An 8-gene mRNA expression profile in circulating tumor cells predicts response to aromatase inhibitors in metastatic breast cancer patients

Background: Molecular characterization of circulating tumor cells (CTC) is promising for personalized medicine. We aimed to identify a CTC gene expression profile predicting outcome to first-line aromatase inhibitors in metastatic breast cancer (MBC) patients. Methods: CTCs were isolated from 78 MBC patients before treatment start. mRNA expression levels of 96 genes were measured by quantitative reverse transcriptase polymerase chain reaction. After applying predefined exclusion criteria based on lack of sufficient RNA quality and/or quantity, the data from 45 patients were used to construct a gene expression profile to predict poor responding patients, defined as disease progression or death <9 months, by a leave-one-out cross validation. Results: Of the 45 patients, 19 were clinically classified as poor responders. To identify them, the 75 % most variable genes were used to select genes differentially expressed between good and poor responders. An 8-gene CTC predictor was significantly associated with outcome (Hazard Ratio [HR] 4.40, 95 % Confidence Interval [CI]: 2.17-8.92, P < 0.001). This predictor identified poor responding patients with a sensitivity of 63 % and a positive predictive value of 75 %, while good responding patients were correctly predicted in 85 % of the cases. In multivariate Cox regression analysis, including CTC count at baseline, the 8-gene CTC predictor was the only factor independently associated with outcome (HR 4.59 [95 % CI: 2.11-9.56], P < 0.001). This 8-gene signature was not associated with outcome in a group of 71 MBC patients treated with systemic treatments other than AI. Conclusions: An 8-gene CTC predictor was identified which discriminates good and poor outcome to first-line aromatase inhibitors in MBC patients. Although results need to be validated, this study underscores the potential of molecular characterization of CTCs

History of Anvers-Hugo Trough, western Antarctic Peninsula shelf, since the Last Glacial Maximum. Part I: Deglacial history based on new sedimentological and chronological data

Reconstructing the advance and retreat of past ice sheets provides important long-term context for recent change(s) and enables us to better understand ice sheet responses to forcing mechanisms and external boundary conditions that regulate grounding line retreat. This study applies various radiocarbon dating techniques, guided by a detailed sedimentological analyses, to reconstruct the glacial history of Anvers-Hugo Trough (AHT), one of the largest bathymetric troughs on the western Antarctic Peninsula (WAP) shelf. Existing records from AHT indicate that the expanded Antarctic Peninsula Ice Sheet (APIS) advanced to, or close to, the continental shelf edge during the Last Glacial Maximum (LGM; 23-19 cal kyr BP [ = calibrated kiloyears before present]), with deglaciation of the outer shelf after ∼16.3 cal kyr BP. Our new chronological data show that the APIS had retreated to the middle shelf by ∼15.7 cal kyr BP. Over this 600-year interval, two large grounding-zone wedges (GZW) were deposited across the middle (GZW2) and inner shelf (GZW3), suggesting that their formation occurred on centennial rather than millennial timescales. Expanded sequences of sub-ice shelf sediments occur seaward of the inner GZW3, which suggests that the grounding line remained stationary for a prolonged period over the middle shelf. Grounding-line retreat rates indicate faster retreat across the outer to middle shelf compared to retreat across the middle to inner shelf. We suggest that variable retreat rates relate to the broad-scale morphology of the trough, which is characterised by a relatively smooth, retrograde seabed on the outer to middle shelf and rugged morphology with a locally landward shallowing bed and deep basin on the inner shelf. A slowdown in retreat rate could also have been promoted by convergent ice flow over the inner shelf and the availability of pinning points associated with bathymetric highs around Anvers Island and Hugo Island

Anvers-Hugo Trough palaeo-ice stream, Antarctic Peninsula: geomorphological evidence for the role of subglacial water in facilitating ice stream flow

We will present new multibeam bathymetry data that make the Anvers-Hugo Trough west of the Antarctic Peninsula one of the most completely surveyed palaeo-ice stream pathways in Antarctica. We interpret landforms revealed by these data as indicating that subglacial water availability played an important role in facilitating ice stream flow in the trough during late Quaternary glacial periods. Specifically, we observe a set of northward-shoaling valleys that are eroded into the upstream edge of a sedimentary basin, extend northwards from a zone containing landforms typical of erosion by subglacial water flow, and coincide spatially with the onset of mega-scale glacial lineations. Water was likely supplied to the ice stream bed episodically as a result of outbursts from a subglacial lake previously hypothesized to have been located in the Palmer Deep basin on the inner continental shelf. In a palaeo-ice stream confluence area, close juxtaposition of mega-scale glacial lineations with landforms that are characteristic of slow, dry-based ice flow, suggests that water availability was also an important control on the lateral extent of these palaeo-ice streams. These interpretations are consistent with the hypothesis that subglacial lakes or areas of elevated geothermal heat flux play a critical role in the onset of many large ice streams. The interpretations also have implications for the dynamic behaviour of the Anvers-Hugo Trough palaeo-ice stream and, potentially, of several other Antarctic palaeo-ice streams. Keywords: multibeam bathymetry, ice stream, subglacial water, landfor

History of the Anvers-Hugo Trough, western Antarctic Peninsula shelf, since the Last Glacial Maximum. Part II: Palaeo-productivity and palaeoceanographic changes during the Last Glacial Transition

Following the Last Glacial Maximum (LGM; ca. 23-19 calibrated [cal.] kyr before present [BP]), atmospheric and oceanic warming, together with global sea-level rise, drove widespread deglaciation of the Antarctic Ice Sheet, increasing the flux of freshwater to the ocean and leading to substantial changes in marine biological productivity. On the Antarctic continental shelf, periods of elevated biological productivity, often preserved in the sediment record as laminated (and sometimes varved) diatomaceous oozes (LDO), have been reported from several locations and are typically associated with the formation of calving bay re-entrants during ice sheet retreat. Understanding what drives the formation and deposition of LDOs, and the impact of deglacial processes on biogenic productivity more generally, can help inform how Antarctic coastal environments will respond to current and future ice sheet melting. In this study we utilise a suite of sediment cores recovered from Anvers-Hugo Trough (AHT), western Antarctic Peninsula shelf, which documents the transition from subglacial to glacimarine conditions following retreat of an expanded ice stream after the LGM. We present quantitative absolute diatom abundance (ADA) and species assemblage data, to investigate changes in biological productivity during the Last Glacial Transition (19-11 cal kyr BP). In combination with radiocarbon dating, we show that seasonally open marine conditions were established on the mid-shelf by 13.6 cal kyr BP, but LDOs did not start to accumulate until ∼11.5 cal kyr BP. The ∼1.4 kyr delay between the onset of seasonally open marine conditions and LDO deposition indicates that physiographic changes, and specifically the establishment of a calving bay in AHT, is insufficient to explain LDO deposition alone. LDO deposition in AHT coincides with the early Holocene climatic optimum (∼11.5 – 9.0 kyr) and is therefore explained in terms of increased atmospheric/ocean temperatures, high rates of sea and glacial ice melt and the formation of a well-stratified water column in the austral spring. An implication of our study is that extensive bathymetric mapping in conjunction with detailed core analyses is required to reliably infer environmental controls on LDO deposition