The configuration, sensitivity and rapid retreat of the Late Weichselian Icelandic ice sheet

The fragmentary glacial-geological record across the Icelandic continental shelf has hampered reconstruction of the volume, extent and chronology of the Late Weichselian ice sheet particularly in key offshore zones. Marine geophysical data collected over the last two decades reveal that the ice sheet likely attained a continental shelf-break position in all sectors during the Last Glacial Maximum, though its precise timing and configuration remains largely unknown. Within this context, we review the available empirical evidence and use a well-constrained three-dimensional thermomechanical model to investigate the drivers of an extensive Late Weichselian Icelandic ice-sheet, its sensitivity to environmental forcing, and phases of deglaciation. Our reconstruction attains the continental shelf break across all sectors with a total ice volume of 5.96×105km3 with high precipitation rates being critical to forcing extensive ice sheet flow offshore. Due to its location astride an active mantle plume, a relatively fast and dynamic ice sheet with a low aspect ratio is maintained. Our results reveal that once initial ice-sheet retreat was triggered through climate warming at 21.8 ka BP, marine deglaciation was rapid and accomplished in all sectors within c. 5 ka at a mean rate of 71 Gt of mass loss per year. This rate of ice wastage is comparable to contemporary rates observed for the West Antarctic ice sheet. The ice sheet subsequently stabilised on shallow pinning points across the near shelf for two millennia, but abrupt atmospheric warming during the Bølling Interstadial forced a second, dramatic collapse of the ice sheet onshore with a net wastage of 221 Gt a−1 over 750 years, analogous to contemporary Greenland rates of mass loss. Geothermal conditions impart a significant control on the ice sheet's transient response, particularly during phases of rapid retreat. Insights from this study suggests that large sectors of contemporary ice sheets overlying geothermally active regions, such as Siple Coast, Antarctica, and NE Greenland, have the potential to experience rapid phases of mass loss and deglaciation once initial retreat is initiated

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding: Cancer Research UK

An in vitro quantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias.

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects

An in vitro quantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias.

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects

Sounding the Antarctic ice sheet from space: a feasibility study based on airborne P-band radar data

Space-based radio echo sounding of the continental ice sheets can potentially provide full coverage with uniform sampling and data quality as well as detection of change in environmentally sensitive areas. This paper addresses the feasibility of sounding the Antarctic ice sheets with a space-based P-band radar. The assessment firstly makes use of an electromagnetic model of the ice sheets where the key model parameters are determined from data that have been acquired in Antarctica with an airborne P-band ice sounding radar. The performance of a space-based radar with a nadir-looking geometry but otherwise similar to ESA's Biomass SAR, is then simulated for a set of Antarctic scenarios that are defined based on the statistics of key ice regions. It is found that in about 2/3 of the simulation scenarios clutter and/or thermal noise will obscure the echo from the ice bed

Electrochemical aspects of display technology based on nanostructured titanium dioxide with attached viologen chromophores

Progress in recent years in the field of electrochromic displays based on viologen modified high-surface area TiO2 electrodes (Vio2+/TiO2) has moved the technol. towards commercialization. Viologen mols. (Vio2+), derivatized with phosphonic acid attachment groups can be chemisorbed on nanostructured TiO2 layers of thickness 2-10 μm. Characterization by cyclic voltammetry, spectroelectrochem. and impedance spectroscopy demonstrates that colorless Vio2+/TiO2 is reversibly reduced to the strongly colored cation radical species Vio+•TiO2. This system can constitute the working electrode of an electrochromic display with a capacitive doped SnO2 electrode as counter electrode, the latter coated by an electrochem. inert white light-reflecting layer. Such a device is stable upon repeated coloration-bleaching cycles with a bleached-to-colored state contrast ratio exceeding 5. Multicolor displays can be achieved by patterning different electrochromophores onto different areas of one working electrode