Local partial likelihood estimation in proportional hazards regression

Fan, Gijbels and King [Ann. Statist. 25 (1997) 1661--1690] considered the estimation of the risk function $\psi (x)$ in the proportional hazards model. Their proposed estimator is based on integrating the estimated derivative function obtained through a local version of the partial likelihood. They proved the large sample properties of the derivative function, but the large sample properties of the estimator for the risk function itself were not established. In this paper, we consider direct estimation of the relative risk function $\psi (x_2)-\psi (x_1)$ for any location normalization point $x_1$. The main novelty in our approach is that we select observations in shrinking neighborhoods of both $x_1$ and $x_2$ when constructing a local version of the partial likelihood, whereas Fan, Gijbels and King [Ann. Statist. 25 (1997) 1661--1690] only concentrated on a single neighborhood, resulting in the cancellation of the risk function in the local likelihood function. The asymptotic properties of our estimator are rigorously established and the variance of the estimator is easily estimated. The idea behind our approach is extended to estimate the differences between groups. A simulation study is carried out.Comment: Published at http://dx.doi.org/10.1214/009053606000001299 in the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

New MRI Techniques for Nanoparticle Based Functional and Molecular Imaging

Although in clinical use for several decades, magnetic resonance imaging: MRI) is undergoing a transition from a qualitative anatomical imaging tool to a quantitative technique for evaluating myriad diseases. Furthermore, MRI has made great strides as a potential tool for molecular imaging of cellular and tissue biomarkers. Of the candidate contrast agents for molecular MRI, the excellent bio-compatibility and adaptability of perfluorocarbon nanoparticles: PFC NP) has established these agents as a potent targeted imaging agent and as a functional platform for non-invasive oxygen tension sensing. Direct readout and quantification of PFC NP can be achieved with fluorine: 19F) MRI because of the unique 19F signal emanating from the core PFC molecules. However, the signal is usually limited by the modest accumulated concentrations as well as several special NMR considerations for PFC NP, which renders 19F MRI technically challenging in terms of detection sensitivity, scan time, and image reconstruction. In the present dissertation, some of the pertinent NMR properties of PFC NP are investigated and new 19F MRI techniques developed to enhance their performance and expand the biomedical applications of 19F MRI with PFC NP. With the use of both theoretical and experimental methods, we evaluated J-coupling modulation, chemical shift and paramagnetic relaxation enhancement of PFC molecules in PFC NP. Our unique contribution to the technical improvement of 19F MRI of small animal involves:: 1) development of general strategies for RF 1H/19F coil design;: 2) design of novel MR pulse sequences for 19F T1 quantification; and: 3) optimization of imaging protocols for distinguishing and visualizing multiple PFC components: multi-chromatic 19F MRI). The first pre-clinical application of our novel 19F MRI techniques is blood vessel imaging and rapid blood oxygen tension measurement in vivo. Blood vessel anatomy and blood oxygen tension provide pivotal physiological information for routine diagnosis of cardiovascular disease. Using our novel Blood: flow)-Enhanced-Saturation-Recovery: BESR) sequence, we successfully visualized reduced flow caused by thrombosis in carotid arteries and jugular veins, and we quantified the oxygen tension in the cardiac ventricles of the mouse. The BESR sequence depicted the expected oxygenation difference between arterial and venous blood and accurately registered the response of blood oxygen tension to high oxygen concentration in 100% oxygen gas. This study demonstrated the potential application of PFC NP as a blood oxygen tension sensor and blood pool MR contrast agent for angiography. Another pre-clinical application investigated was functional kidney imaging with 19F MRI of circulating PFC NP. Conventional functional kidney imaging typically calls for the injection of small molecule contrast agents that may be nephrotoxic, which raises concerns for their clinical applications in patients with renal insufficiency. We demonstrated that our 19F MRI technique offers a promising alternative functional renal imaging approach that generates quantitative measurement of renal blood volume and intrarenal oxygenation. We successfully mapped the expected heterogeneous distribution of renal blood volume and confirmed the presence of an oxygenation gradient in healthy kidneys. We validated the diagnostic capability of 19F MRI in a mouse model of acute ischemia/reperfusion kidney injury. We also employed 19F MRI as a tool to test the therapeutic efficacy of a new nanoparticle-based drug, i. e. PPACK: D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) PFC NP, which was postulated to inhibit microvascular coagulation during acute kidney injury. Based on our preliminary 19F MRI findings, we observed that PPACK PFC NP effectively reduced coagulation in our animal model, as evidenced by lesser accumulation of particles trapped by the clotting process. This finding suggests the potential for 19F MRI to be used as a drug monitoring tool as well in common medical emergencies such as acute kidney failure

Development of 3-D Neutronic Kinetic Model and Control for CANDU Reactors

The development of a three dimensional (3-D) neutronic kinetic modeling process aiming at control system design for CANadian Deuterium Uranium (CANDU) reactors is carried out in this thesis using a modal synthesis method. In this method, the reactor space-time neutron flux is synthesized by a time-weighted series of precalculated neutron flux modes. These modes are eigenfunctions of the governing neutron diffusion equation at reference steady-state operating conditions. The xenon effect has also been considered. A special attention has been paid to compare the performance of the developed 3-D model with that of a traditional coupled point kinetic model. The 3-D reactor model is implemented by MATLAB/SIMULINK software environment. A nondimensionalized SIMULINK representation of the reactor model is established. The performance of the developed 3-D reactor neutronic kinetic model is then evaluated in a closed-loop environment with the help of a CANDU reactor regulating system (RRS) simulation platform. The dynamic behavior of the reactor model in a practical load-following mode has also been examined. The accuracy of the model has been validated against actual plant measurements under transient conditions. Through the analysis and simulation studies, it has convincingly demonstrated that the developed 3-D reactor model has significant advantages over the traditional coupled point kinetic model in terms of the improved accuracy and the higher resolution in modeling the reactor internal flux behaviors. Furthermore, using Graphic User Interface (GUI) techniques a user-friendly software package for the RRS simulation platform is developed. Based on the 3-D reactor model and identified deficiencies of existing RRS’ functions, an advanced 3-D reactor power distribution control is proposed and investigated. Linearization of the reactor model is performed and the performance of the linearized reactor model is evaluated in a closed-loop RRS environment. Using the feedback control law, a newly designed control strategy tries to suppress the effects of high order neutron flux modes and to emphasize behaviors of the dominant mode – the fundamental flux distribution adopted by the nominal design. Thereby, the 3-D power distribution shape during transients is optimally maintained closer to the nominal design shape than by the traditional RRS. The benefits of 3-D power distribution include not only the improved economical operation, but also improved safety as the uncertainties and the uneven power distribution are reduced. These have been confirmed by extensive simulation studies to Regional Overpower Protection (ROP) detectors’ flux transients during load following processes

Underlying Mechanisms Of Arsenic-Induced Tumorigenesis: From Epigenetics To Malignancy

Arsenic is a well-recognized environmental health threat with the capability of inducing a number of human diseases, including cancer. The aim of this dissertation is to unveil the mechanisms underlying the carcinogenic activities of environmental arsenic. The biological functions of arsenic had been studied for decades. However, there are still many questions that remain to be fully answered, such as whether and how arsenic contributes to the epigenetic regulations and migration or metastasis control of the cancer cells. In this regard, we focused our attention on both histone modifications and miRNA regulations in the arsenic-induced malignant transformation of the cells, and tried to establish the signaling cascades that mediate arsenic-induced transformation. Furthermore, we investigated the downstream functional pathways related to malignancy through biochemical and proteomics analyses. Based on the results from the first specific aim, we had demonstrated that long term treatment of the cells with arsenic at concentrations that are comparable to environment arsenic exposure is able to induce EZH2 phosphorylation that facilitates its cytoplasmic localization, and the expression of c-myc. Meanwhile, we also noted that long-term treatment of the cells with arsenic induces expression of miR-214 and miR-199a along with a metabolic reprogramming of the cells from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis (Warburg Effects). In the second specific aim, we further identified interaction of mdig and Filamin A phosphorylation that is involved in cell motility and migration induced by arsenic. Collectively, our studies on the novel pathways induced by arsenic provide new insights for the carcinogenetic mechanism of arsenic and shed light on the prevention and promising therapeutic strategies for human cancers that are associated with environmental arsenic exposure

Investigations of supernovae and supernova remnants in the era of SKA

Two main physical mechanisms are used to explain supernova explosions: thermonuclear explosion of a white dwarf(Type Ia) and core collapse of a massive star (Type II and Type Ib/Ic). Type Ia supernovae serve as distance indicators that led to the discovery of the accelerating expansion of the Universe. The exact nature of their progenitor systems however remain unclear. Radio emission from the interaction between the explosion shock front and its surrounding CSM or ISM provides an important probe into the progenitor star's last evolutionary stage. No radio emission has yet been detected from Type Ia supernovae by current telescopes. The SKA will hopefully detect radio emission from Type Ia supernovae due to its much better sensitivity and resolution. There is a 'supernovae rate problem' for the core collapse supernovae because the optically dim ones are missed due to being intrinsically faint and/or due to dust obscuration. A number of dust-enshrouded optically hidden supernovae should be discovered via SKA1-MID/survey, especially for those located in the innermost regions of their host galaxies. Meanwhile, the detection of intrinsically dim SNe will also benefit from SKA1. The detection rate will provide unique information about the current star formation rate and the initial mass function. A supernova explosion triggers a shock wave which expels and heats the surrounding CSM and ISM, and forms a supernova remnant (SNR). It is expected that more SNRs will be discovered by the SKA. This may decrease the discrepancy between the expected and observed numbers of SNRs. Several SNRs have been confirmed to accelerate protons, the main component of cosmic rays, to very high energy by their shocks. This brings us hope of solving the Galactic cosmic ray origin's puzzle by combining the low frequency (SKA) and very high frequency (Cherenkov Telescope Array: CTA) bands' observations of SNRs.Comment: To be published in: "Advancing Astrophysics with the Square Kilometre Array", Proceedings of Science, PoS(AASKA14