Low-density lipoprotein and scavenger receptor activities are modulated by secretory products derived from cells of the arterial wall

The atherosclerotic lesion consists of cholesterol-loaded macrophages, smooth muscle cells, and other cells of the arterial wall. Conditioned medium from human monocyte-derived macrophages (HMDM) stimulated both acetylated and native low-density lipoprotein (Ac-LDL and LDL, respectively) degradation in autologous cells by 25% and 90%, respectively, and this was due to an increase in the number of both LDL and Ac-LDL receptors. Macrophage conditioned medium also resulted in an approximate doubling of LDL degradation by human arterial smooth muscle cells (HASMC), endothelial cells (HEC), and skin fibroblasts (HSF). Macrophage degradation of both Ac-LDL and LDL was enhanced 15% to 45% by conditioned medium derived from HASMC and HSF, respectively, but not by HEC-conditioned medium. Conditioned medium from HASMC, like that from macrophages, could also enhance LDL degradation by smooth muscle cells, fibroblasts, endothelial cells, and macrophages. Thus, the current study demonstrated that arterial wall cells secretory products can affect cellular lipoprotein receptor activities. This phenomenon could lead to increased cellular cholesterol accumulation and foam cell formation.     

Derivatives of butyric acid as potential anti-neoplastic agents

A novel derivative of butyric acid, pivalyloxymethyl butyrate (AN-9) has been shown, in vitro, to: (a) induce cytodifferentiation and inhibit the proliferation of leukemic cells; (b) inhibit the growth and formation of Lewis lung carcinoma colonies in semi-solid agar. AN-9 affect cells at about 10-fold lower concentration and at a faster rate than does butyric acid. The pivalyloxymethyl esters of propionic, isobutyric and valeric acids do not elicit effects similar to those of AN-9, while the isobutyryloxymethyl butyrate does, which strongly suggests that the activity of AN-9 stems from intracellular metabolic degradation of the pro-drug to butyric acid. In vivo, AN-9, increased the survival of mice in Lewis lung carcinoma primary cancer model and significantly decreased the number of lung lesions of the animals inoculated with highly metastatic cells, but did not affect their life span. Acute LD50 studies have shown that AN-9 possesses low toxicity. These results suggest that AN-9 is a potential anti-neoplastic agent as well as a tool for investigation of the differentiation induction mechanism.     

Combination of endometrial thickness and time since menopause in predicting endometrial cancer in women with postmenopausal bleeding

PURPOSE: This study was conducted to assess the combination of endometrial thickness, as measured by transvaginal sonography, and time since menopause, in predicting the presence of endometrial cancer in women with postmenopausal bleeding. METHODS: The study group consisted of 95 women with postmenopausal bleeding who underwent sonographic measurement of endometrial thickness followed by endometrial biopsy. No patient had ever received hormone replacement therapy. RESULTS: The mean endometrial thickness was significantly lower in the absence of endometrial carcinoma (6.9 +/- 4.3 mm) than in its presence (13.5 +/- 7.7 mm) (p < 0.005). The incidence of endometrial carcinoma increased with increases in endometrial thickness and the number of years since menopause. No patient had carcinoma when the endometrium was less than 5 mm thick, but 18.5% did when the thickness exceeded 9 mm. The incidence of cancer was 2.6% in women who had undergone menopause less than 5 years earlier but was 21.4% in women who had undergone menopause more than 15 years prior. Multiple logistic regression analysis showed that time since menopause and endometrial thickness were statistically significant predictors of endometrial carcinoma. CONCLUSIONS: Time since menopause and endometrial thickness together define cutoff points for the diagnostic biopsy of tissue samples for endometrial carcinoma; that is, within a particular time interval, sampling should not be performed if the thickness is below a given value. When using cutoff points of 6 mm of endometrial thickness for women experiencing menopause 5-15 years prior and 5 mm in those going through menopause 15 or more years prior, approximately 60% of invasive procedures may be avoided. In addition, models derived by multiple logistic regression can be used to calculate a patient's risk of cancer based on her age and endometrial thickness.     

Detection of severe pulmonary hypertension based on computed tomography pulmonary angiography

The International Journal of Cardiovascular Imaging - Pulmonary hypertension (PH) is often diagnosed late in the disease course. As many patients may undergo computed tomography pulmonary...     

Comparison between the effect of butyric acid and its prodrug pivaloyloxymethylbutyrate on histones hyperacetylation in an HL-60 leukemic cell line

A butyric acid pro-drug, pivaloyioxymethyl butyrate, AN-9, developed in our laboratory, was previously shown to act as a differentiation-inducing and an anti-cancer agent. In this study we have shown that both AN-9 and butyric acid caused a transient hyperacetylation of histones, which returned to basal levels after 6 and 12 hr, respectively. This activity precedes the induction of differentiation elicited by both agents. AN-9 induced acetylation of histones at a concentration one order of magnitude lower than butyric acid. Pre-treatment of the cells with esterase(s) inhibitors diminished the ability of AN-9 to inhibit proliferation and induce differentiation. The above suggests that the intracellular release of butyric acid fragment, from the pro-drug, is catalyzed by cellular esterase(s).     

Novel anticancer prodrugs of butyric acid. 2.

The antitumor activity of novel prodrugs butyric acid was examined. The in vitro effect of the compounds on induction of cytodifferentiation and on inhibition of proliferation and clonogenicity showed that (pivaloyloxy)methyl butyrate (1a) (labeled AN-9) was the most active agent. SAR's suggested that its activity stemmed from hydrolytically released butyric acid. In vivo, 1a displayed antitumor activity in B16F0 melanoma primary cancer model, manifested by a significant increase in the life span of the treated animals. Murine lung tumor burden, induced by injection of the highly metastatic melanoma cells (B16F10.9), was decreased by 1a. It also displayed a significant therapeutic activity against spontaneous metastases which were induced by 3LL Lewis lung carcinoma cells. Moreover, 1a has the advantage of low toxicity, with an acute LD50 = 1.36 +/- 0.1 g/kg (n = 5). These results suggest that 1a is a potential antineoplastic agent.     

Adrenocortical carcinoma: clinical, morphologic, and molecular characterization.

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005).The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.