Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects

Self-Affirmation Improves Problem-Solving under Stress

High levels of acute and chronic stress are known to impair problem-solving and creativity on a broad range of tasks. Despite this evidence, we know little about protective factors for mitigating the deleterious effects of stress on problem-solving. Building on previous research showing that self-affirmation can buffer stress, we tested whether an experimental manipulation of self-affirmation improves problem-solving performance in chronically stressed participants. Eighty undergraduates indicated their perceived chronic stress over the previous month and were randomly assigned to either a self-affirmation or control condition. They then completed 30 difficult remote associate problem-solving items under time pressure in front of an evaluator. Results showed that self-affirmation improved problem-solving performance in underperforming chronically stressed individuals. This research suggests a novel means for boosting problem-solving under stress and may have important implications for understanding how self-affirmation boosts academic achievement in school settings. © 2013 Creswell et al

Bystander responses to a violent incident in an immersive virtual environment

Under what conditions will a bystander intervene to try to stop a violent attack by one person on another? It is generally believed that the greater the size of the crowd of bystanders, the less the chance that any of them will intervene. A complementary model is that social identity is critical as an explanatory variable. For example, when the bystander shares common social identity with the victim the probability of intervention is enhanced, other things being equal. However, it is generally not possible to study such hypotheses experimentally for practical and ethical reasons. Here we show that an experiment that depicts a violent incident at life-size in immersive virtual reality lends support to the social identity explanation. 40 male supporters of Arsenal Football Club in England were recruited for a two-factor between-groups experiment: the victim was either an Arsenal supporter or not (in-group/out-group), and looked towards the participant for help or not during the confrontation. The response variables were the numbers of verbal and physical interventions by the participant during the violent argument. The number of physical interventions had a significantly greater mean in the ingroup condition compared to the out-group. The more that participants perceived that the Victim was looking to them for help the greater the number of interventions in the in-group but not in the out-group. These results are supported by standard statistical analysis of variance, with more detailed findings obtained by a symbolic regression procedure based on genetic programming. Verbal interventions made during their experience, and analysis of post-experiment interview data suggest that in-group members were more prone to confrontational intervention compared to the out-group who were more prone to make statements to try to diffuse the situation

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant

Statistical Inference for Valued-Edge Networks: Generalized Exponential Random Graph Models

Across the sciences, the statistical analysis of networks is central to the production of knowledge on relational phenomena. Because of their ability to model the structural generation of networks, exponential random graph models are a ubiquitous means of analysis. However, they are limited by an inability to model networks with valued edges. We solve this problem by introducing a class of generalized exponential random graph models capable of modeling networks whose edges are valued, thus greatly expanding the scope of networks applied researchers can subject to statistical analysis

I Me Mine: on a Confusion Concerning the Subjective Character of Experience

In recent debates on phenomenal consciousness, a distinction is sometimes made, after Levine (2001) and Kriegel (2009), between the “qualitative character” of an experience, i.e. the specific way it feels to the subject (e.g. blueish or sweetish or pleasant), and its “subjective character”, i.e. the fact that there is anything at all that it feels like to her. I argue that much discussion of subjective character is affected by a conflation between three different notions. I start by disentangling the three notions in question, under the labels of “for-me-ness”, “me-ness” and “mineness”. Next, I argue that these notions are not equivalent; in particular, there is no conceptual implication from for-me-ness to me-ness or mineness. Empirical considerations based on clinical cases additionally suggest that the three notions may also correspond to different properties (although the claim of conceptual non-equivalence does not depend on this further point). The aim is clarificatory, cautionary but also critical: I examine four existing arguments from subjective character that are fuelled by an undifferentiated use of the three notions, and find them to be flawed for this reason

Zinc Finger Nuclease mediated knockout of ADP dependent Glucokinase in Cancer cell lines: Effects on cell survival and Mitochondrial Oxidative Metabolism

<div><p>Zinc finger nucleases (ZFN) are powerful tools for editing genes in cells. Here we use ZFNs to interrogate the biological function of <i>ADPGK</i>, which encodes an ADP-dependent glucokinase (ADPGK), in human tumour cell lines. The hypothesis we tested is that ADPGK utilises ADP to phosphorylate glucose under conditions where ATP becomes limiting, such as hypoxia. We characterised two ZFN knockout clones in each of two lines (H460 and HCT116). All four clones had frameshift mutations in all alleles at the target site in exon 1 of <i>ADPGK,</i> and were ADPGK-null by immunoblotting. <i>ADPGK</i> knockout had little or no effect on cell proliferation, but compromised the ability of H460 cells to survive siRNA silencing of hexokinase-2 under oxic conditions, with clonogenic survival falling from 21±3% for the parental line to 6.4±0.8% (p = 0.002) and 4.3±0.8% (p = 0.001) for the two knockouts. A similar increased sensitivity to clonogenic cell killing was observed under anoxia. No such changes were found when <i>ADPGK</i> was knocked out in HCT116 cells, for which the parental line was less sensitive than H460 to anoxia and to hexokinase-2 silencing. While knockout of <i>ADPGK</i> in HCT116 cells caused few changes in global gene expression, knockout of <i>ADPGK</i> in H460 cells caused notable up-regulation of mRNAs encoding cell adhesion proteins. Surprisingly, we could discern no consistent effect on glycolysis as measured by glucose consumption or lactate formation under anoxia, or extracellular acidification rate (Seahorse XF analyser) under oxic conditions in a variety of media. However, oxygen consumption rates were generally lower in the <i>ADPGK</i> knockouts, in some cases markedly so. Collectively, the results demonstrate that <i>ADPGK</i> can contribute to tumour cell survival under conditions of high glycolytic dependence, but the phenotype resulting from knockout of <i>ADPGK</i> is cell line dependent and appears to be unrelated to priming of glycolysis in these lines.</p></div

The liquid-glass-jamming transition in disordered ionic nanoemulsions

In quenched disordered out-of-equilibrium many-body colloidal systems, there are important distinctions between the glass transition, which is related to the onset of nonergodicity and loss of low-frequency relaxations caused by crowding, and the jamming transition, which is related to the dramatic increase in elasticity of the system caused by the deformation of constituent objects. For softer repulsive interaction potentials, these two transitions become increasingly smeared together, so measuring a clear distinction between where the glass ends and where jamming begins becomes very difficult or even impossible. Here, we investigate droplet dynamics in concentrated silicone oil-in-water nanoemulsions using light scattering. For zero or low NaCl electrolyte concentrations, interfacial repulsions are soft and longer in range, this transition sets in at lower concentrations, and the glass and the jamming regimes are smeared. However, at higher electrolyte concentrations the interactions are stiffer, and the characteristics of the glass-jamming transition resemble more closely the situation of disordered elastic spheres having sharp interfaces, so the glass and jamming regimes can be distinguished more clearly