GP-2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP-Kinase and impairs the NF-kB pathway in pancreatic cancer cells.

GP-2250, a novel anticancer agent, severely limits the energy metabolism, as demonstrated by the inhibition of hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase and a decrease of ATP. Rescue experiments with supplementary pyruvate or oxaloacetate demonstrated that a TCA cycle deficit largely contributed to cytotoxicity. Activation of the energy-deficit sensor, AMP-dependent protein kinase, was associated with increased phosphorylation of acetyl-CoA carboxylase and Raptor, pointing to a possible deficit in the synthesis of fatty acids and proteins as essential cell components.

Analysis of Environmental Data to Support Quantification of Historical Releases from a Former Uranium Processing Facility in Apollo, Pennsylvania.

This paper describes how environmental measurement data were used to help quantify the spatial impact and behavior of uranium released to the environment from a uranium manufacturing facility in Apollo, PA. The Apollo facility released enriched uranium to the environment while it operated between 1957 and 1983. Historical monitoring data generated by the site, along with other independent data sources, provided a long-term record documenting the presence and behavior of uranium in the local environment.

Conspecific and heterospecific grass litter effects on seedling emergence and growth in ragwort (Jacobaea vulgaris).

Jacobaea vulgaris Gaertn. or common ragwort is a widespread noxious grassland weed that is subject to different regulation measures worldwide. Seedling emergence and growth are the most crucial stages for most plants during their life cycle.

Use of Routine Environmental Monitoring Data to Establish a Dose-based Compliance System for a Low-level Radioactive Waste Disposal Site.

A dose-based compliance methodology was developed for Waste Control Specialists, LLC, low-level radioactive waste facility in Andrews, Texas, that allows routine environmental measurement data to be evaluated not only at the end of a year to determine regulatory compliance, but also throughout the year as new data become available, providing a continuous assessment of the facility. The first step in the methodology is a screening step to determine the potential presence of site emissions in the environment, and screening levels are established for each environmental media sampled. The screening accounts for spatial variations observed in background for soil and temporal fluctuations observed in background for air.

Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience.

The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression.

Asbestos exposure and mesothelioma mortality among atomic veterans.

Background: The United States (U.S.) conducted 230 above-ground atmospheric nuclear weapons tests between 1945 and 1962 involving over 250,000 military personnel.

Dosimetry associated with veterans who participated in nuclear weapons testing.

Background: This article summarizes the methodology, results, and challenges of the reconstruction of red bone marrow and male breast doses for a 1982-person sub-cohort of ∼114,270 U.S. military veterans who participated in eight atmospheric nuclear weapons tests between 1945 and 1962.

Impact on GABA systems in monogenetic developmental CNS disorders: Clues to symptomatic treatment.

Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found.

The immunohistochemical distribution of the GABA receptor α, α, α, β and γ subunits in the human thalamus.

The GABA receptor is the most abundant inhibitory receptor in the human brain and is assembled from a variety of different subunit subtypes which determines their pharmacology and physiology. To determine which GABA receptor subunit proteins are found in the human thalamus we investigated the distribution of five major GABA receptor subunits α, α, α, β and γ using immunohistochemical techniques. The α-, β- and γ- subunits which combine to form a benzodiazepine sensitive GABA receptor showed the most intense levels of staining and were the most common subunits found throughout the human thalamus especially in the ventral and posterior nuclear groups.

Disinhibition, an emerging pharmacology of learning and memory.

Learning and memory are dependent on interactive excitatory and inhibitory mechanisms. In this review, we discuss a mechanism called disinhibition, which is the release of an inhibitory constraint that effectively results in an increased activity in the target neurons (for example, principal or projection neurons). We focus on discussing the role of disinhibition in learning and memory at a basic level and in disease models with cognitive deficits and highlight a strategy to reverse cognitive deficits caused by excess inhibition, through disinhibition of α5-containing GABA receptors mediating tonic inhibition in the hippocampus, based on subtype-selective negative allosteric modulators as a novel class of drugs.

Red Bone Marrow and Male Breast Doses for a Cohort of Atomic Veterans.

Both red bone marrow and male breast doses with associated uncertainty have been reconstructed for a 1,982-person subset of a cohort of 114, 270 military personnel (referred to as "atomic veterans") who participated in U.S. atmospheric nuclear weapons testing from 1945 to 1962.

The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in Down syndrome and social interaction in autism.

The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts.

Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (review).

Targeting the oxygen stress response pathway is considered a promising strategy to exert antineoplastic activity in a broad spectrum of tumor types. Supporting this view, we summarize the mechanism of action of Taurolidine and Piperlongumine, two antineoplastic agents with strikingly broad tumor selectivity. Taurolidine enhances the oxidative stress (ROS) selectively in tumor cells.

Military participants at U.S. Atmospheric nuclear weapons testing--methodology for estimating dose and uncertainty.

Methods were developed to calculate individual estimates of exposure and dose with associated uncertainties for a sub-cohort (1,857) of 115,329 military veterans who participated in at least one of seven series of atmospheric nuclear weapons tests or the TRINITY shot carried out by the United States. The tests were conducted at the Pacific Proving Grounds and the Nevada Test Site. Dose estimates to specific organs will be used in an epidemiological study to investigate leukemia and male breast cancer.

Endogenous benzodiazepine site peptide ligands operating bidirectionally in vivo in neurogenesis and thalamic oscillations.

By binding to the benzodiazepine site, diazepam binding inhibitor (DBI) is associated with negative allosteric modulation (NAM) of GABAA receptors (Costa and Guidotti in Life Sci 49:325-344, 1991). However, the demonstration of a true physiological role of DBI and its fragments has only recently been reported. Based on DBI gain- and loss-of-function experiments in vivo, DBI and its fragment ODN were found to promote neurogenesis in the subventricular zone in vivo.

GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism.

The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome.

Cognitive enhancement by pharmacological and behavioral interventions: the murine Down syndrome model.

The cognitive deficits in Down syndrome (DS) are attributed to an excessive hippocampal inhibition, which obstructs neuronal plasticity and normal learning and memory, a view which is largely based on studies of Ts65Dn mice, the best characterized mouse model of DS. The cognitive behavioral deficits of Ts65Dn mice can be rescued by reducing GABAergic inhibition, most selectively by partial inverse agonists acting on α(5) GABA-A receptors, of which one compound has recently entered clinical trials in DS. Most remarkably, the improved cognitive performance of Ts65Dn can persist for weeks and months after cessation of drug treatment, as demonstrated for the non-specific GABA antagonist pentylenetetrazole.

An integrated approach to data management, risk assessment, and decision making.

This paper describes a methodology called Risk Analysis, Communication, Evaluation, and Reduction (RACER) that converts environmental data directly to human health risk to enhance decision making and communication. The methodology was developed and implemented following the Cerro Grande fire in New Mexico that burned approximately 7,500 acres of Los Alamos National Laboratory in May 2000. The absence of a coordinated and comprehensive approach to managing and understanding environmental data was a major weakness in the responding agencies' ability to make and communicate decisions.

RACER: dynamic use of environmental measurement data for decision making and communication.

To facilitate access to and use of environmental measurement data, Risk Assessment Corporation has developed a data management system as part of its Risk Analysis, Communication, Evaluation, and Reduction process. The concepts of data consistency are not new, but many data management applications are developed around managing the entire data life cycle, rather than on using the data to reach meaningful conclusions. The RACER process is specifically focused on the efficient use of available data to promote sound decision making.

The GABA system in anxiety and depression and its therapeutic potential.

In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. Therapeutically, modulators of α(2)/α(3) GABA(A) receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support.

Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms.

Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction.

Glycine transporter 1 as a potential therapeutic target for schizophrenia-related symptoms: evidence from genetically modified mouse models and pharmacological inhibition.

Schizophrenia is characterized by positive symptoms such as hallucinations, negative symptoms such as blunted affect, and symptoms of cognitive deficiency such as deficits in working memory and selective attention. N-methyl-d-aspartate receptor (NMDAR) hypofunction has been implicated in all three pathophysiological aspects of the disease. Due to the severe side effects of direct NMDAR agonists, targeting the modulatory co-agonist glycine-B site of the NMDAR is considered to be a promising strategy to ameliorate NMDAR hypofunction.