29 research outputs found
Novel Mouse Model for Analysis of Macrophage Function in Neuroblastoma
Background: Neuroblastoma is the third most common childhood cancer and accounts for 12% of cancer-associated deaths in children under the age of 15. Patients with high risk neuroblastoma have a poor 5-year survival rate of less than 50%. Neuroblastoma tumors treated with the histone deacetylase inhibitor (HDACi) vorinostat have increased infiltration of macrophages with upregulated immune cell-surface receptors. Neuroblastoma cells release VEGF and M-CSF, which may alter intratumoral macrophage populations. VEGF has also been implicated in alteration of amyloid precursor protein family processing. Our lab demonstrated that amyloid precursor protein 2 (APLP2), a member of the amyloid precursor protein family, plays an important role in the migration of tumor cells. APLP2 is known to be expressed by macrophages, but no studies have previously examined macrophage functions that are impacted by APLP2 in the context of neuroblastoma disease and its treatment by HDACi drugs.
Significance of Problem: Because of the high morbidity and mortality associated with neuroblastoma, studies such as this one that are designed to comprehend the interaction of immunity and treatment in neuroblastoma are clinically significant. The results from this study are also expected to expand our comprehension of macrophage function and regulation, and thus will be of broad value in the immunology and oncology fields.
Experimental Design and Results: We have treated neuroblastoma tumor cells in vitro with M344, an HDACi with structural similarity to vorinostat, and showed that M344 decreases neuroblastoma cell growth. In addition, we have generated mice that lack APLP2 expression in cells expressing the Csf-1 receptor (a protein characteristically expressed by macrophages and dendritic cells). We discovered that following polarization, macrophages collected from the bone marrow of these mice have an altered distribution of M1 and M2 sub-populations, which are macrophage sub-populations known to differ in their migratory capabilities. Furthermore, we have shown that M1 and M2 subpopulations of bone marrow-derived macrophages from normal mice differ in their expression of APLP2. Thus, APLP2 is influential in macrophage biology, and we have created a novel mouse model for defining its specific contributions in mice treated with HDACi that influence macrophage biology.
Conclusions: Based on the data that we have acquired, we are well positioned to fully explore both the impact of HDACi drugs on macrophage/dendritic cell populations in a syngeneic neuroblastoma mouse model, and to define the role of APLP2 in the function of these cell populations in the context of neuroblastoma.https://digitalcommons.unmc.edu/chri_forum/1000/thumbnail.jp
Amyloid Precursor-like Protein 2 Expression Increases during Pancreatic Cancer Development and Shortens the Survival of a Spontaneous Mouse Model of Pancreatic Cancer.
In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered mouse models of spontaneous pancreatic ductal adenocarcinoma were used to investigate APLP2\u27s role in cancer development. We found that APLP2 expression intensifies significantly during pancreatic cancer initiation and progression in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model, as shown by immunohistochemistry analysis. In studies utilizing pancreas-specific heterozygous and homozygous knockout of APLP2 in the KPC mouse model background, we observed significantly prolonged survival and reduced metastatic progression of pancreatic cancer. These results demonstrate the importance of APLP2 in pancreatic cancer initiation and metastasis and indicate that APLP2 should be considered a potential therapeutic target for this disease
The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: Analysis of potential systematics
We analyze the density field of galaxies observed by the Sloan Digital Sky
Survey (SDSS)-III Baryon Oscillation Spectroscopic Survey (BOSS) included in
the SDSS Data Release Nine (DR9). DR9 includes spectroscopic redshifts for over
400,000 galaxies spread over a footprint of 3,275 deg^2. We identify,
characterize, and mitigate the impact of sources of systematic uncertainty on
large-scale clustering measurements, both for angular moments of the
redshift-space correlation function and the spherically averaged power
spectrum, P(k), in order to ensure that robust cosmological constraints will be
obtained from these data. A correlation between the projected density of stars
and the higher redshift (0.43 < z < 0.7) galaxy sample (the `CMASS' sample) due
to imaging systematics imparts a systematic error that is larger than the
statistical error of the clustering measurements at scales s > 120h^-1Mpc or k
< 0.01hMpc^-1. We find that these errors can be ameliorated by weighting
galaxies based on their surface brightness and the local stellar density. We
use mock galaxy catalogs that simulate the CMASS selection function to
determine that randomly selecting galaxy redshifts in order to simulate the
radial selection function of a random sample imparts the least systematic error
on correlation function measurements and that this systematic error is
negligible for the spherically averaged correlation function. The methods we
recommend for the calculation of clustering measurements using the CMASS sample
are adopted in companion papers that locate the position of the baryon acoustic
oscillation feature (Anderson et al. 2012), constrain cosmological models using
the full shape of the correlation function (Sanchez et al. 2012), and measure
the rate of structure growth (Reid et al. 2012). (abridged)Comment: Matches version accepted by MNRAS. Clarifications and references have
been added. See companion papers that share the "The clustering of galaxies
in the SDSS-III Baryon Oscillation Spectroscopic Survey:" titl
The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: measurements of the growth of structure and expansion rate at z=0.57 from anisotropic clustering
We analyze the anisotropic clustering of massive galaxies from the Sloan
Digital Sky Survey III Baryon Oscillation Spectroscopic Survey (BOSS) Data
Release 9 (DR9) sample, which consists of 264,283 galaxies in the redshift
range 0.43 < z < 0.7 spanning 3,275 square degrees. Both peculiar velocities
and errors in the assumed redshift-distance relation ("Alcock-Paczynski
effect") generate correlations between clustering amplitude and orientation
with respect to the line-of-sight. Together with the sharp baryon acoustic
oscillation (BAO) standard ruler, our measurements of the broadband shape of
the monopole and quadrupole correlation functions simultaneously constrain the
comoving angular diameter distance (2190 +/- 61 Mpc) to z=0.57, the Hubble
expansion rate at z=0.57 (92.4 +/- 4.5 km/s/Mpc), and the growth rate of
structure at that same redshift (d sigma8/d ln a = 0.43 +/- 0.069). Our
analysis provides the best current direct determination of both DA and H in
galaxy clustering data using this technique. If we further assume a LCDM
expansion history, our growth constraint tightens to d sigma8/d ln a = 0.415
+/- 0.034. In combination with the cosmic microwave background, our
measurements of DA, H, and growth all separately require dark energy at z >
0.57, and when combined imply \Omega_{\Lambda} = 0.74 +/- 0.016, independent of
the Universe's evolution at z<0.57. In our companion paper (Samushia et al.
prep), we explore further cosmological implications of these observations.Comment: 19 pages, 11 figures, submitted to MNRAS, comments welcom
JWST reveals a possible galaxy merger in triply-lensed MACS0647JD
MACS0647JD is a triply-lensed galaxy originally discovered with
the Hubble Space Telescope. Here we report new JWST imaging, which clearly
resolves MACS0647JD as having two components that are either merging
galaxies or stellar complexes within a single galaxy. Both are very small, with
stellar masses and radii . The brighter
larger component "A" is intrinsically very blue (), likely due
to very recent star formation and no dust, and is spatially extended with an
effective radius . The smaller component "B" appears redder
(), likely because it is older () with mild dust
extinction (), and a smaller radius . We
identify galaxies with similar colors in a high-redshift simulation, finding
their star formation histories to be out of phase. With an estimated stellar
mass ratio of roughly 2:1 and physical projected separation ,
we may be witnessing a galaxy merger 400 million years after the Big Bang. We
also identify a candidate companion galaxy C away, likely
destined to merge with galaxies A and B. The combined light from galaxies A+B
is magnified by factors of 8, 5, and 2 in three lensed images JD1, 2, and
3 with F356W fluxes , , (AB mag 25.1, 25.6, 26.6).
MACS0647JD is significantly brighter than other galaxies recently discovered
at similar redshifts with JWST. Without magnification, it would have AB mag
27.3 (). With a high confidence level, we obtain a photometric
redshift of based on photometry measured in 6 NIRCam filters
spanning , out to rest-frame. JWST NIRSpec
observations planned for January 2023 will deliver a spectroscopic redshift and
a more detailed study of the physical properties of MACS0647JD.Comment: 27 pages, 14 figures, submitted to Natur
SDSS-III: Massive Spectroscopic Surveys of the Distant Universe, the Milky Way Galaxy, and Extra-Solar Planetary Systems
Building on the legacy of the Sloan Digital Sky Survey (SDSS-I and II),
SDSS-III is a program of four spectroscopic surveys on three scientific themes:
dark energy and cosmological parameters, the history and structure of the Milky
Way, and the population of giant planets around other stars. In keeping with
SDSS tradition, SDSS-III will provide regular public releases of all its data,
beginning with SDSS DR8 (which occurred in Jan 2011). This paper presents an
overview of the four SDSS-III surveys. BOSS will measure redshifts of 1.5
million massive galaxies and Lya forest spectra of 150,000 quasars, using the
BAO feature of large scale structure to obtain percent-level determinations of
the distance scale and Hubble expansion rate at z<0.7 and at z~2.5. SEGUE-2,
which is now completed, measured medium-resolution (R=1800) optical spectra of
118,000 stars in a variety of target categories, probing chemical evolution,
stellar kinematics and substructure, and the mass profile of the dark matter
halo from the solar neighborhood to distances of 100 kpc. APOGEE will obtain
high-resolution (R~30,000), high signal-to-noise (S/N>100 per resolution
element), H-band (1.51-1.70 micron) spectra of 10^5 evolved, late-type stars,
measuring separate abundances for ~15 elements per star and creating the first
high-precision spectroscopic survey of all Galactic stellar populations (bulge,
bar, disks, halo) with a uniform set of stellar tracers and spectral
diagnostics. MARVELS will monitor radial velocities of more than 8000 FGK stars
with the sensitivity and cadence (10-40 m/s, ~24 visits per star) needed to
detect giant planets with periods up to two years, providing an unprecedented
data set for understanding the formation and dynamical evolution of giant
planet systems. (Abridged)Comment: Revised to version published in The Astronomical Journa
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
Teacher evaluation: how New York’s APPR shapes a suburban elementary teacher’s professional learning
Thesis (Ed. D.)--University of Rochester. Margaret Warner Graduate School of Education and Human Development, 2017.This dissertation study examined how the professional learning of a suburban elementary school teacher was shaped through the experience of New York’s teacher evaluation system, the APPR. The primary rationale behind teacher evaluation systems is to ensure that every year, every school has an effective leader and every classroom has an effective teacher so that every child can learn and achieve their full potential. It is the teachers - their knowledge, beliefs, and practices - who play an integral role in achieving the purpose of teacher evaluation. This study utilized a qualitative instrumental case study approach to focus on the individual evaluation experiences of a fourth grade teacher at Liberty Elementary School, a diverse suburban elementary school in Western New York. In this study, the uniqueness and complexity of an individual teacher’s constructions of her experiences within New York’s APPR were used to understand how teacher evaluation shaped learning. Through a deeper understanding of how learning is currently being shaped through the evaluation process, teachers, administrators, and policy makers will be able to revise current evaluation practices to foster school structures and policies that place greater emphasis on learning and growth throughout the school organization
The histone deacetylase inhibitor M344 as a multifaceted therapy for pancreatic cancer.
The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment
M344 decreases orthotopic pancreatic tumor growth when used as a treatment alone or in combination with gemcitabine.
(A) S2-013 cells were orthotopically implanted into the pancreas of female NU/J mice. After 8 days, the tumor volume for each mouse was monitored twice weekly with the VisualSonic Vevo 3100 Imaging System. At 15 days post-implantation of tumor cells, the mice were randomized into control or treatment groups with matched average tumor volumes. M344 was administered intraperitoneally at 10 mg/kg for 5 days per week (5 days on, 2 days off). Gemcitabine was given every 3 days intraperitoneally at 50 mg/kg. On Day 25 post-tumor implantation, the mice were euthanized and the tumors were resected and weighed. The changes in tumor volume over time are shown in (B) and representative images of tumors at 25 days post implantation are shown in (C). For statistical analysis, ordinary One-way ANOVA with Dunnett’s Multiple Comparisons test in GraphPad Prism Version 8.4.2 was used. The asterisks indicate the following p values: * p<0.05, ** p< 0.01, *** p<0.001.</p