2,212 research outputs found
A new approach for sizing trials with composite binary endpoints using anticipated marginal values and accounting for the correlation between components
Composite binary endpoints are increasingly used as primary endpoints in
clinical trials. When designing a trial, it is crucial to determine the
appropriate sample size for testing the statistical differences between
treatment groups for the primary endpoint. As shown in this work, when using a
composite binary endpoint to size a trial, one needs to specify the event rates
and the effect sizes of the composite components as well as the correlation
between them. In practice, the marginal parameters of the components can be
obtained from previous studies or pilot trials, however, the correlation is
often not previously reported and thus usually unknown. We first show that the
sample size for composite binary endpoints is strongly dependent on the
correlation and, second, that slight deviations in the prior information on the
marginal parameters may result in underpowered trials for achieving the study
objectives at a pre-specified significance level. We propose a general strategy
for calculating the required sample size when the correlation is not specified,
and accounting for uncertainty in the marginal parameter values. We present the
web platform CompARE to characterize composite endpoints and to calculate the
sample size just as we propose in this paper. We evaluate the performance of
the proposal with a simulation study, and illustrate it by means of a real case
study using CompARE
Differential expression analysis with global network adjustment
<p>Background: Large-scale chromosomal deletions or other non-specific perturbations of the transcriptome can alter the expression of hundreds or thousands of genes, and it is of biological interest to understand which genes are most profoundly affected. We present a method for predicting a gene’s expression as a function of other genes thereby accounting for the effect of transcriptional regulation that confounds the identification of genes differentially expressed relative to a regulatory network. The challenge in constructing such models is that the number of possible regulator transcripts within a global network is on the order of thousands, and the number of biological samples is typically on the order of 10. Nevertheless, there are large gene expression databases that can be used to construct networks that could be helpful in modeling transcriptional regulation in smaller experiments.</p>
<p>Results: We demonstrate a type of penalized regression model that can be estimated from large gene expression databases, and then applied to smaller experiments. The ridge parameter is selected by minimizing the cross-validation error of the predictions in the independent out-sample. This tends to increase the model stability and leads to a much greater degree of parameter shrinkage, but the resulting biased estimation is mitigated by a second round of regression. Nevertheless, the proposed computationally efficient “over-shrinkage” method outperforms previously used LASSO-based techniques. In two independent datasets, we find that the median proportion of explained variability in expression is approximately 25%, and this results in a substantial increase in the signal-to-noise ratio allowing more powerful inferences on differential gene expression leading to biologically intuitive findings. We also show that a large proportion of gene dependencies are conditional on the biological state, which would be impossible with standard differential expression methods.</p>
<p>Conclusions: By adjusting for the effects of the global network on individual genes, both the sensitivity and reliability of differential expression measures are greatly improved.</p>
Field's Logic of Truth
Saving Truth from Paradox is a re-exciting development. The 70s and 80s were a time of excitement among people working on the semantic paradoxes. There were continual formal developments, with the constant hope that these results would yield deep insights. The enthusiasm wore off, however, as people became more cognizant of the disparity between what they had accomplished, impressive as it was, and what they had hoped to accomplish. They moved onto other problems that they hoped would prove more yielding. That, at least, was how it seemed to me, so I was delighted to see a dramatically new formal development that is likely to rekindle our enthusiasm
Multiple Conclusion Rules in Logics with the Disjunction Property
We prove that for the intermediate logics with the disjunction property any
basis of admissible rules can be reduced to a basis of admissible m-rules
(multiple-conclusion rules), and every basis of admissible m-rules can be
reduced to a basis of admissible rules. These results can be generalized to a
broad class of logics including positive logic and its extensions, Johansson
logic, normal extensions of S4, n-transitive logics and intuitionistic modal
logics
Neutron Stars in Teleparallel Gravity
In this paper we deal with neutron stars, which are described by a perfect
fluid model, in the context of the teleparallel equivalent of general
relativity. We use numerical simulations to find the relationship between the
angular momentum of the field and the angular momentum of the source. Such a
relation was established for each stable star reached by the numerical
simulation once the code is fed with an equation of state, the central energy
density and the ratio between polar and equatorial radii. We also find a regime
where linear relation between gravitational angular momentum and moment of
inertia (as well as angular velocity of the fluid) is valid. We give the
spatial distribution of the gravitational energy and show that it has a linear
dependence with the squared angular velocity of the source.Comment: 19 pages, 14 figures. arXiv admin note: text overlap with
arXiv:1206.331
Crown Lengthening Revisited
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141178/1/cap0233.pd
Alpha-Tomatine Induces Apoptosis and Inhibits Nuclear Factor-Kappa B Activation on Human Prostatic Adenocarcinoma PC-3 Cells
BACKGROUND: Alpha-tomatine (α-tomatine) is the major saponin in tomato (Lycopersicon esculentum). This study investigates the chemopreventive potential of α-tomatine on androgen-independent human prostatic adenocarcinoma PC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of highly aggressive human prostate cancer PC-3 cells with α-tomatine resulted in a concentration-dependent inhibition of cell growth with a half-maximal efficient concentration (EC(50)) value of 1.67±0.3 µM. It is also less cytotoxic to normal human liver WRL-68 cells and normal human prostate RWPE-1 cells. Assessment of real-time growth kinetics by cell impedance-based Real-Time Cell Analyzer (RTCA) showed that α-tomatine exhibited its cytotoxic effects against PC-3 cells as early as an hour after treatment. The inhibitory effect of α-tomatine on PC-3 cancer cell growth was mainly due to induction of apoptosis as evidenced by positive Annexin V staining and decreased in mitochondrial membrane potential but increased in nuclear condensation, polarization of F-actin, cell membrane permeability and cytochrome c expressions. Results also showed that α-tomatine induced activation of caspase-3, -8 and -9, suggesting that both intrinsic and extrinsic apoptosis pathways are involved. Furthermore, nuclear factor-kappa B (NF-κB) nuclear translocation was inhibited, which in turn resulted in significant decreased in NF-κB/p50 and NF-κB/p65 in the nuclear fraction of the treated cells compared to the control untreated cells. These results provide further insights into the molecular mechanism of the anti-proliferative actions of α-tomatine. CONCLUSION/SIGNIFICANCE: α-tomatine induces apoptosis and inhibits NF-κB activation on prostate cancer cells. These results suggest that α-tomatine may be beneficial for protection against prostate cancer development and progression
Multilevel Deconstruction of the In Vivo Behavior of Looped DNA-Protein Complexes
Protein-DNA complexes with loops play a fundamental role in a wide variety of
cellular processes, ranging from the regulation of DNA transcription to
telomere maintenance. As ubiquitous as they are, their precise in vivo
properties and their integration into the cellular function still remain
largely unexplored. Here, we present a multilevel approach that efficiently
connects in both directions molecular properties with cell physiology and use
it to characterize the molecular properties of the looped DNA-lac repressor
complex while functioning in vivo. The properties we uncover include the
presence of two representative conformations of the complex, the stabilization
of one conformation by DNA architectural proteins, and precise values of the
underlying twisting elastic constants and bending free energies. Incorporation
of all this molecular information into gene-regulation models reveals an
unprecedented versatility of looped DNA-protein complexes at shaping the
properties of gene expression.Comment: Open Access article available at
http://www.plosone.org/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1371%2Fjournal.pone.000035
MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo
Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice.
Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV.
Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls.
Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD
- …