Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer.

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT

Regional Climate Trends and Scenarios for the U.S. National Climate Assessment Part 4. Climate of the U.S. Great Plains

This document is one of series of regional climate descriptions designed to provide input that can be used in the development of the National Climate Assessment (NCA). As part of a sustained assessment approach, it is intended that these documents will be updated as new and well-vetted model results are available and as new climate scenario needs become clear. It is also hoped that these documents (and associated data and resources) are of direct benefit to decision makers and communities seeking to use this information in developing adaptation plans. There are nine reports in this series, one each for eight regions defined by the NCA, and one for the contiguous U.S. The eight NCA regions are the Northeast, Southeast, Midwest, Great Plains, Northwest, Southwest, Alaska, and Hawai‘i/Pacific Islands. These documents include a description of the observed historical climate conditions for each region and a set of climate scenarios as plausible futures – these components are described in more detail below. While the datasets and simulations in these regional climate documents are not, by themselves, new, (they have been previously published in various sources), these documents represent a more complete and targeted synthesis of historical and plausible future climate conditions around the specific regions of the NCA. There are two components of these descriptions. One component is a description of the historical climate conditions in the region. The other component is a description of the climate conditions associated with two future pathways of greenhouse gas emissions

Nutrient Restoration of a Large, Impounded, Ultra-Oligotrophic Western River to Recover Declining Native Fishes

Declines in many fish populations in large, western rivers have been primarily attributed to the anthropogenic reduction of nutrient inputs and subsequent impacts to the food web. The largest known river fertilization program was implemented starting in 2005 on the Kootenai River in northern Idaho to restore resident fisheries. Annual electrofishing surveys were conducted at multiple sites in Idaho and Montana before and during nutrient addition to evaluate assemblage and population-level responses. Although few responses in fish assemblage structure were observed, the addition of liquid ammonium polyphosphate fertilizer (3 μg/L) to the Kootenai River increased fish abundance and biomass over the 20-km stretch of river downstream of the treatment site. Increases were most notable in Largescale Suckers Catostomus macrocheilus, Mountain Whitefish Prosopium williamsoni, and Rainbow Trout Oncorhynchus mykiss populations, although increases in catch and biomass were detected for nearly all fish species. The Kootenai River is approximately 30 times larger in discharge than other rivers that have been experimentally fertilized and provides compelling evidence that the mitigation of nutrient declines in rivers of similar size can result in positive influences on the fish populations where primary and secondary production are limiting growth, survival, and recruitment. However, results from our study also highlight the importance of completing evaluations across varying levels of biological organization (e.g., assemblage and population) and over biologically relevant timeframes

Is there an integrative center in the vertebrate brain-stem? A robotic evaluation of a model of the reticular formation viewed as an action selection device

Neurobehavioral data from intact, decerebrate, and neonatal rats, suggests that the reticular formation provides a brainstem substrate for action selection in the vertebrate central nervous system. In this article, Kilmer, McCulloch and Blum’s (1969, 1997) landmark reticular formation model is described and re-evaluated, both in simulation and, for the first time, as a mobile robot controller. Particular model configurations are found to provide effective action selection mechanisms in a robot survival task using either simulated or physical robots. The model’s competence is dependent on the organization of afferents from model sensory systems, and a genetic algorithm search identified a class of afferent configurations which have long survival times. The results support our proposal that the reticular formation evolved to provide effective arbitration between innate behaviors and, with the forebrain basal ganglia, may constitute the integrative, ’centrencephalic’ core of vertebrate brain architecture. Additionally, the results demonstrate that the Kilmer et al. model provides an alternative form of robot controller to those usually considered in the adaptive behavior literature

An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients

While clozapine is the acknowledged superior pharmacotherapeutic for the treatment of schizophrenia, the side effect profile, which includes potentially fatal complications, limits its usefulness. Central administration of clozapine directly into the brain could circumvent many of the side effect issues due to the dramatic reduction in dose and the limitation of the drug primarily to the CNS. The present study demonstrates that clozapine can be formulated as a stable solution at physiological pH, which does not have in vitro neurotoxic effects at concentrations which may be effective at treating symptoms. Acute central administration improved auditory gating deficits in a mouse model of schizophrenia-like deficits. Assessment of behavioral alterations in rats receiving chronic central infusions of clozapine via osmotic minipump was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the infusion. While these data represent only an initial investigation, they none-the-less suggest that central administration of clozapine may be a viable alternate therapeutic approach for schizophrenia patients which may be effective in symptom reduction without causing behavioral or neurotoxic effects

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Long-term site fidelity of endangered smalltooth sawfish (Pristis pectinata) from different mothers

Understanding how endangered species use nursery habitats is vital for recovery planning. Research on the smalltooth sawfish (Pristis pectinata) has shown that areas of estuarine nurseries, called hotspots, are used consistently. The objectives of our study were 1) to determine whether 10 young-of-the-year smalltooth sawfish in an artificial, non-main-stem portion (i.e., a seawall canal system) of a hotspot were descended from one or different mothers and 2) to document long-term habitat use by these individuals. At least 4 mothers contributed to the group, which comprised siblings, half-siblings, and unrelated individuals. Young sawfish exhibited site fidelity to their capture location, spending 61% of their time there. Continuous residency lasted as long as 86 days, but these fish made small-scale diel