The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with ...treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma.
Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n=29).
ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20months. ctDNA detection predicted patients at high risk of relapse at baseline relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5–5.6; P=0.002 and postoperatively (HR 10; 95% CI 4.3–24; P<0.001). ctDNA detection at baseline HR 2.9; 95% CI 1.3–5.7; P=0.003 and postoperatively (HR 11; 95% CI 4.3–27; P<0.001 was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status.
Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.
Next-generation sequencing studies have provided further evidence to support the notion that cancer is a disease characterized by Darwinian evolution. Today, we often fail to capture this evolution ...and treatment decisions, even in the metastatic setting, are often based on analysis of primary tumor diagnosed years ago. Currently, this is considered a major reason for treatment failures in cancer care. Recent technological advances in the detection and characterization of circulating tumor cells and circulating tumor DNA might address this and allow for treatment tailoring based on real-time monitoring of tumor evolution. In this review, we summarize the most important recent findings in the field, focusing on challenges and opportunities in moving these tools forward in clinical practice.
•Transport networks underpin economic cities competiveness and society functioning.•During flooding transport infrastructure can be directly or indirectly damaged.•This paper reviewed modelling ...studies of the impacts of weather on transport.•The paper derived a new empirical function to relate flood depth and vehicle speed.•The function move forwards from the binary consideration of flood roads.•The function can be incorporated into flood risk analysis and transport appraisal.
Transport networks underpin economic activity by enabling the movement of goods and people. During extreme weather events transport infrastructure can be directly or indirectly damaged, posing a threat to human safety, and causing significant disruption and associated economic and social impacts. Flooding, especially as a result of intense precipitation, is the predominant cause of weather-related disruption to the transport sector. Existing approaches to assess the disruptive impact of flooding on road transport fail to capture the interactions between floodwater and the transport system, typically assuming a road is fully operational or fully blocked, which is not supported by observations. In this paper we develop a relationship between depth of standing water and vehicle speed. The function that describes this relationship has been constructed by fitting a curve to video analysis supplemented by a range of quantitative data that has be extracted from existing studies and other safety literature. The proposed relationship is a good fit to the observed data, with an R-squared of 0.95. The significance of this work is that it is simple to incorporate our function into existing transport models to produce better estimates of flood induced delays and we demonstrate this with an example from the 28th June 2012 flood in Newcastle upon Tyne, UK.
Amending contaminated soils with organic wastes can influence trace element mobility and toxicity. Soluble concentrations of metals and arsenic were measured in pore water and aqueous soil extracts ...following the amendment of a heavily contaminated mine soil with compost and biochar (10% v:v) in a pot experiment. Speciation modelling and toxicity assays (Vibrio fischeri luminescence inhibition and Lolium perenne germination) were performed to discriminate mechanisms controlling metal mobility and assess toxicity risk thereafter. Biochar reduced free metal concentrations furthest but dissolved organic carbon primarily controlled metal mobility after compost amendment. Individually, both amendments induced considerable solubilisation of arsenic to pore water (>2500 μg l−1) related to pH and soluble phosphate but combining amendments most effectively reduced toxicity due to simultaneous reductions in extractable metals and increases in soluble nutrients (P). Thus the measure–monitor-model approach taken determined that combining the amendments was most effective at mitigating attendant toxicity risk.
•Compost and biochar addition to a mine soil decreased metal solubility.•Inorganic arsenic solubility was increased furthest by compost alone.•Combining amendments most effectively reduced toxicity, assessed by bio-assays.•Field study should verify the efficacy of the amendment in the longer term.
Individual compost and biochar amendments to a contaminated mine soil decreased metal and increased arsenic solubility, but combining amendments most effectively reduced toxicity.
► Nitrogen fertiliser inputs to agriculture are essential for global production of sufficient food. ► Methane is the most efficient hydrogen feedstock and energy source for nitrogen fixation, and ...reserves should be protected in the absence of alternative hydrogen sources. ► Current known and potential reserves of phosphate rock are quantified. ► The requisite aggregate annual intake of phosphorus in food by the global population is estimated. ► It is essential that phosphorus is recycled to avoid exhaustion of reserves of this unsubstitutable nutrient.
Without the input of fertiliser nitrogen it is estimated that only about half of the current global population can be supplied with sufficient food energy and protein. The anticipated increase in the population to 2050 will increase the dependency on fertiliser inputs. The paper examines the different potential sources of energy and hydrogen required for this essential fixation of atmospheric nitrogen into plant-available nitrogenous fertiliser and concludes that methane from natural gas is clearly the most suitable source. In the absence of a cost-effective alternative source of hydrogen it is recommended that an on-going requirement for methane is acknowledged and that consideration be given to strategic reserves for the production of food. Phosphorus is also an essential and unsubstitutable nutrient for plants and animals, but while the global reserves of atmospheric nitrogen are effectively unlimited, the reserves of phosphate rock are finite. Recent estimates of the reserve suggest that at the current rate of use this resource will become exhausted within some hundreds of years. The annual increment of phosphorus contained in the human population is estimated to be in the order of 1 Mt/yr, which is a small proportion of the quantity mined. There is a clear requirement to ensure that phosphorus is recycled to a large extent, so that the rate of exhaustion of the reserves of phosphate rock is significantly reduced. Legislation relating to the management of phosphorus appears entirely associated with its potential to upset natural ecosystems, with apparently no regulations yet requiring the efficient use and reuse of a scarce resource.
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied ...them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
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•Unlike the germline, somatic cells evolve predominantly by positive selection•Nearly all (∼99%) coding mutations are tolerated and escape negative selection•Exome-wide estimates of the total number of driver coding mutations per tumor•Half of the coding driver mutations occur outside of known cancer genes
Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.
The impact climate change will have on the alpine ski sector has received increasing attention from tourism scholars and industry representatives. This paper uses the US Northeast as a case study to ...examine the integrated regional impacts of climate change by modeling local-level impacts at all 103-ski areas operating in the region. Failing to examine an entire marketplace – as has been done in much of the climate change and ski tourism literature – means it is difficult to understand the regional implications that vulnerability at one ski area could mean for an adjacent ski area, for the regional ski marketplace, or for communities and individuals reliant on the sector generally. This paper presents the results of this comprehensive analysis, provides a discussion of the implications of change, and proposes a decision-making tool intended to help guide ski resort management in light of projected climate change.
► The impact of climate change is modeled for all 103 operating ski areas in the US Northeast. ► Modeling techniques are refined through the inclusion of generic lapse rates. ► Many ski areas are not expected to be economically viable as early as mid-century. ► Ski areas remaining viable could take advantage of a reduction in marketplace competition. ► A decision-making flowchart is proposed to assist ski resort managers deal with climate change.
Multidrug transporters of the ABC family facilitate the export of diverse cytotoxic drugs across cell membranes. This is clinically relevant, as tumour cells may become resistant to agents used in ...chemotherapy. To understand the molecular basis of this process, we have determined the 3.0 A crystal structure of a bacterial ABC transporter (Sav1866) from Staphylococcus aureus. The homodimeric protein consists of 12 transmembrane helices in an arrangement that is consistent with cross-linking studies and electron microscopic imaging of the human multidrug resistance protein MDR1, but critically different from that reported for the bacterial lipid flippase MsbA. The observed, outward-facing conformation reflects the ATP-bound state, with the two nucleotide-binding domains in close contact and the two transmembrane domains forming a central cavity--presumably the drug translocation pathway--that is shielded from the inner leaflet of the lipid bilayer and from the cytoplasm, but exposed to the outer leaflet and the extracellular space.
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