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Biomedical subjects

L Berstein

Publications and source records attributed to L Berstein.

17 recordsLinked to original sources
PubMed2005

Aromatase and comparative response to its inhibitors in two types of endometrial cancer.

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.

Adult↗
PubMed2005

Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment.

Breast tumors in women can adapt to endocrine deprivation therapy by developing hypersensitivity to estradiol. For this reason, aromatase inhibitors can be effective in women relapsing after treatment with tamoxifen or following oophorectomy. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term estradiol deprivation (LTED) causes "adaptive hypersensitivity". The primary mechanisms responsible involve up-regulation of ER alpha as well as the MAP kinase, PI-3 kinase, and mTOR growth factor pathways. ER alpha is 4-10-fold up-regulated and co-opts a classical growth factor pathway using Shc, Grb2, and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. Estradiol binds to cell membrane associated ER alpha, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk activation and by morphologic changes in cell membranes. Additional effects include activation of PI-3 kinase and mTOR pathways through estradiol induced binding of ER alpha to the IGF-1 and EGF receptors. Further proof of the non-genomic effects of estradiol involved use of "designer" cells which selectively express ER alpha in nucleus, cytosol, and cell membrane. We have used a new downstream inhibitor of these pathways, farnesyl-thio-salicylic acid (FTS), to block proliferation in hypersensitive cells as a model for a potentially effective strategy for treatment of patients.

Animals↗
PubMed2005

Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity.

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

CYP19 gene expression and aromatase activity in endometrial cancer tissue: importance of the type of the disease.

Aromatase (CYP19) activity in malignant endometrium presents local mechanism with potential ability to support tumor growth. The data on interrelation between activity of this enzyme and its mRNA signal in endometrial cancer (EC) tissue are very scarce and inconclusive. To correct this gap we studied aromatase activity and gene expression totally in 19 samples of EC (17 of them -- from postmenopausal women) collected during surgery. Aromatase activity was evaluated by tritium water release assay and CYP19 gene expression -- with rt-PCR. Additionally, all studied EC cases were divided on the basis of case history and some characteristics of host and tumor and in accordance with existing classification into cases belonging to type I or II of the disease (correspondingly, 13 and 6 observations). Positive correlation between enzyme activity and CYP19 mRNA signal (R(s)=+0.63, p<0.05) was revealed in the whole group of studied samples. Aromatase activity varied in evaluated material between 1.45 fM/mg prot./hr and 11.49 fM/mg prot./hr, and in type II cases it was higher (7.27+/-0.96 fM/mg prot/hr) than in type I observations (4.96+/-0.66 fM/mg prot./hr, p=0.066). CYP19 mRNA expression was not revealed in 6 cases and all of them belonged to the type I of disease. Thus, although type II of EC is frequently considered as hormone non-dependent, increased ability of this tumor type to estrogen biosynthesis (on CYP19 gene and protein level) may lead to reconsideration of such conclusion and warrants further investigation.

Adult↗
PubMed2003

Adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention.

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E(2)). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E(2) deprivation (LTED) causes "adaptive hypersensitivity". The enhanced responses to E(2) do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E(2) on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERalpha is 4- to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E(2) binds to cell membrane-associated ERalpha, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E(2) produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E(2) involved use of cells which selectively expressed ERalpha in the nucleus, cytosol and cell membrane. We created these COS-1 "designer cells" by transfecting ERalpha lacking a nuclear localization signal and containing a membrane localizing signal. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E(2). Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

Adaptation, Physiological↗
PubMed2002

Switching (overtargeting) of estrogen effects and its potential role in hormonal carcinogenesis.

Peculiarities of the estrogens influence on target tissues is one of the crucial problems in understanding of the estrogen-induced carcinogenesis and anticarcinogenesis mechanisms. Conditions or factors enhancing the genotoxic component in total effect of estrogens (on the uterine tissue, in particular) are very important, since these factors may influence both the hormonal carcinogenesis type and biological properties of the developing hormone-dependent tumors. In this study female rats (3 months of age at the beginning of experiment) have been given plain water (group 1) or 5% ethanol solution over 4 months. Rats which received ethanol were further divided into 6 groups (groups 2-7). During last 2 months of the experiment N-acetylcysteine was given to rats in group 3, ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E)--to group 4, melatonin--to group 5, carnosine--to group 6; the rats in group 7 swam for 5 days a week according to the so called developing schedule. 2.5 weeks before the end of experiment all rats underwent bilateral ovariectomy, and over 11 days preceding the last day of the experiment they received injections of estradiol (2 microg intramuscularly daily). When the experiment was over, estradiol and cholesterol blood levels, progesterone receptors content, peroxidase activity, proliferation index, percent of cells in S and G2/M phases, thickness of endometrium and rate of DNA damage in uterine tissue (COMET assay) and estradiol 2-hydroxylase activity in liver tissue were measured. The conclusion was that administration of 5% ethanol combined with estrogen injections results in genotoxic (G) changes in the uterus, which may be prevented by giving N-acetylcysteine or melatonin. Combination of vitamins C and E enhances some features of hormonal (H) estrogen effects (uterine weight, induction of progesterone receptors), but attenuates the other (proliferation index). Consequently, the combination of N-acetylcysteine and optimal doses of ascorbic acid and alpha-tocopherol may be recommended for prevention of the phenomenon of switching of estrogen effects [PSEE] (e.g. enhancement of G-component and decrease of H-component), observed particularly in cases of the treatment with tobacco smoke or ethanol consumption in more than moderate (15%) concentrations, which lead to the increased risk of genotoxic type of hormonal carcinogenesis.

Animals↗
PubMed2000

Tissue-specific synthesis and oxidative metabolism of estrogens.

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.

Aromatase↗
PubMed1999

Protein status of infants with phenylketonuria undergoing nutrition management.

OBJECTIVES: The objectives of this study were to determine if Phenex-1, amino-acid modified medical food with iron maintained normal indices of protein status in infants with phenylketonuria (PKU) and to investigate factors that influence plasma amino acid concentrations. METHODS: A study was conducted for six months in 35 infants with classical PKU diagnosed in the neonatal period. Diet diaries and plasma amino acid concentrations were obtained monthly. Blood for analysis of plasma albumin, blood urea nitrogen (BUN), retinol binding protein (RBP) and transthyretin was obtained at one, three and six months of study. RESULTS: Mean (+/-SEM) total daily intake of medical food and nutrients was 79+/-4 g; 17.3+/-0.6 g protein, 660+/-18 kcal, 255+/-10 mg phenylalanine (Phe), and 1423+/-56 mg tyrosine (Tyr). Mean concentrations of plasma amino acids, except cystine (during entire study), glycine (first month) and Phe were in the normal range. Mean concentrations of plasma Phe were in the treatment range (120 to 360 micromol/L). Plasma concentrations of arginine, methionine, Phe, tryptophan, Tyr, and valine were positively correlated with intakes at various months of study. Concentrations of aspartic and glutamic acids, Phe, and Tyr were positively correlated and 17 amino acids were negatively correlated with the interval between feeding and blood draw. At six months of study, concentration of plasma albumin was 4.1+/-0.1 g/dL, RBP was 3.74+/-0.2 mg/dL, transthyretin was 17.9+/-0.9 mg/dL, and urea nitrogen was 11.9+/-0.5 mg/dL. CONCLUSION: During study, all mean plasma indices of protein status were in normal reference ranges. Phenex-1 supports normal mean plasma amino acid, albumin, RBP, transthyretin, and BUN concentrations when fed in adequate amounts.

Amino Acids↗
PubMed1999

The potential of aromatase inhibitors in breast cancer prevention.

Substantial evidence supports the concept that estrogens cause breast cancer in animals and in women but the precise mechanism is unknown. The most commonly held theory is that estrogens stimulate proliferation of breast cells and thus statistically increase the chances for genetic mutations which could result in cancer. Another theory is that estrogen metabolism generates oxygen-free radicals and quinones which produce both stable and unstable DNA adducts. Both result in genetic mutations which accumulate and could ultimately cause cancer. A major criticism of the latter hypothesis is that breast tissue contains insufficient concentrations of estrogen for accumulation of genotoxic metabolites. Our hypothesis is that breast tissue estrogen levels, as a result of in situ synthesis, are much higher than previously thought. We and others have shown that estrogen can be made in the breast itself through conversion of androgens to estrogens, a process catalyzed by the enzyme aromatase. The levels of estrogen in the breast increase when aromatase is overexpressed. With sufficient amounts of aromatase in breast tissue, enough estradiol as substrate should be available to allow formation of substantial amounts of genotoxic metabolites. We postulate that aromatase overexpression may in this way cause breast cancer. As evidence supporting this concept, four animal models of aromatase overexpression and either breast cancer or premalignant lesions have been described. We have provided evidence that normal breast tissue can make estrogen and that certain stimulatory compounds can increase aromatase activity in the breast by nearly 10,000-fold. If our concepts are correct, it might be possible to prevent breast cancer by blocking the aromatase enzyme. Drugs are currently available to inhibit aromatase nearly completely without causing significant side-effects. Aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer because of their dual role to block both initiation and promotion of breast cancer. To inhibit the initiation process, these inhibitors would reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentrations in tissue. At the same time, aromatase inhibitors would inhibit the process of tumor promotion by lowering tissue levels of estradiol and thus blocking cell proliferation. These concepts provide a strong rationale for studies of aromatase inhibitors to prevent breast cancer.

Animals↗
PubMed1985

Hospice effectiveness in controlling pain.

Terminal cancer patients were randomly assigned to receive comprehensive hospice care or traditional medical care. Patients were followed up for two years or until death. Pain was measured by the McGill Pain Scale. Frequency and intensity of cancer-related symptoms were also noted. Over the course of the study, 34% of hospice patients and 21% of control patients never reported pain. No significant differences between the two groups could be detected in either the proportion of patients with pain at any time or the intensity of pain. Neither were there differences in the intensity or frequency of cancer-related symptoms. The presence of pain was associated with the presence of other symptoms; a significant correlation was found between the levels of depression and anxiety and pain scores.

Analgesics↗
PubMed1985

Absence of respiratory effects in subjects exposed to low concentrations of TDI and MDI: a reevaluation.

Because of criticisms of the authors' previously reported study showing absence of respiratory effects in subjects exposed to low concentrations of toluene diisocyanate (TDI) and diphenylmethane diisocyanate (MDI), the data have been reanalyzed. This reanalysis confirms the accuracy of the results and the conclusions based on them. Subjects exposed to 0.0010 to 0.0015 ppm of TDI and around 0.0003 to 0.0006 ppm of MDI demonstrated a normal age- and smoking-related rate of decline in forced expiratory volume in 1 s and no evidence that it was related to isocyanate exposures. Control of isocyanate exposure sufficient to protect industrial workers against measurable deterioration in lung function appears feasible.

Cyanates↗
PubMed1977

Mandibular fractures: a review of 156 consecutive cases.

This report deals with a consecutive series of 156 mandibular fractures that were managed during a three-year period. The age and sex incidence are presented and the causative factors of the trauma are discussed. The fractures are classified according to anatomic site and laterality. The majority of the patients were treated with closed reduction techniques and the reasons for open reduction are tabulated. The results and complications of the treatment are enumerated. A conservative technique is described for open reduction of fracture-dislocations of the condylar head.

Adolescent↗