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101.
In the West, in countries where many serious infectious diseases
have been eliminated or brought under control, cardiovascular disease
has become the most frequent cause of death among adults(I). Illness
from heart failure causes an enormous loss of time and money, so that
the economic aspects of heart djsease loom la.rge(2). Its prevention is,
therefore, a most important problem of public health, taking rank next
after tuberculosis (3) Realization of this need is growing rapidly, as is
shown by the formation of national associations with the principal pur-
pose of attacking the.problem. State public health, administrations have
hardly entered the field as yet, but they must soon do so. . 相似文献
102.
Tissue-specific synthesis and oxidative metabolism of estrogens 总被引:11,自引:0,他引:11
Jefcoate CR Liehr JG Santen RJ Sutter TR Yager JD Yue W Santner SJ Tekmal R Demers L Pauley R Naftolin F Mor G Berstein L 《Journal of the National Cancer Institute. Monographs》2000,2000(27):95-112
Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (E2) to E2-3,4-quinone metabolites by an E2-4-hydroxylase in breast tissue provides a rational hypothesis to explain the mammary carcinogenic effects of estrogen in women because this metabolite is directly genotoxic and can undergo redox cycling to form genotoxic reactive oxygen species. In this chapter, evidence in support of this hypothesis and of the role of P4501B1 as the 4-hydroxylase expressed in human breast tissue is reviewed. However, the plausibility of this hypothesis has been questioned on the grounds that insufficient E2 is present in breast tissue to be converted to biologically significant amounts of metabolite. This critique is based on the assumption that plasma and tissue E2 levels are concordant. However, breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than predicted from plasma levels. Consequently, factors must be present to alter breast tissue E2 levels independently of plasma concentrations. One such factor may be the local production of E2 in breast tissue through the enzyme aromatase, and the evidence supporting the expression of aromatase in breast tissue is also reviewed in this chapter. If correct, mutations or environmental factors enhancing aromatase activity might result in high tissue concentrations of E2 that would likely be sufficient to serve as substrates for CYP1B1, given its high affinity for E2. This concept, if verified experimentally, would provide plausibility to the hypothesis that sufficient E2 may be present in tissue for formation of catechol metabolites that are estrogenic and which, upon further oxidative metabolism, form genotoxic species at levels that may contribute to estrogen carcinogenesis. 相似文献
103.
To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors. 相似文献
104.
Characterization of four N-3-thymidine adducts formed in vitro by the reaction of thymidine and butadiene monoxide 总被引:1,自引:0,他引:1
Four products were characterized from the reaction of thymidine with
butadiene monoxide (BM), a known human mutagen and possible human
carcinogen. These products were purified by HPLC and characterized as
diastereomeric pairs of N-3-(1-hydroxy-3-buten-2-yl)thymidine and N-3-
(2-hydroxy-3-buten-1-yl)thymidine based upon their UV spectra, 1H NMR and
fast atom bombardment mass spectra. Incubation of thymidine with an excess
of BM at pH 7.4 and 37 degrees C allowed calculation of the
pseudo-first-order kinetic rate constants for the adduct formation, but
when these rate constants were compared with the rates we previously
determined with guanosine, adenosine and deoxycytidine, the results
suggested a lower reactivity with thymidine in comparison with the other
nucleosides. When incubations were carried out at lower BM concentrations,
the formation of adducts appeared to be linearly dependent on BM
concentration. The four thymidine adducts were completely stable for 1 week
when incubated at 37 degrees C in pH 7.4 phosphate buffer. These results
suggest that the interactions of BM with thymidine may play a role in the
molecular mechanisms of mutagenesis and carcinogenesis of BM.
相似文献
105.
106.
Simeone JF; Edelman RR; Stark DD; Wittenberg J; White EM; Butch RJ; Mueller PR; Brady TJ; Ferrucci JT Jr 《Radiology》1985,157(2):437-441
Eight healthy volunteers and 11 patients with pancreatic abnormalities were studied using a conventional body coil and a prototype magnetic resonance (MR) surface coil. Final pathologic diagnoses included carcinoma of the head (six), body (one), and tail of the pancreas (two) and chronic pancreatitis (two). In surface coil images of the volunteers, the body and tail of the pancreas was visualized in all cases but one, and the pancreatic duct was seen in five of eight cases. In-plane spatial resolution of 0.9 X 0.9 mm and 5-mm section thickness was obtained. At the same time, pancreatic surface coil images had a twofold improvement in the signal-to-noise ratio (SNR) compared with body coil images. T1-weighted spin-echo images gave greater SNR, reduced motion artifacts, provided superior anatomic detail, and offered more diagnostic information than comparable T2-weighted images. Significant abnormalities detected only by surface coil imaging included a small tumor surrounded by reactive edema and periglandular tumor invasion. This study demonstrates that surface coil imaging of the pancreas not only is feasible but provides an improved method for examining the pancreas by MR. 相似文献
107.
108.
Plasma-derived vitamin D binding protein (DBP) is an important physiologic regulator of the neutrophil chemotactic response to activated complement. A cell-associated form of DBP has been observed in numerous cell types. We now report that mature, circulating human neutrophils also contain cell-associated DBP. Immunofluorescence studies of normal untreated neutrophils showed the presence of DBP on the cell surface. Western blotting of detergent-soluble neutrophil lysates with a polyclonal anti-DBP showed two major immunoreactive bands, one with an apparent molecular weight of 56 Kd (identical to purified plasma-derived DBP) and a second less prominent band at 12 to 14 Kd. Quantitation of the immunoreactive bands by video densitometry indicated that normal human neutrophils contain 1.5 +/- 0.8 ng DBP/10(6) cells (n = 9). Immunoprecipitation of detergent-soluble lysates with the polyclonal anti-DBP showed only the 56-Kd form by Western blotting. In contrast, a monoclonal anti-DBP immunoprecipitated the 12 to 14 Kd form of DBP from lysates of surface-radioiodinated cells. Western blots of subcellular fractions showed that immunoreactive bands were found in the specific (secondary) granule and plasma-membrane fractions. In addition, pretreatment of neutrophils with 10 nmol/L phorbol myristate acetate (PMA) resulted in approximately a 50% reduction in the amount of DBP in both the specific granule and plasma-membrane fractions. Finally, analysis of the cell- free supernates showed that DBP was spontaneously released into the extracellular milieu: moreover, this release was enhanced if the cells were first stimulated with C5a, formyl-norleucyl-leucyl-phenylalanine (fNLP) or PMA. 相似文献
109.
To overcome the problem of recurrence of stenosis after vascular balloon dilatations, we developed an expandable, intraluminal graft that allows dilatation of the lesion and simultaneous placement of a supportive endoprosthesis to prevent recoil of the arterial wall. The graft is made of continuous, woven, stainless steel wire. The resulting tubular mesh has a wall thickness of 200-450 micron and 80% open surface. The grafts, mounted on angioplasty catheters, are introduced through 8-12-F Teflon sheaths. Eleven grafts of 6, 8, and 10 mm in diameter by 20 mm long were placed in the aorta, common carotid, superior mesenteric, iliac, and renal arteries of dogs. Six grafts showed no stenosis in follow-up studies of up to 8 weeks. Two grafts had moderate stenosis as a result of neointimal hyperplasia. Two partial and one complete graft thrombosis occurred in nonheparinized animals in which the graft outflow was restricted. Anticoagulant was not used on a long-term basis. Light and electron microscopy studies showed complete covering of the graft's inner surface by endothelium at 3 weeks. 相似文献
110.
Adrenal abscess in the neonate is a rare complication of adrenal hemorrhage. The radiographic and clinical findings of 12 previously published cases and two new cases of adrenal abscess in the newborn are presented. Sonography was the most helpful examination in distinguishing a suprarenal lesion from an intrarenal lesion and in demonstrating the morphology of the abscess. 相似文献