Neil T. Wright

Cancer-Drug Associations: A Complex System

Background Network analysis has been performed on large-scale medical data, capturing the global topology of drugs, targets, and disease relationships. A smaller-scale network is amenable to a more detailed and focused analysis of the individual members and their interactions in a network, which can complement the global topological descriptions of a network system. Analysis of these smaller networks can help address questions, i.e., what governs the pairing of the different cancers and drugs, is it driven by molecular findings or other factors, such as death statistics. Methodology/Principal Findings We defined global and local lethality values representing death rates relative to other cancers vs. within a cancer. We generated two cancer networks, one of cancer types that share Food and Drug Administration (FDA) approved drugs (FDA cancer network), and another of cancer types that share clinical trials of FDA approved drugs (clinical trial cancer network). Breast cancer is the only cancer type with significant weighted degree values in both cancer networks. Lung cancer is significantly connected in the FDA cancer network, whereas ovarian cancer and lymphoma are significantly connected in the clinical trial cancer network. Correlation and linear regression analyses showed that global lethality impacts the drug approval and trial numbers, whereas, local lethality impacts the amount of drug sharing in trials and approvals. However, this effect does not apply to pancreatic, liver, and esophagus cancers as the sharing of drugs for these cancers is very low. We also collected mutation target information to generate cancer type associations which were compared with the cancer type associations derived from the drug target information. The analysis showed a weak overlap between the mutation and drug target based networks. Conclusions/Significance The clinical and FDA cancer networks are differentially connected, with only breast cancer significantly connected in both networks. The networks of cancer-drug associations are moderately affected by the death statistics. A strong overlap does not exist between the cancer-drug associations and the molecular information. Overall, this analysis provides a systems level view of cancer drugs and suggests that death statistics (i.e. global vs. local lethality) have a differential impact on the number of approvals, trials and drug sharing.

Comparison of Models of Post-Hyperthermia Cell Survival

Several existing mathematical models of the survival of mammalian cells in culture following heating are compared. These models describe the fraction of cells that survive in a normal culture environment following a relatively brief period of heating between approximately 43 °C and 60 °C. The models have been developed either from rate process or mechanistic arguments. Little quantitative comparison between such models has been made using the same sets of data. The models are compared using the Akaike Information Criterion (AICc) after the model parameters have been estimated for two sets of existing data: human prostate cancer cells and Chinese hamster ovary cells. Most of the models capture the cell survival response. Scaled sensitivity coefficients show that some of the models have parameters that are difficult to estimate reliably. Relatively small variations in the AICc suggest that more measurements are needed before ranking the models.

Comparison of the Role of Moderate Heat Treatment Temperatures on the Thermal Conductivity of Ingot Niobium

The thermal conductivity of superconducting niobium varies, in a yet unknown way, due to the processing history of the ingots and manufacturing processes during fabrication into cavities. Here, a theoretically based model is used to relate thermal conductivity to the metallurgy and processing history of niobium. Parameter groups are estimated using novel parameter estimation techniques on temperature and heat flux measurements on specimens cut from niobium ingots and having different processing histories. Results indicate a strong relation of one parameter group with RRR, and another with the temperature of heat treatment. After heat treating, a mild phonon peak was observed for specimens treated at 600° C for 6 hours, while a prominent phonon peak was observed in specimens treated at 750° C or 800° C for 2 hours. No change in conductivity in the electron dominated regime was observed, nor was there an effect due to tantalum at concentrations of less than 1322 ppm.

On the Computation of Stress in Affine Versus Nonaffine Fibril Kinematics Within Planar Collagen Network Models

Some recent analyses modeled the response of collagenous tissues, such as epicardium, using a hypothetical network consisting of interconnected springlike fibers. The fibers in the network were organized such that internal nodes served as the connection point between three such collagen springs. The results for assumed affine and nonaffine deformations are contrasted after a homogeneous deformation at the boundary. Affine deformation provides a stiffer mechanical response than nonaffine deformation. In contrast to nonaffine deformation, affine deformation determines the displacement of internal nodes without imposing detailed force balance, thereby complicating the simplest intuitive notion of stress, one based on free body cuts, at the single node scale. The standard notion of stress may then be recovered via average field theory computations based on large micromesh realizations. An alternative and by all indications complementary viewpoint for the determination of stress in these collagen fiber networks is discussed here, one in which stress is defined using elastic energy storage, a notion which is intuitive at the single node scale. It replaces the average field theory computations by an averaging technique over randomly oriented isolated simple elements. The analytical operations do not require large micromesh realizations, but the tedious nature of the mathematical manipulation is clearly aided by symbolic algebra calculation. For the example case of linear elastic deformation, this results in material stiffnesses that relate the infinitesimal strain and stress. The result that the affine case is stiffer than the nonaffine case is recovered, as would be expected. The energy framework also lends itself to the natural inclusion of changes in mechanical response due to the chemical, electrical, or thermal environment.

Parameter Correlation in Models of Hyperthermic Cell Death

A number of mathematical models have been developed to predict the survival of cells after heating. Some of these models have been based on first principle arguments, while others have been empirically motivated. Some models have been inspired by analogs of damage to cells by ionizing radiation. Evidence exists for multiple targets leading to cell death, although precise definition of the pathways for the various temperature ranges and environmental conditions remains in question. For reviews of the cellular targets of heating, see [1], [2], or [3].Copyright

DEVELOPMENT OF A CRYOGENIC MECHANICAL PROPERTY TESTING STATION FOR SUPERCONDUCTING RF CAVITY MATERIAL

Recent concerns with pressure vessel codes as they relate to the construction of superconducting linacs have raised questions about mechanical proprieties of materials used in their fabrication at cryogenic temperatures. Pressure vessel engineering codes will require demonstration of a level of safety equivalent to that provided by the various ASME pressure and piping codes, so low temperature mechanical properties of niobium, titanium, and their alloys are needed. Michigan State University (MSU), in collaboration with Fermi National Accelerator Laboratory (FNAL) and Florida State University (FSU), is constructing a materials testing station for tensile tests of materials at room and cryogenic temperatures (300, 77, and 4 K). Once complete, the testing station will allow researchers to relate effects of different microstructures arising from manufacturing pathways, including annealing processes, crystal orientations and microstructure characteristics (e.g. welds) to the resulting mechanical properties at ...

Deformation mechanisms, defects, heat treatment, and thermal conductivity in large grain niobium

The physical and mechanical metallurgy underlying fabrication of large grain cavities for superconducting radio frequency accelerators is summarized, based on research of 1) grain orientations in ingots, 2) a metallurgical assessment of processing a large grain single cell cavity and a tube, 3) assessment of slip behavior of single crystal tensile samples extracted from a high purity ingot slice before and after annealing at 800 °C / 2 h, 4) development of crystal plasticity models based upon the single crystal experiments, and 5) assessment of how thermal conductivity is affected by strain, heat treatment, and exposure to hydrogen. Because of the large grains, the plastic anisotropy of deformation is exaggerated, and heterogeneous strains and localized defects are present to a much greater degree than expected in polycrystalline material, making it highly desirable to computationally anticipate potential forming problems before manufacturing cavities.

Temperature Excursions in Nb Sheets With Imbedded Delamination Cracks

Delamination cracks can form in rolled Nb sheets, and between layers with different micro-structures. Such cracks cause resistance to heat conduction from the RF surface to the liquid He bath. A delamination crack can negate the advances in manufacturing processes that have enhanced the thermal conductivity of Nb. Here, temperature excesses are calculated as functions of crack size and location, and the power dissipated at an imperfection in the RF surface. A disk shape of Nb sheet is modeled as having adiabatic sides. A hemispherical defect is located on the RF surface at the center of this section. A crack is modeled as a void within the Nb disk. The Kapitza resistance between the Nb surface and liquid He is varied. The results indicate that an incipient crack leads to a decrease in the magnetic flux required to cause thermal breakdown. The decrease in the field is gradual with increasing crack radius, until the crack radius nearly equals the section radius, after which the field required for breakdown decreases sharply. To a lesser extent, the field strength for thermal breakdown also decreases with increased crack depth.

Foundations for quantitative microstructural models to track evolution of the metallurgical state during high purity Nb cavity fabrication

The goal of the Materials Science SRF Cavity Group of Michigan State University and the National Superconducting Cyclotron has been (and continues to be) to understand quantitatively the effects of process history on functional properties. These relationships were assessed via studies on Nb samples and cavity parts, which had various combinations of forming processes, welding, heat treatments, and surface preparation. A primary focus was on large-grain cavity building strategies. Effects of processing operations and exposure to hydrogen on the thermal conductivity has been identified in single and bi-crystal samples, showing that the thermal conductivity can be altered by a factor of 5 depending on process history. Characterization of single crystal tensile samples show a strong effect of crystal orientation on deformation resistance and shape changes. Large grain half cells were examined to characterize defect content and surface damage effects, which provided quantitative information about the depth damage layers from forming.

Parameter estimation in models of cell survival using scaled time

Many individual samples are needed to measure cell survival following heating at multiple temperatures and multiple heating durations. For example, if eight time points are considered for each of seven treatment temperatures with three replicates at each condition, then 168 separate samples are needed. In addition, physical considerations may limit the number of points that can be measured, especially as treatment temperature increases and the heating duration decreases. For a reasonable sample size, there may be a limit to the treatment temperature as the time required to heat the culture to the target temperature becomes comparable to the treatment time. Then, using an isothermal analysis of the data introduces error and the temperature must be considered time varying, requiring estimates of the very parameters being sought. Conversely, for long treatment times, it may be difficult to insure that the temperature remains constant and that the temperature is the only modified experimental condition in the culture medium. These challenges typically lead to relatively small data sets. Furthermore, treating each temperature as a separate experiment leads to challenging statistical analysis of the data, as the few data points lead to difficulty in finding the confidence intervals of the parameters in a given model.Copyright