15-deoxy-delta 12, 14-Prostaglandin J(2 )prevents reactive oxygen species generation and mitochondrial membrane depolarization induced by oxidative stress

BACKGROUND: With the use of cultured human retinal pigment epithelial cells, we have previously described a number of cellular responses to oxidative stress caused by H(2)O(2). We also demonstrated that the cytotoxicity caused by H(2)O(2 )could be prevented by the prostaglandin derivative, 15-deoxy-delta 12, 14-Prostaglandin J(2 )(15d-PGJ(2)). RESULTS: Further characterization of the experimental system indicated that the half-life of H(2)O(2 )in cultures was ~1 hour. At a fixed H(2)O(2 )concentration, the cytotoxicity was dependent on the volume of H(2)O(2 )solution used in the culture, such that higher volume caused more cytotoxicity. Most cells were committed to die if the culture was treated for 2 hours with a cytotoxic concentration of H(2)O(2). The prostaglandin derivative, 15d-PGJ(2), could prevent oxidative damage caused by t-butyl hydroperoxide, in addition to H(2)O(2). Further studies indicated that both H(2)O(2 )and tBH caused an increase in reactive oxygen species and depolarization of mitochondrial membrane potential. Pretreatment of cells with 1 μM 15d-PGJ(2 )led to a modest decrease in reactive oxygen species generation, and a significant restoration of mitochondrial membrane potential. CONCLUSION: This agent may be used in the future as a pharmacological tool for preventing cellular damage caused by oxidative stress

EUS-guided portal pressure gradient measurement with a simple novel device: a human pilot study.

Background and aimsPortal hypertension is a serious adverse event of liver cirrhosis. Recently, we developed a simple novel technique for EUS-guided portal pressure gradient (PPG) measurement (PPGM). Our animal studies showed excellent correlation between EUS-PPGM and interventional radiology-acquired PPGM. In this video we demonstrate the results of the first human pilot study of EUS-PPGM in patients with liver disease.MethodsEUS-PPGM was performed by experienced endosonographers using a linear echoendoscope, a 25-gauge FNA needle, and a novel compact manometer. The portal vein and hepatic vein (or inferior vena cava) were targeted by use of a transgastric or transduodenal approach. Feasibility was defined as successful PPGM in each patient. Safety was based on adverse events captured in a postprocedural interview.ResultsTwenty-eight patients underwent EUS-PPGM with 100% technical success and no adverse events. PPG ranged from 1.5 to 19 mm Hg and had excellent correlation with clinical parameters of portal hypertension, including the presence of varices (P = .0002), PH gastropathy (P = .007), and thrombocytopenia (P = .036).ConclusionThis novel technique of EUS-PPGM using a 25-gauge needle and compact manometer is feasible and appears safe. Given the availability of EUS and the simplicity of the manometry setup, EUS-guided PPG may represent a promising breakthrough for procuring indispensable information in the management of patients with liver disease

Single-cell epigenomic variability reveals functional cancer heterogeneity.

BackgroundCell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally.ResultsWe develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity.ConclusionSingle-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution

Diabetes and corneal endothelial cell characteristics: a study based on Eye Bank data

The aim of the article is to determine whether corneal endothelial cell density and other characteristics, such as cell area, pleomorphism and polymegathism, are affected by diabetes. Corneal endothelial cell density and other characteristics of donor eyes collected during 2007 and 2008 in a local Eye Bank were measured by the HAI Eyebank Specular Microscope System. Adult donors aged 21 or older who consented to research were divided into healthy versus compromised eye-status groups based on eye disease or past eye surgeries. Differences in corneal measures between diabetic and non-diabetic subjects were analyzed separately in each group via Mixed Models ANCOVA, with Diabetes as the fixed effect, Donor as the random effect, and Age as the continuous covariate. A total of 253 subjects met study criteria, of which 81 (32%) had diabetes. In the 180 subjects with healthy eye status, the medians (ranges) of age were 62 (29-78) years among 52 diabetics (29%), versus 57 (21-79) years among non-diabetics (P=0.013). In the 73 subjects with compromised eye status, the medians (ranges) of age were 70 (32-78) years among 29 diabetics (40%), versus 70 (29-79) years among nondiabetics (P=0.77). Between diabetics and non-diabetics, eye disease and past eye surgeries were well-balanced in the compromised eye-status group, while race and sex were wellbalanced in both eye-status groups. Results from separate analyses on the two groups indicated that diabetes did not affect corneal cell density or other corneal-cell characteristics analyzed. Even though diabetics constituted a large percentage of the Eye Bank donor population, this disease did not have a statistically significant impact on corneal endothelial cell density, cell area, pleomorphism or polymegathism

Nanoscale structuring of tungsten tip yields most coherent electron point-source

This report demonstrates the most spatially-coherent electron source ever reported. A coherence angle of 14.3 +/- 0.5 degrees was measured, indicating a virtual source size of 1.7 +/-0.6 Angstrom using an extraction voltage of 89.5 V. The nanotips under study were crafted using a spatially-confined, field-assisted nitrogen etch which removes material from the periphery of the tip apex resulting in a sharp, tungsten-nitride stabilized, high-aspect ratio source. The coherence properties are deduced from holographic measurements in a low-energy electron point source microscope with a carbon nanotube bundle as sample. Using the virtual source size and emission current the brightness normalized to 100 kV is found to be 7.9x10^8 A/sr cm^2

Transcript-indexed ATAC-seq for precision immune profiling.

T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy

Safety and efficacy of endoscopic submucosal dissection for rectal neoplasia: a multicenter North American experience.

Background and aims  Rectal lesions traditionally represent the first lesions approached during endoscopic submucosal dissection (ESD) training in the West. We evaluated the safety and efficacy of rectal ESD in North America. Methods  This is a multicenter retrospective analysis of rectal ESD between January 2010 and September 2018 in 15 centers. End points included: rates of en bloc resection, R0 resection, adverse events, comparison of pre- and post-ESD histology, and factors associated with failed resection. Results  In total, 171 patients (median age 63 years; 56 % men) underwent rectal ESD (median size 43 mm). En bloc resection was achieved in 141 cases (82.5 %; 95 %CI 76.8-88.2), including 24 of 27 (88.9 %) with prior failed endoscopic mucosal resection (EMR). R0 resection rate was 74.9 % (95 %CI 68.4-81.4). Post-ESD bleeding and perforation occurred in 4 (2.3 %) and 7 (4.1 %), respectively. Covert submucosal invasive cancer (SMIC) was identified in 8.6 % of post-ESD specimens. There was one case (1/120; 0.8 %) of recurrence at a median follow-up of 31 weeks; IQR: 19-76 weeks). Older age and higher body mass index (BMI) were predictors of failed R0 resection, whereas submucosal fibrosis was associated with a higher likelihood of both failed en bloc and R0 resection. Conclusion  Rectal ESD in North America is safe and is associated with high en bloc and R0 resection rates. The presence of submucosal fibrosis was the main predictor of failed en bloc and R0 resection. ESD can be considered for select rectal lesions, and serves not only to establish a definitive tissue diagnosis but also to provide curative resection for lesions with covert advanced disease

Exploration of Artificial Multiferroic Thin-Film Heterostructures using Composition Spreads

We have fabricated a series of composition spreads consisting of ferroelectric BaTiO3 and piezomagnetic CoFe2O4 layers of varying thicknesses modulated at nanometer level in order to explore artificial magnetoelectricthin-film heterostructures. Scanning microwavemicroscopy and scanning superconducting quantum interference device microscopy were used to map the dielectric and magnetic properties as a function of continuously changing average composition across the spreads, respectively. Compositions in the middle of the spreads were found to exhibit ferromagnetism while displaying a dielectric constant as high as ≈120