Dendritic Cell Vaccination, Immune Regulation, and Clinical Outcomes in Ovarian Cancer

Clinical optimism for dendritic cell vaccination against ovarian cancer has been tempered by the knowledge that tumors avail themselves of multiple mechanisms of immune evasion, thus blunting the efficacy of therapeutic vaccination. Mechanisms of immune suppression include infiltration by regulatory T cells (Treg) and myeloid suppressor cell populations, expression of co-inhibitory receptors, and expression of indoleamine 2,3-dioxygenase (IDO). Expression of both B7-H1 and IDO are associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in ovarian cancer patients. In sharp contrast, recent studies have indicated that Th17 cell infiltration in ovarian cancer correlates with improved patient outcomes and prolonged overall survival. Given that IDO plays a pivotal role in the balance between Treg and Th17 immunity, elucidation of the mechanisms that regulate IDO activity and immune suppression may lead to novel adjuvants to boost the clinical efficacy of dendritic cell vaccination against ovarian cancer and other malignancies

Extended Tidal Structure In Two Lyman Alpha-Emitting Starburst Galaxies

We present new VLA C-configuration HI imaging of the Lyman Alpha-emitting starburst galaxies Tol 1924-416 and IRAS 08339+6517. The effective resolution probes neutral gas structures larger than 4.7 kpc in Tol 1924-416, and larger than 8.1 kpc in IRAS 08339+6517. Both systems are revealed to be tidally interacting: Tol 1924-416 with ESO 338-IG04B (6.6 arcminutes = 72 kpc minimum separation), and IRAS 08339+6517 with 2MASX J08380769+6508579 (2.4 arcminutes = 56 kpc minimum separation). The HI emission is extended in these systems, with tidal tails and debris between the target galaxies and their companions. Since Lyman Alpha emission has been detected from both of these primary systems, these observations suggest that the geometry of the ISM is one of the factors affecting the escape fraction of Lyman Alpha emission from starburst environments. Furthermore, these observations argue for the importance of interactions in triggering massive star formation events.Comment: ApJ, in press; 11 pages, 2 color figure

The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated N-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than phar-macologic blockage of Notch activation via γ-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence

Return to employment following critical illness and its association with psychosocial outcomes: a systematic review and meta-analysis

Background: Patients who survive critical illness have well-defined physical, cognitive, emotional, and familial problems. However, the impact of these problems on survivors’ ability to return to work and other financial outcomes are less clear. Objective: To determine the financial and employment consequences of an intensive care stay, we performed a systematic review and meta-analysis. Data Source We searched MEDLINE, Embase, and CINAHL (1970-2018). All study designs except narrative reviews, case reports, case control studies, and editorials were included. Included studies assessed financial outcomes in patients admitted to critical care, and their caregivers. Data Extraction: Two reviewers independently applied eligibility criteria, assessed quality and extracted data. The primary outcome reported was return to employment among those previously employed. We also examined financial stress and the impact financial outcomes had on quality of life and psychosocial health. Data Synthesis: From 5765 eligible abstracts, 51 studies were included, which provided data on 858 caregivers/family members and 7267 patients. Forty-two papers reported on patient outcomes and 11 papers on caregiver/family members. Two papers included data from both patients and caregivers/family members. Return to employment was the most commonly reported financial outcome for critical care survivors. The pooled estimate for return to employment—among those who were employed prior to critical illness—was 33% (95% CI: 21%-48%), 55% (95% CI: 45%-64%) and 56% (95% CI: 45%-66%) at 3, 6, and 12 months, respectively. Across the studies included in this review, there was a positive association with psychosocial health if patients returned to employment. This included improved health related quality of life and fewer depressive symptoms. With caregivers/family members, six studies reported changes to employment such as reduced hours and lost earnings. Conclusions: Following critical illness, many patients who were previously employed do not return to work, even one year later. This new job loss is associated with worse health related quality of life amongst survivors and worse psychological function amongst survivors and caregivers/family members. More interventional research is required to understand how best to support employability after critical illness

Two Hands Are Better Than One (up to constant factors): Self-Assembly In The 2HAM vs. aTAM

We study the difference between the standard seeded model (aTAM) of tile self-assembly, and the "seedless" two-handed model of tile self-assembly (2HAM). Most of our results suggest that the two-handed model is more powerful. In particular, we show how to simulate any seeded system with a two-handed system that is essentially just a constant factor larger. We exhibit finite shapes with a busy-beaver separation in the number of distinct tiles required by seeded versus two-handed, and exhibit an infinite shape that can be constructed two-handed but not seeded. Finally, we show that verifying whether a given system uniquely assembles a desired supertile is co-NP-complete in the two-handed model, while it was known to be polynomially solvable in the seeded model.National Science Foundation (U.S.) (NSF grant CDI-0941538

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 ± 33 mm Hg; left ventricular systolic pressure, 196 ± 33 mm Hg, mean ± 1 SD) had significantly lower coronary resistance (0.85 ± 0.18 versus 1.32 ± 0.44 mm Hg min/ml, p < 0.001) and higher basal coronary flow (106 ± 20 versus 80 ± 25 ml/min, p < 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 ± 3.6 versus 8.9 ± 3.3 ml oxygen/min, p < 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 ± 18 mm Hg, p < 0.001).Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups.Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress

The Lyman alpha reference sample. VII. Spatially resolved Hα\alpha kinematics

We present integral field spectroscopic observations with the Potsdam Multi Aperture Spectrophotometer of all 14 galaxies in the $z\sim 0.1$ Lyman Alpha Reference Sample (LARS). We produce 2D line of sight velocity maps and velocity dispersion maps from the Balmer $\alpha$ (H$\alpha$) emission in our data cubes. These maps trace the spectral and spatial properties of the LARS galaxies' intrinsic Ly$\alpha$ radiation field. We show our kinematic maps spatially registered onto the Hubble Space Telescope H$\alpha$ and Lyman $\alpha$ (Ly$\alpha$) images. Only for individual galaxies a causal connection between spatially resolved H$\alpha$ kinematics and Ly$\alpha$ photometry can be conjectured. However, no general trend can be established for the whole sample. Furthermore, we compute non-parametric global kinematical statistics -- intrinsic velocity dispersion $\sigma_0$, shearing velocity $v_\mathrm{shear}$, and the $v_\mathrm{shear}/\sigma_0$ ratio -- from our kinematic maps. In general LARS galaxies are characterised by high intrinsic velocity dispersions (54\,km\,s$^{-1}$ median) and low shearing velocities (65\,km\,s$^{-1}$ median). $v_\mathrm{shear}/\sigma_0$ values range from 0.5 to 3.2 with an average of 1.5. Noteworthy, five galaxies of the sample are dispersion dominated systems with $v_\mathrm{shear}/\sigma_0 <1$ and are thus kinematically similar to turbulent star forming galaxies seen at high redshift. When linking our kinematical statistics to the global LARS Ly$\alpha$ properties, we find that dispersion dominated systems show higher Ly$\alpha$ equivalent widths and higher Ly$\alpha$ escape fractions than systems with $v_\mathrm{shear}/\sigma_0 > 1$. Our result indicates that turbulence in actively star-forming systems is causally connected to interstellar medium conditions that favour an escape of Ly$\alpha$ radiation.Comment: 26 pages, 15 figures, accepted for publication in A&

Warm Dust and Spatially Variable PAH Emission in the Dwarf Starburst Galaxy NGC 1705

We present Spitzer observations of the dwarf starburst galaxy NGC 1705 obtained as part of SINGS. The galaxy morphology is very different shortward and longward of ~5 microns: short-wavelength imaging shows an underlying red stellar population, with the central super star cluster (SSC) dominating the luminosity; longer-wavelength data reveals warm dust emission arising from two off-nuclear regions offset by ~250 pc from the SSC. These regions show little extinction at optical wavelengths. The galaxy has a relatively low global dust mass (~2E5 solar masses, implying a global dust-to-gas mass ratio ~2--4 times lower than the Milky Way average). The off-nuclear dust emission appears to be powered by photons from the same stellar population responsible for the excitation of the observed H Alpha emission; these photons are unassociated with the SSC (though a contribution from embedded sources to the IR luminosity of the off-nuclear regions cannot be ruled out). Low-resolution IRS spectroscopy shows moderate-strength PAH emission in the 11.3 micron band in the eastern peak; no PAH emission is detected in the SSC or the western dust emission complex. There is significant diffuse 8 micron emission after scaling and subtracting shorter wavelength data; the spatially variable PAH emission strengths revealed by the IRS data suggest caution in the interpretation of diffuse 8 micron emission as arising from PAH carriers alone. The metallicity of NGC 1705 falls at the transition level of 35% solar found by Engelbracht and collaborators; the fact that a system at this metallicity shows spatially variable PAH emission demonstrates the complexity of interpreting diffuse 8 micron emission. A radio continuum non-detection, NGC 1705 deviates significantly from the canonical far-IR vs. radio correlation. (Abridged)Comment: ApJ, in press; please retrieve full-resolution version from http://www.astro.wesleyan.edu/~cannon/pubs.htm

The Nature of Infrared Emission in the Local Group Dwarf Galaxy NGC 6822 As Revealed by Spitzer

We present Spitzer imaging of the metal-deficient (Z ~30% Z_sun) Local Group dwarf galaxy NGC 6822. On spatial scales of ~130 pc, we study the nature of IR, H alpha, HI, and radio continuum emission. Nebular emission strength correlates with IR surface brightness; however, roughly half of the IR emission is associated with diffuse regions not luminous at H alpha (as found in previous studies). The global ratio of dust to HI gas in the ISM, while uncertain at the factor of ~2 level, is ~25 times lower than the global values derived for spiral galaxies using similar modeling techniques; localized ratios of dust to HI gas are about a factor of five higher than the global value in NGC 6822. There are strong variations (factors of ~10) in the relative ratios of H alpha and IR flux throughout the central disk; the low dust content of NGC 6822 is likely responsible for the different H alpha/IR ratios compared to those found in more metal-rich environments. The H alpha and IR emission is associated with high-column density (> ~1E21 cm^-2) neutral gas. Increases in IR surface brightness appear to be affected by both increased radiation field strength and increased local gas density. Individual regions and the galaxy as a whole fall within the observed scatter of recent high-resolution studies of the radio-far IR correlation in nearby spiral galaxies; this is likely the result of depleted radio and far-IR emission strengths in the ISM of this dwarf galaxy.Comment: ApJ, in press; please retrieve full-resolution version from http://www.astro.wesleyan.edu/~cannon/pubs.htm