N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer.     

Contrast of response to dacarbazine,mitomycin, doxorubicin,and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas

BACKGROUND: Previous observations have suggested that leiomyosarcomas, and especially gastrointestinal leiomyosarcomas, may be less responsive to cancer chemotherapy than other histologic types of non-osseous sarcomas; however, this difference has not been characterized well until quite recently, with the recognition of the special identity of gastrointestinal stromal tumors (GIST). Prior to the general acceptance of this new histologic classification, we decided to study patients with gastrointestinal leiomyosarcomas in concert with other leiomyosarcomas for relative responsivity to a combination cytotoxic regimen developed specifically for leiomyosarcomas. PATIENTS AND METHODS: Adult patients with advanced leiomyosarcomas received intravenous chemotherapy as outpatients with dacarbazine 750 micrograms/m2, mitomycin 6 mg/m2, doxorubicin 40 mg/m2, and cisplatin 60 mg/m2 on day 0, with granulocyte macrophage colony stimulating factor (GM-CSF, sagramostim) 250 mcg/m2 given s.c. every 12 hr on days -6 to -3 and on days 1-14 of each 4-week treatment cycle. Our original plan to escalate dacarbazine doses to 1000 mg/m2 following cycle one was abandoned after the first six patients because of toxicity. RESULTS: We studied 21 patients with GIST and 18 patients with other types of leiomyosarcomas, for a total of 131 treatment cycles, with a median of four cycles per patient in each of the two groups of patients. Toxicity was significant, with 33% having grade 3 vomiting at some time during treatment. Grade 3 leukopenia occurred in 42%, and grade 3 thrombocytopenia was observed in 68% of our patients. In one patient, grade 4 pulmonary toxicity developed during the fourth cycle, and this was considered a major factor in her death. Objective tumor regression was observed in one of 21 (1.8%) (95%CI = 0-14.5%) GIST and in 11 of 18 (61%) (95%CI = 38-84%) other leiomyosarcomas, including eight of 10 uterine cases. In five cases, we interrupted chemotherapy to attempt complete surgical excision of residual tumor, and four of the patients were rendered apparently free of disease. Median survivals for the two groups have been similar with 16.7 months (95%CI = 8.8-27.5 months) for the GIST and 17.5 mos (95%CI = 10.9-35.3%) for the other leiomyosarcomas. Three patients with uterine leiomyosarcomas are still alive more than 2 years after completing this chemotherapy and subsequent secondary surgical excision (+/- irradiation) and two of them are free of disease. CONCLUSIONS: While this regimen is ineffective against GIST, its value against uterine leiomyosarcomas deserves further study in a larger population.     

ERK signalling and oncogene transformation are not impaired in cells lacking A-Raf

Previous studies have indicated an important role for the Raf family of protein kinases in controlling cellular responses to extracellular stimuli and activated oncogenes, through their ability to activate the MEK/ERKs. To investigate the specific role of A-Raf in this process we generated A-Raf deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells by gene targeting and characterized their ability to undergo proliferation, differentiation, apoptosis, ERK activation, and transformation by oncogenic Ras and Src. The A-Raf deficient cells are not disrupted for any of these processes, despite the fact that this protein is normally expressed at high levels in both cell types. This implies either that A-Raf plays no role in MEK/ERK activation, that its function is fully compensated by other Raf proteins or MEK kinases or that its role in MEK/ERK activation is highly tissue-specific. Interestingly, B-Raf and Raf-1 activity towards MEK as measured by the immunoprecipitation kinase cascade assay are both significantly increased in the A-Raf deficient MEFs.     

Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation

During the last decade, several novel members of the Epidermal Growth Factor family of peptide growth factors have been identified. Most prominent among these are the Neuregulins or Heregulins. To date, four different Neuregulin genes have been identified (Neuregulin1-4) and several different splicing isoforms have been identified for at least two of these genes (Neuregulin1 and Neuregulin2). While Neuregulin1 isoforms have been extensively studied, comparatively little is known about Neuregulin3, Neuregulin4, or the Neuregulin2 isoforms. Indeed, there has been no systematic comparison of the activities of these molecules. Here we demonstrate that Neuregulin2alpha and Neuregulin2beta stimulate ErbB3 tyrosine phosphorylation and coupling to biological responses. In contrast, Neuregulin3 and Neuregulin4 fail to activate ErbB3 signaling. Furthermore, Neuregulin2beta, but not Neuregulin2alpha, stimulates ErbB4 tyrosine phosphorylation and coupling to biological responses. Finally, both Neuregulin3 and Neuregulin4 stimulate modest amounts of ErbB4 tyrosine phosphorylation. However, whereas Neuregulin3 stimulates a modest amount of ErbB4 coupling to biological responses, Neuregulin4 fails to stimulate ErbB4 coupling to biological responses. This suggests that there are qualitative as well as quantitative differences in ErbB family receptor activation by Neuregulin isoforms.     

DNA image cytometry and fluorescence in situ hybridization for noninvasive detection of urothelial tumors in voided urine

BACKGROUND: Cystoscopy and histologic examination remain the standard methods for initial tumor diagnosis and monitoring for early detection of recurrences, since the sensitivity of conventional urinary cytology for the detection of urothelial tumors in urinary specimens is low. DNA image cytometry (ICM) and fluorescence in situ hybridization (FISH) have been suggested as ancillary tools. The goal of the current study was to compare the diagnostic value of DNA image cytometry and FISH for the noninvasive detection of urothelial tumors in voided urine. METHODS: Cytospin preparations were prepared from voided urine collected prior to the resection of 26 noninvasive (pTa) and 11 invasive (pT1-2) tumors. Specimens from 14 patients with benign prostatic hyperplasia were used as negative controls. DNA ICM was performed using the AUTOCYTE trade mark cell analytical system on Feulgen-stained cytospin specimens. The commercially available UroVysion trade mark FISH multiprobe was used to analyze chromosomes 3, 7, and 17, and 9p21. RESULTS: The overall sensitivity of cytology improved from 24% to 54% and to 78% if supplemented by ICM or FISH, respectively. Image cytometry detected all invasive tumors (pT1-2), while FISH missed one; FISH identified 19 of 26 (73%) pTa tumors, while only 9 (35%) of these tumors were aneuploid by ICM. The results of ICM and FISH were concordant in 37 of 51 (72%) cases. CONCLUSIONS: The current study shows that both FISH and ICM can successfully be used as supplementary methods to detect the clinically most relevant group of invasive bladder carcinomas. However, UroVysion FISH is more sensitive in the detection of pTa tumors than ICM, as it recognizes individual chromosomal alterations that frequently prevail in urothelial tumors.     

Religious coping,health, and health service use among bereaved adults

OBJECTIVE: This report examined associations between religious coping, health, and health service use among a sample of 265 recently bereaved adults. METHOD: Participants were interviewed an average of 6.3 (SD = 7.4) months after their loss and again 4 months later. Multivariate regression models and repeated measures ANOVA analyses estimated the influence of religious coping on health and health service use at baseline and follow-up, controlling for significant confounding influences, such as health promoting behaviors. RESULTS: At baseline, those high on religious coping had significantly more functional disabilities than did those low on religious coping. Controlling for health status, participants with higher religious coping scores were significantly less likely to visit their doctor during the 60 days prior to the baseline interview. Despite worse health and less health service use at baseline, those high on religious coping had equivalent health status to those low on religious coping at follow-up. CONCLUSIONS: Greater use of religious coping is associated with more functional disabilities and fewer outpatient physical health care visits at baseline, but a lack of decline in health at 4-month follow-up among the bereaved, a sub-group at risk for numerous health impairments. Possible reasons for this association and its implications are discussed.     

Estrogenic properties of raloxifene,but not tamoxifen,on D2 and D3 dopamine receptors in the rat forebrain

The present study investigated the estrogenic specificity of the modulation of dopamine D(2) and D(3) receptors by comparing the effects of estradiol with tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic activity depending on the target tissue. Two weeks after ovariectomy of female rats, we observed a 60% decrease in the uterine weight, which was prevented by a replacement therapy of 2 weeks with 17beta-estradiol. A tamoxifen or raloxifene treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but significantly less than estradiol treatment. Ovariectomy decreased dopamine D(2) receptor specific binding (20%) in the dorsolateral part of the anterior striatum and these receptors were left unchanged in the other parts of the striatum as well as in the olfactory tubercle and the nucleus accumbens. 17beta-Estradiol and raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left dopamine D(3) receptor specific binding unchanged. However, estradiol and raloxifene treatment decreased dopamine D(3) receptor binding in the islands of Calleja, the core and shell of the nucleus accumbens and the dorsal part of the anterior striatum, compared with ovariectomized rats. Our results show that raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine receptors. Furthermore, estradiol and raloxifene have opposite effects on specific binding to dopamine D(2) and D(3) receptors.     

Altered sexual and social behaviors in trp2 mutant mice

We have used gene targeting to generate mice with a homozygous deficiency in trp2, a cation channel expressed in the vomeronasal organ (VNO). Trp2 mutant animals reveal a striking reduction in the electrophysiological response to pheromones in the VNO, suggesting that trp2 plays a central role in mediating the pheromone response. These mutants therefore afford the opportunity to examine the role of the VNO in the generation of innate sexual and social behaviors in mice. Trp2 mutant males and nursing females are docile and fail to initiate aggressive attacks on intruder males. Male-female sexual behavior appears normal, but trp2 mutant males also vigorously mount other males. These results suggest that the cation channel trp2 is required in the VNO to detect male-specific pheromones that elicit aggressive behaviors and dictate the choice of sexual partners.     

Mechanical disruption of individual nucleosomes reveals a reversible multistage release of DNA

The dynamic structure of individual nucleosomes was examined by stretching nucleosomal arrays with a feedback-enhanced optical trap. Forced disassembly of each nucleosome occurred in three stages. Analysis of the data using a simple worm-like chain model yields 76 bp of DNA released from the histone core at low stretching force. Subsequently, 80 bp are released at higher forces in two stages: full extension of DNA with histones bound, followed by detachment of histones. When arrays were relaxed before the dissociated state was reached, nucleosomes were able to reassemble and to repeat the disassembly process. The kinetic parameters for nucleosome disassembly also have been determined.