T Cells Bearing a Chimeric Antigen Receptor Against the Tumor Vasculature Destroy the Tumor Endothelium and Result in Tumor Regression

Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here I describe the development of two chimeric antigen receptors (CAR)s against the tumor vasculature, targeting either tumor endothelial marker 1 (TEM1) or prostate-specific membrane antigen (PSMA). CAR T cells incorporating scFv78, an scFv isolated against TEM1, were able to recognize immobilized plate-bound TEM1 protein, but were unable to recognize TEM1 on the surface of endothelial cell targets. In contrast, anti-PSMA CAR T cells, which incorporate the J591 scFv, were able to recognize human PSMA (hPSMA) both in vitro and in vivo. To elucidate the role of intracellular signaling domains on endothelial cell killing, a panel of the J591-based CAR T cells was characterized, each harboring a different combination of the intracellular signaling domains, CD3 zeta (z), CD28 (28), and CD137/4-1BB (BB). I found that all anti-hPSMA CAR T cells were able to recognize and eliminate PSMA+ endothelial targets in vitro, regardless of signaling domain. Furthermore, T cells bearing the 3rd generation anti-hPSMA CAR, P28BBz, were able to recognize and kill primary human endothelial cells isolated from gynecological cancers. In addition, the P28BBz CAR T cells were able to mediate regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine ovarian cancers models populated by murine vessels expressing hPSMA, the P28BBz CAR T cells were able to ablate PSMA+ vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA

Wandering words: Tracing changes in words used by teacher tweeters over time

Public school teachers in the United States are often constrained in terms of their ability to express their moral views on issues that affect their schools, classrooms, students, and teaching practices, but are able to express their ideas, concerns, and frustrations as private citizens using social media. Previously we developed the Tweet Capture and Clustering System (TCCS) in order to explore how teachers use Twitter, looking at word usage among a group of teacher tweeters, and attempting to find clusters of teachers who have similar patterns of word usage in their tweets. In the work reported here, we look at teacher tweeters across the 12 months of 2016, seeking to understand how the clusters and the words used in these clusters vary from month to month. In this initial look at the dynamics of the system, we see some evidence of word usage changing across the 12-month period. This initial work suggests that extending TCCS to have temporal topic tracing as a core capability will be a meaningful addition to of the system. Copyright held by the author(s)

Subtypes of complex regional pain syndrome-a systematic review of the literature

To systematically identify and summarize possible subtypes of complex regional pain syndrome (CRPS), we searched MEDLINE, Embase, Cochrane, Scopus, and Web of Science for original studies reporting or investigating at least one subtype within a group of patients with CRPS. The search retrieved 4239 potentially relevant references. Twenty-five studies met our inclusion criteria and were included in the analysis. Complex regional pain syndrome phenotypes were investigated based on the following variables: clinical presentation/sensory disturbances, dystonia, skin temperature, disease duration, onset type, CRPS outcome, and neuropsychological test performance. Support was found for the following CRPS subtypes: CRPS type I, CRPS type II, acute CRPS, chronic CRPS, centralized CRPS, cold CRPS, warm CRPS, inflammatory CRPS, dystonic CRPS, nondystonic CRPS, familial CRPS, and nonfamilial CRPS. It is unclear whether these are distinct or overlapping subtypes. The results of this comprehensive review can facilitate the formulation of well-defined CRPS subtypes based on presumed underlying mechanisms. Our findings provide a foundation for establishing and defining clinically meaningful CRPS subtypes, with the ultimate goal of developing targeted and enhanced treatments for CRPS

Venom proteomes of South and North American opisthoglyphous (Colubridae and Dipsadidae) snake species: A preliminary approach to understanding their biological roles

Opisthoglyphous snake venoms remain under-explored despite being promising sources for ecological, evolutionary and biomedical/biotechnological research. Herein, we compared the protein composition and enzymatic properties of the venoms of Philodryas baroni (PbV), Philodryas olfersii olfersii (PooV) and Philodryas patagoniensis (PpV) from South America, and Hypsiglena torquata texana (HttV) and Trimorphodon biscutatus lambda (TblV) from North America. All venoms degraded azocasein, and this metalloproteinase activity was significantly inhibited by EDTA. PooV exhibited the highest level of catalytic activity towards synthetic substrates for serine proteinases. All venoms hydrolyzed acetylthiocholine at low levels, and only TblV showed phospholipase A2 activity. 1D and 2D SDS-PAGE profile comparisons demonstrated species-specific components as well as several shared components. Size exclusion chromatograms from the three Philodryas venoms and HttV were similar, but TblV showed a notably different pattern. MALDI-TOF MS of crude venoms revealed as many as 49 distinct protein masses, assigned to six protein families. MALDI-TOF/TOF MS analysis of tryptic peptides confirmed the presence of cysteine-rich secretory proteins in all venoms, as well as a phospholipase A2 and a three-finger toxin in TblV. Broad patterns of protein composition appear to follow phylogenetic lines, with finer scale variation likely influenced by ecological factors such as diet and habitat.Fil: Peichoto, María Elisa. Governo do Estado de Sao Paulo. Secretaria da Saude. Instituto Butantan; Brasil. Univeristy of Northern Colorado; Estados Unidos. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Tavares, Flávio Luiz. Univeristy of Northern Colorado; Estados UnidosFil: Santoro, Marcelo Larami. Governo do Estado de Sao Paulo. Secretaria da Saude. Instituto Butantan; BrasilFil: Mackessy, Stephen. Univeristy of Northern Colorado; Estados Unido

Working group written presentation: Trapped radiation effects

The results of the Trapped Radiation Effects Panel for the Space Environmental Effects on Materials Workshop are presented. The needs of the space community for new data regarding effects of the space environment on materials, including electronics are listed. A series of questions asked of each of the panels at the workshop are addressed. Areas of research which should be pursued to satisfy the requirements for better knowledge of the environment and better understanding of the effects of the energetic charged particle environment on new materials and advanced electronics technology are suggested

Flexibility windows and compression of monoclinic and orthorhombic silicalites

n/

eHabitat: A Contribution to the Model Web for Habitat Assessments and Ecological Forecasting

In striving to improve the predictive capabilities of ecological forecasting we face three basic choices ¿ develop new models, improve existing ones or increase the connectivity of models so they can work together. The latter approach of chaining different interoperable models is of particular interest, as technical developments have made it increasingly viable to combine models that can answer more questions than the individual models alone, allowing users to address complex questions, often of a multi-disciplinary nature. This concept of a Model Web encourages the setting up of a dynamic network of interoperating models, communicating with each other using standardized web services. It is the purpose of this paper to introduce the potential contribution of e-Habitat to the Model Web. e-Habitat is conceived as a Web Processing Service for computing the likelihood of finding ecosystems with equal properties. By developing e-Habitat according to Model Web principles, end-users can define the thematic layers for input to the model from various sources. These input layers are discovered using standards-based catalogues, which are a fundamental component of Model Web and generic Spatial Data Infrastructures. e-Habitat integrates data ranging from remote sensing data to socio-economical indicators, thus offering a huge potential for multi-disciplinary modelling. We will show that e-Habitat can be used for the identification of habitats that are most vulnerable or of the optimal locations for monitoring stations or, when coupled with climate change model services, for ecological forecasting. As such, it is an excellent example of the Model Web in practice.JRC.H.3-Global environement monitorin