Determinants of tissue estradiol levels and biologic responsiveness in breast tumors

Estradiol stimulates the growth of breast tumor cells in both pre- and post menopausal women. Following the menopause, the levels of estradiol in breast tumor tissues are similar to those from tumors obtained prior to cessation of ovarian function, even though plasma estrogen levels are 10–50 fold lower in post- than in premenopausal women. These observations suggested the possibility of enhanced estradiol uptake from plasma or in situ synthesis in post-menopausal women. We systematically studied these possibilities in a series of model systems. Initially we demonstrated a very high affinity estradiol binding site in tissues from castrated rats. Enhanced uptake occurred under conditions of low plasma estrogen levels when compared to animals with higher estradiol levels. In situ synthesis also occurred both through the sulfatase and aromatase pathways. In further studies, we compared uptake from plasma with in situ synthesis via aromatase in a nude mouse model. Under the conditions utilized, in situ synthesis resulted in much higher tissue estradiol levels and tumor growth rates than did uptake from plasma. During these studies we demonstrated that tumors deprived of estradiol developed mechanisms rendering them more sensitive to estrogen. This involved the ability of cells to adapt to estradiol deprivation to allow them to be responsive to four log lower amounts of estrogen than when studied under wild type conditions. In addition, cells adapted by increasing their level of aromatase and thus developing the capability to become more sensitive to estrogen precursors. Taken together, these studies demonstrate that breast cancer tissue is highly plastic and can adapt to conditions of estrogen deprivation via a variety of mechanisms.     

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.      

Smoking practices in New York City: The use of a population-based survey to guide policy-making and programming

To inform New York City’s (NYC’s) tobacco control program, we identified the neighborhoods with the highest smoking rates, estimated the burden of second-band smoke exposure, assessed the early response to state taxation, and examined cessation practices. We used a stratified random design to conduct a digit-dialed telephone survey in 2002 among 9,674 New York City adults. Our main outcome measures included prevalence of cigarette smoking, exposure to second-hand smoke, the response of smokers to state tax increases, and cessation practices. Even after controlling for sociodemographic factors (age, racelethnicity, income, education, marital status, employment status, and foreign-born status) smoking rates were highest in Central Harlem and in the South Bronx. Sixteen percent of nonsmokers reported frequent exposure to second-hand smoke at home or in a workplace. Among smokers with a child with asthma, only 33% reported having a no-smoking policy in their homes. More than one fifth of smokers reported reducing the number of cigarettes they smoked in response to the state tax increase. Of current smokers who tried to quit, 65% used no cessation aid. These data were used to inform New York City’s smoke-free legislation, taxation, public education, and a free nicotine patch give-away program. In conclusion, large, local surveys can provide essential data to effectively advocate for, plan, implement, and evaluate a comprehensive tobacco control program. Dr. Mostashari (the guarantor) made substantial contributions to the conception, design, and supervision of this paper, the analysis and interpretation of data, the drafting of the paper, critical revisions of the paper for important intellectual content, and the acquisition of data and funding for this research. Dr. Kerker made substantial contributions to the analysis and interpretation of data, the drafting of the paper and critical revisions of the paper for important intellectual content. Ms. Hajat made substantial contributions to the acquisition of data and critical revisions of the paper for important intellectual content. Dr. Miller made substantial contributions to the conception of this paper and critical revisions of the paper for important intellectual content. Dr. Frieden made substantial contributions to the conception, design, and supervision of this paper and critical revisions of the paper for important intellectual content.     

Male Rape,Some Notes on the Laboratory Investigation

The incidence of sexual assault continues to escalate, and it is under-reported. Recent literature discusses the medical, legal, and psychological management of the female sexual assault victim, but little has been written regarding appropriate management of male sexual assault. This article focuses on the laboratory investigation in male rape case.     

The Effects of the Going Places Program on Early Adolescent Substance Use and Antisocial Behavior

This study evaluated the effects of a school-based intervention on growth trajectories of smoking, drinking, and antisocial behavior among early adolescents. Seven middle schools were randomized to intervention or comparison conditions and students in two successive cohorts (n = 1484) provided five waves of data from sixth to ninth grade. The Going Places Program, included classroom curricula, parent education, and school environment components. Latent growth curve analyses demonstrated significant treatment group effects, including reducing increases in friends who smoke, outcome expectations for smoking, and smoking progression, but had non-significant effects on drinking or antisocial behavior. The Going Places Program was effective in preventing increases in smoking progression, but its efficacy as a more cross-cutting problem behavior preventive intervention was not confirmed.     

Morphology, toxin composition and pigment content of Prorocentrum lima strains isolated from a coastal lagoon in southern UK.

Prorocentrum lima was isolated from the coastal Fleet lagoon, Dorset, UK in 2000 and a number of clonal cultures established. These were analyzed for okadaic acid (OA), dinophysistoxin-1 (DTX-1), DTX-2, DTX-4 and diol esters by liquid chromatography coupled to mass spectrometry. OA concentrations varied from 0.4 to 17.1pg OAcell(-1) and DTX-1 from 0.4 to 11.3pg DTX-1cell(-1); DTX-2 was not detected in these isolates. OA and DTX-1 were detected in the culture media, as a result of toxin excretion. DTX-4 and a selection of DTX-4 diol esters were identified using selected ion monitoring, although not all strains produced these compounds. Cell size and number of marginal and valve pores of each strain were observed using scanning electron microscopy. OA and DTX-1 concentrations, pigment content and changes in nitrate and phosphate concentrations in the culture media were followed during growth of one strain of P. lima in batch culture. Diarrhetic shellfish poisoning (DSP) toxins have been previously detected in shellfish cultivated in the Fleet lagoon, but in the absence of any Dinophysis sp. cells. The identification of toxic P. lima strains from the Fleet suggests that this dinoflagellate is the most probable source of occasional DSP detected in the lagoon.     

A comparative study of the utility of two superdisintegrants in microcrystalline cellulose pellets prepared by extrusion-spheronization.

This study evaluated the utility of including superdisintegrants (croscarmellose sodium or sodium starch glycolate) in microcrystalline cellulose extrusion-spheronization pellets as a means of increasing the dissolution rate of poorly water-soluble drugs. The model drug was hydrochlorothiazide, with water or water/ethanol as wetting agent for pellet preparation. Neither disintegrant had significant effects on pellet morphology, flow properties or mechanical resistance. Neither disintegrant caused disintegration of the pellet in drug dissolution medium. Nevertheless, the disintegrants afforded a modest increase in drug dissolution rate, attributable to the observed increase in pellet micropore volume. Drug dissolution rate was slightly higher in pellets prepared with sodium starch glycolate, probably because of this disintegrant's higher swelling capacity.