Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer.

BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer

A Decision Support Model for Routing and Scheduling a Fleet of Fuel Supply Vessels

We consider a real fuel supply vessel routing and scheduling problem faced by a Hellenic oil company with a given fleet of fuel supply vessels used to supply customer ships outside Piraeus Port. The supply vessels are loading fuel at refineries in the port area before delivering it to a given set of customer ships within specified time windows. A customer ship may place orders of more than one fuel type, and all orders placed by a customer ship do not have to be serviced by the same vessel, meaning customer splitting is possible. Fuel transported to the customer ships is allocated to compartments on board the supply vessels, and fuels of different types cannot be mixed in the same compartment. The objective is to design routes and schedules for the supply vessels while maximizing the company’s profit. We propose a mixed-integer programming (MIP) model for the problem and provide a computational study based on real instances.acceptedVersionThis is a post-peer-review, pre-copyedit version of a chapter published in [International Conference on Computational Logistics]. The final authenticated version is available online at: https://link.springer.com/chapter/10.1007%2F978-3-319-24264-4_

Chemolithoautotrophic bacteria flourish at dark water–ice interfaces of an emerged Arctic cold seep

Below their ice shells, icy moons may offer a source of chemical energy that could support microbial life in the absence of light. In the Arctic, past and present glacial retreat leads to isostatic uplift of sediments through which cold and methane-saturated groundwater travels. This fluid reaches the surface and freezes as hill-shaped icings during winter, producing dark ice–water interfaces above water ponds containing chemical energy sources. In one such system characterized by elevated methane concentrations — the Lagoon Pingo in Adventdalen, Svalbard, Norway (∼10 mg/L CH4, 2, −0.25◦C, pH 7.9), we studied amplicons of the bacterial and archaeal (microbial) 16S rRNA gene and transcripts in the water pond and overlaying ice. We found that active chemolithoautotrophic sulfuroxidizing microorganisms (Sulfurimonas, Thiomicrorhabdus) dominate a niche at the bottom of the ice that is in contact with the anoxic water reservoir. There, the growing ice offers surfaces that interface with water and hosts favorable physico-chemical conditions for sulfide oxidation. The detection of anaerobic methanotrophs further suggests that throughout the winter, a steady-state dark and cold methane sink occurs under the ice in two steps: first, methane is oxidized to carbon dioxide and sulfates are concomitantly reduced to sulfides by the activity of anaerobic methanotrophs (ANME) ANME-1a and sulfate-reducing bacteria (SRB) SEEP-SRB1 consortia; and second, energy from sulfides is used by sulfur-oxidizing microorganisms to fix carbon dioxide into organic carbon. Our results underscore that ice-covered and dark ecosystems are hitherto overlooked oases of microbial life and emphasize the need to study microbial communities in icy habitats

Prion protein-specific antibodies that detect multiple TSE agents with high sensitivity

This paper describes the generation, characterisation and potential applications of a panel of novel anti-prion protein monoclonal antibodies (mAbs). The mAbs were generated by immunising PRNP null mice, using a variety of regimes, with a truncated form of recombinant ovine prion protein spanning residues 94–233. Epitopes of specific antibodies were mapped using solid-phase Pepscan analysis and clustered to four distinct regions within the PrP molecule. We have demonstrated the utility of these antibodies by use of Western blotting and immunohistochemistry in tissues from a range of different species affected by transmissible spongiform encephalopathy (TSE). In comparative tests against extensively-used and widely-published, commercially available antibodies, similar or improved results can be obtained using these new mAbs, specifically in terms of sensitivity of detection. Since many of these antibodies recognise native PrPC, they could also be applied to a broad range of immunoassays such as flow cytometry, DELFIA analysis or immunoprecipitation. We are using these reagents to increase our understanding of TSE pathogenesis and for use in potential diagnostic screening assays

Tundra microbial community taxa and traits predict decomposition parameters of stable, old soil organic carbon.

The susceptibility of soil organic carbon (SOC) in tundra to microbial decomposition under warmer climate scenarios potentially threatens a massive positive feedback to climate change, but the underlying mechanisms of stable SOC decomposition remain elusive. Herein, Alaskan tundra soils from three depths (a fibric O horizon with litter and course roots, an O horizon with decomposing litter and roots, and a mineral-organic mix, laying just above the permafrost) were incubated. Resulting respiration data were assimilated into a 3-pool model to derive decomposition kinetic parameters for fast, slow, and passive SOC pools. Bacterial, archaeal, and fungal taxa and microbial functional genes were profiled throughout the 3-year incubation. Correlation analyses and a Random Forest approach revealed associations between model parameters and microbial community profiles, taxa, and traits. There were more associations between the microbial community data and the SOC decomposition parameters of slow and passive SOC pools than those of the fast SOC pool. Also, microbial community profiles were better predictors of model parameters in deeper soils, which had higher mineral contents and relatively greater quantities of old SOC than in surface soils. Overall, our analyses revealed the functional potential of microbial communities to decompose tundra SOC through a suite of specialized genes and taxa. These results portray divergent strategies by which microbial communities access SOC pools across varying depths, lending mechanistic insights into the vulnerability of what is considered stable SOC in tundra regions

Managing caries:the need to close the gap between the evidence base and current practice

Underpinned by a changing knowledge of the aetiology of caries and its sequelae, and assisted by established and advancing dental materials, there is growing evidence supporting less invasive management of dental caries based on the principles of minimal intervention dentistry. This narrative review assesses both the evidence and the adoption of less invasive caries management strategies and describes ways in which the gap between evidence and practice might be overcome. While there is increasing data supporting less invasive management of carious lesions, these are not standard in most dental practices worldwide. Usually, clinical studies focused on efficacy as outcome, and did not take into consideration the views and priorities of other stakeholders, such as primary care dentists, educators, patients and those financing services. Involving these stakeholders into study design and demonstrating the broader advantages of new management strategies might improve translation of research into practice. In theory, clinical dentists can rely on a growing evidence in cariology regarding less invasive management options. In practice, further factors seem to impede adoption of these strategies. Future research should address these factors by involving major stakeholders and investigating their prioritised outcomes to narrow or close the evidence gap.</p

Exercise and bone health across the lifespan

With ageing, bone tissue undergoes significant compositional, architectural and metabolic alterations potentially leading to osteoporosis. Osteoporosis is the most prevalent bone disorder, which is characterised by progressive bone weakening and an increased risk of fragility fractures. Although this metabolic disease is conventionally associated with ageing and menopause, the predisposing factors are thought to be established during childhood and adolescence. In light of this, exercise interventions implemented during maturation are likely to be highly beneficial as part of a long-term strategy to maximise peak bone mass and hence delay the onset of age- or menopause-related osteoporosis. This notion is supported by data on exercise interventions implemented during childhood and adolescence, which confirmed that weight-bearing activity, particularly if undertaken during peripubertal development, is capable of generating a significant osteogenic response leading to bone anabolism. Recent work on human ageing and epigenetics suggests that undertaking exercise after the fourth decade of life is still important, given the anti-ageing effect and health benefits provided, potentially occurring via a delay in telomere shortening and modification of DNA methylation patterns associated with ageing. Exercise is among the primary modifiable factors capable of influencing bone health by preserving bone mass and strength, preventing the death of bone cells and anti-ageing action provided