BRCA1 - A good predictive marker of drug sensitivity in breast cancer treatment?

There are currently only two predictive markers of response to chemotherapy for breast cancer in routine clinical use, namely the Estrogen receptor-alpha and the HER2 receptor. The breast and ovarian cancer susceptibility gene BRCA1 is an important genetic factor in hereditary breast and ovarian cancer and there is increasing evidence of an important role for BRCA1 in the sporadic forms of both cancer types. Our group and numerous others have shown in both preclinical and clinical studies that BRCA1 is an important determinant of chemotherapy responses in breast cancer. In this review we will outline the current understanding of the role of BRCA1 as a determinant of response to DNA damaging and microtubule damaging chemotherapy. We will then discuss how the known functions of this multifaceted protein may provide mechanistic explanations for its role in chemotherapy responses. (c) 2006 Elsevier B.V. All rights reserved.

Transmission and Trapping of Cold Electrons in Water Ice

Experiments are reported which show that currents of low energy ("cold") electrons pass unattenuated through crystalline ice at 135 K for energies between zero and 650 meV, up to the maximum studied film thickness of 430 bilayers, indicating negligible apparent trapping. By contrast, both porous amorphous ice and compact crystalline ice at 40 K show efficient electron trapping. Ice at intermediate temperatures reveals metastable trapping that decays within a few hundred seconds at 110 K. Our results are the first to demonstrate full transmission of cold electrons in high temperature water ice and the phenomenon of temperature-dependent trapping.

Web crippling behaviour of cold-formed steel channel sections with offset web holes subjected to interior-two-flange loading

Cold-formed steel sections are often used as wall studs or floor joists; such sections often include web holes for ease of installation of the services. Cold-formed steel design codes, however, do not consider the effect of such web holes. In this paper, a combination of experimental tests and non-linear elasto-plastic finite element analyses are used to investigate the effect of such holes on web crippling under interior-two-flange (ITF) loading conditions; the cases of both flange fastened and flange unfastened are considered. A good agreement between the experimental tests and finite element analyses was obtained. The finite element model was then used for the purposes of a parametric study on the effect of different sizes and position of holes in the web. It was demonstrated that the main factors influencing the web crippling strength are the ratio of the hole depth to the depth of the web, and the ratio of the distance from the edge of the bearing to the flat depth of web. Design recommendations in the form of web crippling strength reduction factors are proposed, that are conservative to both the experimental and finite element results.

Short Isoforms of the Cold Receptor TRPM8 Inhibit Channel Gating by Mimicking Heat Action Rather than Chemical Inhibitors

Transient receptor potential (TRP) channels couple various environmental factors to changes in membrane potential, calcium influx, and cell signaling. They also integrate multiple stimuli through their typically polymodal activation. Thus, although the TRPM8 channel has been extensively investigated as the major neuronal cold sensor, it is also regulated by various chemicals, as well as by several short channel isoforms. Mechanistic understanding of such complex regulation is facilitated by quantitative single-channel analysis. We have recently proposed a single-channel mechanism of TRPM8 regulation by voltage and temperature. Using this gating mechanism, we now investigate TRPM8 inhibition in cell-attached patches using HEK293 cells expressing TRPM8 alone or coexpressed with its short sM8-6 isoform. This is compared with inhibition by the chemicals N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) and clotrimazole or by elevated temperature. We found that within the seven-state single-channel gating mechanism, inhibition of TRPM8 by short sM8-6 isoforms closely resembles inhibition by increased temperature. In contrast, inhibition by BCTC and that by clotrimazole share a different set of common features. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Fasciola hepatica: Comparative effects of host resistance and parasite intra-specific interactions on size and reproductive histology in flukes from rats infected with isolates differing in triclabendazole sensitivity

The efficacies of putative fasciolicides and vaccines against Fasciola hepatica are frequently monitored in clinical and field trials by determination of fluke egg output in host faeces and by worm counts in the host liver at autopsy. Less often used are parameters based on fluke size and histology, yet these can provide important indications of specific effects on the development of particular germ-line or somatic tissues, especially in relation to the timing and profligacy of egg production. In this study. F. hepatica metacercariae of two distinct isolates, the triclabendazole (TCBZ)-sensitive Cullompton isolate and the TCBZ-resistant Oberon isolate, were administered to rats as single-isolate or mixed-isolate infections. At autopsy 16 weeks later individual adult flukes were counted, measured and the reproductive organs were examined histologically. The degree of development of the testis tubules in each fluke was represented by a numerical score, based on the proportion of the histological section profiles occupied by testis tissue. The level of anti-F. hepatica antibody in the serum of each rat was determined by ELISA. It was found that Cullompton flukes were significantly larger than Oberon flukes, and that significantly more Cullompton metacercariae developed to adults than Oberon metacercariae. The Cullompton flukes showed histological evidence of aspermy and spermatogenic arrest, which was reflected in quantitatively reduced testicular development, as compared with the Oberon isolate. In Cullompton flukes, parthenogenetic egg development is implied. The size of Cullompton and Oberon flukes was significantly related to the number of adult flukes recovered, to the number of metacercariae administered, and to the percentage success of infection. The testis development score in both isolates was significantly related to the number of adult flukes recovered but not to the number of metacercariae administered, or to the percentage success of infection. Fluke size was positively related to testis score for both isolates, and a significant negative relationship was found between percentage success of infection and metacercarial dose. The results are interpreted in terms of differing interactions between various numbers of young flukes and host immunity during invasion of and migration in the hepatic parenchyma, and of fluke intra-specific (possibly pheromonal) stimulatory effects in the final stages of development, within the host bile ducts. No significant relationships were found between host antibody levels and fluke size or testis score. False positive serological reactions were found in some rats that had been infected, but found to harbour no flukes at autopsy. Clearly the act of eliminating the flukes involved generation of an immune response. (C) 2011 Elsevier B.V. All rights reserved.

Effect of plasticizer viscosity on the sensitivity of an [RU(bpy)(3)(2+)(Ph4B-)(2)]-based optical oxygen sensor

The quenching of the electronically-excited, lumophoric state of [Ru(bpy)(3)(2+)(Ph4B-)(2)] by oxygen is studied in a wide variety of neat plasticizers. The Stern-Volmer constant, K-SV, is found to be inversely dependent upon the viscosity of the quenching medium, although the natural lifetime of the electronically excited state of [RU(bPY)(3)(2+)(Ph4B-)(2)] is largely independent of medium. The least viscous of the plasticizers tested, triethyl phosphate, did not, however, produce highly sensitive optical oxygen sensors when used to plasticize [RU(bPY)(3)(2+)(Ph4B-)(2)]-containing cellulose acetate butyrate (CAB) and poly(methyl methacrylate) (PMMA) films, Instead, the compatibility of the polymer-plasticizer combination, as measured by the difference in the values of the solubility parameter of the two, appears to be a major factor in determining the overall oxygen sensitivity of the thin plastic films. For highly compatible polymer-plasticizer combinations, the plasticizer with the lowest viscosity produces films of the highest oxygen sensitivity. This situation arises because in the film the quenching process is partly diffusion-controlled and, as a result, the quenching rate constant is inversely proportional to the effective viscosity of the reaction medium.