Big Bang Nucleosynthesis with Independent Neutrino Distribution Functions

We have performed new Big Bang Nucleosynthesis calculations which employ arbitrarily-specified, time-dependent neutrino and antineutrino distribution functions for each of up to four neutrino flavors. We self-consistently couple these distributions to the thermodynamics, the expansion rate and scale factor-time/temperature relationship, as well as to all relevant weak, electromagnetic, and strong nuclear reaction processes in the early universe. With this approach, we can treat any scenario in which neutrino or antineutrino spectral distortion might arise. These scenarios might include, for example, decaying particles, active-sterile neutrino oscillations, and active-active neutrino oscillations in the presence of significant lepton numbers. Our calculations allow lepton numbers and sterile neutrinos to be constrained with observationally-determined primordial helium and deuterium abundances. We have modified a standard BBN code to perform these calculations and have made it available to the community.Comment: 9 pages, 5 figure

Simulating perfect channels with probabilistic lossy channels

AbstractWe consider the problem of deciding whether an infinite-state system (expressed as a Markov chain) satisfies a correctness property with probability 1. This problem is, of course, undecidable for general infinite-state systems. We focus our attention on the model of probabilistic lossy channel systems consisting of finite-state processes that communicate over unbounded lossy FIFO channels. Abdulla and Jonsson have shown that safety properties are decidable while progress properties are undecidable for non-probabilistic lossy channel systems. Under assumptions of “sufficiently high” probability of loss, Baier and Engelen have shown how to check whether a property holds of probabilistic lossy channel system with probability 1. In this paper, we consider a model of probabilistic lossy channel systems, where messages can be lost only during send transitions. In contrast to the model of Baier and Engelen, once a message is successfully sent to channel, it can only be removed through a transition which receives the message. We show that checking whether safety properties hold with probability 1 is undecidable for this model. Our proof depends upon simulating a perfect channel, with a high degree of confidence, using lossy channels

Marketing authorization procedures for advanced cancer drugs: exploring the views of patients, oncologists, healthcare decision makers and citizens in France

International audienceBackground. The past decades have seen advances in cancer treatments in terms of toxicity and side effects but progress in the treatment of advanced cancer has been modest. New drugs have emerged improving progression free survival but with little impact on overall survival, raising questions about the criteria on which to base decisions to grant marketing authorizations and about the authorization procedure itself. For decisions to be fair, transparent and accountable, it is necessary to consider the views of those with relevant expertise and experience. Methods. We conducted a Q-study to explore the views of a range of stakeholders in France, involving: 54 patients (18 months after diagnosis); 50 members of the general population; 27 oncologists; 19 healthcare decision makers; and 2 individuals from the pharmaceutical industry. Results. Three viewpoints emerged, focussing on different dimensions entitled: 1) ‘Quality of life (QoL), opportunity cost and participative democracy’; 2)‘QoL and patient-centeredness’; and 3) ‘Length of life’. Respondents from all groups were associated with each viewpoint, except for healthcare decision makers, who were only associated with the first one. Conclusion. Our results highlight plurality in the views of stakeholders, emphasize the need for transparency in decision making processes, and illustrate the importance of a re-evaluation of treatments for all 3 viewpoints. In the context of advanced cancer, our results suggest that QoL should be more prominent amongst authorization criteria, as it is a concern for 2 of the 3 viewpoints

Spectral Analysis of Protein-Protein Interactions in Drosophila melanogaster

Within a case study on the protein-protein interaction network (PIN) of Drosophila melanogaster we investigate the relation between the network's spectral properties and its structural features such as the prevalence of specific subgraphs or duplicate nodes as a result of its evolutionary history. The discrete part of the spectral density shows fingerprints of the PIN's topological features including a preference for loop structures. Duplicate nodes are another prominent feature of PINs and we discuss their representation in the PIN's spectrum as well as their biological implications.Comment: 9 pages RevTeX including 8 figure

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer.

Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer

Toward a Regional Classification to Provide a More Inclusive Examination of the Ocean Biogeochemistry of Iron-Binding Ligands

Iron-binding ligands are paramount to understanding iron biogeochemistry and its potential to set the productivity and the magnitude of the biological pump in >30% of the ocean. However, the nature of these ligands is largely uncharacterized and little is known about their sources, sensitivity to photochemistry and biological transformation, or scavenging behavior. Despite many uncertainties, there is no doubt that ligands are produced by a wide range of biotic and abiotic processes, and that the bulk ligand pool encompasses a diverse range of molecules. Despite widespread recognition of the likelihood of a continuum of ligand classes making up the bulk ligand pool, studies to date largely focused on the dominant ligand. Thus, most studies have overlooked the need to assess where these targeted molecules fit across the spectrum of ligands that comprise the bulk ligand pool. Here we summarize present knowledge to critically assess the source(s), function(s), production pathways, and loss mechanisms of three important iron-binding organic ligand groups in order to assess their distinctive characteristics and how they link with observed ligand distributions. We considered that ligands are contained in broad groupings of exopolymer substances (EPS), humic substances (HS), and siderophores; using literature data for speciation modeling suggested that this adequately described the iron speciation reported in the ocean. We hypothesize that a holistic viewpoint of the multi-faceted controls on ligands dynamics is essential to begin to understand why some ligands can be expected to dominate in particular oceanic regions, depth strata, or exhibit seasonality and/or lateral gradients. We advocate that the development of a regional classification will enhance our understanding of the changing composition of the bulk ligand pool across the global ocean and to help address to what extent seasonality influences the makeup of this pool. This classification, based on selected functional ligand classes, can act as a bridge to use future ligand datasets to fill in the gaps in the continuum

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

To Give Chinese Children "a Memorable China":the Trend of Chinese Indigenous Picture Books

To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties. Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TG(LC)), Captex355 (medium-chain triglyceride; TG(MC)), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests. Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure. Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TG(MC) versus TG(LC), and PS80 versus PEG400. We also show, for the first time, that solubility in TG(MC) and TG(LC) can be predicted from rapidly calculated molecular descriptors