left knee was exposed to increased weight bearing. The remobilisation period lasted 50 weeks. Litter mates served as controls. The concentration in joint lavage fluid of interleukin 1alpha (IL1alpha) was measured by immunoassay, the activity of phospholipase A(2) (PLA(2)) was determined by an extraction method, chondroitin sulphate (CS) concentration by precipitation with Alcian blue, hyaluronan (HA) by an ELISA-like assay using biotinylated HA-binding complexes, matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinases 1 (TIMP-1) by sandwich ELISA, and synovitis was scored by light microscopy. RESULTS: Synovitis or effusion was absent in all experimental and control groups. Immobilisation decreased the joint lavage fluid levels of IL1alpha (p<0.05), TIMP (p< 0.05), and the concentration of CS down to 38% (p<0.05) in comparison with untreated litter mates with normal weight bearing. Immobilisation did not affect the activity of PLA(2), or the concentration of MMP-3 or HA in synovial fluid. Joint remobilisation restored the decreased concentrations of markers to control levels. Increased weight bearing did not change the concentrations of markers in comparison with the control joints with normal weight bearing. CONCLUSIONS: 11 weeks' joint immobilisation decreased the concentration of markers of cartilage and synovium metabolism in the synovial fluid, and remobilisation restored the concentrations to control levels. The changes in joint metabolism induced by immobilisation, as reflected by the markers, are thus different from those found in osteoarthritis, where increased levels of these markers are associated with enhanced degradation and synthesis. These findings suggest that the change induced in joint metabolism by immobilisation is reversible in its early stages.

Animals↗

PubMed2001

Nuclear beta catenin expression is related to unfavourable outcome in oropharyngeal and hypopharyngeal squamous cell carcinoma.

AIMS: To investigate the expression of alpha, beta, and gamma catenins in oropharyngeal and hypopharyngeal squamous cell carcinoma and their relations to each other, as well as to clinical data, tumour differentiation, and prognosis. METHODS: Primary tumours for analysis were obtained from 138 patients diagnosed with squamous cell carcinoma of the oropharynx or hypopharynx between 1975 and 1998 in eastern Finland. Immunohistochemistry was used to evaluate the expression of alpha, beta, and gamma catenins. The expression patterns of all catenins were related to clinical data and survival. RESULTS: The expression patterns of all three catenins were significantly interrelated. Reduced gamma catenin expression was significantly associated with poor histological differentiation. No association was found between alpha or beta catenin expression and clinicopathological characteristics. In univariate analysis, patients whose tumours had nuclear beta catenin expression had shorter overall survival than patients with no nuclear expression. In Cox multivariate analysis, nuclear beta catenin expression, tumour status (T class), and Karnofsky performance index were independent prognostic factors of overall survival. CONCLUSIONS: Reduced expression of gamma catenin is associated with dedifferentiation in primary squamous cell carcinoma of the oropharynx and hypopharynx. The fact that nuclear beta catenin expression independently predicts short overall survival suggests that it might be a valuable prognostic marker in pharyngeal squamous cell carcinoma.

Adult↗

PubMed2001

Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer.

AIMS: To investigate the expression of catenins (alpha, beta, and gamma) in non-small cell lung carcinoma (NSCLC) and its relation to clinicopathological factors and prognosis. METHODS: The expression of catenins was analysed immunohistochemically in 261 patients with resected NSCLC, diagnosed between 1978 and 1996 in eastern Finland: The cell proliferation index of the tumours was analysed by means of an image analyser. The staining results were compared with clinicopathological characteristics and survival. RESULTS: Normal catenin staining was found significantly more often in adenocarcinomas than in squamous cell carcinomas or anaplastic/large cell carcinomas. Reduced staining of alpha-catenin, beta-catenin, and gamma-catenin was related to poor differentiation of the tumour. The tumours with reduced staining of beta-catenin or gamma-catenin often had higher cell proliferation activity. Nuclear staining of beta-catenin and gamma-catenin was found in 16 (7%) and 29 (13%) cases, respectively. This nuclear staining correlated directly with increased cell proliferation and inversely with membranous staining. In survival analyses the predictors of overall and disease free survival were stage and tumour type. The expression of catenins did not affect survival. CONCLUSIONS: The expression of alpha-catenin, beta-catenin, and gamma-catenin is related to histological type and differentiation in NSCLC, although catenins have no independent prognostic value. However, this study supports the important role of the nuclear accumulation of beta-catenin and gamma-catenin in highly proliferative cells.

Aged↗

PubMed2001

Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation.

AIMS: To investigate whether the three different AP-2 isoforms are expressed differently in colorectal adenomas and carcinomas. METHODS: The study comprised 43 randomly selected patients diagnosed and treated at Kuopio University Hospital in 1996 for colorectal adenocarcinoma (n = 30) and colorectal adenoma (n = 13). The expression of AP-2alpha, AP-2beta, and AP-2gamma was analysed by immunohistochemistry (IHC) and the mRNA status of AP-2alpha was determined by in situ hybridisation (ISH) and confirmed by reverse transcription polymerase chain reaction (RT-PCR). AP-2 expression patterns were correlated with clinicopathological variables. RESULTS: In adenomas and carcinomas, AP-2beta cytoplasmic positivity was higher than that of AP-2alpha or AP-2gamma. AP-2alpha expression was reduced in advanced Dukes's stage carcinomas. In high grade carcinomas, both AP-2alpha and AP-2gamma expression was reduced. ISH demonstrated increased AP-2alpha values in high grade carcinomas. Seven of 30 carcinoma specimens displayed a moderate or strong mRNA signal, despite being negative for AP-2alpha protein. RT-PCR from AP-2alpha mRNA and protein positive tumours confirmed that the positive signal in ISH originated from the exon 2 of TFAP2A. CONCLUSIONS: AP-2alpha was reduced in advanced Dukes's stage adenocarcinomas. Together with reduced AP-2gamma expression in high grade carcinomas, this might contribute to tumour progression. The discrepancy between mRNA and protein expression suggests that post-transcriptional regulatory mechanisms might modify the availability of functional AP-2alpha protein in colorectal carcinoma.

Adenocarcinoma↗

PubMed2001

Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer.

BACKGROUND: The adhesion molecule CD44 standard (CD44s), and its variant isoforms v3 and v6 are associated with cell-to-cell adhesion. The down-regulation of CD44 standard and its variant isoform CD44v6 is linked with early cancer cell dissemination, but the relationship between CD44v3 and malignant features of prostate cancer (PC) has not been established previously. METHODS: The expression of CD44s and its CD44v3 and CD44v6 isoforms was analysed by immunohistochemistry in 209 archival PC biopsy specimens to establish their prognostic value. RESULTS: Down-regulation of CD44s and CD44v6 was related to high T classification, metastasis, high Gleason score, DNA aneuploidy, high S-phase fraction, high mitotic index, perineural growth and dense amount of tumour infiltrating lymphocytes (p < 0.03 for all). Down-regulation of CD44s and CD44v6 was related to poor survival in the entire cohort (p < 0.0001), in M0 tumours (p < 0.001) and in T1-2M0 tumours (p < 0.05). In needle biopsies and TURP specimens, the prognostic impact of the investigated parameters was similar. In the multivariate analysis, T classification (p = 0.0009), presence of metastases (p < 0.0001), Gleason score (p = 0.0060) and CD44v6 (p = 0.0220) expression were independent prognostic factors. In M0 tumours, T classification (p < 0.0001) and CD44v6 (p = 0.003) independently predicted survival. CONCLUSION: Down-regulation of CD44s and its CD44v6 isoform is related to tumour malignancy and unfavourable prognosis in PC.

Aged↗

PubMed2001

Effects of mobile phone radiation on X-ray-induced tumorigenesis in mice.

The increased use of mobile phones has raised the question of possible health effects of such devices, particularly the risk of cancer. It seems unlikely that the low-level radiofrequency (RF) radiation emitted by them would damage DNA directly, but its ability to act as a tumor promoter is less well characterized. In the current study, we evaluated the effect of low-level RF radiation on the development of cancer initiated in mice by ionizing radiation. Two hundred female CBA/S mice were randomized into four equal groups at the age of 3 to 5 weeks. The mice in all groups except the cage-control group were exposed to ionizing radiation at the beginning of the study and then to RF radiation for 1.5 h per day, 5 days a week for 78 weeks. One group was exposed to continuous NMT (Nordic Mobile Telephones)-type frequency-modulated RF radiation at a frequency of 902.5 MHz and a nominal average specific absorption rate (SAR) of 1.5 W/kg. Another group was exposed to pulsed GSM (Global System for Mobile)-type RF radiation (carrier-wave frequency 902.4 MHz, pulse frequency 217 Hz) at a nominal average SAR of 0.35 W/kg. The control animals were sham-exposed. Body weight, clinical signs, and food and water consumption were recorded regularly. Hematological examinations and histopathological analyses of all lesions and major tissues were performed on all animals. The RF-radiation exposures did not increase the incidence of any neoplastic lesion significantly. We conclude that the results do not provide evidence for cancer promotion by RF radiation emitted by mobile phones.

Animals↗

PubMed2001

The incidence and etiology of postlaryngectomy pharyngocutaneous fistulae.

BACKGROUND: The pharyngocutaneous fistula is troublesome complication after total laryngectomy. Despite a large number of studies, there is still disagreement on factors predisposing to this complication. METHODS: A retrospective analysis of pharyngocutaneous fistulas in 133 patients in whom total laryngectomy was performed. RESULTS: Fistulas were found in 15% of the patients. Spontaneous closure was noted in 80%. Simultaneous laryngectomy and partial pharyngectomy or neck dissection increased the risk of fistula formation. Preoperative irradiation, short interval between radiotherapy and operation, and cobalt/roentgen radiation instead of photons predispose to this complication. The fistulas appeared earlier, and the sizes of fistulas were significantly larger in patients with previous irradiation than those in patients with no preoperative irradiation. CONCLUSIONS: Postoperative pharyngocutaneous fistulas significantly increase patients' morbidity and hospital stay. Good surgical technique and postoperative treatment should be paid attention to patients with an increased risk of pharyngocutaneous fistula formation.

Carcinoma, Squamous Cell↗

PubMed2001

Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer.

This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.

Adult↗

PubMed2001

Polymorphic catechol-O-methyltransferase gene and breast cancer risk.

We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index ( 30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (<or=12 years) at menarche (OR, 8.59; 95% CI, 1.85-39.8). Our study, therefore, suggests that the COMT genotype may define a portion of the individual breast cancer susceptibility that is associated with reproductive events and hormone exposure even if it does not seem to be a major overall risk factor for this malignancy.

Aged↗

PubMed2000

Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains.

Risk assessment of dioxins is currently based on induction of liver tumors in rats. The toxicity of dioxins is characterized by large sensitivity differences among animal species and even strains of the same species, which complicates the risk assessment. The significance of these differences in dioxin-induced carcinogenicity is not known. We therefore studied the liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats differing >1000-fold in their sensitivity to the acute lethaity of TCDD. Female rats were partially hepatectomized, initiated with nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered hepatic foci (AHF) were stereologically quantitated using glutathione S-transferase P as a marker. AHF were significantly (P < 0.001) and dose dependently increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at 1000 ng/kg/day and above, indicating a remarkable (approximately 100-fold) sensitivity difference between L-E and H/W rats. The same sensitivity difference but 10-fold less foci were observed between nonhepatectomized/noninitiated L-E and H/W rats. Induction of AHF was related to hepatotoxicity but not to cytochrome P4501A1 activity in the liver. Liver TCDD concentrations were similar in both strains. H/W rats are exceptionally resistant to induction of AHF by TCDD, and the resistance is associated with an altered transactivation domain of the aryl hydrocarbon receptor. Genetic differences may account for significant interindividual/intraspecies sensitivity differences in dioxin-induced carcinogenesis. Understanding the role of transactivation domain of the aryl hydrocarbon receptor in carcinogenesis is therefore likely to improve dioxin risk assessment.

Alanine Transaminase↗