Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis

HER2 (erbB2/neu) is a member of the erbB family of receptor tyrosine kinases and is involved in regulating the growth of several types of human carcinomas. HER2 represents a successful therapeutic target of the biotechnology era as exemplified by the drug Herceptin (trastuzumab), which has clinical activity in a subset of breast cancer patients. Using DNA microarrays, we identified a cohort of genes that are differentially regulated by HER2 in breast epithelial cells. One of the HER2-regulated genes discovered was fatty acid synthase (FAS), which has been shown to be overexpressed in breast cancer as well as other cancers. FAS is implicated in tumorigenesis through its role in cell proliferation and membrane lipid incorporation of neoplastic cells. Here, we demonstrate that HER2-mediated induction of FAS is inhibitable by Herceptin and tyrosine kinase inhibitors of HER2. Through a phosphatidylinositol 3'-kinase-dependent pathway, HER2 stimulates the FAS promoter and ultimately mediates increased fatty acid synthesis. Interestingly, pharmacological inhibition of FAS preferentially induced apoptosis of HER2-overexpressing breast epithelial cells relative to matched vector control cells. These studies characterize a molecular connection between two genes individually implicated in tumorigenesis but never linked together.     

Analyzing data in which the outcome is time to an event part II: The presence of multiple covariates

In this article, the second of a series on the analysis of time to event data, we address the case in which multiple predictors (covariates) that may influence the time to an event are taken into account. The hazard function is introduced, and is given in a form useful for assessing the impact of multiple covariates on time to an event. Methods for the assessment of model fitting are also discussed and an example with cancer survival as outcome with the presence or absence of multiple genes as covariates is presented.     

Pregnancy and birth complications in patients with schizophrenia in Trinidad and London

It has been shown that an excess of pregnancy and birth complications (PBCs) does not contribute to the excess rates of schizophrenia reported for the population of Caribbean origin in Britain compared with the native Caucasian British population. We therefore attempted to compare the rate of PBCs between a sample of schizophrenics in Britain with that of a sample from Trinidad where some of the Caribbean migrants to Britain originated. First contact patients with schizophrenia according to the CATEGO system diagnosis were identified in Trinidad and London. Their mothers, where available, were interviewed using the Lewis-Murray scale for pregnancy and birth complications. Data from Trinidad and Tobago concerning 56 patients were compared with those of the Caucasian (n = 61) and African-Caribbean (n = 50) patients in London. The rate of PBCs was similar for the Caucasian British patients (24.6%) and the patients in Trinidad and Tobago (21.7%). The rates were lowest in the African-Caribbean patients in London (14.0%), though this difference was not statistically significant. These findings suggest that pregnancy and birth complications are a risk factor for a substantial minority of patients with schizophrenia in Trinidad and London. It also confirms that the excess rates of schizophrenia reported for the Caribbean population in Britain are not due to these complications.     

Regulation of Cytochrome P4501A Metabolism by Glutathione

Abstract: Gene expression of cytochrome P4501A (CYP1A) in the rainbow trout Oncorhynchus mykiss is dependent on aromatic hydrocarbon receptor signal transduction, and is markedly sensitive to tissue thiol status. Tissue glutathione (GSH) status was manipulated by exogenous GSH, L-buthionine-[S, R]-sulfoximine (BSO), lipoate or 1, 3-bis(2-chloroe-thyl)-1-nitrosourea (BCNU). Tissue GSH contents were significantly elevated in GSH- and lipoate-supplemented trout. Hepatic, renal and plasma GSH levels were markedly arrested in BSO-treated trout. Oxidized glutathione (oxidized GSH) levels were significantly elevated in the BCNU-supplemented group. Both BCNU treatment and BSO-induced GSH deficiency increased steady-state levels of hepatic CYP1A mRNA. Additional exposure to 0.1 mg/kg 3, 3′, 4, 4′-tetrachloro-biphenyl marginally suppressed the tetrachlorobiphenyl-dependent CYP1A induction in BSO-treated livers compared with the respective thiol treatment groups. Tetrachlorobiphenyl exposures altered efficiencies of thiol treatments and increased oxidized GSH content in all but the BSO-treated groups. However, exposure to 5 mg/kg tetrachlorobiphenyl altered effects of thiol treatments on CYP1A mRNA to a small extent, but catalytic activity of CYP1A was many times suppressed in BSO-treated and lipoate-supplemented fish. These results suggest that thiol status interferes with CYP1A metabolism in a two-way mode of action and provide further evidence for a cross-talk between cytochrome P4501A and glutathione.     

Emergency video-assisted thoracoscopic foreign body removal and decortication of lung after chest trauma

Video-assisted thoracoscopy can be a useful tool in selected chest trauma patients for diagnostic and therapeutic purposes. A metallic foreign body, embedded in peripheral lung parenchyma, was removed successfully with blood clot evacuation and limited decortication of lung in a hemodynamically stable 10-year-old patient using a video-assisted thoracoscopic technique.     

Hepatoprotective effects of Wedelia calendulacea

The alcoholic extract of whole plant Wedelia calendulacea exhibited protective activity against carbon tetrachloride-induced liver injury in vivo. The extract also increased the bile flow in rats suggesting a stimulation of liver secretory capacity. The minimum lethal dose was greater than 200 mg/kg p.o. in mice.     

Diagnostic accuracy of extended biopsies for the staging of microfocal prostate cancers in autopsy specimen

Clinically insignificant prostate cancers may be predicted when biopsies show a microfocal cancer (MiFC). However, at least one-third of MiFC are underestimated by biopsies. The aim of this study was to evaluate the staging accuracy of different biopsy regimen showing a MiFC. We performed 18 biopsy cores on 164 autopsy prostates. Six cores were taken from the mid-peripheral zone (MPZ), 6 from the lateral PZ (LPZ) and 6 from the central zone (CZ). We tested seven different biopsy regimens by distinguishing the MPZ, LPZ or CZ biopsies either separately or associated with each other. Of the cancers detected by biopsies, we selected those showing a MiFC and compared our findings with whole mount analysis. The positive predictive value of a MiFC referred to how often, when needle biopsies showed a MiFC, there was a clinically insignificant cancer on whole mount prostate analysis. We found that the positive predictive value of a MiFC on 6 or 12 biopsy cores was similar irrespective of biopsy location (P approximately 1). On MPZ, MPZ plus LPZ and all 18 biopsies, it was 40, 70 and 87%, respectively (P<0.1). Tumor volume of cancers showing a MiFC on MPZ biopsies was significantly higher than those showing a MiFC on MPZ plus LPZ, or all 18 biopsies (P<0.05). These results show that performing additional cores in case of MiFC on sextant biopsies may help differentiating significant from insignificant cancers.