Contributions to HEVC Prediction for Medical Image Compression

Medical imaging technology and applications are continuously evolving, dealing with images of increasing spatial and temporal resolutions, which allow easier and more accurate medical diagnosis. However, this increase in resolution demands a growing amount of data to be stored and transmitted. Despite the high coding efficiency achieved by the most recent image and video coding standards in lossy compression, they are not well suited for quality-critical medical image compression where either near-lossless or lossless coding is required. In this dissertation, two different approaches to improve lossless coding of volumetric medical images, such as Magnetic Resonance and Computed Tomography, were studied and implemented using the latest standard High Efficiency Video Encoder (HEVC). In a first approach, the use of geometric transformations to perform inter-slice prediction was investigated. For the second approach, a pixel-wise prediction technique, based on Least-Squares prediction, that exploits inter-slice redundancy was proposed to extend the current HEVC lossless tools. Experimental results show a bitrate reduction between 45% and 49%, when compared with DICOM recommended encoders, and 13.7% when compared with standard HEVC.

Enhanced spectral compression in nonlinear optical fibres

We propose two new approaches to enhance the spectral compression process arising from nonlinear pulse propagation in an optical fibre. We numerically show that an additional sinusoidal temporal phase modulation of the pulse enables efficient reduction of the intensity level of side lobes in the spectrum. Another strategy is to select a regime of propagation in which normal group-velocity dispersion reshapes the initial stretched pulse to a near-Fourier-transform-limited rectangular waveform.

Enhanced nonlinear spectral compression in fiber by external sinusoidal phase modulation

We propose a new, simple approach to enhance the spectral compression process arising from nonlinear pulse propagation in an optical fiber. We numerically show that an additional sinusoidal temporal phase modulation of the pulse enables efficient reduction of the intensity level of the side lobes in the spectrum that are produced by the mismatch between the initial linear negative chirp of the pulse and the self-phase modulation-induced nonlinear positive chirp. Remarkable increase of both the extent of spectrum narrowing and the quality of the compressed spectrum is afforded by the proposed approach across a wide range of experimentally accessible parameters.

Enhanced nonlinear spectral compression in fibre by sinusoidal phase modulation

We propose a simple approach to enhance the spectral compression arising from nonlinear pulse propagation in a Kerr medium. We numerically show that an additional sinusoidal temporal phase modulation enables efficient reduction of the intensity level of spectral side lobes.

Content-aware compression for big textual data analysis

A substantial amount of information on the Internet is present in the form of text. The value of this semi-structured and unstructured data has been widely acknowledged, with consequent scientific and commercial exploitation. The ever-increasing data production, however, pushes data analytic platforms to their limit. This thesis proposes techniques for more efficient textual big data analysis suitable for the Hadoop analytic platform. This research explores the direct processing of compressed textual data. The focus is on developing novel compression methods with a number of desirable properties to support text-based big data analysis in distributed environments. The novel contributions of this work include the following. Firstly, a Content-aware Partial Compression (CaPC) scheme is developed. CaPC makes a distinction between informational and functional content in which only the informational content is compressed. Thus, the compressed data is made transparent to existing software libraries which often rely on functional content to work. Secondly, a context-free bit-oriented compression scheme (Approximated Huffman Compression) based on the Huffman algorithm is developed. This uses a hybrid data structure that allows pattern searching in compressed data in linear time. Thirdly, several modern compression schemes have been extended so that the compressed data can be safely split with respect to logical data records in distributed file systems. Furthermore, an innovative two layer compression architecture is used, in which each compression layer is appropriate for the corresponding stage of data processing. Peripheral libraries are developed that seamlessly link the proposed compression schemes to existing analytic platforms and computational frameworks, and also make the use of the compressed data transparent to developers. The compression schemes have been evaluated for a number of standard MapReduce analysis tasks using a collection of real-world datasets. In comparison with existing solutions, they have shown substantial improvement in performance and significant reduction in system resource requirements.

Petri Net Siphon Analysis and Network Centrality Measures for Identifying Combination Therapies in Signaling Pathways

Aberrant behavior of biological signaling pathways has been implicated in diseases such as cancers. Therapies have been developed to target proteins in these networks in the hope of curing the illness or bringing about remission. However, identifying targets for drug inhibition that exhibit good therapeutic index has proven to be challenging since signaling pathways have a large number of components and many interconnections such as feedback, crosstalk, and divergence. Unfortunately, some characteristics of these pathways such as redundancy, feedback, and drug resistance reduce the efficacy of single drug target therapy and necessitate the employment of more than one drug to target multiple nodes in the system. However, choosing multiple targets with high therapeutic index poses more challenges since the combinatorial search space could be huge. To cope with the complexity of these systems, computational tools such as ordinary differential equations have been used to successfully model some of these pathways. Regrettably, for building these models, experimentally-measured initial concentrations of the components and rates of reactions are needed which are difficult to obtain, and in very large networks, they may not be available at the moment. Fortunately, there exist other modeling tools, though not as powerful as ordinary differential equations, which do not need the rates and initial conditions to model signaling pathways. Petri net and graph theory are among these tools. In this thesis, we introduce a methodology based on Petri net siphon analysis and graph network centrality measures for identifying prospective targets for single and multiple drug therapies. In this methodology, first, potential targets are identified in the Petri net model of a signaling pathway using siphon analysis. Then, the graph-theoretic centrality measures are employed to prioritize the candidate targets. Also, an algorithm is developed to check whether the candidate targets are able to disable the intended outputs in the graph model of the system or not. We implement structural and dynamical models of ErbB1-Ras-MAPK pathways and use them to assess and evaluate this methodology. The identified drug-targets, single and multiple, correspond to clinically relevant drugs. Overall, the results suggest that this methodology, using siphons and centrality measures, shows promise in identifying and ranking drugs. Since this methodology only uses the structural information of the signaling pathways and does not need initial conditions and dynamical rates, it can be utilized in larger networks.

Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

Behavior of Granular Materials Under Triaxial Compression with Pulsating Deviator Stress, HR-131, Special Report

Behavior of granular material subjected to repeated load triaxial compression tests is characterized by a model based on rate process theory. Starting with the Arrhenius equation from chemical kinetics, the relationship of temperature, shear stress, normal stress and volume change to deformation rate is developed. The proposed model equation includes these factors as a product of exponential terms. An empirical relationship between deformation and the cube root of the number of stress applications at constant temperature and normal stress is combined with the rate equation to yield an integrated relationship of temperature, deviator stress, confining pressure and number of deviator stress applications to axial strain. The experimental program consists of 64 repeated load triaxial compression tests, 52 on untreated crushed stone and 12 on the same crushed stone material treated with 4% asphalt cement. Results were analyzed with multiple linear regression techniques and show substantial agreement with the model equations. Experimental results fit the rate equation somewhat better than the integrated equation when all variable quantities are considered. The coefficient of shear temperature gives the activation enthalpy, which is about 4.7 kilocalories/mole for untreated material and 39.4 kilocalories/mole for asphalt-treated material. This indicates the activation enthalpy is about that of the pore fluid. The proportionality coefficient of deviator stress may be used to measure flow unit volume. The volumes thus determined for untreated and asphalt-treated material are not substantially different. This may be coincidental since comparison with flow unit volumes reported by others indicates flow unit volume is related to gradation of untreated material. The flow unit volume of asphalt-treated material may relate to asphalt cement content. The proposed model equations provide a more rational basis for further studies of factors affecting deformation of granular materials under stress similar to that in pavement subjected to transient traffic loads.

Virtual Clinical Trials in PET Imaging for Improved Diagnosis of and Evaluation of Therapies for Cancer

Thesis (Ph.D.)--University of Washington, 2016-08

Role for cell-to-cell communication in stem cell specification toward pancreatic progenitors: relevance to the design of novel therapies for diabetes.

Thesis (Ph.D.)--University of Washington, 2016-08

Characterization of the glial scar tissue in a murine model of spinal cord compression, with focus on hyaluronan

Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of people each year. Although in recent decades significant progress has been made in relation to understanding the molecular and cellular events underlying the nervous damage, spinal cord injury is still a highly disabling condition for which there is no curative therapy. People affected by spinal cord injuries manifested dysfunction or loss, temporary or permanent, of motor, sensory and / or autonomic functions depending on the spinal lesion damaged. Currently, the incidence rate of this type of injury is approximately 15-40 cases per million people worldwide. At the origin of these lesions are: road accidents, falls, interpersonal violence and the practice of sports. In this work we placed the hypothesis that HA is one of the component of the scar tissue formed after a compressive SCI, that it is likely synthetised by the perilesional glial cells and that it might support the permeation of the glial scar during the late phase of SCI. Nowadays, much focus is drawn on the recovery of CNS function, made impossible after SCI due to the high content of sulfated proteoglycans in the extracellular matrix. Counterbalancing the ratio between these proteoglycans and hyaluronic acid could be one of the experimental therapy to re-permeate the glial scar tissue formed after SCI, making possible axonal regrowth and functional recovery. Therefore, we established a model of spinal cord compression in mice and studied the glial scar tissue, particularly through the characterization of the expression of enzymes related to the metabolism of HA and the subsequent concentration thereof at different distances of the lesion epicenter. Our results show that the lesion induced in mice shows results similar to those produced in human lesions, in terms of histologic similarities and behavioral results. but these animals demonstrate an impressive spontaneous reorganization mechanism of the spinal cord tissue that occurs after injury and allows for partial recovery of the functions of the CNS. As regards the study of the glial scar, changes were recorded at the level of mRNA expression of enzymes metabolizing HA i.e., after injury there was a decreased expression of HA synthases 1-2 (HAS 1-2) and an increase of the expression HAS3 synthase mRNA, as well as the enzymes responsible for the HA catabolism, HYAL 1-2. But the amount of HA measured through the ELISA test was found unchanged after injury, it is not possible to explain this fact only with the change of expression of enzymes. At two weeks and in response to SCI, we found synthesized HA by reactive astrocytes and probably by others like microglial cells as it was advanced by the HA/GFAP+ and HA/IBA1+ cells co-location.