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.     

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.     

The relationship between bioelectrical impedance phase angle and subjective global assessment in advanced colorectal cancer

Background  

Bioelectrical Impedance (BIA) derived phase angle is increasingly being used as an objective indicator of nutritional status in advanced cancer. Subjective Global Assessment (SGA) is a subjective method of nutritional status. The objective of this study was to investigate the association between BIA derived phase angle and SGA in advanced colorectal cancer.     

Youth gambling behaviors: An examination of the role of resilience.

The study of resilient children has overturned many deficit-focused models concerning the ontogenesis of children raised in adversity. This study explored the relationship between risk and protective factors, resilience, and youth gambling behavior. More specifically, this study examined the relative contribution of various risk and protective domains in relation to problem gambling behavior and examined whether youth identified as resilient (high risk exposure- high internalized protection) were as likely as those identified as vulnerable (high risk exposure-low internalized protection) to engage in excessive gambling behavior. The sample consisted of 1,273 students ages 12 to 19. The findings demonstrated that risk and protective factors each provide a unique contribution to the prediction model of gambling problems. Resilient and vulnerable youth differed significantly in their self-reported gambling severity. As well, resilient youth were not statistically distinguishable from low-risk exposure groups in terms of their gambling severity. Findings are interpreted with respect to resilience and prevention research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In Situ Performance Testing of Deteriorating Water Tanks for Durability Assessment

Reports of failure of existing concrete structures due to a lack of durability, rather than a deficiency in structural strength, has made concrete technologists, engineers, and researchers focus research on the parameters influencing durability performance with respect to time. Systematic performance monitoring, with respect to chosen durability parameters of existing concrete structures, will decide the direction of future research in this area. Inferences based on laboratory simulations and testing need to be confirmed by in situ field measurements and studies. In situ condition rating and performance monitoring surveys have been conducted by many researchers, scientists, and professional associations, and reported in literature. Inferences of few such studies are summarized and discussed. Deterioration of concrete structures constructed in recent times is observed at relatively faster rates, and has been mainly attributed to cracking. Cracking is associated with the use of faster-hydrating portland cements with increased fineness and the tricalcium silicate (C3S) content to support the high speed of modern construction. In the present research, a case study of deteriorated water tank structures situated in the semitropical region of India is presented. Some selected parameters—such as concrete cover, carbonation depth, chloride concentration, compressive strength, etc. which influence long term durability of structures—have been measured.     

Effect of type of processing on the microstructural features and mechanical properties of Al-Cu/SiC metal matrix composites

In this study, an aluminum based metallic matrix (Al-2wt.% Cu) was reinforced with SiC particulates using a conventional casting technique and a new disintegrated melt deposition technique. Microstructural characterization studies conducted on the samples taken from disintegrated melt deposition technique revealed a more uniform distribution of SiC particulates and good interfacial integrity between SiC particulates and metallic matrix when compared to the conventionally cast composite samples. Results of ambient temperature mechanical tests demonstrate an increase in 0.2% YS and ultimate tensile strength of samples taken from disintegrated melt deposition technique when compared with the unreinforced and conventionally cast composite samples. The results of microstructural characterization and mechanical testing were finally rationalized in terms of the nature of processing technique employed to reinforce Al-2wt.% Cu metallic matrix with SiC particulates.