Grain Growth in Thin Films with a Fibre Texture Studied by Phase-Field Simulations and Mean Field Modelling

The evolution of fiber textured structures is simulated in 2 dimensions using a generalized phase field model assuming two forms for the misorientation, a steady-state regime is reached after a finite amount of grain growth, where the numer and length weighted misorientation distribution functions (MDF) are constant in time, and the mean grain area A as a function of time t follows a power growth law A - A0 = kt^n with n close to 1 and A0 the initial mean grain area. The final shape of the MDF and value of the prefactor k in the power growth law clearly correlate with the misorientation dependence of the grain boundary energy. From a quantitative point of view, the fraction of special boundaries obtained in simulations is quite sensitive to the number of possible discrete orientations. Furthermore, a mean field approach is worked out to predict the growth exponent for systems with nonuniform grain boundary energy. The conclusions from the mean field approach are consistent with the simulation results.Physic

HER-2/neu Testing and Therapy in Gastroesophageal Adenocarcinoma

Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy

A phase-field simulation study of irregular grain boundary migration during recrystallization

We present simulation results based on a phase-field model that describes the migration of recrystallization boundaries into spatially varying deformation energy fields. Energy fields with 2-dimensional variations representing 2 sets of dislocation boundaries lying at equal, but opposite, angles to the moving boundary are considered. The simulations show that the shape and overall migration rate of the recrystallization front is considerably affected by spatial variations in the deformation microstructure. It is seen that, depending on characteristics of the variations in the deformation microstructure, highly asymmetrical protrusions and retrusions can develop on the migrating recrystallization front resulting in a migration velocity considerably larger than that expected from standard recrystallization models. It is also seen that, when the wavelength of the variations in a deformation microstructure along the grain boundary is larger than the wavelength of the variations in the direction of migration, parts of the boundary show a stop-and-go type of migration, resulting in a lower overall migration rate. These simulations thus reproduce and explain many of the typical features observed in recrystallization experiments. They give new insights in the way deformation microstructures can affect the migration behavior of recrystallization boundaries and can lead to a stop-and-go type of migration of the recrystallization boundary even in pure materials.status: publishe

Low frequency of HER2 amplification and overexpression in early onset gastric cancer

BACKGROUND: The recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques. METHODS: Tissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen). RESULTS: Overall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p = 0.085 and p = 0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p = 0.181 and p = 0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p = 0.029). A similar association was seen for HER2 IHC and histologic type (p = 0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type. CONCLUSIONS: Even focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression

Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. Although DCIS is generally highly curable, some women with DCIS will develop life-threatening invasive breast cancer, but the determinants of progression to infiltrating ductal cancer (IDC) are largely unknown. In the current study, we used multiplex ligation-dependent probe amplification (MLPA), a multiplex PCR-based test, to compare copy numbers of 21 breast cancer related genes between laser-microdissected DCIS and adjacent IDC lesions in 39 patients. Genes included in this study were ESR1, EGFR, FGFR1, ADAM9, IKBKB, PRDM14, MTDH, MYC, CCND1, EMSY, CDH1, TRAF4, CPD, MED1, HER2, CDC6, TOP2A, MAPT, BIRC5, CCNE1 and AURKA

Phase-field simulation study of the migration of recrystallization boundaries

We present simulation results based on a phase-field model that describes the local migration of recrystallization boundaries into varying deformation energy fields. An important finding from the simulations is that the overall migration rate of the recrystallization front can be considerably affected by the variations in the deformed microstructure, resulting in two regimes. For variations with low amplitude, the overall boundary velocity scales with the average stored deformation energy density. This behavior is in agreement with generally accepted theories of recrystallization. For larger amplitudes, however, the velocity scales with the maximum of the deformation energy density along the variation, resulting in a considerably larger velocity than that obtained from standard recrystallization models. The shape of the migrating grain boundary greatly depends on the local characteristics of the varying stored deformation energy field. For different deformation energy fields, the simulation results are in good qualitative agreement with experiments and add information which cannot be directly derived from experiments.status: publishe

Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer

<p>Aims: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1α (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.</p> <p>Methods and Results: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1α, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ERα, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1α and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ERα and c-Met in a HIF-1α dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1α.</p> <p>Conclusions: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1α and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.</p&gt