Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo

The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.     

Paget's disease of the breast in a man without underlying breast carcinoma

A case of histologically confirmed Paget's disease of the breast in a 72 year old man, without underlying breast carcinoma, is reported. This report raises questions about the pathogenesis of this condition and suggests that Paget's disease is an independent, intraepidermal carcinoma rather than a direct extension of intraductal carcinoma of the breast to the nipple and areola.     

Successful pregnancies in the presence of spinal muscular atrophy: two case reports

We report two cases of successful pregnancy in women with chronic, infantile onset, or type II spinal muscular atrophy, both of whom delivered healthy, unaffected babies. The patients required concurrent management by a physiatrist, pulmonologist, and perinatologist throughout the pregnancy. Complications included recurrent urinary tract infections, dyspnea and worsening of pulmonary function, wheelchair seating and positioning problems, and musculoskeletal and low back pain. These problems resolved postpartum. One woman had vaginal delivery, the other had caesarean section, both of which were well-tolerated. Because of severe musculoskeletal deformity, pelvic assessment is necessary to determine the mode of delivery. The uterus has normal contractility and effective labor patterns can be established. Spinal/epidural anesthesia may be contraindicated because of spine deformity. The pregnancies had no deleterious effect on the progression of the disease in our patients, both of whom reported a positive experience with great personal fulfillment.     

Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro

The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.     

Neuropeptide Y and luteinizing hormone releasing hormone synergize to stimulate the development of cellular follicle-stimulating hormone in the hamster adenohypophysis

Luteinizing hormone releasing hormone (LHRH) stimulates the development of cellular FSH immunoreactivity in the perinatal hamster adenohypophysis. Because neuropeptide Y (NPY) can act directly on rat adenohypophysial cells to stimulate FSH and LH release and potentiate the stimulatory effect of LHRH on FSH and LH release, we investigated the effects of NPY alone and in combination with a low, ineffective dose of LHRH on inducing cellular FSH immunoreactivity in the neonatal hamster adenohypophysis. Neonatal female pituitary glands were grafted beneath the right renal capsules of hypophysectomized-ovariectomized adult hamster hosts with a catheter implanted in the external jugular vein. After treatment, hosts were decapitated and graft tissue was stained for FSH and LH immunoreactivity. The mean percentage of adenohypophysial cells that stained for FSH was low (2.8%) in grafts in hosts infused continuously with heparinized saline vehicle for 7 days. In other hosts, peptides were pulsed through the catheter every 12 h for 7 days. The mean percentage of FSH cells also was low after pulsing 6 ng LHRH or 2 micrograms NPY but increased substantially when the two peptides were pulsed simultaneously. No differences in the mean percentage of LH cells existed between any of the groups. The results demonstrate that NPY and LHRH can synergize to induce cellular FSH immunoreactivity in the neonatal female hamster.     

A survey on the occurrence of Fusarium mycotoxins in Bavarian cereals from the 1987 harvest

Summary Bavarian cereals and wheat flour from the 1987 harvest were analysed for nivalenol (NIV) and deoxynivalenol (DON) using high performance liquid chromatography (HPLC) and for T-2 toxin and zearalenone (ZEA) by enzyme-linked-immunosorbent as say (ELISA). The study included 190 field samples of wheat, barley, rye and oat with visibly damaged ears, 45 samples of wheat intended for feed production and two series of wheat flour (type 550) and whole wheat flour collected in October 1987 and June 1988. The field samples examined showed a high DON contamination of wheat (87%) with an average of 3.96 mg/kg and a maximum of 43.8 mg/kg. Mean levels between 0.33 mg/kg and 0.27 mg/kg DON could be detected in barley, rye and oat. Of the wheat samples, 58% contained ZEA with a maximum of 1.560 mg/kg. The highest levels of ZEA were detected in samples which also showed high concentrations of DON. The NIV and T-2 toxin levels were comparatively low. Thirty percent of the samples showed NIV concentrations between 0.04 mg/kg and 0.29 mg/kg and 38% contained between 0.005 and 0.60 mg/kg of T-2. In the wheat samples for feed production, only DON was detected with an average of 0.190 mg/kg and a maximum of 0.75 mg/kg. The highest DON levels (0.58 mg/kg) from October 1987 were found in the wheat flour samples which were lower than the highest DON concentration (3.24 mg/kg) detected in the samples collected during June 1988. This fact was probably due to a substantial amount of non-contaminated wheat from 1986. The toxin concentrations in the whole wheat flour were not higher than in the type 550 flour. The regional distribution of the mean DON concentrations showed the highest levels in Middle and Lower-Franconia.

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Vorkommen von Fusarium Mykotoxinen in bayerischem Getreide der Ernte 1987

Zusammenfassung Cerealien und Weizenmehle der bayerischen Ernte 1987 wurden mittels hochauflösender Flüssigchromatographie (HPLC) auf Nivalenol (NIV) und Deoxynivalenol (DON) Bowie mit Enzymimmunoassay auf T-2 Toxin und Zearalenon (ZEA) analysiert. Die Untersuchungen umfaßten 190 Feldproben von Weizen, Gerste, Roggen und Hafer, die alle optisch erkennbaren Fusarienbefall aufwiesen, 45 Futterweizenproben Bowie zwei Probenserien von Weizenmehlen der Type 550 und Vollkornweizenmehlen, die im October 1987 und im Juni 1988 gezogenwurden. — Die Untersuchungen der Feldproben ergaben eine hohe DON-Kontamination des Weizens (87%) mit einem durchschnittlichen Gehalt von 3,96 mg/kg und einem Maximalgehalt von 43,8 mg/kg. In Gerste, Roggen und Hafer konnten durchschnittlich zwischen 0,33 mg/kg und 0,27 mg/kg DON-nachgewiesen werden. 58% der Winterweizenproben wiesen Zearalenon mit einem Maximalgehalt von 1,56 mg/kg auf. Die höchsten ZEA-Werte wurden in Proben ermittelt, die gleichzeitig einen hohen DON-Gehalt aufwiesen. Die Konzentrationen von NIV und T-2 Toxin waren vergleichsweise niedrig. 30% der Proben hatten NIV-Gehalte zwischen 0,04 mg/kg und 0,29 mg/kg und 38% enthielten T-2 Toxin zwischen 0,005 mg/kg und 0,06 mg/kg. In den Futterweizenproben konnte DON als einziges Toxin mit einem Gehalt von durchschnittlich 0,19 mg/kg und maximal 0,75 mg/kg festgestellt werden. Die Weizenmehle, die im October 1987 gezogen wurden, wiesen maximal 0,58 mg/kg DON auf. Die Gehalte lagen damit medriger als die der Mehlproben vom Juni 1988, die maximal 3,24 mg/kg und durchschnittlich 0,26 mg/kg DON enthielten. Dieser Sachverhalt könnte auf Anteile von nicht kontaminiertem Weizen der Ernte 86 an den im October gezogenen Mehlproben zurückgeführt werden. Die Toxingehalte der Vollkornmehle waren nicht höher als die der Weizenmehle der Type 550. Die höchsten Durchschnittsgehalte von DON wurden in Mittel- und Unterfranken festgestellt.

     

Agricola und die Geologie

This paper on the occasion of the 500th birthday of the great Saxon humanistic scholar Georgius Agricola deals with his contributions to geology in the narrow sense. These, contrary to his voluminous works on mining, metallurgy and mineralogy (De re metallica and De natura fossilium, resp.) are parts of the booksDe ortu et causis subterraneorum andDe natura eorum, quae effluunt ex terra. In those we find statements on the causes of earthquakes, on volcanos and the subterranean fire as well as the effects of the running water in mountain-building. Agricola's ideas on geological time and his statements on dynamics of the Earth's crust are remarkable.