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Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
1D-3D hybrid modeling : from multi-compartment models to full resolution models in space and time
(2014)
Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator—which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.
Background: Birch pollen-allergic subjects produce polyclonal cross-reactive IgE antibodies that mediate pollen-associated food allergies. The major allergen Bet v 1 and its homologs in plant foods bind IgE in their native protein conformation. Information on location, number and clinical relevance of IgE epitopes is limited. We addressed the use of an allergen-related protein model to identify amino acids critical for IgE binding of PR-10 allergens.
Method: Norcoclaurine synthase (NCS) from meadow rue is structurally homologous to Bet v 1 but does not bind Bet v 1-reactive IgE. NCS was used as the template for epitope grafting. NCS variants were tested with sera from 70 birch pollen allergic subjects and with monoclonal antibody BV16 reported to compete with IgE binding to Bet v 1.
Results: We generated an NCS variant (Δ29NCSN57/I58E/D60N/V63P/D68K) harboring an IgE epitope of Bet v 1. Bet v 1-type protein folding of the NCS variant was evaluated by 1H-15N-HSQC NMR spectroscopy. BV16 bound the NCS variant and 71% (50/70 sera) of our study population showed significant IgE binding. We observed IgE and BV16 cross-reactivity to the epitope presented by the NCS variant in a subgroup of Bet v 1-related allergens. Moreover BV16 blocked IgE binding to the NCS variant. Antibody cross-reactivity depended on a defined orientation of amino acids within the Bet v 1-type conformation.
Conclusion: Our system allows the evaluation of patient-specific epitope profiles and will facilitate both the identification of clinically relevant epitopes as biomarkers and the monitoring of therapeutic outcomes to improve diagnosis, prognosis, and therapy of allergies caused by PR-10 proteins.
Background: Tracks of pigeons homing to the Frankfurt loft revealed an odd phenomenon: whereas birds returning from the North approach their loft more or less directly in a broad front, pigeons returning from the South choose, from 25 km from home onward, either of two corridors, a direct one and one with a considerable detour to the West. This implies differences in the navigational process.
Methodology/Principle Findings: Pigeons released at sites at the beginning of the westerly corridor and in this corridor behave just like pigeons returning from farther south, deviating to the west before turning towards their loft. Birds released at sites within the straight corridors, in contrast, take more or less straight routes. The analysis of the short-term correlation dimension, a quantity reflecting the complexity of the system and with it, the number of factors involved in the navigational process, reveals that it is significantly larger in pigeons choosing the westerly corridor than in the birds flying straight - 3.03 vs. 2.85. The difference is small, however, suggesting a different interpretation of the same factors, with some birds apparently preferring particular factors over others.
Conclusions: The specific regional distribution of the factors which pigeons use to determine their home course seems to provide ambiguous information in the area 25 km south of the loft, resulting in the two corridors. Pigeons appear to navigate by deriving their routes directly from the locally available navigational factors which they interpret in an individual way. The fractal nature of the correlation dimensions indicates that the navigation process of pigeons is chaotic-deterministic; published tracks of migratory birds suggest that this may apply to avian navigation in general.
Background: Highly infectious diseases (HIDs) are (i) easily transmissible from person to person; (ii) cause a life-threatening illness with no or few treatment options; and (iii) pose a threat for both personnel and the public. Hence, even suspected HID cases should be managed in specialised facilities minimizing infection risks but allowing state-of-the-art critical care. Consensus statements on the operational management of isolation facilities have been published recently. The study presented was set up to compare the operational management, resources, and technical equipment among European isolation facilities. Due to differences in geography, population density, and national response plans it was hypothesized that adherence to recommendations will vary.
Methods and Findings: Until mid of 2010 the European Network for Highly Infectious Diseases conducted a cross-sectional analysis of isolation facilities in Europe, recruiting 48 isolation facilities in 16 countries. Three checklists were disseminated, assessing 44 items and 148 specific questions. The median feedback rate for specific questions was 97.9% (n = 47/48) (range: n = 7/48 (14.6%) to n = 48/48 (100%). Although all facilities enrolled were nominated specialised facilities' serving countries or regions, their design, equipment and personnel management varied. Eighteen facilities fulfilled the definition of a High Level Isolation Unit'. In contrast, 24 facilities could not operate independently from their co-located hospital, and five could not ensure access to equipment essential for infection control. Data presented are not representative for the EU in general, as only 16/27 (59.3%) of all Member States agreed to participate. Another limitation of this study is the time elapsed between data collection and publication; e.g. in Germany one additional facility opened in the meantime.
Conclusion: There are disparities both within and between European countries regarding the design and equipment of isolation facilities. With regard to the International Health Regulations, terminology, capacities and equipment should be standardised.
Introduction: On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance.
Aim: To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis.
Methods: We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays.
Results: Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR.
Conclusion: Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.
A phytosociological survey of weed (segetal) vegetation in Slovakia was performed. A total of 508 relevés were sampled in 2002–2008. The aims of this study were to determine the actual distribution of the segetal communities, to analyze their floristic structure, and to evaluate their relationships to selected environmental factors. Thirteen plant communities of the class Stellarietea mediae were distinguished by cluster analysis; 11 communities were included in the subclass Violenea arvensis (Lathyro tuberosi-Adonidetum aestivalis, Consolido-Anthemidetum austriacae, Euphorbio exiguae-Melandrietum noctiflori, Veronicetum trilobae-triphyllidi, Lamio amplexicauli-Thlaspietum arvensis, Taraxacum sect. Ruderalia community, Spergulo arvensis-Scleranthetum annui, Myosotido-Sonchetum arvensis, Echinochloo-Setarietum pumilae, Galinsogo-Setarietum, and Stachyo annui-Setarietum pumilae) and two in the subclass Sisymbrienea (Portulacetum oleraceae and Setario viridis-Erigeronetum canadensis). Communities were characterized by diagnostic, constant, and dominant species and their structure, ecology, and distribution were estimated. The species composition of these communities was documented in synoptic and association tables. DCA ordination and analysis of variance was used to determine the main environmental factors of floristic differentiation and to determine ecological and structural differences among the communities. The analyses showed that the most important factors affecting floristic composition and classification of the weed communities are their time of development (agroecophase), the type of crops and altitude.
River corridor plants in Central Europe account for an above-average proportion of endangered species. The main objective of this study was to examine the effects of habitat fragmentation and abiotic conditions on the survival and changes in population size of four endangered, long-lived river corridor plant species (Euphorbia palustris, Pseudolysimachion longifolium, Sanguisorba officinalis, and Senecio paludosus) over the course of at least ten years. We sampled altogether 138 populations in the Weser and Elbe river systems in Northwestern Germany.
Overall, 33% of the populations went extinct during the study period. Extinction rates and changes in population size were related to initial population sizes, but not to population isolation and only marginally so to habitat quality. Large populations (> 100 individuals) had a much higher probability to survive or increase in size (to > 1000 individuals) than smaller populations. There was no general decline in population size in surviving populations, and extinction rates and changes in population size were independent of time. We therefore conclude that the high extinction rates in small populations are best explained by sudden short-term environmental events, such as changes in land use, rather than by long-term negative effects of, for example, genetic deterioration. A projection matrix for the next 117 years, however, predicted that 85% of the surveyed populations will have gone extinct. Since any establishment of new populations in the study area is unlikely owing to the lack of potential habitats and dispersal limitation, river corridor plants will probably continue to decline. Apart from preventing further habitat deterioration it will be crucial to maintain or establish an appropriate management, and to avoid sudden and adverse changes in land use.
Wet meadows are transitional habitats between wetlands and dry-mesophilous grasslands; thus, they are vital in sustaining biodiversity as sources, stepping stones and green corridors of species dispersal. It is especially valid for inland alkali vegetation, where high landscapescale patchiness is typical and rapid shifts between vegetation types occur frequently. Solonetz meadows (Beckmannion eruciformis) are among the bestpreserved open habitats in Europe harbouring a unique flora including several endemics. Besides their importance, studies on the vegetation of solonetz meadows are scarce even though this knowledge would be vital for their effective conservation and management. Using own records and literature data, we provide a synthesis of the alliance Beckmannion eruciformis to characterise its associations floristically and ecologically in five regions along the river Tisza, East Hungary. We studied three associations of the alliance: (i) Agrostio stoloniferae-Alopecuretum pratensis, (ii) Agrostio stoloniferae-Beckmannietum eruciformis and (iii) Agrostio stoloniferae-Glycerietum pedicellatae. We found that solonetz meadow associations were separated along a moisture gradient with Agrostio stoloniferae-Alopecuretum pratensis at the drier end and Agrostio stoloniferae-Glycerietum pedicellateae at the wet end. This gradient was also justified by the distribution of the phytosociological groups. The proportion of species of Festuco-Brometea division was the highest in Agrostio stoloniferae-Alopecuretum pratensis, while the proportion of Cypero-Phragmitetea species was the highest in Agrostio stoloniferae-Glycerietum pedicellateae. Species of Puccinellio-Salicornetea had the highest proportion in Agrostio stoloniferae-Beckmannietum eruciformis, indicating the high soil salinity of this association. Our results suggest that Agrostio stoloniferae-Alopecuretum pratensis association plays an important role in preserving the continental flora elements of the surrounding dry grasslands. The ecological indicator values for soil moisture and salinity suggest that in case of the studied solonetz meadow associations, humidity increases with decreasing elevation, while salinity is highest at medium elevations. Our results suggest that Agrostio stoloniferae-Beckmannietum eruciformis is a transition towards salt marsh associations, while Agrostio stoloniferae-Glycerietum pedicellatae is a transition towards freshwater marshes. Our results show that preserving solonetz meadows is an important task for nature conservation as they have a crucial role in maintaining landscapescale species and habitat diversity and act as buffer zones around wetlands.