Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the Sleeping Beauty Transposon System

<p>Abstract</p> <p>Background</p> <p>Metastatic colon cancer is one of the leading causes of cancer-related death worldwide, with disease progression and metastatic spread being closely associated with angiogenesis. We investigated whether an antiangiogenic gene transfer approach using the <it>Sleeping Beauty </it>(SB) transposon system could be used to inhibit growth of colorectal tumors metastatic to the liver.</p> <p>Results</p> <p>Liver CT26 tumor-bearing mice were hydrodynamically injected with different doses of a plasmid containing a transposon encoding an angiostatin-endostatin fusion gene (Statin AE) along with varying amounts of SB transposase-encoding plasmid. Animals that were injected with a low dose (10 μg) of Statin AE transposon plasmid showed a significant decrease in tumor formation only when co-injected with SB transposase-encoding plasmid, while for animals injected with a higher dose (25 μg) of Statin AE transposon, co-injection of SB transposase-encoding plasmid did not significantly affect tumor load. For animals injected with 10 μg Statin AE transposon plasmid, the number of tumor nodules was inversely proportional to the amount of co-injected SB plasmid. Suppression of metastases was further evident in histological analyses, in which untreated animals showed higher levels of tumor cell proliferation and tumor vascularization than animals treated with low dose transposon plasmid.</p> <p>Conclusion</p> <p>These results demonstrate that hepatic colorectal metastases can be reduced using antiangiogenic transposons, and provide evidence for the importance of the transposition process in mediating suppression of these tumors.</p

Pipelines for Procedural Information Extraction from Scientific Literature: Towards Recipes using Machine Learning and Data Science

This paper describes a machine learning and data science pipeline for structured information extraction from documents, implemented as a suite of open-source tools and extensions to existing tools. It centers around a methodology for extracting procedural information in the form of recipes, stepwise procedures for creating an artifact (in this case synthesizing a nanomaterial), from published scientific literature. From our overall goal of producing recipes from free text, we derive the technical objectives of a system consisting of pipeline stages: document acquisition and filtering, payload extraction, recipe step extraction as a relationship extraction task, recipe assembly, and presentation through an information retrieval interface with question answering (QA) functionality. This system meets computational information and knowledge management (CIKM) requirements of metadata-driven payload extraction, named entity extraction, and relationship extraction from text. Functional contributions described in this paper include semi-supervised machine learning methods for PDF filtering and payload extraction tasks, followed by structured extraction and data transformation tasks beginning with section extraction, recipe steps as information tuples, and finally assembled recipes. Measurable objective criteria for extraction quality include precision and recall of recipe steps, ordering constraints, and QA accuracy, precision, and recall. Results, key novel contributions, and significant open problems derived from this work center around the attribution of these holistic quality measures to specific machine learning and inference stages of the pipeline, each with their performance measures. The desired recipes contain identified preconditions, material inputs, and operations, and constitute the overall output generated by our computational information and knowledge management (CIKM) system.Comment: 15th International Conference on Document Analysis and Recognition Workshops (ICDARW 2019

Magnetic-field-dependent zero-bias diffusive anomaly in Pb oxide-n-InAs structures: Coexistence of two- and three-dimensional states

The results of experimental and theoretical studies of zero-bias anomaly (ZBA) in the Pb-oxide-n-InAs tunnel structures in magnetic field up to 6T are presented. A specific feature of the structures is a coexistence of the 2D and 3D states at the Fermi energy near the semiconductor surface. The dependence of the measured ZBA amplitude on the strength and orientation of the applied magnetic field is in agreement with the proposed theoretical model. According to this model, electrons tunnel into 2D states, and move diffusively in the 2D layer, whereas the main contribution to the screening comes from 3D electrons.Comment: 8 double-column pages, REVTeX, 9 eps figures embedded with epsf, published versio

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Brain-Derived Neurotrophic Factor Ameliorates Brain Stem Cardiovascular Dysregulation during Experimental Temporal Lobe Status Epilepticus

Background: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20–30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. Methodology/Principal Findings: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47 phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47 phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdn

Migratory Dermal Dendritic Cells Act as Rapid Sensors of Protozoan Parasites

Dendritic cells (DC), including those of the skin, act as sentinels for intruding microorganisms. In the epidermis, DC (termed Langerhans cells, LC) are sessile and screen their microenvironment through occasional movements of their dendrites. The spatio-temporal orchestration of antigen encounter by dermal DC (DDC) is not known. Since these cells are thought to be instrumental in the initiation of immune responses during infection, we investigated their behavior directly within their natural microenvironment using intravital two-photon microscopy. Surprisingly, we found that, under homeostatic conditions, DDC were highly motile, continuously crawling through the interstitial space in a Gαi protein-coupled receptor–dependent manner. However, within minutes after intradermal delivery of the protozoan parasite Leishmania major, DDC became immobile and incorporated multiple parasites into cytosolic vacuoles. Parasite uptake occurred through the extension of long, highly dynamic pseudopods capable of tracking and engulfing parasites. This was then followed by rapid dendrite retraction towards the cell body. DDC were proficient at discriminating between parasites and inert particles, and parasite uptake was independent of the presence of neutrophils. Together, our study has visualized the dynamics and microenvironmental context of parasite encounter by an innate immune cell subset during the initiation of the immune response. Our results uncover a unique migratory tissue surveillance program of DDC that ensures the rapid detection of pathogens

Sensitive Detection and Analysis of Neoantigen-Specific T Cell Populations from Tumors and Blood

Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines