78 research outputs found
Gamma-rays from ultracompact minihalos: potential constraints on the primordial curvature perturbation
Ultracompact minihalos (UCMHs) are dense dark matter structures which can
form from large density perturbations shortly after matter-radiation equality.
If dark matter is in the form of Weakly Interacting Massive Particles (WIMPs),
then UCMHs may be detected via their gamma-ray emission. We investigate how the
{\em{Fermi}} satellite could constrain the abundance of UCMHs and place limits
on the power spectrum of the primordial curvature perturbation. Detection by
{\em Fermi} would put a lower limit on the UCMH halo fraction. The smallest
detectable halo fraction, , is for . If gamma-ray emission from UCMHs is not detected, an
upper limit can be placed on the halo fraction. The bound is tightest, , for . The
resulting upper limit on the power spectrum of the primordial curvature
perturbation in the event of non-detection is in the range on scales . This is substantially tighter than the existing constraints from
primordial black hole formation on these scales, however it assumes that dark
matter is in the form of WIMPs and UCMHs are not disrupted during the formation
of the Milky Way halo.Comment: 5 pages, 2 figures, version to appear in Phys. Rev. D, minor change
Investigating the impact of asymmetric macular sensitivity on visual acuity chart reading in choroideraemia
Introduction: Degeneration in choroideraemia, unlike typical centripetal photoreceptor degenerations, is centred temporal to the fovea. Once the fovea is affected, the nasal visual field (temporal retina) is relatively spared, and the preferred retinal locus shifts temporally. Therefore, when reading left to right, only the right eye reads into a scotoma. We investigate how this unique property affects the ability to read an eye chart. Methods: Standard‐ and low‐luminance visual acuity (VA) for right and left eyes were measured with the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Letters in each line were labelled by column position. The numbers of letter errors for each position across the whole chart were summed to produce total column error scores for each participant. Macular sensitivity was assessed using microperimetry. Central sensitivity asymmetry was determined by the temporal‐versus‐nasal central macular difference and subsequently correlated to a weighted ETDRS column error score. Healthy volunteers and participants with X‐linked retinitis pigmentosa GTPase regulator associated retinitis pigmentosa (RPGR‐RP) were used as controls. Results: Thirty‐nine choroideraemia participants (median age 44.9 years [IQR 35.7–53.5]), 23 RPGR‐RP participants (median age 30.8 years [IQR 26.5–40.5]) and 35 healthy controls (median age 23.8 years [IQR 20.3–29.0]) were examined. In choroideraemia, standard VA in the right eye showed significantly greater ETDRS column errors on the temporal side compared with the nasal side (p = 0.002). This significantly correlated with greater asymmetry in temporal‐versus‐nasal central macular sensitivity (p = 0.04). No significant patterns in ETDRS column errors or central macular sensitivity were seen in the choroideraemia left eyes, nor in RPGR‐RP and control eyes. Conclusion: Difficulty in tracking across lines during ETDRS VA testing may cause excess errors independent of true VA. VA assessment with single‐letter optotype systems may be more suitable, particularly for patients with choroideraemia, and potentially other retinal diseases with asymmetric central macular sensitivity or large central scotomas including geographic atrophy
MMTV-PyMT and derived Met-1 mouse mammary tumor cells as models for studying the role of the androgen receptor in triple-negative breast cancer progression
Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment
Generalised constraints on the curvature perturbation from primordial black holes
Primordial black holes (PBHs) can form in the early Universe via the collapse
of large density perturbations. There are tight constraints on the abundance of
PBHs formed due to their gravitational effects and the consequences of their
evaporation. These abundance constraints can be used to constrain the
primordial power spectrum, and hence models of inflation, on scales far smaller
than those probed by cosmological observations. We compile, and where relevant
update, the constraints on the abundance of PBHs before calculating the
constraints on the curvature perturbation, taking into account the growth of
density perturbations prior to horizon entry. We consider two simple
parameterizations of the curvature perturbation spectrum on the scale of
interest: constant and power-law. The constraints from PBHs on the amplitude of
the power spectrum are typically in the range 10^{-2}-10^{-1} with some scale
dependence.Comment: 10 pages, 2 figures, version to appear in Phys. Rev. D with minor
change to calculation of constraints for spectral index not equal to on
Primordial Black Holes: sirens of the early Universe
Primordial Black Holes (PBHs) are, typically light, black holes which can
form in the early Universe. There are a number of formation mechanisms,
including the collapse of large density perturbations, cosmic string loops and
bubble collisions. The number of PBHs formed is tightly constrained by the
consequences of their evaporation and their lensing and dynamical effects.
Therefore PBHs are a powerful probe of the physics of the early Universe, in
particular models of inflation. They are also a potential cold dark matter
candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X.
Calmet (Springer, 2014
Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells
Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging
Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells
Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging
Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD
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