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

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei-like carbonaceous chondrite

The Mighei-like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine-grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse-grained primary components that are found directly alongside other coarse-grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

The Winchcombe meteorite – a regolith breccia from a rubble-pile CM chondrite asteroid

The Winchcombe meteorite is a CM chondrite breccia composed of eight distinct lithological units plus a cataclastic matrix. The degree of aqueous alteration varies between intensely altered CM2.0 and moderately altered CM2.6. Although no lithology dominates, three heavily altered rock types (CM2.1-2.3) represent >70 area%. Tochilinite-cronstedtite intergrowths (TCIs) are common in several lithologies. Their compositions can vary significantly, even within a single lithology, which can prevent a clear assessment of alteration extent if only TCI composition is considered. We suggest this is due to early alteration under localised geochemical microenvironments creating a diversity of compositions and because later reprocessing was incomplete, leaving a record of the parent body’s fluid history. In Winchcombe fragments of primary accretionary rock are held within a cataclastic matrix (~15 area%). This material is impact-derived fallback debris. Its grain size and texture suggest that the disruption of the original parent asteroid responded by intergranular fracture at grain sizes <100 µm, while larger phases, such as whole chondrules, splintered apart. Re-accretion formed a poorly lithified body. During atmospheric entry, the Winchcombe meteoroid broke apart with new fractures preferentially cutting through the weaker cataclastic matrix and separating the breccia into its component clasts. The strength of the cataclastic matrix imparts a control on the survival of CM chondrite meteoroids. Winchcombe’s unweathered state and diversity of lithologies makes it an ideal sample for exploring the geological history of the CM chondrite group.Additional authors: H. Mansour, S. Piazolo, T. Salge, R. Heard, R. Findlay, A. J. King, H. C. Bates, M. R. Lee, N. R. Stephen, F. M. Willcocks, R. C. Greenwood, I. A. Franchi, S. S. Russell, C. S. Harrison, P. F. Schofield, N. V. Almeida, C. Floyd, P.-E. Martin, K. H. Joy, P. J. Wozniakiewicz, D. Hallatt, M. J. Burchell, L. S. Alesbrook, V. Spathis, L. T. Cornwell, A. Digna

Raman identification of olivine grains in fine grained mineral assemblages fired into aerogel

NASA’s Stardust mission returned from the comet 81P/Wild2 in 2006 and has yielded a plethora of research looking into the composition and attributes of the comet. The mission itself collected thousands of cometary dust particles as it flew through the coma of the comet at a relative speed of 6.1 km s-1. This work focuses on one of the most abundant minerals in the solar system – olivine. Previous work has shown capture affects on this mineral in similar impacts to that experienced during the Stardust mission. However, the past work looked into effects on isolated mineral grains which would be a rare occurrence in the Solar System. A more accurate representation of this would be to investigate the capture effects on olivine as a constituent of an assemblage of minerals. Accordingly, here we used samples from the NWA 10256 CR2 carbonaceous chondrite meteorite. This natural sample contains fine grains of olivine, and brings additional issues when analysing the olivine due to limited homogeneity. Shifts in the Raman spectra for olivine, enstatite and hematite were observed after capture due to shock effects. However, this work suggests that olivine may well experience a different shock effect during capture when part of a mineral assemblage as distinct from that experienced by single grains

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

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Brecciation at the grain scale within the lithologies of the Winchcombe Mighei‐like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

Rhabdomyoblastic Differentiation in Head and Neck Malignancies Other Than Rhabdomyosarcoma

Rhabdomyosarcoma is a relatively common soft tissue sarcoma that frequently affects children and adolescents and may involve the head and neck. Rhabdomyosarcoma is defined by skeletal muscle differentiation which can be suggested by routine histology and confirmed by immunohistochemistry for the skeletal muscle-specific markers myogenin or myoD1. At the same time, it must be remembered that when it comes to head and neck malignancies, skeletal muscle differentiation is not limited to rhabdomyosarcoma. A lack of awareness of this phenomenon could lead to misdiagnosis and, subsequently, inappropriate therapeutic interventions. This review focuses on malignant neoplasms of the head and neck other than rhabdomyosarcoma that may exhibit rhabdomyoblastic differentiation, with an emphasis on strategies to resolve the diagnostic dilemmas these tumors may present. Axiomatically, no primary central nervous system tumors will be discussed.info:eu-repo/semantics/publishedVersio