Anti-Tumor Effects of TRAIL-Expressing Mesenchymal Stromal Cells in a Mouse Xenograft Model of Human Mesothelioma

Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment which contributes to tumor initiation, development, severity, and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further anti-tumor effects of MSCs engineered to over-express TNF-related apoptosis inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSC) or human (hMSC) MSCs were administered either systemically (IV) or intraperitoneally (IP) at various times following tumor inoculation. Both mMSCs and hMSCs localized at sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. In contrast MSC-TRAIL exposure induced apoptosis of TRAIL sensitive MM cells in vitro and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma

A Program for the Collection, Storage, and Analysis of Baseline Environmental Data for Cook Inlet, Alaska

The scope of this report is to provide a general, yet comprehensive, description of the Cook Inlet System which will serve as a basis for understanding the interrelated natural and man-made factors governing its future; to present a program of field research studies for the estuarine environment that will describe the existing state of the Inlet with respect to the water quality and biota; to provide a framework whereby the program of studies can be evaluated and redirected in light of the preliminary results; and, to provide a method of storing and analyzing the data from the investigations so that it can be made available to interested parties in the most efficient manner possible.This report was prepared by the Institute of Water Resources of the University of Alaska for the Alaska Water Laboratory, Federal Water Pollution Control Administration under Contract No. 14-12-449

Trauma related drinking to cope: A phenotypic and molecular genetic investigation of the self-medication model

Posttraumatic stress disorder (PTSD) and alcohol use problems (AUP) commonly co-occur, have shared latent genetic risk, and are associated with many negative public health outcomes. Via a self-medication framework, trauma-related drinking to cope (TRD), an unexplored construct to date, may help explain why these two disorders co-occur, thus serving as an essential target for treatment and prevention efforts. The present study aimed to create a novel measure of TRD and examine its psychometric properties, investigate its indirect influences on the association between PTSD and AUP, as well as explore its potential shared molecular genetic risk with PTSD in a genetically-informative study of college students. A sample of 1,896 students with a history of trauma and alcohol use provided genotypic data and completed an online assessment battery. First, the psychometric properties of TRD and how it relates to relevant constructs were examined using descriptive statistics and structural equation modeling. Findings demonstrated support for the external validation of TRD, both with regard to PTSD and alcohol consumption and related problems, and suggested that TRD is a more specific measure of drinking to cope motives compared to the commonly used Drinking Motives Questionnaire coping subscale. Second, results from a correlated multiple mediator model indicated that, while accounting for the effects of generalized drinking motives, TRD partially mediated the relation between PTSD and AUP and that this relationship was stronger for males than for females. Results were substantiated using longitudinal data. Third, univariate and bivariate genotypic analyses were conducted for TRD and PTSD, most of which resulted in null findings likely due to insufficient sample sizes. However, genome wide association analysis identified several significant genetic variants associated with TRD in participants of European Ancestry. Genes associated with TRD included PRAME, a protein coding gene with antithetical effects to genes commonly implicated in alcohol metabolism, as well as several genes implicated in immune system functioning (e.g., IGH, IGHE, ELK2AP). Polygenic risk for PTSD was associated with PTSD in the present sample and nominally associated with TRD. Findings are discussed in the context of limitations, clinical implications, and future directions

Moving from industry into vocational teaching: an insight

Career change can be initiated upon each of us daily

Nitrogen availability in dune systems and Its effect on root fungal endophyte communities.

As global change persists, changes in resource availability can influence plant-microbe interactions. To understand how resource availability can influence these interactions and species diversity, I focused this research on how varying nitrogen (N) levels affect root endophyte communities in the plant species Ammophila breviligulata, an ecosystem engineer in the dune system. I analyzed the relationship between nitrogen addition and microbial community composition across 60 plots treated with three nitrogen addition levels (control, low, and high) in a long-term experimental field site in the Lake Michigan dunes. I identified Ammophila breviligulata\u27s root endophyte community after creating a culture collection and performing DNA analysis on samples from each of the 60 plots. Our results indicate that any level of nitrogen addition had cascading effects on the endophyte community. I identified sixteen operational taxonomic units (OTUs) and sixty-six morphospecies using genetic sequence clustering techniques. Indicator species analysis identified three species significantly associated with specific treatment levels. This research contributes novel insight to the more extensive discussion of global change and the implications of increased atmospheric nitrogen on microbial communities. Our findings will further research focused on better equipping our environment for the imminent global change threat

Evaluation of a new trauma-related drinking to cope measure: Latent structure and heritability

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur, share latent genetic risk, and are associated with many negative public health outcomes. Via a self-medication framework, trauma-related drinking to cope (TRD), an unexplored phenotype to date, may help explain why these two disorders co-occur, thus serving as an essential target for treatment and prevention efforts. This study sought to create a novel measure of TRD and to investigate its indirect influences on the association between PTSD and AUD, as well as its potential shared molecular genetic risk with PTSD in a genetically-informative study of college students. A sample of 1,896 undergraduate students with a history of trauma and alcohol use provided genotypic data and completed an online assessment battery. The psychometric properties of TRD and how it relates to relevant constructs were examined using descriptive statistics and structural equation modeling. Results of a correlated multiple mediator model indicated that, while accounting for the effects of generalized drinking motives, TRD partially mediated the relation between PTSD and alcohol use problems (β = 0.213, p \u3c .001), consistent with the self-medication hypothesis, and that this relationship was stronger for males (β = 0.804, p \u3c .001) than for females (β = 0.463, p \u3c .001). Results were substantiated using longitudinal data. Genotypic analyses to be presented will include univariate genome wide complex trait analyses (GCTA) to establish SNP-based heritability associated with TRD and PTSD, separately, as well as bivariate GCTA to examine potential overlap in heritability between TRD and PTSD.https://scholarscompass.vcu.edu/gradposters/1047/thumbnail.jp

p107 in the public eye: an Rb understudy and more

p107 and its related family members Rb and p130 are critical regulators of cellular proliferation and tumorigenesis. Due to the extent of functional overlap within the Rb family, it has been difficult to assess which functions are exclusive to individual members and which are shared. Like its family members, p107 can bind a variety of cellular proteins to affect the expression of many target genes during cell cycle progression. Unlike Rb and p130, p107 is most highly expressed during the G1 to S phase transition of the cell cycle in actively dividing cells and accumulating evidence suggests a role for p107 during DNA replication. The specific roles for p107 during differentiation and development are less clear, although emerging studies suggest that it can cooperate with other Rb family members to control differentiation in multiple cell lineages. As a tumor suppressor, p107 is not as potent as Rb, yet studies in knockout mice have revealed some tumor suppressor functions in mice, depending on the context. In this review, we identify the unique and overlapping functions of p107 during the cell cycle, differentiation, and tumorigenesis

Isomonodromic deformations of connections with singularities of parahoric formal type

In previous work, the authors have developed a geometric theory of fundamental strata to study connections on the projective line with irregular singularities of parahoric formal type. In this paper, the moduli space of connections that contain regular fundamental strata with fixed combinatorics at each singular point is constructed as a smooth Poisson reduction. The authors then explicitly compute the isomonodromy equations as an integrable system. This result generalizes work of Jimbo, Miwa, and Ueno to connections whose singularities have parahoric formal type.Comment: 32 pages. One of the main theorems (Theorem 5.1) has been significantly strengthened. It now states that the isomonodromy equations give rise to an integrable system on the moduli space of framed connections with fixed combinatorics instead of only on a principal GL_n bundle over this space. Sections 5 and 6 have been substantially rewritte