2,052 research outputs found
Endothelial dysfunction in a child with Pearson marrow-pancreas syndrome managed with Descemet stripping automated endothelial keratoplasty using a suture pull-through techniqu
A 4-year-old girl with a history of Pearson marrow-pancreas syndrome presenting with severe, progressive photophobia was found to have bilateral, diffuse corneal thickening and peripheral pigmentary retinopathy. She underwent Descemet stripping automated endothelial keratoplasty (DSAEK) surgery in both eyes using a modified suture pull-through technique. Postoperatively there was no evidence of cataract formation or graft detachment; her corneas thinned, and her photophobia improved dramatically
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In vitro infection of human ocular tissues by SARS-CoV-2 lineage A isolates
Background
The purpose of this study was: [1] to evaluate the infectivity of two SARS-CoV-2 lineage A variants on human ocular tissues in vitro, and [2] to evaluate the stability of SARS-CoV-2 lineage A variants in corneal preservation medium.
Methods
Primary cultures of donor corneal, conjunctival, and limbal epithelium were inoculated with two lineage A, GISAID clade S isolates of SARS-CoV-2 (Hong Kong/VM20001061/2020, USA-WA1/2020), to evaluate the susceptibility of the ocular tissue to infection. Flat-mounted Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK) grafts were inoculated with SARS-CoV-2 to evaluate the susceptibility of the endothelium to infection. All inoculated samples were immunostained for SARS-CoV-2 nucleocapsid (N)-protein expression to confirm positive infection. SARS-CoV-2 Hong Kong was then inoculated into cornea preservation media (Life4°C, Numedis, Inc.). Inoculated media was stored at 4oC for 14 days and assayed over time for changes in infectious viral titers.
Results
Corneal, conjunctival, and limbal epithelial cells all demonstrated susceptibility to infection by SARS-CoV-2 lineage A variants. Conjunctiva demonstrated the highest infection rate (78% of samples infected [14/18]); however, infection rates did not differ statistically between cell types and viral isolates. After inoculation, 40% (4/10) of DSAEK grafts had active infection in the endothelium. SARS-CoV-2 lineage A demonstrated < 1 log decline in viral titers out to 14 days in corneal preservation media.
Conclusions
SARS-CoV-2 lineage A variants can infect corneal, limbal, and conjunctival epithelium, as well as corneal endothelium. There was no statistical difference in infectivity between different lineage A variants. SARS-CoV-2 lineage A can survive and remain infectious in corneal preservation media out to 14 days in cold storage
Corneal perforation in ocular graft-versus-host disease
PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome.
METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology.
RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal melt in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar.
CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies
Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors
Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo.National Science Foundation (U.S.) (Grant T32GM007287)National Cancer Institute (U.S.) (Grant F30CA183474)National Institute of General Medical Sciences (U.S.) (Award T32GM007753)National Institutes of Health (U.S.) (Grant P30CA1405141)National Institutes of Health (U.S.) (Grant R01CA168653
Analysis of blood type for SARS-CoV-2 and correlation for disease acquisition in various sociodemographic groups including women of childbearing age.
BACKGROUND: Multiple studies have occurred to determine if a patient\u27s blood type, Rhesus factor (Rh), and sociodemographic attributes contribute to contracting SARS-CoV-2. True association remains unknown.
METHODS: Inclusion criteria included in-patients who were tested for SARS-CoV-2 with blood type assessed. Study endpoints combined ABO, Rh and all-cause inpatient mortality (ACIM) with testing positivity. Pregnancy status was one of several secondary endpoints evaluated. A logistic regression analysis was used to estimate association.
RESULTS: Of the 27,662 patients who met inclusion criteria, Type A blood was associated with increased positivity [1.01 (1.0-1.21), P = .03]. Type B [1.10 (0.99-1.23), P = .08] and AB [0.98 (0.81-1.19), P = .84] showed no association. When evaluating ACIM, type A [1.18 (0.91-1.52), P = .22], B [1.13 (0.82- 1.56), P = .480], and AB [1.06 (0.62-1.81), P = .839] were not associated with increased mortality. The female subgroup was less likely to test positive [0.88 (0.82-0.986), P = .002]. Black patients demonstrated a higher likelihood of positivity when compared to White [1.96 (1.79-2.14), P \u3c .001]. Non-pregnant women exhibited a 2.5 times greater likelihood of testing positive [2.49 (2.04-3.04), P \u3c .001].
CONCLUSIONS: This study confirms results of previous research which showed SARS-Co-V-2 positivity related to blood type. It also confirms more recent research demonstrating inequities related to acquisition of SARS-CoV-2 for certain sociodemographic groups. Larger studies are warranted to confirm and further explore novel pregnancy findings
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images
of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL
maps are derived through computational staining using a convolutional neural network trained to
classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and
correlation with overall survival. TIL map structural patterns were grouped using standard
histopathological parameters. These patterns are enriched in particular T cell subpopulations
derived from molecular measures. TIL densities and spatial structure were differentially enriched
among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial
infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic
patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for
the TCGA image archives with insights into the tumor-immune microenvironment
The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment
The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in
operation since July 2014. This paper describes the second data release from
this phase, and the fourteenth from SDSS overall (making this, Data Release
Fourteen or DR14). This release makes public data taken by SDSS-IV in its first
two years of operation (July 2014-2016). Like all previous SDSS releases, DR14
is cumulative, including the most recent reductions and calibrations of all
data taken by SDSS since the first phase began operations in 2000. New in DR14
is the first public release of data from the extended Baryon Oscillation
Spectroscopic Survey (eBOSS); the first data from the second phase of the
Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2),
including stellar parameter estimates from an innovative data driven machine
learning algorithm known as "The Cannon"; and almost twice as many data cubes
from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous
release (N = 2812 in total). This paper describes the location and format of
the publicly available data from SDSS-IV surveys. We provide references to the
important technical papers describing how these data have been taken (both
targeting and observation details) and processed for scientific use. The SDSS
website (www.sdss.org) has been updated for this release, and provides links to
data downloads, as well as tutorials and examples of data use. SDSS-IV is
planning to continue to collect astronomical data until 2020, and will be
followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14
happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov
2017 (this is the "post-print" and "post-proofs" version; minor corrections
only from v1, and most of errors found in proofs corrected
Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI
Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption
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