Development and Application of New Systems for Modeling Murine Prostate Development and Disease

Animal models have been useful in the study of prostate biology and disease for decades, with continuous refinement and renewal to improve utility and comparative accuracy. This work describes two advances in murine models of prostate development and disease, and details the application of these new models to discover critical aspects of prostate biology. The mechanisms driving epithelial differentiation, proliferation, and invasion during prostate development have been postulated to provide critical insight into similar processes occurring in prostate cancer. Investigations into gene function at the earliest stages of prostate development were limited by the lack of suitable methods for controlled, tissue specific deletion of genes in the urogenital sinus. To remedy this problem, we employed tamoxifen-dependent conditional mutagenesis and developed a method to rapidly and efficiently delete target genes in the developing prostate with precise temporal control. Using this method, we describe the absolute requirement for Wnt signaling through beta-catenin in the initial phase of lineage commitment during prostate morphogenesis. Inflammation promotes cancer initiation and progression in a variety of organs, and has been linked epidemiologically to prostate cancer. Limitations in animal models of prostatitis have hindered efforts to produce definitive evidence that inflammation promotes cancer progression. Here, we characterize the immunologic and morphologic changes induced in the prostate by a new model of murine bacterial prostatitis. This model uses CP1, a strain of Escherichia coli recently isolated from a human and described in acute studies of murine pelvic pain. CP1 induces chronic prostatitis lasting at least one year, with epithelial hyperplasia and immune cell infiltration. Using this model, we show chronic inflammation accelerates prostate cancer progression in the Hi-Myc model of murine prostate cancer and provide the first definitive link between prostate inflammation and prostate cancer progression. A single process unites these two seemingly disparate projects: recognizing a gap in scientific knowledge, fashioning a model that can be used to fill this gap, and finally applying these models to uncover basic and translational aspects of prostate biology. Together, the data presented here expand the understanding of prostate biology and provide new tools for future inquiry

Studies of electron-impact fragmentations of phenyl substituted heterocyclic compounds

Thesis (M.Sc.) -- University of Adelaide, Dept. of Organic, 197

Poor Parenting, Attachment Style, and Dating Violence Perpetration among College Students

Although dating violence is prevalent among college students, little is known about how both attachment style and participation in risky behaviors contribute to this pattern of violence. To address this literature gap, we examine the role of poor parenting, child abuse, attachment style, and risky sexual and drug use behaviors on dating violence perpetration among 1,432 college students (51% female). Path analysis results revealed that females were more likely to report greater attachment anxiety but lower attachment avoidance compared with males. Correlates of attachment anxiety included child physical abuse, witnessing parental violence, and poorer maternal relationship quality whereas attachment avoidant behavior was linked to more physical abuse and poorer maternal relationship quality. Females were more likely to perpetrate dating violence as were those with greater attachment anxiety and lower attachment avoidance. Other correlates of dating violence perpetration included sexual and drug risk behaviors. Finally, distal factors (i.e., more child physical abuse and poorer maternal relationship quality) also were associated with dating violence perpetration. Study implications are also discussed

Carbon-Enhanced Metal-Poor Stars. III. Main-Sequence Turn-Off Stars from the SDSS/SEGUE Sample

The chemical compositions of seven Carbon-Enhanced Metal-Poor (CEMP) turn-off stars are determined from high-resolution spectroscopy. Five of them are selected from the SDSS/SEGUE sample of metal-poor stars. The effective temperatures of these objects are all higher than 6000 K, while their metallicities, parametrized by [Fe/H], are all below -2. Six of our program objects exhibit high abundance ratios of barium ([Ba/H]> +1), suggesting large contributions of the products of former AGB companions via mass transfer across binary systems. Combining our results with previous studies provides a total of 20 CEMP main-sequence turn-off stars for which the abundances of carbon and at least some neutron-capture elements are determined. Inspection of the [C/H] ratios for this sample of CEMP turn-off stars show that they are generally higher than those of CEMP giants; their dispersion in this ratio is also smaller. We take these results to indicate that the carbon-enhanced material provided from the companion AGB star is preserved at the surface of turn-off stars with no significant dilution. In contrast, a large dispersion in the observed [Ba/H] is found for the sample of CEMP turn-off stars, suggesting that the efficiency of the s-process in very metal-poor AGB stars may differ greatly from star to star. Four of the six stars from the SDSS/SEGUE sample exhibit kinematics that are associated with membership in the outer-halo population, a remarkably high fraction.Comment: 45 pages, 10 figures, 10 tables, Astrophysical Journal, in pres

Figuring Out Gas & Galaxies In Enzo (FOGGIE) V: The Virial Temperature Does Not Describe Gas in a Virialized Galaxy Halo

The classical definition of the virial temperature of a galaxy halo excludes a fundamental contribution to the energy partition of the halo: the kinetic energy of non-thermal gas motions. Using simulations of low-redshift, $\sim L^*$ galaxies from the FOGGIE project (Figuring Out Gas & Galaxies In Enzo) that are optimized to resolve low-density gas, we show that the kinetic energy of non-thermal motions is roughly equal to the energy of thermal motions. The simulated FOGGIE halos have $\sim 2\times$ lower bulk temperatures than expected from a classical virial equilibrium, owing to significant non-thermal kinetic energy that is formally excluded from the definition of $T_\mathrm{vir}$. We derive a modified virial temperature explicitly including non-thermal gas motions that provides a more accurate description of gas temperatures for simulated halos in virial equilibrium. Strong bursts of stellar feedback drive the simulated FOGGIE halos out of virial equilibrium, but the halo gas cannot be accurately described by the standard virial temperature even when in virial equilibrium. Compared to the standard virial temperature, the cooler modified virial temperature implies other effects on halo gas: (i) the thermal gas pressure is lower, (ii) radiative cooling is more efficient, (iii) O VI absorbing gas that traces the virial temperature may be prevalent in halos of a higher mass than expected, (iv) gas mass estimates from X-ray surface brightness profiles may be incorrect, and (v) turbulent motions make an important contribution to the energy balance of a galaxy halo.Comment: 30 pages, 14 figures, accepted to Ap

Long-term evaluation of a hospital-based violence intervention program using a regional health information exchange

BACKGROUND: Hospital-based violence intervention programs (HVIP) aim to reduce violent-injury recidivism by providing intensive case management services to high-risk patients who were violently injured. Although HVIP have been found effective at reducing recidivism, few studies have sought to identity how long their effects last. Additionally, prior studies have been limited by the fact that HVIP typically rely on self-report or data within their own healthcare system to identify new injuries. Our aim was to quantify the long-term recidivism rate of participants in an HVIP program using more objective and comprehensive data from a regional health information exchange. METHODS: The study included 328 patients enrolled in Prescription for Hope (RxH), an HVIP, between January 2009 and August 2016. We obtained RxH participants' emergency department (ED) encounter data from a regional health information exchange database from the date of hospital discharge to February 2017. Our primary outcome was violent-injury recidivism rate of the RxH program. We also examined reasons for ED visits that were unrelated to violent injury. RESULTS: We calculated a 4.4% recidivism rate based on 8 years of statewide data, containing 1,575 unique encounters. More than 96% of participants were matched in the state database. Of the 15 patients who recidivated, only five were admitted for their injury. More than half of new violence-related injuries were treated outside of the HVIP-affiliated trauma center. The most common reasons for ED visits were pain (718 encounters), followed by suspected complications or needing additional postoperative care (181 encounters). Substance abuse, unintentional injuries, and suicidal ideation were also frequent reasons for ED visits. CONCLUSION: The low, long-term recidivism rate for RxH indicates that HVIPs have enduring positive effects on the majority of participants. Our results suggest that HVIP may further benefit patients by partnering with organizations that work to prevent suicide, substance use disorders, and other unintentional injuries. LEVEL OF EVIDENCE: Therapeutic study, level III

Figuring Out Gas & Galaxies in Enzo (FOGGIE). III. The Mocky Way:Investigating Biases in Observing the Milky Way's Circumgalactic Medium

The circumgalactic medium (CGM) of the Milky Way is mostly obscured by nearby gas in position-velocity space because we reside inside the Galaxy. Substantial biases exist in most studies on the Milky Way's CGM that focus on easier-to-detect high-velocity gas. With mock observations on a Milky-Way analog from the FOGGIE simulation, we investigate four observational biases related to the Milky Way's CGM. First, QSO absorption-line studies probe a limited amount of the CGM mass: only 35% of the mass is at high Galactic latitudes $|b|>20$ degrees, of which only half is moving at $|v_{\rm LSR}|\gtrsim100$ km s$^{-1}$. Second, the inflow rate ($\dot{M}$) of the cold gas observable in HI 21cm is reduced by a factor of $\sim10$ as we switch from the local standard of rest to the galaxy's rest frame; meanwhile $\dot{M}$ of the cool and warm gas does not change significantly. Third, OVI and NV are promising ions to probe the Milky Way's outer CGM ($r\gtrsim$15 kpc), but CIV may be less sensitive. Lastly, the scatter in ion column density is a factor of 2 higher if the CGM is observed from inside-out than from external views because of the gas radial density profile. Our work highlights that observations of the Milky Way's CGM, especially those using HI 21cm and QSO absorption lines, are highly biased. We demonstrate that these biases can be quantified and calibrated through synthetic observations with simulated Milky-Way analogs.Comment: ApJ in pres

Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model

Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non-biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX)-loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (∼13 % w/w) and prolonged release (∼13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol® (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated with only minimal to mild inflammation. Our findings support PTX/PEG-PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer and potentially other metastatic peritoneal cancers