Cell biological markers of drug resistance in ovarian carcinoma

The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclophosphamide/melphalan), natural drugs (doxorubicin), and "new drugs" (taxol and taxotere). Both platinum and classical alkylating agents mediate their cytotoxicity by the formation of drug-DNA adducts, resulting in DNA damage. Therefore, drug resistance mechanisms are (in part) comparable. In ovarian carcinoma cell lines increased repair of DNA damage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs. Studies on the role of DNA repair mechanisms and glutathione in human ovarian carcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione. Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell by increased expression of membrane glycoproteins acting as a drug efflux pump, such as P-glycoprotein. Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topisomerase (Topo) II. Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presumed other mechanisms such as alterations in tubulin structure, the cellular "target" of taxol, and changes in polymerization of tubulin are still largely unresolved. Several ways to modulate the reviewed resistance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance. The relevance of the identification of most of these factors in ovarian carcinoma patients however remains to be established.     

Applications of tumor markers to the screening of endometrial and ovarian cancers

Several new trials, using tumor markers in the screening for gynecological malignancies, have been conducted. For assisting the cytological diagnosis of uterine endometrial cancers, the new EIA method using cytological specimens and the monoclonal antibody against endometrial cancer cells, MSN-1, was developed. This method could help to discriminate between cancer and normal cells, so this would result in decrease the numbers of suspicious cases on cytological diagnosis. For ovarian cancers, especially to identify high-risk groups, two carbohydrate-related antigens, CA602 and CA546, were employed. The combined use of these two markers showed a high potentiality to detect ovarian cancers. GAT (galactosyltransferase associated with tumor), an isoform of galactosyltransferase, could rescue the false-positive cases with endometriotic cysts. These new methods with tumor markers are supposed to be handy tools in the screening for gynecological malignancies.     

Estradiol, gonadotropins, and tumor markers in ovarian cyst fluid

Amelogenesis imperfecta is a rare dental disease and presents a major challenge to the dentist. With the tremendous advances in the field of esthetic dentistry, especially in bonding to dentin, it is today possible to restore function and esthetics to an acceptable level. The need for full crown preparation has been decreased to an absolute minimum. A case of amelogenesis imperfecta, complicated by a malocclusion, is presented. A combination of periodontal treatment and resin-bonded porcelain onlays and nobel alloys resulted in a highly successful outcome. The virtual absence of enamel was overcome with the aid of dentin bonding.     

Follicular fluid insulin-like growth factor-I and insulin-like growth factor-binding protein-1 and -3 vary as a function of ovarian reserve and ovarian stimulation

PURPOSE: Follicular fluid concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (BP)-1, and IGFBP-3 in 57 women undergoing in vitro fertilization and embryo transfer were examined to determine whether levels reflected differences in patients' exposure to gonadotropin stimulation and a diminished ovarian reserve. METHODS: Preovulatory follicular fluid was obtained from both gonadotropin-stimulated and unstimulated cycles. Subjects were grouped according to normal or decreased ovarian reserve and whether or not they received gonadotropin stimulation. RESULTS: The mean follicular fluid concentrations of IGF-I and IGFBP-1 were significantly lower in the "decreased" ovarian reserve group compared with the "normal" ovarian reserve group, with no change in estradiol or IGF-II levels. This resulted in a decreased molar IGF-I: BP ratio and an increased molar IGF-II:IGFBP-1 ratio. In unstimulated cycles, mean follicular fluid concentrations of IGFs did not differ significantly compared with those in stimulated cycles, whereas concentrations of IGFBP-1 and IGFBP-3 were significantly lower, leading to higher molar ratios of the IGFs to the binding proteins. CONCLUSIONS: Follicular fluid IGF and binding proteins vary as a function of ovarian reserve and gonadotropin stimulation. This may reflect either differences in oocyte quality or a suboptimal follicular fluid environment.     

Proliferative index of human luteinized granulosa cells varies as a function of ovarian reserve

OBJECTIVE: We examined whether the proliferative index of luteinized granulosa cells, as determined by flow cytometry, varied as a function of a woman's ovarian reserve, as reserve, as reflected by follicular-phase day 3 serum follicle-stimulating hormone. STUDY DESIGN: This prospective cohort study consisted of 19 women of similar chronologic age preparing for in vitro fertilization-embryo who met specific day 3 serum follicle-stimulating hormone criteria. The "low follicle-stimulating hormone" group consisted of 11 women with day 3 serum follicle-stimulating hormone levels < or = 6 IU/L. The "high follicle-stimulating hormone" group consisted of eight women with day 3 serum follicle-stimulating hormone levels > or = 18 IU/L. A total of 56 preovulatory follicles containing > or = 10(4) luteinized granulosa cells were examined by flow cytometry. The low follicle-stimulating hormone group was compared with the high follicle-stimulating hormone group to examine proliferative index as a function of serum day 3 follicle-stimulating hormone levels. RESULTS: The low follicle-stimulating hormone group had a greater proliferative index (11.1% +/- 0.4%) than did the high follicle-stimulating hormone group (8.3% +/- 0.6%), p < 0.001). This study demonstrates that in spite of the same chronologic age, luteinized granulosa cells from preovulatory follicles of women with day 3 serum follicle-stimulating hormone levels > or = 18 IU/L have a 25% decreased proliferative index compared with luteinized granulosa cells from women with day 3 serum follicle-stimulating hormone levels < or = 6. CONCLUSIONS: This suggests that granulosa cell proliferation is influenced by ovarian reserve and may explain in part the more favorable response to ovulation induction protocols that younger women demonstrate compared with women of more advanced reproductive age.     

Changes of calcitonin reserve function in patients with primary osteoporosis]

Postpartal determination of lactate and glucose in the umbilical cord whole blood of 139 successive deliveries utilizing biosensors (blood gas analysator 865, Ciba Corning) are presented. The median lactate value in the umbilical arterial blood is 4.45 mmol/l and in the venous blood 4.23 mmol/l. Following categorization into control and high-risk groups, the arterial mean values are 4.23 mmol/l and 6.39 mmol/l and the respective venous values are 3.95 mmol/l and 5.04 mmol/l. Using the U-test these differences between the control and high-risk groups are significant. The mean of the measured lactate correlates significantly with the mean of the calculated base excess (< 0.001). The mean glucose value in the umbilical arterial blood is 78 mg/dl and in the venous 93 mg/dl. Between high-risk and control group no significant difference is found.     

Immunologic characterization of tumor markers in human ovarian cancer cell lines

OBJECTIVE: The purpose of this study was to evaluate the expression of a novel autologous ovarian tumor-associated antigen in eight human ovarian tumor cell lines compared with other ovarian tumor markers and products of oncogenes. METHODS: Autologous antibodies were eluted from human ovarian tumor-membrane fragments purified in our laboratory. These antibodies react with autologous ovarian tumor-associated antigens (AOTA) and have a high degree of specificity for human ovarian tumors. They do not bind to normal ovarian or nonovarian tissues, or to nonovarian neoplastic tissues. We evaluated eight human ovarian adenocarcinoma cell lines (2008, 2774, Caov-3, OVCAR-3, PA-1, SW 626, UCI 101, and UCI 107) by indirect immunofluorescence to determine the expression of AOTA relative to the ovarian cancer tumor marker CA 125 and the products of selected oncogenes (p 53, c-neu, and c-myc). RESULTS: The patterns and intensities of immunofluorescence correlated most closely between AOTA and c-neu. For example, AOTA and c-neu were detected in all eight cell lines and displayed very strong cytoplasmic fluorescence on cell lines 2774, UCI 101, and UCI 107. CA 125 was present in the cytoplasm of four of eight cell lines. A tumor suppressor gene product, p53, exhibited a nuclear staining pattern in six of eight cell lines. CONCLUSIONS: These data suggest that AOTA and the products of the c-neu oncogene may share certain epitopes. Current studies are underway to increase our understanding of the humoral response to ovarian cancer and the possible relationship to the expression of tumor oncogene products. Further characterization of AOTA will be necessary before early diagnostic tests can be developed.     

Evaluating ovarian reserve: follicle stimulating hormone and oestradiol variability during cycle days 2-5

A prospective measurement of follicle stimulating hormone (FSH) and oestradiol between cycle days 2 and 5 was conducted to investigate the intra- and inter-cycle variability in a healthy population of women with regular menstrual intervals. Daily serum samples were obtained from 44 women for a total of 66 cycles on cycle days 2, 3, 4 and 5. FSH concentrations were consistent on all cycle days measured. Oestradiol concentrations on cycle day 2 were not different from cycle day 3, but concentrations on cycle day 4 and cycle day 5 were statistically different from both cycle day 2 and cycle day 3 by analysis of variance (P < or = 0.05). Evaluation of functional ovarian reserved by cycle day 3 FSH measurement has become the standard in most assisted reproductive technology programmes. The recent change in FSH standardization coupled with the inflexibility of cycle day 3 testing has led to a re-evaluation of testing protocols. Cycle day 3 appears to have emerged as a dictum because most ovulation induction protocols are initiated on cycle day 3, 4 or 5. Flexibility of sampling day can be introduced as suggested by these results. The additional information ascertained from oestradiol testing as applied to evaluation of ovarian reserve warrants further investigation.     

Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening

Disseminated tuberculosis was diagnosed at the autopsy of a 65-day-old premature infant who died in a 52-bed neonatal intensive care unit (NICU). Both parents and one sibling had previously had positive tuberculin skin tests (TSTs); none had active pulmonary tuberculosis, but a second sibling had hilar adenopathy. Congenital transmission was confirmed by isolation of Mycobacterium tuberculosis from the mother's endometrium and the infant's lung tissue. Both strains were identical by DNA restriction fragment analysis. TSTs were performed on 14 neonates, 27 NICU visitors, 11 contacts of the family, and 260 health care workers. TST conversion occurred in two nurses (0.8%); both had normal chest radiographs and received isoniazid therapy. Exposed neonates had negative chest radiographs, had negative gastric aspirates for acid-fast bacilli, and received isoniazid preventive therapy. Diagnosis of congenital tuberculosis requires a high index of suspicion. Transmission of tuberculosis in the NICU setting is unusual but can occur.     

Steps in the treatment of ovarian cancer]

The paclitaxel/cisplatin regimen is superior to standard therapy PC based on higher overall response rates, higher negative second-look laparotomy rate and overall survival. The regimen paclitaxel/cisplatin/cyclophosphamide seem to give the best treatment results. Interval debulking surgery after initial laparotomy and intraperitoneal therapy with cisplatin and i.v. cyclophosphamide in patients with residual disease improve overall survival rate.     

Endometrial and placental protein markers and ovarian steroids in serum during in-vitro fertilization cycles

The objective of this study was to find the earliest time at which it was possible to detect clinical pregnancy in an in-vitro fertilization (IVF) treatment cycle supported with human chorionic gonadotrophin (HCG), and also retrospectively to diagnose abnormal ovarian- or endometrium-related situations in failure cycles. Serum samples were taken in 41 IVF cycles at frequent intervals from the beginning of ovarian stimulation until menstrual bleeding occurred or a pregnancy was established. Concentrations of oestradiol, progesterone, placental protein 14 (PP14), pregnancy-specific beta 1-glycoprotein (SP1), and pregnancy-associated plasma protein A (PAPP-A) were determined in the serum samples using commercially available (steroid) or purpose-developed (protein) immunoassays. The cycles were retrospectively distributed into four outcome groups: (i) fertilization failure (FF, n = 8); (ii) implantation failure (IF, n = 10); (iii) 'interaction' (embryo-endometrium) cycle (IC, n = 14), and (iv) clinical pregnancy (CP, n = 9). The embryo-endometrium interaction was detected by a rise in SP1 in 23 cycles (70% of embryo transfers) at a time when endogenous HCG was still masked by external support. Early ('false') positive SP1 concentrations were observed in two out of eight and five out of 14 cases in groups FF and IC respectively, but never amongst the ongoing pregnancies (CP). PAPP-A did not distinguish pregnancy from the other outcomes. The PP14/progesterone ratio was lower, later in the cycle, in CP than in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cognitive neuroanatomy of language: contribution of functional cerebral imaging]

Each year a number of Haitians enter the United States and may become part of the U.S. health care system. Nurses need to be sensitive to cultural differences and should assess clients for special needs that may arise because of cultural diversity. This article provides strategies for interacting with the Haitian American client in a clinical setting to ensure success in providing nursing care.     

The Diagnostic Compass; a new contribution to diagnostics]

The Hospital Council has now issued a Diagnostic Compass besides the Pharmacotherapeutic Compass. Its objective is to contribute to a more rational and effective use of diagnostic examinations. The target group comprises physicians involved in using diagnostic tests. The information supplied is based on results of scientific research and don current habits, standards and guidelines. The book has two different approaches: clinical pictures and diagnostic tests. The two volumes are intended to supplement one another.     

Measurement of contribution from intracellular cysteine to sulfate in phosphoadenosine phosphosulfate in rat ovarian granulosa cells

Synthesis of the large dermatan sulfate (DS) proteoglycan by rat ovarian granulosa cells was studied using metabolic radiolabel precursors in culture media with varying concentrations of environmental sulfate (20-800 microM) and cysteine (130 and 650 microM). Experiments using [3H]glucosamine and [35S]sulfate showed that the average size of the DS chains and the rate of DS proteoglycan synthesis were independent of the sulfate and cysteine concentrations in the medium. Experiments with [35S]cysteine were then used to determine the contribution that metabolic conversion of cysteine sulfur to sulfate makes to the 3'-phosphoadenosine 5'-phosphosulfate (PAPS) pool which provides the substrate for sulfoester formation in DS synthesis. When 35S in cysteine is metabolized into [35S]PAPS, the specific activity is reduced from that of the [35S]cysteine pool, by dilution with other sulfur sources such as extracellular sulfate, and this dilution factor directly reflects the contribution of cysteine to the PAPS pool. The decreases of 35S specific activity were measured under various sulfate-depleted and cysteine-supplemented conditions by comparing the specific activity of [35S]sulfate ester in the DS chains with that of [35S]cysteine residues in the core protein of the DS proteoglycan. The contribution of sulfur in cysteine to the intracellular PAPS pool was 0.03% in culture medium with normal sulfate (800 microM). Depleted environmental sulfate (20 microM) and increased cysteine supply (650 microM) only increased the sulfur contribution from cysteine to PAPS up to 0.74 and 1.5%, respectively, even though the DS chains were greatly undersulfated (55 and 82% of the control value). Thus, the source of sulfur in the intracellular pool of PAPS was mainly derived from environmental sulfate, and the contribution from cysteine was minimal in these cells.