Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia

BACKGROUND:Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways. METHODOLOGY AND PRINCIPAL FINDINGS:Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents. CONCLUSIONS AND SIGNIFICANCE:Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy

Information theory insights into molecular electronic structure and reactivity

Struct Bond (2012) 149: 51–94 DOI: 10.1007/978-3-642-32753-7_2 # Springer-Verlag Berlin Heidelberg 2012 Information Theory Insights into Molecular Electronic Structure and Reactivity Roman F. Nalewajski Abstract Selected concepts and techniques of Information-Theory (IT) are summarized and their use in probing the molecular electronic structure is advocated. The electron redistributions accompanying formation of chemical bonds, relative to the (molecularly placed) free atoms of the corresponding “promolecule,” generate the associated displacements in alternative measures of the amount of information carried by electrons. The latter are shown to provide sensitive probes of information origins of the chemical bonds, allow the spatial localization of bonding regions in molecules, and generate attractive entropy/ information descriptors of the system bond multiplicities. Information-theoretic descriptors of both the molecule as a whole and its diatomic fragments can be extracted. Displacements in the molecular Shannon entropy and entropy deficiency, relative to the promolecular reference, are investigated. Their densities provide efficient tools for detecting the presence of the direct chemical bonds and for monitoring the promotion/hybridization changes the bonded atoms undergo in a molecular environment. The nonadditive Fisher information density in the Atomic Orbital (AO) resolution is shown to generate an efficient Contra-Gradience (CG) probe for locating the bonding regions in molecules. Rudiments of the Orbital Communication Theory (OCT) of the chemical bond are introduced. In this approach molecules are treated as information systems propagating “signals” of electron allocations to basis functions, from AO “inputs” to AO “outputs.” The conditional probabilities defining such an information network are generated using the bond-projected superposition principle of quantum mechanics. They are pro- portional to squares of the corresponding elements of the first-order density matrix in AO representation. Therefore, they are related to Wiberg’s quadratic index of the chemical bond multiplicity. Such information propagation in molecules exhibits typical communication “noise” due to the electron delocalization via the system chemical bonds. In describing this scattering of electron probabilities throughout the network of chemical bonds, due to the system occupied Molecular Orbitals (MO), the OCT uses the standard entropy/information descriptors of communica- tion devices. They include the average communication noise (IT covalency) and information flow (IT ionicity) quantities, reflected by the channel conditional entropy and mutual information characteristics, respectively. Recent examples of applying these novel tools in an exploration of the electronic structure and bonding patterns of representative molecules are summarized. This communication perspec- tive also predicts the “indirect” (through- bridge ) sources of chemical interactions, due to the “cascade” probability propagation realized via AO intermediates. It supplements the familiar through- space mechanism, due to the constructive interference between the interacting AO, which generates the “direct” communi- cations between bonded atoms. Such bridge “bonds” effectively extend the range of chemical interactions in molecular systems. Representative examples of the p systems in benzene and butadiene are discussed in a more detail and recent applications of the information concepts in exploring the elementary reaction mechanisms are mentioned