Mucin and Splice Variant Profiles of Pancreatic Adenocarcinoma Predict Patient Survival and Subtyping

PDAC is a pancreatic epithelial malignancy and demonstrates aggressive progression and bleak patient prognosis. Despite decades of research, the evolution of novel diagnostics and intervention modalities for PDAC is stagnant. This dissertation explores the characteristic aberrant and elevated expression of mucins in PDAC. Beginning with the hypothesis that mucins are associated with disease aggressiveness, analysis of PDAC patient survival in TCGA revealed no associations between single mucin expression and patient survival. This led to the underlying issue of PDAC tumor cellularity since this disease demonstrates variability in the proportion of cancer cells within the tumor. Tumor purity assessed with the ABSOLUTE computational algorithm is reported for all patient samples in the TCGA PDAC dataset. Using these purity scores, a mathematical correction of epithelial-specific mucin expression was devised. Again, no significant association between PDAC patient survival and mucin expression was found. Therefore, I investigated combinatorial expression of mucins by Spearman’s nonparametric PCA, which resulted in four groups of mutual expression: Group One= MUC7/12/17, Group Two= MUC1/3/13/19/20, Group Three= MUC6/15/22, and Group Four= MUC2/4/5AC/5B/16/21. These four groups were associated significantly with survival outcomes. To determine the biological implications of vi these four groups, PCA scores for all patients were correlated to whole transcriptomes. Significantly correlated genes were assessed for biological pathway upregulation. The four pathway composites revealed potential pathological signatures unrelated to previous PDAC classifications, representing novel PDAC subtypes. The role of mucin splice variants (SVs) was assessed and correlated to PDAC patient survival. Bioinformatic studies revealed 12 total mucin SVs significantly associated with survival. Better survival was correlated with expression of four MUC1, one MUC13, and one MUC20 SVs. High expression of two MUC4, one MUC15, one MUC16, one MUC21, and one MUC22 SVs were correlated with worse survival. The correlation between MUC4-sv-215 and MUC13-sv-201 SVs and survival were PCR validated in PDAC patient samples. These MUC4Δ6 prognostic findings contributed to in vitro studies and the development of a novel nanoparticle assay that detects MUC4-sv-215 in patient biofluids. The cumulative impact of the results described here may advance the clinical utility of mucins and associated SVs for improved diagnosis of PDAC

Relativistic Winds from Compact Gamma-Ray Sources: II. Pair Loading and Radiative Acceleration in Gamma-ray Bursts

We consider the effects of rapid pair creation by an intense pulse of gamma-rays propagating ahead of a relativistic shock. Side-scattered photons colliding with the main gamma-ray beam amplify the density of scattering charges. The acceleration rate of the pair-loaded medium is calculated, and its limiting bulk Lorentz factor related to the spectrum and compactness of the photon source. One obtains, as a result, a definite prediction for the relative inertia in baryons and pairs. The deceleration of a relativistic shock in the moving medium, and the resulting synchrotron emissivity, are compared with existing calculations for a static medium. The radiative efficiency is increased dramatically by pair loading. When the initial ambient density exceeds a critical value, the scattering depth traversed by the main gamma-ray pulse rises above unity, and the pulse is broadened. These considerations place significant constraints on burst progenitors: a pre-burst mass loss rate exceeding 10^{-5} M_\odot per year is difficult to reconcile with individual pulses narrower than 10 s, unless the radiative efficiency is low. An anisotropic gamma-ray flux (on an angular scale \Gamma^{-1} or larger) drives a large velocity shear that greatly increases the energy in the seed magnetic field forward of the propagating shock.Comment: 19 pp., LaTeX (aaspp4.sty), revised 12/23/99, Ap. J. in press; summary section added and several minor improvements in presentatio

Making Felt: Joseph Beuys and the Dalai Lama - un-organizing otherness

"Making Felt: Joseph Beuys and the Dalai Lama - un-organizing otherness" examines the histories and legacies of the 1982 meeting between the German artist Joseph Beuys and his Holiness the Fourteenth Dalai Lama of Tibet, an event that has gone all but unnoticed by historians and theorists. The history of the relationships between both the well-known and marginal figures who were involved with it serves as the connective tissue for the thesis' interrelated objectives. These are: 1) to provide a historical account of the life and work of the meeting's organizer, Dutch artist Louwrien Wijers, and her partnerships with Beuys, French artist Robert Filliou, and Dutch artists Ben d' Annagnac and Gerrit Dekker, which are a crucial part of the meeting and its legacies; 2) to theorize several post-war Western artists' and philosophers' engagements with Eastern thought and religious practices, primarily Zen and Tibetan Buddhism; 3) to historicize the Dalai Lama's first visits to the West (1973 and 1981) which set the stage for his meeting with Beuys; 4) to provide a narrative of 20th-century Western artistic and philosophical practices in terms of encounters with cultural difference, and to use these practices to suggest a notion of 'nonviolence' viable in the 21st-century. The thesis employs the material felt - crucial to Beuys' work - as a device for giving cohesion to its methodology and to the play of histories with which it works. Felt, a non-woven fabric, and the process of making it which involves a methodical leaving-to-chance of the formation of the material- offers a mode of approaching the encounter with otherness that provides an alternative to the usual figuration of cultural knowledge as a regularized ''weave'' of various cultural practices. The thesis uses this distinction between woven and non-woven, making knowledge and making felt, to enable the productive ''un-organization'' of otherness

Diagnosing magnetars with transient cooling

Transient X-ray emission, with an approximate t^{-0.7} decay, was observed from SGR 1900+14 over 40 days following the the giant flare of 27 Aug 1998. We calculate in detail the diffusion of heat to the surface of a neutron star through an intense 10^{14}-10^{15} G magnetic field, following the release of magnetic energy in its outer layers. We show that the power law index, the fraction of burst energy in the afterglow, and the return to persistent emission can all be understood if the star is composed of normal baryonic material.Comment: 9 pages, 1 eps figur

Relativistic Winds from Compact Gamma-ray Sources: I. Radiative Acceleration in the Klein-Nishina Regime

We consider the radiative acceleration to relativistic bulk velocities of a cold, optically thin plasma which is exposed to an external source of gamma-rays. The flow is driven by radiative momentum input to the gas, the accelerating force being due to Compton scattering in the relativistic Klein-Nishina limit. The bulk Lorentz factor of the plasma, Gamma, derived as a function of distance from the radiating source, is compared with the corresponding result in the Thomson limit. Depending on the geometry and spectrum of the radiation field, we find that particles are accelerated to the asymptotic Lorentz factor at infinity much more rapidly in the relativistic regime; and the radiation drag is reduced as blueshifted, aberrated photons experience a decreased relativistic cross section and scatter preferentially in the forward direction. The random energy imparted to the plasma by gamma-rays can be converted into bulk motion if the hot particles execute many Larmor orbits before cooling. This `Compton afterburn' may be a supplementary source of momentum if energetic leptons are injected by pair creation, but can be neglected in the case of pure Klein-Nishina scattering. Compton drag by side-scattered radiation is shown to be more important in limiting the bulk Lorentz factor than the finite inertia of the accelerating medium. The processes discussed here may be relevant to a variety of astrophysical situations where luminous compact sources of hard X- and gamma-ray photons are observed, including active galactic nuclei, galactic black hole candidates, and gamma-ray bursts.Comment: LateX, 20 pages, 5 figures, revised version accepted for publication in the Ap

Hard Burst Emission from the Soft Gamma Repeater SGR 1900+14

We present evidence for burst emission from SGR 1900+14 with a power-law high energy spectrum extending beyond 500 keV. Unlike previous detections of high energy photons during bursts from SGRs, these emissions are not associated with high-luminosity burst intervals. Not only is the emission hard, but the spectra are better fit by Band's GRB function rather than by the traditional optically-thin thermal bremsstrahlung model. We find that the spectral evolution within these hard events obeys a hardness/intensity anti-correlation. Temporally, these events are distinct from typical SGR burst emissions in that they are longer (~ 1 s) and have relatively smooth profiles. Despite a difference in peak luminosity of > 1E+11 between these bursts from SGR 1900+14 and cosmological GRBs, there are striking temporal and spectral similarities between the two kinds of bursts, aside from spectral evolution. We outline an interpretation of these events in the context of the magnetar model.Comment: 11 pages (text and figures), submitted to ApJ Letters, corrected erroneous hardness ratio

The Population of Eccentric Binary Black Holes: Implications for mHz Gravitational Wave Experiments

The observed binary black hole (BBH) mergers indicate a large Galactic progenitor population continuously evolving from large orbital separations and low gravitational wave (GW) frequencies to the final merger phase. We investigate the equilibrium distribution of binary black holes in the Galaxy. Given the observed BBH merger rate, we contrast the expected number of systems radiating in the low-frequency $0.1-10\,$mHz GW band under two assumptions: (1) that all merging systems originate from near-circular orbits, as may be indicative of isolated binary evolution, and (2) that all merging systems originate at very high eccentricity, as predicted by models of dynamically-formed BBHs and triple and quadruple systems undergoing Lidov-Kozai eccentricity oscillations. We show that the equilibrium number of systems expected at every frequency is higher in the eccentric case (2) than in the circular case (1) by a factor of $\simeq 2-15$. This follows from the fact that eccentric systems spend more time than circular systems radiating in the low-frequency GW bands. The GW emission comes in pulses at periastron separated by the orbital period, which may be days to years. For a LISA-like sensitivity curve, we show that if eccentric systems contribute significantly to the observed merger rate, then $\simeq 10$ eccentric systems should be seen in the Galaxy.Comment: 12 pages, 6 figures, matches ApJ accepted versio

Diverging volumetric trajectories following pediatric traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory