PIM KINASE INHIBITION: SINGLE AGENT AND COMBINATION APPROACHES IN B-CELL LYMPHOMA

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are Ser/Thr/Tyr kinases. They modulate B-cell development but become oncoproteins and promote cancer development once overexpressed. Containing three isoforms, Pim-1, -2 and -3 are known to phosphorylate various substrates that regulate transcription, translation, cell cycle, and survival pathways in both hematological and solid tumors. Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Elevated Pim kinase levels are common in MCL, and it negatively correlates with patient outcome. SGI-1776 is a small molecule inhibitor selective for Pim-1/-3. We hypothesize that SGI-1776 treatment in MCL will inhibit Pim kinase function, and inhibition of downstream substrates phosphorylation will disrupt transcriptional, translational, and cell cycle processes while promoting apoptosis. SGI-1776 treatment induced moderate to high levels of apoptosis in four MCL cell lines (JeKo-1, Mino, SP-53 and Granta-519) and peripheral blood mononuclear cells (PBMCs) from MCL patients. Phosphorylation of transcription and translation regulators, c-Myc and 4E-BP1 declined in both model systems. Additionally, levels of short-lived Mcl-1 mRNA and protein also decreased and correlated with decline of global RNA synthesis. Collectively, our investigations highlight Pim kinases as viable drug targets in MCL and emphasize their roles in transcriptional and translational regulation. We further investigated a combination strategy using SGI-1776 with bendamustine, an FDA-approved DNA-damaging alkylating agent for treating non-Hodgkin’s lymphoma. We hypothesized this combination will enhance SGI-1776-induced transcription and translation inhibition, while promoting bendamustine-triggered DNA damage and inducing additive to synergistic cytotoxicity in B-cell lymphoma. Bendamustine alone resulted in moderate levels of apoptosis induction in MCL cell lines (JeKo-1 and Mino), and in MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. An additive effect in cell killing was observed when combined with SGI-1776. Expectedly, SGI-1776 effectively decreased global RNA and protein synthesis levels, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. In combination, intensified inhibitory effects in DNA, RNA and protein syntheses were observed. Together, these data suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma, and provided foundation of their mechanism of actions in lymphoma cells.

Dynamic contrast agent -enhanced magnetic resonance imaging assessment of tumor microvasculature

Dynamic contrast agent-enhanced magnetic resonance imaging (DCE MRI) data, when analyzed with the appropriate pharmacokinetic models, have been shown to provide quantitative estimates of microvascular parameters important in characterizing the angiogenic activity of malignant tissue. These parameters consist of the whole blood volume per unit volume of tissue, v b, transport constant from the plasma to the extravascular, extracellular space (EES), k1 and the transport constant from the EES to the plasma, k2. Parameters vb and k1 are expected to correlate with microvascular density (MVD) and vascular permeability, respectively, which have been suggested to serve as surrogate markers for angiogenesis. In addition to being a marker for angiogenesis, vascular permeability is also useful in estimating tumor penetration potential of chemotherapeutic agents. ^ Histological measurements of the intratumoral microvascular environment are limited by their invasiveness and susceptibility to sampling errors. Also, MVD and vascular permeability, while useful for characterizing tumors at a single time point, have shown less utility in longitudinal studies, particularly when used to monitor the efficacy of antiangiogenic and traditional chemotherapeutic agents. These limitations led to a search for a non-invasive means of characterizing the microvascular environment of an entire tumor. ^ The overall goal of this project was to determine the utility of DCE MRI for monitoring the effect of antiangiogenic agents. Further applications of a validated DCE MRI technique include in vivo measurements of tumor microvascular characteristics to aid in determining prognosis at presentation and in estimating drug penetration. DCE MRI data were generated using single- and dual-tracer pharmacokinetic models with different molecular-weight contrast agents. The resulting pharmacokinetic parameters were compared to immunohistochemical measurements. The model and contrast agent combination yielding the best correlation between the pharmacokinetic parameters and histological measures was further evaluated in a longitudinal study to evaluate the efficacy of DCE MRI in monitoring the intratumoral microvascular environment following antiangiogenic treatment. ^

Thermodynamics of zinc insertion in CuGaS2:Ti, used as a modulator agent in an intermediate-band photovoltaic material

An intermediate-bandphotovoltaicmaterial, which has an isolated metallic band located between the top of the valence band and bottom of the conduction band of some semiconductors, has been proposed as third generation solar cell to be used in photovoltaic applications. Density functional theory calculations of Zn in CuGaS2:Ti have previously shown that, the intermediate-band position can be modulated in proportion of Zn insertion in such a way that increasing Zn concentration can lead to aband-gap reduction, and an adjustment of the intermediate-band position. This could be interesting in the formation of an intermediate-bandmaterial, that has the maximum efficiency theoretically predicted for the intermediate-band solar cell. In this work, the energetics of several reaction schemes that could lead to the decomposition of the modulated intermediate-bandphotovoltaicmaterial, CuGaS2:Ti:Zn, is studied in order to assess the thermodynamic stability of this material. Calculations of the total free energy and disorder entropy have been taken into account, to get the reaction energy and free energy of the compound decomposition, which is found to be thermodynamically favorable

The Effect That Project Management Certification Has on Employability: Agent's Perceptions from Spain

This study analyses the effects that the project management certification has on employability. This analysis started with a participative process in which various groups of experts who are involved in the certification of people were consulted. A personal interview was carried out amongst 106 professionals —certifying bodies, training institutions, the civil service, and international organisations— and amongst professional who are certified in project management by the International Project Management Association in Spain. The results show that the certification emerges as a powerful tool for improving employability. The effects are demonstrated across two complementary aspects: internal company aspects and external aspects relating to the labour market. Finally, by compiling the different agents’ opinions, a series of measures emerge for improving the accreditation processes as an employability tool and increasing the mutual learning between public and private actors.

A Multi-Agent System for the Solution of Fuzzy Incidents in Telecommunications

This article presents a multi-agent expert system (SMAF) , that allows the input of incidents which occur in different elements of the telecommunications area. SMAF interacts with experts and general users, and each agent with all the agents? community, recording the incidents and their solutions in a knowledge base, without the analysis of their causes. The incidents are expressed using keywords taken from natural language (originally Spanish) and their main concepts are recorded with their severities as the users express them. Then, there is a search of the best solution for each incident, being helped by a human operator using a distancenotions between them.

Multi-agent Architecture for Heterogeneous Reasoning under Uncertainty Combining MSBN and Ontologies in Distributed Network Diagnosis

This article proposes a MAS architecture for network diagnosis under uncertainty. Network diagnosis is divided into two inference processes: hypothesis generation and hypothesis confirmation. The first process is distributed among several agents based on a MSBN, while the second one is carried out by agents using semantic reasoning. A diagnosis ontology has been defined in order to combine both inference processes. To drive the deliberation process, dynamic data about the influence of observations are taken during diagnosis process. In order to achieve quick and reliable diagnoses, this influence is used to choose the best action to perform. This approach has been evaluated in a P2P video streaming scenario. Computational and time improvements are highlight as conclusions.

A Multi-agent System for Emergency Decision Support

This paper describes the multi-agent organization of a computer system that was designed to assist operators in decision making in the presence of emergencies. The application was developed for the case of emergencies caused by river floods. It operates on real-time receiving data recorded by sensors (rainfall, water levels, flows, etc.) and applies multi-agent techniques to interpret the data, predict the future behavior and recommend control actions. The system includes an advanced knowledge based architecture with multiple symbolic representation with uncertainty models (bayesian networks). This system has been applied and validated at two particular sites in Spain (the Jucar basin and the South basin).

Agent Programming in Ciao Prolog

The agent programming landscape has been revealed as a natural framework for developing “intelligence” in AI. This can be seen from the extensive use of the agent concept in presenting (and developing) AI systems, the proliferation of agent theories, and the evolution of concepts such as agent societies (social intelligence) and coordination.

A survey of agent-oriented methodologies

This article introduces the current agent-oriented methodologies. It discusses what approaches have been followed (mainly extending existing object oriented and knowledge engineering methodologies), the suitability of these approaches for agent modelling, and some conclusions drawn from the survey.