Synergistic Antitumor Effect between Gefitinib and Fractionated Irradiation in Anaplastic Oligodendrogliomas Cannot Be Predicted by the Egfr Signaling Activity

In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment “gefitinib + radiotherapy” and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an “EGFR-addictive” behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for “EGFR-addictive” tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.     

Balancing competition for resources with multiple pest regulation in diversified agroecosystems: a process‐based approach to reconcile diversification and productivity

Agroecosystem plant diversification can enhance pest biological regulation and is a promising alternative to pesticide application. However, the costs of competition for resources between plants may exceed the benefits gained by pest regulation. To disentangle the interactions between pest regulation and competition, we developed a generic process‐based approach that accounts for the effects of an associated plant and leaf and root pests on biomass production. We considered three crop–plant associations that differ in competition profiles, and we simulated biomass production under wide ranges of both pest regulation rates and resources’ availability. We analyzed outputs to quantify the pest regulation service level that would be required to attain monoculture yield and other production goals. Results showed that pest regulation requirements were highly dependent on the profile of resource interception of the associated plant and on resources’ availability. Pest regulation and the magnitude of competition between plants interacted in determining the balance between nitrogen and radiation uptake by the crop. Our findings suggest that productivity of diversified agroecosystems relative to monoculture should be optimized by assembling plants whose characteristics balance crops’ resource acquisition. The theoretical insights from our study draw generic rules for vegetation assemblage to optimize trade‐offs between pest regulation and production. Our findings and approach may have implications in understanding, theorizing and implementing agroecosystem diversification. By its generic and adaptable structure, our approach should be useful for studying the effects of diversification in many agroecosystems.     

Assessment of Overlap of Phylogenetic Transmission Clusters and Communities in Simple Sexual Contact Networks: Applications to HIV-1

Background

Transmission patterns of sexually-transmitted infections (STIs) could relate to the structure of the underlying sexual contact network, whose features are therefore of interest to clinicians. Conventionally, we represent sexual contacts in a population with a graph, that can reveal the existence of communities. Phylogenetic methods help infer the history of an epidemic and incidentally, may help detecting communities. In particular, phylogenetic analyses of HIV-1 epidemics among men who have sex with men (MSM) have revealed the existence of large transmission clusters, possibly resulting from within-community transmissions. Past studies have explored the association between contact networks and phylogenies, including transmission clusters, producing conflicting conclusions about whether network features significantly affect observed transmission history. As far as we know however, none of them thoroughly investigated the role of communities, defined with respect to the network graph, in the observation of clusters.

Methods

The present study investigates, through simulations, community detection from phylogenies. We simulate a large number of epidemics over both unweighted and weighted, undirected random interconnected-islands networks, with islands corresponding to communities. We use weighting to modulate distance between islands. We translate each epidemic into a phylogeny, that lets us partition our samples of infected subjects into transmission clusters, based on several common definitions from the literature. We measure similarity between subjects’ island membership indices and transmission cluster membership indices with the adjusted Rand index.

Results and Conclusion

Analyses reveal modest mean correspondence between communities in graphs and phylogenetic transmission clusters. We conclude that common methods often have limited success in detecting contact network communities from phylogenies. The rarely-fulfilled requirement that network communities correspond to clades in the phylogeny is their main drawback. Understanding the link between transmission clusters and communities in sexual contact networks could help inform policymaking to curb HIV incidence in MSMs.     

Microsatellite Genotyping of Plasmodium vivax Isolates from Pregnant Women in Four Malaria Endemic Countries

Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied.     

Simultaneous Saccharification and Fermentation of Hydrothermal Pretreated Lignocellulosic Biomass: Evaluation of Process Performance Under Multiple Stress Conditions

Industrial lignocellulosic bioethanol processes are exposed to different environmental stresses (such as inhibitor compounds, high temperature, and high solid loadings). In this study, a systematic approach was followed where the liquid and solid fractions were mixed to evaluate the influence of varied solid loadings, and different percentages of liquor were used as liquid fraction to determine inhibitor effect. Ethanol production by simultaneous saccharification and fermentation (SSF) of hydrothermally pretreated Eucalyptus globulus wood (EGW) was studied under combined diverse stress operating conditions (30–38 °C, 60–80 g of liquor from hydrothermal treatment or autohydrolysis (containing inhibitor compounds)/100 g of liquid and liquid to solid ratio between 4 and 6.4 g liquid in SSF/g unwashed pretreated EGW) using an industrial Saccharomyces cerevisiae strain supplemented with low-cost byproducts derived from agro-food industry. Evaluation of these variables revealed that the combination of temperature and higher solid loadings was the most significant variable affecting final ethanol concentration and cellulose to ethanol conversion, whereas solid and autohydrolysis liquor loadings had the most significant impact on ethanol productivity. After optimization, an ethanol concentration of 54 g/L (corresponding to 85 % of conversion and 0.51 g/Lh of productivity at 96 h) was obtained at 37 °C using 60 % of autohydrolysis liquor and 16 % solid loading (liquid to solid ratio of 6.4 g/g). The selection of a suitable strain along with nutritional supplementation enabled to produce noticeable ethanol titers in quite restrictive SSF operating conditions, which can reduce operating cost and boost the economic feasibility of lignocellulose-to-ethanol processes.     

How Do General Practitioners Conceptualise Advance Care Planning in Their Practice? A Qualitative Study

ObjectivesTo explore how GPs conceptualise advance care planning (ACP), based on their experiences with ACP in their practice.MethodsFive focus groups were held with 36 GPs. Discussions were analysed using a constant comparative method.ResultsFour overarching themes in the conceptualisations of ACP were discerned: (1) the organisation of professional care required to meet patients’ needs, (2) the process of preparing for death and discussing palliative care options, (3) the discussion of care goals and treatment decisions, (4) the completion of advance directives. Within these themes, ACP was both conceptualised in terms of content of ACP and/or in terms of tasks for the GP. A specific task that was mentioned throughout the discussion of the four different themes was (5) the task of actively initiating ACP by the GP versus passively waiting for patients’ initiation.ConclusionsThis study illustrates that GPs have varying conceptualisations of ACP, of which some are more limited to specific aspects of ACP. A shared conceptualisation and agreement on the purpose and goals of ACP is needed to ensure successful implementation, as well as a systematic integration of ACP in routine practice that could lead to a better uptake of all the important elements of ACP.     

Experimental test of the ecosystem impacts of the keystone predator Triops cancriformis (Branchiopoda: Notostraca) in temporary ponds

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