Biomedical subjects

T Nemoto

Publications and source records attributed to T Nemoto.

At least 37 records · Page 2Linked to original sources

PubMed2001

Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.

BACKGROUND: The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. METHODS: Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. RESULTS: Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. CONCLUSIONS: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Acute Kidney Injury↗

PubMed2001

Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure.

BACKGROUND: The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use. METHODS: An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured. RESULTS: EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy. CONCLUSIONS: Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.

Acute Kidney Injury↗

PubMed2001

Preoperative ampiroxicam reduces postoperative pain after hand surgery.

We performed a double blind randomised controlled study to assess whether the preoperative administration of ampiroxicam reduced the level of postoperative pain in 120 patients who underwent surgery to a hand under brachial plexus block. We found that preoperative (pre-emptive) administration of ampiroxicam significantly reduced the postoperative pain levels and the need for postoperative analgesia.

Adult↗

PubMed2001

Immunohistological analysis of thymoma by molecules differentially expressed in the thymic cortex and medulla, and its application in the differential diagnosis of thymoma from esophageal and lung cancer.

The purpose of this study was to verify the WHO classification of thymic tumors using immunohistological methods, and to discover whether these methods can be applied to differentiate thymoma from squamous cell carcinoma (SCC) of the esophagus and the lung. Twenty-nine thymoma cases were classified according to WHO and were then immunohistologically examined for the positivity of these molecules. All thymoma cases investigated in this study were positive for IL-1R, and most of them were also positive for bek. In contrast, UH-1 was highly positive in B1 and B2 type thymomas, but negative or weakly positive in A, AB and B3 type thymomas. Twelve esophageal cancers and 21 lung cancers were also examined for the positivity of the same molecules. All esophageal cancers were negative for UH-1. Three of 12 cases were weakly positive for IL-1R, and four of these 12 cases were also weakly positive for bek. Twelve of 21 lung cancer cases were adenocarcinomas, all of them negative for IL-1R, bek and UH-1. Nine of 21 lung cancer cases were SCCs, all of them negative for UH-1. Eight of nine SCC cases were strongly positive for IL-1R, while seven of these were weakly positive for bek. We conclude that the WHO classification of thymic tumors is still valid as demonstrated by immunohistological analysis and that the positivity of UH-1, IL- 1R and bek might be helpful in differentiating thymoma from SCC of the esophagus and the lung.

Adenocarcinoma↗

PubMed2001

Loss of syndecan-1 and increased expression of heparanase in invasive esophageal carcinomas.

Heparan sulfate proteoglycans play important biological roles in cell-cell and cell-matrix adhesion, and are closely associated with growth factor actions. Loss of syndecan-1, a cell surface-bound heparan sulfate proteoglycan, has been reported for advanced head and neck carcinomas, and expression of endoglycosidic heparanase, which cleaves heparan sulfate glycosaminoglycans (HS-GAGs), is associated with invasion and metastatic potential of malignant tumors. Paraffin sections of 103 primary esophageal squamous cell carcinomas were immunohistochemically examined for the expression of syndecan-1 core protein, HS-GAGs and heparanase protein, and the results were compared with various clinicopathological parameters, such as invasion depth. For 16 cases, fresh tumor samples were quantitatively analyzed for heparanase and syndecan-1 mRNA expression by real-time RT-PCR in addition to the immunohistochemical studies. Syndecan-1 core protein and HS-GAGs expression was significantly decreased in pT2 and pT3 cases compared with their pTis and pT1 counterparts. Decreased expression of core protein and HS-GAGs was correlated with the incidence of lymphatic invasion, and venous involvement. Furthermore, decreased expression of HS-GAGs was correlated positively with the incidence of nodal metastasis and distant organ metastasis, and negatively with the grade of tumor cell differentiation. The percentage of cytoplasmic heparanase protein-positive cases increased significantly in pT2 and pT3 cases compared to that in pTis and pT1 cases, and this was associated with lymphatic invasion, and venous and lymph nodal involvement. The level of heparanase mRNA was inversely correlated with the degree of HS-GAGs expression rather than core protein. In conclusion, loss of syndecan-1 and heparanase overexpression in esophageal squamous cell carcinomas are closely associated with malignant potential. Regarding the mechanism of loss of HS-GAGs, heparanase upregulation appears to play an important role.

Adult↗

PubMed2001

Overexpression of fatty acid synthase in oesophageal squamous cell dysplasia and carcinoma.

OBJECTIVE: The expression of fatty acid synthase (FAS), an enzyme necessary for de novo fatty acid synthesis, has been examined in several types of tumours so far, but not in oesophageal cancer and dysplasia. METHODS: We examined the immunohistochemical reactivity of FAS in 4 normal adult oesophagi, 14 dysplastic oesophageal lesions, and 80 squamous cell carcinomas and 6 cases with 4 special types of malignancies of the oesophagus. We also analysed the correlation between FAS expression and various clinicopathological features and long-term survival in patients with oesophageal cancer. RESULTS: In the normal oesophagus, only faint cytoplasmic FAS expression was observed in cells of the basal layer. In contrast, FAS-positive cells were found in 92.9% of cases of dysplasia and 96.5% of cases of carcinoma including 6 cases with a specific histological subtype. However, high expression of FAS did not correlate with either clinicopathological features or prognosis of patients with oesophageal cancer. CONCLUSION: Our results demonstrate that FAS is expressed in almost all oesophageal carcinomas of both usual and special types and dysplastic lesions, suggesting that FAS may be upregulated continuously from the early stage of oesophageal squamous cell carcinogenesis to established carcinoma.

Adult↗

PubMed2001

Severe hypercholesterolemia in a double heterozygote for lipoprotein lipase deficiency (LPL(Arita)) and apolipoprotein epsilon4: a report of a family with LPL(Arita).

Although heterozygous lipoprotein lipase (LPL) deficiency is not rare, only part of the phenotypes may have been reported in Japan. Here we describe a Japanese family with LPL(Arita), the most common mutation linked to familial LPL deficiency in Japan, and show for the first time a heterozygote for the mutation who had marked hypercholesterolemia due to increased low-density lipoprotein (LDL) cholesterol. The proband's mother, one of the heterozygotes for LPL(Arita) in the family, had both severe hypercholesterolemia (total cholesterol 306 mg/dl) with an especially increase in LDL-cholesterol and mild hypertriglyceridemia (180 mg/dl). She had normal LDL receptor activity and did not show clear evidence of possible causes of secondary hyperlipidemia. In addition to being heterozygous for LPL deficiency, she was also heterozygous for apo epsilon4. Because the epsilon4 allele is known to be associated with higher LDL-cholesterol, heterozygous apo epsilon4 may be one of causes of her LDL-cholesterol elevation. The other three heterozygotes for LPL(Arita) were moderate drinkers, and all of them had both remarkable hypertriglyceridemia and mild hypercholesterolemia due to increased very-low-density lipoproteins (VLDL). The results suggest that heterozygotes for LPL(Arita) can exhibit various phenotypes of hyperlipidemia, that is, hypertrigliceridemia and/or hypercholesterolemia due to not only increased VLDL but also increased LDL. The phenotypes appear to depend on some other genetic and environmental factors.

Adult↗

PubMed2001

[Efficacy of low-dose mutant tissue-type plasminogen activator followed by planned rescue percutaneous transluminal coronary angioplasty as reperfusion therapy for acute myocardial infarction].

OBJECTIVES: The efficacy of injection of a low-dose mutant tissue-type plasminogen activator (mt-PA), monteplase, followed by planned rescue percutaneous transluminal coronary angioplasty (PTCA) was compared with that of primary PTCA. METHODS: A total of 164 patients with acute myocardial infarction within 12 hr from onset were randomly assigned to a treatment with 80 x 10(4) U bolus of monteplase (Group M) or no administration (Group P) by the envelope method, followed by immediate angiography with angioplasty in patients with Thombolysis in Myocardial Infarction (TIMI) flow grade 0, 1 or 2. RESULTS: There were no differences in baseline characteristics between the two groups. Initial angiography showed a higher reperfusion rate (TIMI 2 + 3: 21% + 38% vs 13% + 9%, p < 0.001) and the median time to TIMI 3 was shorter (63 vs 78 min, p < 0.005) in Group M than in Group P, but the final TIMI 3 rate was similar (93% vs 96%). Peak creatine kinase was lower, and predischarge left ventricular ejection fraction measured in 70% of all patients was higher (59 +/- 9% vs 54 +/- 14%, p = 0.02) in Group M than in Group P. Recurrent ischemia with ST elevation occurred in three patients in Group M, but death, re-acute myocardial infarction or stroke did not occur in either group and the rate of bleeding complication was similar (4.9% vs 3.7%). PTCA was performed less frequently in Group M, but medical expenses were comparable in both groups. CONCLUSIONS: Low-dose mt-PA followed by rescue PTCA is effective for early recanalization and preservation of left ventricular function without increases in bleeding complications or medical expenses. These results suggest that low-dose mt-PA should be given to all patients with acute myocardial infarction who are scheduled to undergo primary PTCA.

Aged↗

PubMed2001

[CA19-9-producing idiopathic pulmonary fibrosis with diffuse alveolar damage and a high titer of KL-6--an autopsy case].

A 73-year-old woman with CA19-9-producing idiopathic interstitial pneumonia was admitted to the hospital when her condition was exacerbated. Chest radiography and computed tomography showed an additional patchy shadow. The serum CA19-9 level remained high during the clinical course, whereas KL-6 increased only at exacerbation. No therapy was effective, and the patient died 5 days later. The lung obtained at autopsy showed hyaline membrane formation, hemorrhage, and squamous metaplasia, suggesting that acute exacerbation had resulted in diffuse alveolar damage. Immunohistochemical staining using either anti-CA19-9 mAb or anti-KL-6 mAb showed the localization of CA19-9 and KL-6 antigen in the dilated bronchiolar epithelial cells. In conclusion, although CA19-9 can be an indicator for the degree of fibrotic and destructive change of lung structure, KL-6 seemed more sensitively to reflect the disease state of the diffuse alveolar damage.

Aged↗

PubMed2000

The Difference in Saccadic Parameters among Several Visually Guided Tasks-Saccadic Reaction Time.

Purpose: The saccadic reaction time (SRT) was measured as a saccadic movement parameter using visually guided tasks.Subjects and Method: The SRT was measured for nine healthy adult subjects aged from 28 to 49 years. The visually guided tasks for saccadic movement induction were simultaneous, gap, overlap, delayed-memory, and anti-SM tasks.Results: The median of the SRT (msec) for each task in the actual measurements was as follows: 216 for the simultaneous task, 180 for the gap task, 240 for the overlap task, 234 for the delayed-memory task, and 292 for the anti-SM task. The SRT distribution of each subject exhibited two peaks for the gap task but mostly one peak for each of the other tasks. The first peak, observed in the SRT distribution for the gap task was an eysress saccade.Conclusion: The SRT for the gap task was the shortest and the SRT got longer in the order of the simultaneous task, and the overlap task, and the anti-SM task. Some subjects easily showed an express saccade in the gap task, but others did not.

Journal Article↗

PubMed2000

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines.

Farnesyltransferase inhibitor (FTI) induces apoptosis of transformed cells. This involves changes in mitochondria, including decrease of mitochondrial membrane potential and the release of cytochrome c. The released cytochrome c then induces events leading to the activation of caspase-3. In this study, we report that purine derivative cyclin-dependent kinase (Cdk) inhibitors, roscovitine and olomoucine, dramatically enhance this FTI-induced apoptosis of human cancer cell lines. We noticed the synergy between Cdk inhibitors and FTI through our screen to identify compounds that enhance FTI-induced apoptosis of promyelocytic leukemic cell line HL-60. The Cdk inhibitors by themselves do not induce apoptosis at the concentrations used. Roscovitine synergizes with FTI to release cytochrome c from mitochondria. In addition, we detected synergistic effects of FTI and roscovitine to inhibit hyperphosphorylation of retinoblastoma protein. Enhancement of FTI-induced apoptosis by roscovitine is not unique to HL-60 cells, since similar synergy was observed with a leukemic cell line CEM and a prostate cancer cell line LNCaP. In LNCaP cells, in addition to roscovitine and olomoucine, phophatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, was effective in enhancing FTI-induced apoptosis. However, the effects of roscovitine appear to be distinct from those of LY294002, since roscovitine did not affect Akt activity while LY294002 significantly decreased the activity of Akt. Our finding of the synergy between FTI and Cdk inhibitor is significant for understanding the mechanism of action of FTI as well as for clinical use of FTI.

Alkyl and Aryl Transferases↗

PubMed2000

Increased expression of matrix metalloproteinase 7 and 9 and membrane type 1-matrix metalloproteinase in esophageal squamous cell carcinomas.

BACKGROUND: The 5-year survival rate of patients with submucosal (sm) esophageal carcinoma continues to be much worse than that with intramucosal (m) lesions. The reasons are unclear, but matrix metalloproteinases (MMPs) and membrane type matrix metalloproteinases (MT-MMPs) are known to be involved in degradation of extracellular matrix macromolecules associated with tumor cell invasion. Expression of these enzymes may have some relation to the difference in survival between patients with sm and m esophageal carcinomas. METHODS: Surgical specimens from 148 primary esophageal squamous cell carcinomas were examined for expression of MMP-1, 2, 3, 7, and 9; tissue inhibitor of MMP (TIMP)-1 and 2; MT1-MMP; and MT2-MMP by immunohistochemical staining. The results were compared with tumor progression and other clinicopathologic parameters. Localization of gelatinase activity was also confirmed in carcinoma cells by in situ zymography. RESULTS: Expression of MMP-7 and 9, expression of MT1-MMP, and gelatinase activity were elevated in the carcinomas, correlating with depth of tumor invasion. Percentages of positive sm cases were 44.0%, 51.9%, and 52.0%, respectively, significantly higher than for the m cases. Percentages of venous invasion positive cases were 61.9%, 65.1%, and 65.1%, respectively. CONCLUSIONS: Expression of MMP-7 and 9 and MT1-MMP is closely associated with invasion depth and venous invasion in esophageal squamous cell carcinomas.

Carcinoma, Squamous Cell↗

PubMed2000

Human rhabdomyosarcoma cells retain insulin-regulated glucose transport activity through glucose transporter 1.

We evaluated the expression of glucose transporter (glut) isoforms and its function in RD cells, human rhabdomyosarcoma, which retain the potential to differentiate into muscle. Gluts 1, 3, and 4 were expressed in RD cells, as detected by reverse-transcription polymerase chain reaction and immunocytochemistry. Supraphysiological concentration (1 microM) of insulin treatment increased 2-deoxy glucose transport by up to 1.68-fold together with concomitant tyrosine phosphorylation of the insulin receptor beta subunit and of insulin receptor substrate 1. Suppression of glut 1 mRNA by 38% by antisense oligonucleotide transfection led to a reduction of basal and insulin-stimulated 2-deoxy glucose transport by 38 and 55%, respectively. Suppression of gluts 3 and 4 by antisense oligonucleotide transfection did not affect both basal and insulin-stimulated 2-deoxy glucose transport. Thus, glut 1 accounts for the major part of basal and insulin-stimulated glucose transport in RD cells. Next, we transfected expression vectors carrying human gluts 1 and 4 cDNAs into RD cells to add further support for the role of glut 1 in glucose transport. Overexpression of glut 1 stimulated basal and insulin-stimulated 2-deoxy glucose transport by 1.66- and 1.43-fold, respectively. Glut 4 overexpression did not affect basal and insulin-stimulated 2-deoxy glucose transport. Western blot analysis using glut 1 antibody showed that glut 1 was redistributed from intracellular membrane to plasma membrane. These observations support the notion that RD cells, with the potential to differentiate into muscle, retain insulin responsiveness. As human muscle cell lines are not available at this point, RD cells can serve as a useful alternative to human muscle for studies related to insulin signal transduction and glucose transport.

3-O-Methylglucose↗

PubMed2000

Expression of protein tyrosine phosphatases and its significance in esophageal cancer.

Expression of mRNA protein tyrosine phosphatases (PTPs) was surveyed in an esophageal cancer cell line by RT-PCR using degenerate primers. The mRNAs for eight kinds of PTPs were expressed in the cell line. We examined mRNA expression of these PTPs in 12 cases of esophageal cancer by Northern analysis. Significant signals were obtained for three kinds of PTPs, PTP1B, PTPH1, and PTPD1. The magnitude of expression of each PTP was measured as the ratio of the signal intensity of each PTP to that of a control gene (NADPH), and the ratio was then compared to normal mucosa around the cancer lesion. Among the three kinds of PTPs, the expression of PTP1B mRNA was significantly depressed in cancer lesions compared with that in the surrounding normal mucosa. In contrast, the expression of PTPH1 mRNA was significantly increased in cancer lesions compared with that in normal mucosa. PTPD1 did not show any significant trend in comparisons of cancer and surrounding normal mucosa. The results suggest that PTP1B and PTPH1 are engaged in opposing signaling pathways, the tumor-suppressive and tumor-promoting pathways, respectively, in esophageal carcinogenesis.

Adult↗

PubMed2000

[The difference in saccadic parameters among several visually guided tasks--saccadic reaction time].

PURPOSE: The saccadic reaction time (SRT) was measured as a saccadic movement parameter using visually guided tasks. SUBJECTS AND METHOD: The SRT was measured for nine healthy adult subjects aged from 28 to 49 years. The visually guided tasks for saccadic movement induction were simultaneous, gap, overlap, delayed-memory, and anti-SM tasks. RESULTS: The median of the SRT (msec) for each task in the actual measurements was as follows: 216 for the simultaneous task, 180 for the gap task, 240 for the overlap task, 234 for the delayed-memory task, and 292 for the anti-SM task. The SRT distribution of each subject exhibited two peaks for the gap task but mostly one peak for each of the other tasks. The first peak, observed in the SRT distribution for the gap task was an eysress saccade. CONCLUSION: The SRT for the gap task was the shortest and the SRT got longer in the order of the simultaneous task, and the overlap task, and the anti-SM task. Some subjects easily showed an express saccade in the gap task, but others did not.

Adult↗

PubMed2000

HIV risk behaviors among Asian drug users in San Francisco.

This study identified patterns of drug use and HIV risk behaviors in relation to cultural factors among Asian drug users in San Francisco. A sample of 92 Asian drug users (35 Chinese, 31 Filipino, 26 Vietnamese) who were not currently enrolled in drug treatment programs were recruited through targeted sampling methods and interviewed using a questionnaire with open-ended questions. The study evaluated responses of the participants based on content analyses. Compared with Chinese and Vietnamese, Filipino drug users had engaged in riskier behaviors in terms of injection drug use, having sex while on drugs, and having sex with injection drug users (IDUs). Cultural factors such as stigma of injection drug use and fear of needles were cited as reasons for not injecting drugs. Among IDUs, half cited trust as a reason for having shared needles. AIDS prevention programs targeting Asian drug users should consider specific cultural factors among high-risk groups (i.e., Filipinos, immigrants, women, and IDUs).

Adult↗

PubMed2000

[Two cases of idiopathic membranous nephropathy with focal and segmental glomerulosclerotic lesions in which renal function progressively deteriorated].

Previous reports have clarified that focal and segmental glomerulosclerosis(FSGS) appearing in membranous nephropathy(MN) is associated with a poorer prognosis than that of MN without FSGS. However, the etiology and pathogenesis of such FSGS lesions may show substantial individual differences. In some patients, hemodynamic alterations secondary to hypertension and vascular disorders seem to play a crucial role in the development of such FSGS lesions. In such instances, steady regulation of blood pressure might slow down further progression of FSGS lesions. Here we describe two cases of biopsy-proven MN with FSGS. Case I was a 44-year-old man who had shown massive proteinuria with hematuria at the age of 39 years. Renal biopsy specimens obtained at the age of 40 and 41 years showed MN without FSGS and MN with FSGS, respectively. His blood pressure control was fairly good throughout the course. Although he was on a steroid, an immunosuppressant, a low protein diet, and an ACE inhibitor, his renal function declined in 5 years. Case 2 was a 61-year-old woman who showed nephrotic syndrome at the age of 39 years. A renal biopsy specimen obtained at the age of 58 years showed MN with FSGS and remarkable atherosclerotic changes of the interlobular arteries. Her blood pressure control was rather poor throughout the course. Her renal function gradually declined over 22 years. Since parts of the FSGS lesions of the second case may have been caused by hypertension, it is tempting to speculate that day-to-day control of blood pressure could improve the long-term prognosis. We believe that, at least in some patients of MN with FSGS, careful management may lead to a more favorable course of decline in renal function.

Adult↗

PubMed1999

Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer.

Oxidative stress, resulting from the imbalance between prooxidant and antioxidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of antioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substitution that seems to alter transport of the enzyme into the mitochondrion, changing its efficacy in fighting oxidative stress, was associated with breast cancer risk and that a diet rich in sources of antioxidants could ameliorate the effects on risk. Data were collected in a case-control study of diet and breast cancer in western New York from 1986 to 1991. Caucasian women with incident, primary, histologically confirmed breast cancer were frequency-matched on age and county of residence to community controls. Blood specimens were collected and processed from a subset of participants in the study (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk. We also evaluated the effect of the polymorphism on risk among low and high consumers of fruits and vegetables. Premenopausal women who were homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confidence interval, 1.7-10.8). Risk was most pronounced among women below the median consumption of fruits and vegetables and of dietary ascorbic acid and alpha-tocopherol, with little increased risk for those with diets rich in these foods. Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (odds ratio, 1.8; confidence interval, 0.9-3.6). No appreciable modification of risk by diet was detected for these older women. These data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women. The finding that risk was greatest among women who consumed lower amounts of dietary antioxidants and was minimal among high consumers indicates that a diet rich in sources of antioxidants may minimize the deleterious effects of the MnSOD polymorphism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against cancer.

Aged↗