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Rates of ice-sheet grounding-line retreat can be quantified from the spacing of corrugation ridges on deglaciated regions of the seafloor1,2, providing a long-term context for the approximately 50-year satellite record of ice-sheet change3-5. However, the few existing examples of these landforms are restricted to small areas of the seafloor, limiting our understanding of future rates of grounding-line retreat and, hence, sea-level rise. Here we use bathymetric data to map more than 7,600 corrugation ridges across 30,000 km2 of the mid-Norwegian shelf. The spacing of the ridges shows that pulses of rapid grounding-line retreat, at rates ranging from 55 to 610 m day-1, occurred across low-gradient (±1°) ice-sheet beds during the last deglaciation. These values far exceed all previously reported rates of grounding-line retreat across the satellite3,4,6,7 and marine-geological1,2 records. The highest retreat rates were measured across the flattest areas of the former bed, suggesting that near-instantaneous ice-sheet ungrounding and retreat can occur where the grounding line approaches full buoyancy. Hydrostatic principles show that pulses of similarly rapid grounding-line retreat could occur across low-gradient Antarctic ice-sheet beds even under present-day climatic forcing. Ultimately, our results highlight the often-overlooked vulnerability of flat-bedded areas of ice sheets to pulses of extremely rapid, buoyancy-driven retreat.

Supplementary Figure 1. Study flowchart

Supplementary table 1. Main characteristics of patients receiving different dose levels

Supplementary table 3. Multivariate model for Overall Survival (Cytotoxic Agents)

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

Supplementary table 2. Multivariate model for overall survival (Molecularly Targeted Agents).

In this study, the present bioclimatic conditions and the estimated changes of the bioclimate over natural and agricultural areas of the Adriatic territory (Albania, Bosnia and Herzegovina, Croatia, Italy, Montenegro, and Slovenia) are analysed and presented. For this purpose, a survey on De Martonne’s bioclimate categories’ spatial distribution over the entire examined area and individual countries is conducted for the reference period (1981–2010) and for three more future time periods (2011–2040; 2041–2070; 2071–2100) under two emissions scenarios (ssp370/RCP7 and ssp585/RCP8.5). The very high spatial resolution (~300 m) results demonstrate that the potential future alterations of the Adriatic territory’s bioclimate indicate the probable acceleration of the trend towards warmer and dryer conditions by 2100 under the RCP8.5 scenario, with the Italian region’s agricultural areas mainly being influenced. Moreover, as the studied scenarios project, the bioclimatic impact will affect natural and agricultural areas. For the agricultural areas, the semi-dry class (the most xerothermic in the study area) will expand from 4.9% (reference period) to 17.7% according to the RCP8.5 scenario for the period 2071–2100. When over the natural areas, the related variation of the same class is from 0.9% to 5.6%. In general, the western part of the Adriatic coastline is more vulnerable to climate results than the eastern one.

A rapid retreat Are the rates at which we observe ice shelves shrinking today representative of how fast they shrank in the past? Dowdeswell et al. report observations of the Antarctic seafloor that reveal the presence of submarine grounding-zone wedges on the Larsen continental shelf (see the Perspective by Jakobsson). The authors interpret these ridges as being caused by the tidal rise and fall of the ice shelf at the grounding line, which squeezes the underlying sediments when it rests on the seafloor. From this, they calculated that ice shelf retreat at this location about 14,000 years ago was at times as much as 100 times as fast as the average over the past 10,000 years. Science , this issue p. 1020 ; see also p. 939

PWE-46 Figure 1Overall Survival of all patients with HCC discussed in the MDT in 2019 (Pre COVID) vs 2020 (During COVID)[Figure omitted. See PDF]

Qualitat de vida relacionada amb la salut; Olaparib; Càncer de pàncrees Calidad de vida relacionada con la salud; Olaparib, Cáncer de páncreas Health-related quality of life; Olaparib; Pancreatic cancer Background Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. Patients and methods Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. Results Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was

Linear to curvilinear depressions interpreted as iceberg ploughmarks are identified on the continental shelf beyond Larsen C Ice Shelf in about 350 m water depth using multibeam echo-sounding at sub-metre horizontal resolution. Detailed imaging of ploughmark morphology demonstrates the presence of irregularly spaced ridges extending across the full ploughmark width. These ridges have an arcuate shape in plan-view, are up to 2 m high, 20-40 m wide, show occasional presence of subdued debris-flow lobes on their distal side and have an asymmetric cross-profile in which the seafloor deepens beyond their slightly steeper side. The ridges are interpreted to have been produced when the iceberg moved backwards under the falling tide, which pushed up a ridge of sediment behind the iceberg keel, before it continued on its original trajectory under the rising tide. Similar features, which we term ‘iceberg tidal ridges’, can be identified at lower resolution on bathymetric and three-dimensional seismic data from the mid-Norwegian margin, suggesting the broader implications of the interpretations presented here. For example, the mapping of delicate ridges preserved within iceberg ploughmarks can be used to reconstruct past oceanic circulation including the former direction and strength of ocean currents.

Multibeam echo-sounders were deployed from Autonomous Underwater Vehicles (AUVs) flying close to the seafloor of the Weddell Sea shelf in order to investiagte the glacial landforms there with a view to understanding processes and patterns associated with deglaciation from the Last Glacial Maximum on the eastern side of the Antarctic Peninsula. A horizontal resolution of 0.5 m (using conventional mulitbeam systems), and in some cases 0.05 m (using interferometric multibeam equipment), allowed delicate seafloor landforms to be mapped in several areas of the shelf beyond the Larsen C and former Larsen A and B ice shelves. A number of glacial landform assemblages were observed, including suites of delicate ridges associated with grounding-zone wedges and the grounding of icebergs on the shelf. These landforms are probably related to the action of tides moving the ice up and down through a series of tidal cycles. At the highest spatial resolution, individual dropstones derived from rain-out during the melting of floating ice were imaged clearly. Imaging the seafloor at such high resolution allows both very detailed descriptions of submarine landform morphology and also the complexity of such landforms and landform assemblages to be better understood, aiding the interpretation of the glacial and related processes that led to their formation.

Pancreatic ductal adenocarcinoma (PDAC) has a 5‐year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10−8). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p

Mountain glaciers at the periphery of the Greenland ice sheet are a crucial freshwater and sediment source to the North Atlantic and strongly impact Arctic terrestrial, fjord and coastal biogeochemical cycles. In this study we mapped the extent of 1848 mountain glaciers in NE Greenland at the Little Ice Age (LIA). We determined area and volume changes for the time periods LIA to 1980s and 1980s to 2014 and ELAs. There was at least 172.76 ± 34.55 km3 volume lost between 1910 and 1980s, i.e. a rate of 2.61 ± 0.52 km3 yr-1. Between 1980s and 2014 the volume lost was 90.55 ± 18.11 km3, i.e. a rate of 3.22 ± 0.64 km3 yr-1, implying an increase of ~ 23 % in the rate of ice volume loss. Overall, at least ~ 7 % of mass loss from Greenland mountain glaciers and ice caps has come from the NE sector.

Autonomous Underwater Vehicles (AUVs) deployed close to the seafloor can acquire high-resolution geophysical data about the topography and shallow stratigraphy of the seabed, yet have had limited application within the fields of glacial geomorphology and ice sheet reconstruction. Here, we present multibeam echo-sounding, side-scan sonar, sub-bottom profiler and High-Resolution Synthetic Aperture Sonar (HISAS) data acquired during three AUV dives on the northeast Antarctic Peninsula continental shelf. These data enable glacial landforms, including mega-scale glacial lineations (MSGLs), grounding-zone wedges (GZWs) and iceberg ploughmarks, to be imaged at a horizontal resolution of a few tens of centimetres, allowing for the identification of subtle morphological features. We map tidal ridges that are interpreted as having been formed 1) along the ice-sheet grounding line by the squeezing up of soft seafloor sediments by vertical motion of the grounding line during tidal cycles, and 2) by the tidally driven motion of grounded or near-grounded icebergs. These data also enable the mapping of small GZWs that show the location of short-term still-stands or re-advances of the ice-sheet grounding zone. No meltwater channels are identified from our data, suggesting that free-flowing meltwater may not be essential for the formation of GZWs or MSGLs. The examples presented here show how high-resolution AUV-derived geophysical data provide a step-change in our ability to image seafloor glacial landforms, enabling new interpretations about past ice dynamics and glacial sedimentation at fine temporal and spatial scales.