Differential In Vitro Pharmacological Profiles of Structurally Diverse Nociceptin Receptor Agonists in Activating G Protein and Beta-Arrestin Signaling at the Human Nociceptin Opioid Receptor.

Agonists at the nociceptin opioid peptide receptor (NOP) are under investigation as therapeutics for nonaddicting analgesia, opioid use disorder, Parkinson's disease, and other indications. NOP full and partial agonists have both been of interest, particularly since NOP partial agonists show a reduced propensity for behavioral disruption than NOP full agonists. Here, we investigated the in vitro pharmacological properties of chemically diverse NOP receptor agonists in assays measuring functional activation of the NOP receptor such as guanosine 5'-O-[gamma-thio]triphosphate (GTPS) binding, cAMP inhibition, G protein-coupled inwardly rectifying potassium (GIRK) channel activation, phosphorylation, β-arrestin recruitment and receptor internalization.

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting.

Automated Information Extraction on Treatment and Prognosis for Non-Small Cell Lung Cancer Radiotherapy Patients: Clinical Study.

Background: In outcome studies of oncology patients undergoing radiation, researchers extract valuable information from medical records generated before, during, and after radiotherapy visits, such as survival data, toxicities, and complications. Clinical studies rely heavily on these data to correlate the treatment regimen with the prognosis to develop evidence-based radiation therapy paradigms. These data are available mainly in forms of narrative texts or table formats with heterogeneous vocabularies.

Improved Identification of Venous Thromboembolism From Electronic Medical Records Using a Novel Information Extraction Software Platform.

Introduction: The United States federally mandated reporting of venous thromboembolism (VTE), defined by Agency for Healthcare Research & Quality Patient Safety Indicator 12 (AHRQ PSI-12), is based on administrative data, the accuracy of which has not been consistently demonstrated. We used IDEAL-X, a novel information extraction software system, to identify VTE from electronic medical records and evaluated its accuracy.

Methods: Medical records for 13,248 patients admitted to an orthopedic specialty hospital from 2009 to 2014 were reviewed.

Effective Information Extraction Framework for Heterogeneous Clinical Reports Using Online Machine Learning and Controlled Vocabularies.

Background: Extracting structured data from narrated medical reports is challenged by the complexity of heterogeneous structures and vocabularies and often requires significant manual effort. Traditional machine-based approaches lack the capability to take user feedbacks for improving the extraction algorithm in real time.

Objective: Our goal was to provide a generic information extraction framework that can support diverse clinical reports and enables a dynamic interaction between a human and a machine that produces highly accurate results.

Support patient search on pathology reports with interactive online learning based data extraction.

Background: Structural reporting enables semantic understanding and prompt retrieval of clinical findings about patients. While synoptic pathology reporting provides templates for data entries, information in pathology reports remains primarily in narrative free text form. Extracting data of interest from narrative pathology reports could significantly improve the representation of the information and enable complex structured queries.

ASLForm: an adaptive self learning medical form generating system.

To facilitate the process of extracting information from narrative medical reports and transforming extracted data into standardized structured forms, we present an interactive, incrementally learning based information extraction system - ASLForm. ASLForm provides users a convenient interface that can be used as a simple data extraction and data entry system. It is unique, however, in its ability to transparently analyze and quickly learn, from users' interactions with a small number of reports, the desired values for the data fields.

A novel mechanism is involved in cationic lipid-mediated functional siRNA delivery.

A key challenge for therapeutic application of RNA interference is to efficiently deliver synthetic small interfering RNAs (siRNAs) into target cells that will lead to the knockdown of the target transcript (functional siRNA delivery). To facilitate rational development of nonviral carriers, we have investigated by imaging, pharmacological and genetic approaches the mechanisms by which a cationic lipid carrier mediates siRNA delivery into mammalian cells. We show that approximately 95% of siRNA lipoplexes enter the cells through endocytosis and persist in endolysosomes for a prolonged period of time.

Cytosolic delivery mediated via electrostatic surface binding of protein, virus, or siRNA cargos to pH-responsive core-shell gel particles.

We recently described a strategy for intracellular delivery of macromolecules, utilizing pH-responsive "core-shell" structured gel particles. These cross-linked hydrogel particles disrupt endosomes with low toxicity by virtue of physical sequestration of an endosome-disrupting "proton sponge" core inside a nontoxic hydrophilic shell. Here we tested the efficacy of this system for cytosolic delivery of a broad range of macromolecular cargos, and demonstrate the delivery of proteins, whole viral particles, or siRNA oligonucleotides into the cytosol of dendritic cells and epithelial cells via core-shell particles.

FRIL: A tool for comparative record linkage.

A fine-grained record integration and linkage tool (FRIL) is presented. The tool extends traditional record linkage tools with a richer set of parameters. Users may systematically and iteratively explore the optimal combination of parameter values to enhance linking performance and accuracy.

Fine-grained record integration and linkage tool.

Background: As part of the surveillance program to monitor the occurrence of birth defects in the metropolitan Atlanta area, we developed a record linkage software tool that provides latitude in the choice of linkage parameters, allows for efficient and accurate linkages, and enables objective assessments of the quality of the linked data.

Methods: We developed and implemented a Java-based fine-grained probabilistic record integration and linkage tool (FRIL) that incorporates a rich collection of record distance metrics, search methods, and analysis tools. Along its workflow, FRIL provides a rich set of user-tunable parameters augmented with graphic visualization tools to assist users in understanding the effects of parameter choices.

Non-viral siRNA delivery to the lung.

SiRNAs exert their biological effect by guiding the degradation of their cognate mRNA sequence, thereby shutting down the corresponding protein production (gene silencing by RNA interference or RNAi). Due to this property, siRNAs are emerging as promising therapeutic agents for the treatment of inherited and acquired diseases, as well as research tools for the elucidation of gene function in both health and disease. Because of their lethality and prevalence, lung diseases have attracted particular attention as targets of siRNA-mediated cures.

Identification of novel superior polycationic vectors for gene delivery by high-throughput synthesis and screening of a combinatorial library.

Purpose: Low efficiency and toxicity are two major drawbacks of current non-viral gene delivery vectors. Since DNA delivery to mammalian cells is a multi-step process, generating and searching combinatorial libraries of vectors employing high-throughput synthesis and screening methods is an attractive strategy for the development of new improved vectors because it increases the chance of identifying the most overall optimized vectors.

Materials And Methods: Based on the rationale that increasing the effective molecular weight of small PEIs, which are poor vectors compared to the higher molecular weight homologues but less toxic, raises their transfection efficiency due to better DNA binding, we synthesized a library of 144 biodegradable derivatives from two small PEIs and 24 bi- and oligo-acrylate esters.

Cervical laminectomy: technique.

Spinal canal decompression via cervical laminectomy with or without foraminotomy is a mainstay of treatment of cervical spondylotic myelopathy and myeloradiculopathy. The goal of this surgery is to expand the cervical canal dorsally by removing the spinous processes, laminae, ligamentum flavum, and bony hypertrophy that are contributing to the canal stenosis. In selecting this particular approach to decompression, the surgeon must take into account the spinal geometry and the primary pathology of the patient: an "effective" cervical kyphosis is a contraindication to a dorsal approach, and spinal canal compromise secondary to ventral compression is best addressed through a ventral or a combined ventral and dorsal approach.

Polycation-mediated delivery of siRNAs for prophylaxis and treatment of influenza virus infection.

Influenza A virus causes one of the most prevalent infections in humans. In a typical year, 10-20% of the population of the US is infected by influenza virus, resulting in up to 40,000 deaths and 200,000 hospitalisations. Vaccination is the most effective preventative measure that can protect 70-90% of healthy adults aged < 65; however, the protection rate is much lower in those most susceptible to infection, namely infants, the elderly and individuals with weakened immune systems.

Cross-linked small polyethylenimines: while still nontoxic, deliver DNA efficiently to mammalian cells in vitro and in vivo.

Purpose: Polyethylenimine (PEI) is among the most efficient nonviral gene delivery vectors. Its efficiency and cytotoxicity depend on molecular weight, with the 25-kDa PEI being most efficient but cytotoxic. Smaller PEIs are noncytotoxic but less efficient.

Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung.

High-molecular-mass polyethylenimines (PEIs) are widely used vectors for nucleic acid delivery. We found that removal of the residual N-acyl moieties from commercial linear 25-kDa PEI enhanced its plasmid DNA delivery efficiency 21 times in vitro, as well as 10,000 times in mice with a concomitant 1,500-fold enhancement in lung specificity. Several additional linear PEIs were synthesized by acid-catalyzed hydrolysis of poly(2-ethyl-2-oxazoline), yielding the pure polycations.

Poly(ethylene glycol) (PEG) enhances dynamic surface activity of a bovine lipid extract surfactant (BLES).

Shortage or malfunction of pulmonary surfactant in alveolar space leads to a critical condition termed respiratory distress syndrome (RDS). Surfactant replacement therapy, the major method to treat RDS, is an expensive treatment. In this paper, the effect of poly(ethylene glycol) (PEG) to improve dynamic surface activity of a bovine lipid extract surfactant (BLES) was studied by axisymmetric drop shape analysis (ADSA) and a captive bubble method.

Poly(ethylene glycol) enhances the surface activity of a pulmonary surfactant.

The primary role of lung surfactant is to reduce surface tension at the air-liquid interface of alveoli during respiration. Axisymmetric drop shape analysis (ADSA) was used to study the effect of poly(ethylene glycol) (PEG) on the rate of surface film formation of a bovine lipid extract surfactant (BLES), a therapeutic lung surfactant preparation. PEG of molecular weights 3,350; 8,000; 10,000; 35,000; and 300,000 in combination with a BLES mixture of 0.

Constrained sessile drop as a new configuration to measure low surface tension in lung surfactant systems.

Existing methodology for surface tension measurements based on drop shapes suffers from the shortcoming that it is not capable to function at very low surface tension if the liquid dispersion is opaque, such as therapeutic lung surfactants at clinically relevant concentrations. The novel configuration proposed here removes the two big restrictions, i.e.