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.     

Potentiation of tumour necrosis factor-mediated cell killing by VP16 on human ovarian cancer cell lines. In vitro results and clinical implications

Synergism between recombinant human tumour necrosis factor (rHuTNF) and DNA topoisomerase II inhibitor VP16 during the killing of cells has been studied in six human ovarian cancer cell lines (A2774, A2780, SW626, IGROV-1, SKOV3, Pa1) and a cervical carcinoma cell line (Me180). Studies were performed using an assay of colony formation inhibition (drug treatment for 1 h) and a growth inhibition assay (continuous exposure for 20 h). Concomitant treatment of cells with VP16+rHuTNF enhanced cell killing in all the cell lines tested--an effect observed in both short- and long-term cytotoxicity assays. This study suggests that the activity of VP16 in ovarian cancer cell lines might be enhanced by rHuTNF in in vitro models.     

A neural network that predicts psychiatric length of stay

One hundred and twelve bilateral thyroidectomies for solitary thyroid nodules with suspected malignancy were performed. The incidence of malignancy in the 112 primary nodules was 42%. Twenty-nine of the 112 contralateral lobes (26%) contained malignancy, which was unsuspected in 80%. Of these 29, 20 were foci of papillary cancer < or = 5 mm and 9 were larger papillary tumors or follicular carcinoma. We analyzed these 112 patients to determine whether there was a simple method to identify those patients at risk for contralateral, unsuspected malignancy. With use of the AMES clinical staging retrospectively, 70 of the 112 patients were classified as having low-stage disease. Fifty percent (35) had cancers on the primary side and 27% (19) on the contralateral side. Of these 19 contralateral cancers, 14 were papillary cancers < or = 5 mm, 4 were papillary cancer > 5 mm and one was a 1.5 cm follicular carcinoma, a similar distribution as in the whole group of 112. When the AMES analysis then excluded those thought to be at risk for multicentricity or papillary carcinoma and examined female patients only with nonpapillary frozen sections, nonpapillary aspiration cytological results, and no history of radiation exposure, no further reduction in the proportion of contralateral cancers (7 of 26, 27%) was found. Fifty-five of the 112 patients underwent preoperative ultrasound scans. In those cases in whom the contralateral lobe had no intraoperative palpable or preoperative sonographic mass, 5 of 20 still had contralateral cancers, but all were papillary < or = 5 mm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary sternal osteomyelitis presenting as a pleural-based mass

Osteomyelitis in uncommon locations can present unusual diagnostic difficulties. A patient with primary sternal osteomyelitis who presented with pain over the right supraclavicular area and a radiologic picture of a pleural-based right upper lung mass is discussed. A triple-phase bone scan was consistent with the diagnosis, and a needle aspiration of the mass revealed a staphylococcal abscess. Percutaneous drainage of the contiguous abscess and a prolonged course of antibiotic therapy cured the infection.     

岩心PI值试验研究及应用

主要论述了在多功能采油化学用剂评价仪上进行的岩心ＰＩ值试验的步骤，现象及结论。重点考察了岩心ＰＩ值与渗透率、流量及注入截面面积的关系；平行管岩心复合ＰＩ值和其中单管岩心ＰＩ值的关系。     

Preexercise meal composition alters plasma large neutral amino acid responses during exercise and recovery

This study was designed to determine metabolic and physical performance responses to ingestion of pre-exercise meals with different macronutrient and fiber profiles. Twelve physically active subjects (6 males and 6 females) were used to investigate the metabolic and physical performance consequences of consuming pre-exercise meals consisting of oat, corn, or wheat cereals. A fasting trial served as the control, and all subjects received each treatment in a Latin-square design. Blood samples were drawn before and 85 min after meal ingestion, during 90 min of cycling exercise (60% VO2peak), after a 6.4 km performance ride, and during 60 min of recovery. Expired air samples were collected to determine nutrient utilization. Resting carbohydrate oxidation rates and plasma insulin concentrations after oat ingestion were less than after wheat, and corn and wheat ingestion, respectively (P < 0.05). During exercise, the change in plasma glucose from pre-exercise was greater after consuming wheat and corn compared with oat (P < 0.05), and it was inversely related to pre-exercise plasma insulin concentration (r = -0.55, P = 0.0001). Plasma free fatty acid concentrations were inversely related to plasma lactate concentrations (r = -0.58, P = 0.0001). Free fatty acid concentrations and fat oxidation were greater in fasting trials than all others, but performance ride times did not differ among treatments. Plasma branched-chain amino acid concentrations resembled their respective meal profiles throughout exercise, the performance ride, and recovery. These results indicate that pre-exercise meal composition can influence glucose homeostasis during early exercise and plasma branched-chain amino acid concentrations over a substantial range of metabolic demands.     

Carbachol can potentiate N-methyl-D-aspartate responses in the rat hippocampus by a staurosporine and thapsigargin-insensitive mechanism

Experiments were performed to investigate the mechanism underlying the potentiation of N-methyl-D-aspartate (NMDA) responses by carbachol (CCh) in the CA1 region of rat hippocampal slices. CCh (300 nM) potentiated responses to NMDA, but not to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), in a readily reversible manner. Potentiation occurred in slices treated with 200 nM tetrodotoxin and perfused with Mg(2+)-free medium. It also occurred in slices treated with either staurosporine (1 microM), which is a potent inhibitor of a variety of protein kinases including protein kinase C (PKC), or thapsigargin (10 microM), which depletes intracellular Ca2+ stores by preventing their refilling. However, CCh-induced potentiation was abolished in slices perfused with Ca(2+)-free medium. These data suggest that low concentrations of CCh can acutely potentiate NMDA responses in the hippocampus by a Ca(2+)-sensitive process that is probably independent of both the activation of PKC and the release of Ca2+ from intracellular stores. This mechanism is similar to that underlying the potentiation of NMDA responses by the metabotropic glutamate receptor (mGluR) agonist, aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD).     

Repair of DNA methylphosphotriesters through a metalloactivated cysteine nucleophile

The Escherichia coli Ada protein repairs methylphosphotriesters in DNA by direct, irreversible methyl transfer to one of its own cysteines. Upon methyl transfer, Ada acquires the ability to bind specific DNA sequences and thereby to induce genes that confer resistance to methylating agents. The amino-terminal domain of Ada, which comprises the methylphosphotriester repair and sequence-specific DNA binding elements, contains a tightly bound zinc ion. Analysis of the zinc binding site by cadmium-113 nuclear magnetic resonance and site-directed mutagenesis revealed that zinc participates in the autocatalytic activation of the active site cysteine and may also function as a conformational switch.