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Overexpression of human epidermal growth factor receptor 2 (HER-2/neu) characterizes a molecular subtype of breast cancer associated with poor clinical outcome. Preventive strategies for HER-2/neu-positive breast cancer, which is often estrogen and progesterone receptor negative, remain undefined. Activators of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor also expressed in breast cancer, hold potential as cancer prevention agents. PPARgamma ligands include specific fatty acids and synthetic compounds, such as the thiazolidinediones, which appear to inhibit cell proliferation and tumorigenesis. We hypothesized that a thiazolidinedione, rosiglitazone, may serve as a chemopreventive agent for HER-2/neu-associated mammary carcinogenesis, but that efficacy may be influenced by dietary fat content. We studied the effects of diets enriched with corn or fish oil (25% of energy) with and without rosiglitazone (12 g/kg) in a 2 x 2 factorial design on mammary tumorigenesis in murine mammary tumor virus (MMTV)-HER-2/neu transgenic mice. Despite in vitro evidence of antiproliferative effects in an MMTV-HER-2/neu tumor cell line, rosiglitazone did not affect mammary carcinogenesis in vivo. Interestingly, fish oil-based diets markedly suppressed breast tumor incidence (57% of mice vs. 87% of corn oil-fed mice, P = 0.0001) as well as tumor multiplicity (P = 0.001) and mammary gland dysplasia (P = 0.001). These findings demonstrate a potent preventive effect of (n-3) PUFA on HER-2/neu-mediated mammary carcinogenesis, without interaction with a synthetic PPARgamma activator. Further studies focusing on the mechanisms by which (n-3) fatty acids suppress HER-2/neu signaling pathways involved in the pathogenesis of breast cancer are warranted. 相似文献
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BACKGROUND: Bone metastases are common in humans and dogs with late-stage prostate cancer. A unique feature of prostate cancer metastases is new bone formation at metastatic sites ("osteoblastic metastases"). Many carcinomas that metastasize to bone cause bone destruction, not new bone formation. The mechanisms by which prostate cancer induces bone formation at sites of bone metastasis are not well understood. We hypothesized that stimulation of osteoblasts by prostate tissue at metastatic sites was due to the paracrine actions of growth factors produced by prostate epithelial cells. METHODS: We have previously shown that normal canine prostate tissue induced new bone formation when implanted adjacent to the calvarium of nude mice. To complement this in vivo model, we developed an in vitro system of prostate-stimulated osteoblast function to investigate mechanisms of prostate-induced new bone formation. RESULTS: We found that treatment of cultured rat calvaria for 24 hr with proteins from normal dog prostate stimulated alkaline phosphatase activity in a dose-dependent manner 4-6 fold compared to controls. Stimulation began approximately 8 hr after treatment, and was diminished after 72 hr. Calvaria treated with homogenates of normal dog salivary gland, kidney, bladder, and muscle did not increase ALP activity. Pretreatment of the calvaria for 1 hr with endothelin antagonists, but not anti-parathyroid hormone-related protein (PTHrP) antibody or indomethacin, abrogated the stimulation of ALP. CONCLUSIONS: Our results indicated that osteoblast activation by canine prostate occurs via an endothelin-dependent mechanism, and that PTHrP or prostaglandin synthase-mediated pathways are likely not involved. This is a reliable, reproducible assay for determining the roles of molecules important in the activation of osteoblasts by the prostate. 相似文献
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Background
The adiposity rebound is the second rise in body mass index that occurs between 3 and 7 years. An early age at adiposity rebound is known to be a risk factor for later obesity. The aim here is to clarify the connection between the age at rebound and the corresponding pattern of body mass index change, in centile terms, so as to better understand its ability to predict later fatness. 相似文献55.
Adrenal gland: structure, function, and mechanisms of toxicity 总被引:2,自引:0,他引:2
The adrenal gland is one of the most common endocrine organs affected by chemically induced lesions. In the adrenal cortex, lesions are more frequent in the zona fasciculata and reticularis than in the zona glomerulosa. The adrenal cortex produces steroid hormones with a 17-carbon nucleus following a series of hydroxylation reactions that occur in the mitochondria and endoplasmic reticulum. Toxic agents for the adrenal cortex include short-chain aliphatic compounds, lipidosis inducers, amphiphilic compounds, natural and synthetic steroids, and chemicals that affect hydroxylation. Morphologic evaluation of cortical lesions provides insight into the sites of inhibition of steroidogenesis. The adrenal cortex response to injury is varied. Degeneration (vacuolar and granular), necrosis, and hemorrhage are common findings of acute injury. In contrast, chronic reparative processes are typically atrophy, fibrosis, and nodular hyperplasia. Chemically induced proliferative lesions are uncommon in the adrenal cortex. The adrenal medulla contains chromaffin cells (that produce epinephrine, norepinephrine, chromogranin, and neuropeptides) and ganglion cells. Proliferative lesions of the medulla are common in the rat and include diffuse or nodular hyperplasia and benign and malignant pheochromocytoma. Mechanisms of chromaffin cell proliferation in rats include excess growth hormone or prolactin, stimulation of cholinergic nerves, and diet-induced hypercalcemia. There often are species specificity and age dependence in the development of chemically induced adrenal lesions that should be considered when interpreting toxicity data. 相似文献
56.
Effects of 1,25(OH)2D3, EB1089, and analog V on PTHrP production, PTHrP mRNA expression and cell growth in SCC 2/88 总被引:2,自引:0,他引:2
Kunakornsawat S Rosol TJ Capen CC Middleton RP Hannah SS Inpanbutr N 《Anticancer research》2001,21(5):3355-3363
BACKGROUND: We investigated the effects of 1,25(OH)2D3 and selected analogs on canine squamous carcinoma cells (SCC 2/88) and tested whether these compounds could effectively decrease proliferation, induce differentiation, and inhibit PTHrP production and PTHrP mRNA expression. MATERIALS AND METHODS: SCC 2/88 cells were cultured and treated with three substrates. The media were collected for PTHrP immunoradiometric assay. The cells were analyzed for DNA concentration and PTHrP mRNA expression by Northern blot analysis, involucrin by Western blot analysis and 1,25(OH)2D3-receptor (VDR) and PTHrP by immunohistochemistry. RESULTS: The SCC 2/88 cells were stained positively for VDR and PTHrP by immunohistochemistry. 1,25(OH)2D3 and its analogs inhibited cell growth and stimulated differentiation in a dose-dependent manner. All three substrate-treated groups had significantly increased PTHrP secretion at 10(-7) M. Cells treated with 1,25(OH)2D3 at 10(-7) M had 2- to 4-fold increased PTHrP mRNA expression at 12 and 24 hours compared to the vehicle-treated controL PTHrP mRNA in cells treated with TGF-beta (1.5 ng/ml) was increased 7- to 17-fold at 6, 12 and 24 hours compared to the vehicle-treated controL PTHrP mRNA expression was reduced by 0.5- to 2-fold in cells treated with 1,25(OH)2D3 at 10(-7) M and TGF-beta (1.5 ng/ml) together compared to cells treated with TGF-beta alone. CONCLUSION: 1,25(OH)2D3, EB1089, and analog V inhibited SCC 2/88 growth and induced differentiation in a dose-dependent manner, but did not inhibit PTHrP production. 1,25(OH)2D3 treatment led to increased PTHrP mRNA expression and reduced the stimulatory effect of TGF-beta on PTHrP mRNA expression in SCC 2/88 cells. 相似文献
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59.
Daniels DL; Czervionke LF; Millen SJ; Haberkamp TJ; Meyer GA; Hendrix LE; Mark LP; Williams AL; Haughton VM 《Radiology》1989,171(3):807-809
The authors evaluated magnetic resonance (MR) images obtained with intravenously administered gadolinium in ten patients who had facial paralysis and no facial nerve tumor. In patients with either Bell palsy (four patients) or facial paralysis after temporal bone surgery (six patients), intratemporal facial nerve enhancement was seen. Facial nerve enhancement on MR images proved to be a nonspecific finding. 相似文献
60.
IM Gardiner F Ahmed TJ Steiner A McBain C Kennard J de Belleroche 《Cephalalgia : an international journal of headache》1998,18(4):192-196
The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs—Gsα, Giα, and Gqα were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Giα mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gsα or Gqα mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gsα. mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Giα mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Giα mRNA make individuals more susceptible to migraine. 相似文献