A stochastic programming approach for clinical trial planning in new drug development

The paper presents a multi-stage stochastic programming formulation for the planning of clinical trials in the pharmaceutical research and development (R&D) pipeline. Scenarios are used to account for the endogenous uncertainty in clinical trial outcomes. Given a portfolio of potential drugs and limited resources, the model determines the trials to be performed in each planning period and scenario. To reduce the size of the formulation we employ a reduced set of scenarios without compromising the quality of uncertainty representation. Furthermore, we present a number of ideas that allow us to reduce the number of non-anticipativity constraints necessary to model indistinguishable scenarios. The proposed approach is the first stochastic programming formulation to address this problem.     

Superparamagnetic polyvinylpyrrolidone/chitosan/Fe3O4 electrospun nanofibers as effective U(VI) adsorbents

Magnetoactive electrospun fibrous membranes consisting of polyvinylpyrrolidone (PVP), chitosan (CS) and pre-fabricated, double-layer oleic acid-coated magnetite nanoparticles (OA.OA.Fe₃O₄) were fabricated and evaluated as new adsorbent materials for the removal and recovery of uranium (U(VI)) from aqueous solutions. The adsorption has been investigated by batch-type experiments and the solid material has been characterized by X-ray diffraction spectroscopy (XRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy/energy dispersive X-ray analysis (TEM/EDX) and vibration sample magnetometry (VSM) measurements prior and after uranium adsorption. The experimental adsorption data were found to be well fitted with the Langmuir isotherm and the pseudo-second order kinetic model. The results indicate that PVP/CS/OA.OA.Fe₃O₄ fibrous adsorbents exhibit good adsorption properties towards U(VI) in aqueous solutions, achieving a q_max value of 0.77 mol kg⁻¹ (183.3 mg g⁻¹) at pH 6.0. The experiments regarding the regeneration and reuse of the magnetoactive adsorbents were carried out using Na₂CO₃, at pH ~11. After four cycles, the percentage relative adsorption remained stable (~100%) whereas the desorption percentage decreased from 31.9% to 21.0%. Generally, the presented results demonstrate that the incorporation of the Fe₃O₄ NPs has a positive effect on the adsorption efficiency of U(VI) from aquatic environments.     

A general framework and optimization models for the scheduling of continuous chemical processes

We present a framework for the formulation and solution of continuous process scheduling problems. We focus on modeling transient operations such as startups, shutdowns, and transitions between steady states. First, we show how the concept of processing tasks can be generalized to represent continuous processes, including their transient operations. Second, we discuss how to systematically calculate the parameters describing material consumption/production and utility consumption during transient operations. Finally, we present new mixed-integer linear programming formulations for the scheduling of continuous chemical production.     

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.     

The Mystery of Extramitochondrial Proteins Lysine Succinylation

Lysine succinylation is a post-translational modification which alters protein function in both physiological and pathological processes. Mindful that it requires succinyl-CoA, a metabolite formed within the mitochondrial matrix that cannot permeate the inner mitochondrial membrane, the question arises as to how there can be succinylation of proteins outside mitochondria. The present mini-review examines pathways participating in peroxisomal fatty acid oxidation that lead to succinyl-CoA production, potentially supporting succinylation of extramitochondrial proteins. Furthermore, the influence of the mitochondrial status on cytosolic NAD⁺ availability affecting the activity of cytosolic SIRT5 iso1 and iso4—in turn regulating cytosolic protein lysine succinylations—is presented. Finally, the discovery that glia in the adult human brain lack subunits of both alpha-ketoglutarate dehydrogenase complex and succinate-CoA ligase—thus being unable to produce succinyl-CoA in the matrix—and yet exhibit robust pancellular lysine succinylation, is highlighted.     

Nitrogen dynamics during the seed-filling period in safflower under dryland Mediterranean conditions

Nutrient Cycling in Agroecosystems - Precise knowledge of safflower (Carthamus tinctorius L.) nitrogen (N) dynamics is essential to optimize crop nutrition and minimize environmental impacts of...     

Hot Chips Turns 20 [Guest editors' introduction]

The five papers in this special issue are extended versions of papers presented at the Hot Chips conference in August 1008.     

Strong equivalence of logic programs under the infinite-valued semantics

We consider the notion of strong equivalence [V. Lifschitz, D. Pearce, A. Valverde, Strongly equivalent logic programs, ACM Transactions on Computational Logic 2 (4) (2001) 526-541] of normal propositional logic programs under the infinite-valued semantics [P. Rondogiannis, W.W. Wadge, Minimum model semantics for logic programs with negation-as-failure, ACM Transactions on Computational Logic 6 (2) (2005) 441-467] (which is a purely model-theoretic semantics that is compatible with the well-founded one). We demonstrate that two such programs are strongly equivalent under the infinite-valued semantics if and only if they are logically equivalent in the corresponding infinite-valued logic. In particular, we show that strong equivalence of normal propositional logic programs is decidable, and more specifically coNP-complete. Our results have a direct implication for the well-founded semantics since, as we demonstrate, if two programs are strongly equivalent under the infinite-valued semantics, then they are also strongly equivalent under the well-founded semantics.     

Energy research and technology development data collection strategies: The case of Greece

The European Union (EU) from the beginning of 2007 has focused its emphasis on the development of a new policy that puts energy back at the heart of EU action. Indeed, it has very often been stated that the difficulty and complexity of achieving green energy targets in the EU will require strengthened measures to promote implementation of new energy technologies (NET), as well as measures to support the related energy Research and Technology Development (R&TD). Often forgotten is the fact, that most of all, a European-wide co-ordinated forum is needed to continuously develop and sophisticate the monitoring and methodology results, bringing together specialised statisticians, energy researchers and experts on energy socio-economics. Today a nebulous picture prevails on the existence of categorized data with regards to energy Research and Technology Development (R&TD) expenditure. In this context, aim of this paper is the presentation of energy R&TD data collection strategies, as well as the related findings for the Greek energy market.     

Optimization methodology of dynamic data structures based on genetic algorithms for multimedia embedded systems

Modern multimedia application exhibit high resource utilization. In order to efficiently run this kind of applications in embedded systems, the dynamic memory subsystem needs to be optimized. A key role in this optimization is played by the dynamic data structures that reside in every real-life application. This paper presents a novel and automated way to optimize dynamic data structures. The search space is pruned using genetic algorithms that converge to the best multilayered data structure implementation for the targeted applications.