CDK4/6 inhibition in luminal breast cancer

Endocrine therapy represents the basis for the treatment of estrogen receptor-positive breast cancer, but several tumors harbor intrinsic resistance and acquired resistance to endocrine therapy is inevitable in metastatic disease. Combination strategies of endocrine therapy with targeted agents are aimed to overcome endocrine resistance. The selective CDK4/6 inhibitor palbociclib has shown promising results in metastatic luminal breast cancer when used in combination with endocrine therapy both in the first-line setting as in pretreated women. The drug showed a manageable safety profile with uncomplicated neutropenia as the most frequent side effect. Approval was already granted in the US and is also awaited during 2016 for Europe

Cardiovascular magnetic resonance:Diagnostic utility and specific considerations in the pediatric population

Cardiovascular magnetic resonance is a non-invasive imaging modality which is emerging as important tool for the investigation and management of pediatric cardiovascular disease. In this review we describe the key technical and practical differences between scanning children and adults, and highlight some important considerations that must be taken into account for this patient population. Using case examples commonly seen in clinical practice, we discuss the important clinical applications of cardiovascular magnetic resonance, and briefly highlight key future developments in this field

Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.453

Conductive TiC/Ti–Cu/C composites fabricated by Ti–Cu alloy reactive infiltration into 3D-printed carbon performs

The microstructure and electrical properties of dense TiC/Ti–Cu/C composites fabricated by pressureless reactive infiltration of Ti–Cu alloy into porous starch-derived carbon preforms prepared by 3D printing was evaluated. Porosities in the range of 65–78 vol% were varied by post-isostatic pressing the as-printed preforms at pressures of 50–400 MPa. The reactive melt infiltration was carried out at 1100℃ in a flowing Ar atmosphere and resulted in formation of a composite comprised predominantly of substoichiometric TiC, binary intermetallic Ti–Cu phases and residual carbon. Scanning electron microscopy analyses revealed a microstructure consisting of dispersed fine-grained TiC in a Ti–Cu matrix surrounded by a continuous carbon phase. Electrical resistivity measurements using the four-probe method were carried out and correlated to the composite microstructure. The electrical resistivity was evaluated in terms of carbon and TiC volume fractions

Crystallisation Kinetics of a β

LZSA (Li2O-ZrO2-SiO2-Al2O3) glass ceramic system has shown high potential to obtain LTCC laminate tapes at low sintering temperature (<1000°C) for several applications, such as screen-printed electronic components. Furthermore, LZSA glass ceramics offer interesting mechanical, chemical, and thermal properties, which make LZSA also a potential candidate for fabricating multilayered structures processed by Laminated Objects Manufacturing (LOM) technology. The crystallization kinetics of an LZSA glass ceramic with a composition of 16.9Li2O⋅5.0ZrO2⋅65.1SiO2⋅8.6Al2O3 was investigated using nonisothermal methods by differential thermal analysis and scanning electronic microscopy. Apparent activation energy for crystallization was found to be in the 274–292 kJ⋅mol−1 range, and an Avrami parameter n of 1 was obtained that is compared very favorably with SEM observations

The Effect of Ga-Ion Irradiation on Sub-Micron-Wavelength Spin Waves in Yttrium-Iron-Garnet Films

We investigate the effect of focused-ion-beam (FIB) irradiation on spin waves with sub-micron wavelengths in Yttrium-Iron-Garnet (YIG) films. Time-resolved scanning transmission X-ray (TR-STXM) microscopy was used to image the spin waves in irradiated regions and deduce corresponding changes in the magnetic parameters of the film. We find that the changes of Ga$^+$ irradiation can be understood by assuming a few percent change in the effective magnetization $M_\mathrm{eff}$ of the film due to a trade-off between changes in anisotropy and effective film thickness. Our results demonstrate that FIB irradiation can be used to locally alter the dispersion relation and the effective refractive index $n_\textrm{eff}$ of the film, even for submicron wavelengths. To achieve the same change in $n_\textrm{eff}$ for shorter wavelengths, a higher dose is required, but no significant deterioration of spin wave propagation length in the irradiated regions was observed, even at the highest applied doses.5 pages, 6 figure

DNA methylation signatures predicting bevacizumab efficacy in metastatic breast cancer

Background: Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Methods: Genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in archival FFPE specimens of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (learning set). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (>0.15 or <-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients (optimization set) and in 15 patients treated with chemotherapy alone (control set) using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the optimization set but not in the control set using Spearman rank correlation, Cox regression, and logrank test. Results: Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the optimization set, but not in the control set. Using information from the optimization set, the panel was reduced to a 9-gene signature, which could divide patients from the learning set into 2 clusters, thereby predicting response with an OR of 40 (p<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of predicted responders with longer PFS in the learning and optimization set even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Conclusion: Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab.(VLID)251037