An international reproducibility study validating quantitative determination of ERBB2, ESR1, PGR, and MKI67 mRNA in breast cancer using MammaTyper (R)

Background: Accurate determination of the predictive markers human epidermal growth factor receptor 2 (HER2/ERBB2), estrogen receptor (ER/ESR1), progesterone receptor (PgR/PGR), and marker of proliferation Ki67 (MKI67) is indispensable for therapeutic decision making in early breast cancer. In this multicenter prospective study, we addressed the issue of inter- and intrasite reproducibility using the recently developed reverse transcription-quantitative real-time polymerase chain reaction-based MammaTyper (R) test. Methods: Ten international pathology institutions participated in this study and determined messenger RNA expression levels of ERBB2, ESR1, PGR, and MKI67 in both centrally and locally extracted RNA from formalin-fixed, paraffin-embedded breast cancer specimens with the MammaTyper (R) test. Samples were measured repeatedly on different days within the local laboratories, and reproducibility was assessed by means of variance component analysis, Fleiss' kappa statistics, and interclass correlation coefficients (ICCs). Results: Total variations in measurements of centrally and locally prepared RNA extracts were comparable; therefore, statistical analyses were performed on the complete dataset. Intersite reproducibility showed total SDs between 0.21 and 0.44 for the quantitative single-marker assessments, resulting in ICC values of 0.980-0.998, demonstrating excellent agreement of quantitative measurements. Also, the reproducibility of binary single-marker results (positive/negative), as well as the molecular subtype agreement, was almost perfect with kappa values ranging from 0.90 to 1.00. Conclusions: On the basis of these data, the MammaTyper (R) has the potential to substantially improve the current standards of breast cancer diagnostics by providing a highly precise and reproducible quantitative assessment of the established breast cancer biomarkers and molecular subtypes in a decentralized workup.Peer reviewe

Low-temperature exchange coupling between Fe[sub 2]O[sub 3] and FeTiO[sub 3]: Insight into the mechanism of giant exchange bias in a natural nanoscale intergrowth

Exchange bias 1 T at 10 K has been observed in natural sample of Fe2O3 containing abundant nanoscale exsolution lamellae of FeTiO3. Exchange bias is first observed below the Néel temperature of FeTiO3 55 K. Possible interface magnetic structures are explored within the framework of a classical Heisenberg model using Monte Carlo simulations. The simulations predict a threshold value of the Fe2O3 anisotropy constant, below which Fe3+ spins become tilted out of the basal plane in the vicinity of the interfaces. This tilting creates a c-axis component of magnetization in the Fe2O3 host that couples to the c-axis magnetization of the FeTiO3 lamellae. Exchange interactions across the interfaces are frustrated when the FeTiO3 lamellae contain an even number of Fe2+ layers, resulting in zero net exchange bias. Lamellae containing an odd number of Fe2+ layers, however, are negatively exchange coupled to the Fe2O3 host across both 001 bounding surfaces, and are the dominant source of exchange bias. Exchange bias is observed whenever there is a significant c-axis component to both the Fe2O3 magnetization and the applied field. An exchange bias of 0.9 T was obtained with an anisotropy constant of 0.1 K

The application of Lorentz transmission electron microscopy to the study of lamellar magnetism in hematite-ilmenite

Lorentz transmission electron microscopy has been used to study fine-scale exsolution microstructures in ilmenite-hematite, as part of a wider investigation of the lamellar magnetism hypothesis. Pronounced asymmetric contrast is visible in out-of-focus Lorentz images of ilmenite lamellae in hematite. The likelihood that lamellar magnetism may be responsible for this contrast is assessed using simulations that incorporate interfacial magnetic moments on the (001) basal planes of hematite and ilmenite. The simulations suggest qualitatively that the asymmetric contrast is magnetic in origin. However, the magnitude of the experimental contrast is higher than that in the simulations, suggesting that an alternative origin for the observed asymmetry cannot be ruled out. Electron tomography was used to show that the lamellae have lens-like shapes and that (001) planes make up a significant proportion of the interfacial surface that they share with their host