Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

The status of epidermal growth factor receptor in borderline ovarian tumours

The majority of borderline ovarian tumours (BOTs) behave in a benign fashion, but some may show aggressive behavior. The reason behind this has not been elucidated. The epidermal growth factor receptor (EGFR) is known to contribute to cell survival signals as well as metastatic potential of some tumours. EGFR expression and gene status have not been thoroughly investigated in BOTs as it has in ovarian carcinomas. In this study we explore protein expression as well as gene mutations and amplifications of EGFR in BOTs in comparison to a subset of other epithelial ovarian tumours. We studied 85 tumours, including 61 BOTs, 10 low grade serous carcinomas (LGSCs), 9 high grade serous carcinomas (HGSCs) and 5 benign epithelial tumours. EGFR protein expression was studied using immunohistochemistry. Mutations were investigated by Sanger sequencing exons 18-21 of the tyrosine kinase domain of EGFR. Cases with comparatively higher protein expression were examined for gene amplification by chromogenic in situ hybridization. We also studied the tumours for KRAS and BRAF mutations. Immunohistochemistry results revealed both cytoplasmic and nuclear EGFR expression with variable degrees between tumours. The level of nuclear localization was relatively higher in BOTs and LGSCs as compared to HGSCs or benign tumours. The degree of nuclear expression of BOTs showed no significant difference from that in LGSCs (mean ranks 36.48, 33.05, respectively, p=0.625), but was significantly higher than in HGSCs (mean ranks: 38.88, 12.61 respectively, p<0.001) and benign tumours (mean ranks: 35.18, 13.00 respectively, p=0.010). Cytoplasmic expression level was higher in LGSCs. No EGFR gene mutations or amplification were identified, yet different polymorphisms were detected. Five different types of point mutations in the KRAS gene and the V600E BRAF mutation were detected exclusively in BOTs and LGSCs. Our study reports for the first time nuclear localization of EGFR in BOTs. The nuclear localization similarities between BOTs and LGSCs and not HGSCs support the hypothesis suggesting evolution of LGSCs from BOTs. We also confirm that EGFR mutations and amplifications are not molecular events in the pathogenesis of BOTs

A Comparative Study of Kinetics of Flotation of a Copper-Nickel Ore by N-Hydrocinnamoyl-N-Phenylhydroxylamine (HCNPHA) Vis-A-Vis Potassium Amyl Xanthate (PAX)

Flotation kinetics was studied for the flotation of Canad-ian nickel ore using N-hydrocinnamoyl- N-phenyl-hydrox-ylamine (HCNPHA) as the collector. The differential flotation between pentlandite and pyrrhotite of HCNPHA was compared by repeating the experiments with potassium amyl xanthate (PAX). However, the pH for the flotation was 9.0 and 9.5, respectively, for using HCNPHA or PAX as collec-tor. Time-recovery plots were fit using the modified first order rate equation for flotation kinetics, namely, 12, = ev"), and flotation rate constant and the cumulative recovery at time infinite (R,) were computed. HCNPHA was found to react with pentlandite slightly faster than PAX. However, HCNPHA was found to float more pyrrhotite and silica than PAX thus the grade of the concentrates were adversely affected

Breast-Lesion Characterization using Textural Features of Quantitative Ultrasound Parametric Maps

© 2017 The Author(s). This study evaluated, for the first time, the efficacy of quantitative ultrasound (QUS) spectral parametric maps in conjunction with texture-analysis techniques to differentiate non-invasively benign versus malignant breast lesions. Ultrasound B-mode images and radiofrequency data were acquired from 78 patients with suspicious breast lesions. QUS spectral-analysis techniques were performed on radiofrequency data to generate parametric maps of mid-band fit, spectral slope, spectral intercept, spacing among scatterers, average scatterer diameter, and average acoustic concentration. Texture-analysis techniques were applied to determine imaging biomarkers consisting of mean, contrast, correlation, energy and homogeneity features of parametric maps. These biomarkers were utilized to classify benign versus malignant lesions with leave-one-patient-out cross-validation. Results were compared to histopathology findings from biopsy specimens and radiology reports on MR images to evaluate the accuracy of technique. Among the biomarkers investigated, one mean-value parameter and 14 textural features demonstrated statistically significant differences (p < 0.05) between the two lesion types. A hybrid biomarker developed using a stepwise feature selection method could classify the legions with a sensitivity of 96%, a specificity of 84%, and an AUC of 0.97. Findings from this study pave the way towards adapting novel QUS-based frameworks for breast cancer screening and rapid diagnosis in clinic

Structure-Activity (Flotation) Relationship Modeling of Flotation of Sphalerite by N-Arylhydroxamic Acids

Molecular structure is known to play a vital role in the efficiency of chleating collectors in mineral flotation. Hence, flotation efficiencies of congeneric organic compounds used as mineral collectors are amenable to QSAR modeling. Sphalerite grade of the floats of a set of flotation tests conducted with a copper-zinc ore using a series of twenty seven Narylhydroxamic acids of the generic structure Ar-N(OH)C(=0)-R (R= arylialkyliaaralkyl) were modeled using calculated molecular descriptors such as, topochemical, topostructural, quantum chemical, and geometrical parameters. In addition to these molecular descriptors, calculated physicochemical properties such as octanol-water partition coefficient (ClogP), and orga-nic carbon-water partition coefficient (logKoe) were also used to build the regression models. The collectors were classified into C-aryl, C-alkyl, and C-aralkyl. Octanol-water partition coefficient (ClogP) was found to give the best quadratic fit for C-aryl, and the combined set of C-aralkyl and C-alkyl. It was interesting to note that the data for individual sets namely, C-alkyl, and C-aralkyl gave linear fits with positive and negative slopes, resp-ectively. This indicated that the points were distributed on the right hand and left hand sides of the parabola that fits the combined data set

Processing of fine size minerals : Studies on some Indian uranium ores

Conventionally uranium ores are processed by direct chemical leaching techniques. However, the application of chemical leaching for lean tenor and high tonnage uranium- ores is being desisted due to obvious environmental concerns. It is in this context that the physical benefi-ciation methods for the pre-concentration of uranium ores, if feasible, are gaining importance. Adoption of physical beneficiation helps in containing uranium and daughter nuclides in a smaller mass of pre-concentrate, which can be further subjected to conventional chemical processing, leaving bulk of the ore safe for disposal. In the application of physical beneficiation techniques, particle size plays a significant role. Both the economic mineral of uranium - uraninite and pitchblend, are brittle and report in very fine sizes during comminution, an oper-ation meant for their liberation.It is well established fact that concentration of particles finer than 25um by conventional physical beneficiation methods is very difficult due to the low mass and high surface area. However with the advent of new fine particle concentrators and techniques the situation has shown tremendous impr-ovement. This paper highlights the studies carried out on the use of both physical (gravity and magnetic) and physico-chemical beneficiation methods for recovering fine size uranium values from some low grade uranium bearing ores of India

Translational genomics of ovarian clear cell carcinoma.

Ovarian clear cell carcinomas (OCCC) are rare aggressive, chemo-resistant tumours comprising approximately 13% of all epithelial ovarian cancers, which have distinct clinical and molecular features, when compared to other gynaecological malignancies. At present, there are no specific licensed targeted therapies for OCCC, although a number of candidate targets have been identified. This review focuses on recent knowledge underpinning our understanding of the pathogenesis of OCCC including direct and synthetic-lethal therapeutic strategies in particular focussing on ARID1A deficiency. We also discuss current targeted clinical trials and immunotherapeutic approaches

Covalent attachment of active enzymes to upconversion phosphors allows ratiometric detection of substrates

Upconverting phosphors (UCPs) convert multiple low energy photons into higher energy emission via the process of photon upconversion and offer an attractive alternative to organic fluorophores for use as luminescent probes. Here, UCPs were capped with functionalized silica in order to provide a surface to covalently conjugate proteins with surface?accessible cysteines. Variants of green fluorescent protein (GFP) and the flavoenzyme pentaerythritol tetranitrate reductase (PETNR) were then attached via maleimide?thiol coupling in order to allow energy transfer from the UCP to the GFP or flavin cofactor of PETNR, respectively. PETNR retains its activity when coupled to the UCPs, which allows reversible detection of enzyme substrates via ratiometric sensing of the enzyme redox state