Faculty Bibliography

Radiotherapy (RT) is employed to achieve local cancer control. However, in rare patients, regression of metastases outside of the radiation field has been reported after irradiation of one tumor site, a phenomenon known as abscopal effect. We have previously shown in experimental tumor models that the abscopal effect is mediated by activation of antitumor immune responses by radiotherapy, which can convert the irradiated tumor into an in situ vaccine. However, effective induction of anti-tumor immunity by radiation is rare. To study the barriers to the induction of an abscopal effect we have employed a mouse model of metastatic breast cancer. Ionizing radiation activates Transforming Growth Factor-b (TGFbeta), a strongly immunosuppressive cytokine that promotes DNA damage repair (DDR) and metastasis. We therefore hypothesized that neutralization of TGFbeta may improve the development of anti-tumor immune responses induced by RT, leading to an abscopal effect. To test this hypothesis, mouse mammary carcinoma TSA cells were injected s.c. at day 0 into syngeneic immunocompetent BALC/c mice at two separate sites, a "primary" site that was irradiated, and a secondary site outside of the radiation field. TGFbeta neutralizing 1D11 mAb was given i.p. starting one day before radiation. On day 12 when both tumors were palpable, mice were randomly assigned to groups receiving either 1D11 mAb or isotype control (MOPC-21) every other day for 16 days, with or without radiation (6 Gy doses given to the primary tumor on days 13-17). Radiation alone effectively delayed primary but not secondary tumor growth. 1D11 alone did not have a significant effect on either primary or secondary tumors. Combination of 1D11 with RT enhanced significantly inhibition of the primary irradiated tumor, with complete tumor regression in 4 out of 6 mice by day 28 (p=0.0059 radiation+1D11 versus radiation). Importantly, an abscopal effect was seen only in mice treated with radiation + 1D11, with significantly smaller secondary tumors on day 28 (p=0.0329 radiation+1D11 versus MOPC-21). Data indicate that blocking TGFbeta in the context of radiation not only improves local tumor control, but also induces an abscopal effect with systemic tumor inhibition. Overall, data provide further support for the use of agents targeting TGFbeta during radiotherapy, a concept currently tested in a phase I/II clinical trial in metastatic breast cancer patients (NCT01401062)

This paper describes a novel application of information-asymmetric (signalling) games to molecular biology in which utility is determined by the message complexity (rate) in addition to the error in information transfer (distortion). We show using a computational model how it is possible for the agents in one such game to evolve a signalling convention (separating equilibrium) that is suboptimal in terms of information transfer, but is nonetheless stable. In the context of an RNA world merging with a nascent amino acid one, such a game's equilibrium is alluded to by the genetic code, which is nearly optimal in terms of information transfer, but is also near-universal and nearly immutable. Such a framework suggests that cellularity may have emerged to encourage coordination between RNA species and sheds light on other aspects of RNA world biochemistry yet to be fully understood.

Atherosclerosis (also known as arteriosclerotic vascular disease) is a chronic inflammatory disease of the arterial wall, characterized by the formation of lipid-laden lesions. The activation of endothelial cells at atherosclerotic lesion-prone sites in the arterial tree results in the up-regulation of cell adhesion molecules and chemokines, which mediate the recruitment of circulating monocytes. Accumulation of monocytes and monocyte-derived phagocytes in the wall of large arteries leads to chronic inflammation and the development and progression of atherosclerosis. The lesion experiences the following steps: foam cell formation, fatty streak accumulation, migration and proliferation of vascular smooth muscle cells, and fibrous cap formation. Finally, the rupture of the unstable fibrous cap causes thrombosis in complications of advanced lesions that lead to unstable coronary syndromes, myocardial infarction and stroke. MicroRNAs have recently emerged as a novel class of gene regulators at the post-transcriptional level. Several functions of vascular cells, such as cell differentiation, contraction, migration, proliferation and inflammation that are involved in angiogenesis, neointimal formation and lipid metabolism underlying various vascular diseases, have been found to be regulated by microRNAs and are described in the present review as well as their potential therapeutic application.

The Proteome Informatics Research Group (iPRG) this year performed a study to evaluate the benefits of using databases derived from RNA-Seq data for peptide identification. The proteomic dataset provided consisted of high mass accuracy tandem mass spectra acquired when analyzing human peripheral blood mononuclear cells. A variety of different types of sequence databases were supplied. These included a standard protein sequence database; a database containing only sequences of proteins expressed in the sam- ple based on RNA-Seq data; a database that included sequence and splice variants; a database of sequences that could not be reconciled to known expressed gene sequences. Participants were asked to report spectral identifications in the form of an Excel spreadsheet, highlighting those identifications that were only identified using one of the RNA-Seq derived specialized sequence databases. Participants were also required to complete a web-based questionnaire summarizing the tools and methods they used. Additional peptide identifications were achieved by the use of each of the different RNA-Seq derived databases, although the number of additional identifications was modest. Nevertheless, these new identifications could have potential biological significance, so this type of analysis may still be worthwhile

The Proteome Informatics Research Group (iPRG) this year performed a study to evaluate the benefits of using databases derived from RNA-Seq data for peptide identifi-cation. The proteomic dataset provided consisted of high mass accuracy tandem mass spectra acquired when analyzing human peripheral blood mononuclear cells. A variety of different types of sequence databases were supplied. These included a standard protein sequence database; a database containing only sequences of proteins expressed in the sample based on RNA-Seq data; a database that included sequence and splice variants; a database of sequences that could not be reconciled to known expressed gene sequences. Participants were asked to report spectral identifications in the form of an Excel spreadsheet, highlighting those identifications that were only identified using one of the RNA-Seq derived specialized sequence databases. Participants were also required to complete a web-based questionnaire summarizing the tools and methods they used. Additional peptide identifications were achieved by the use of each of the different RNA-Seq derived databases, although the number of additional identifications was modest. Nevertheless, these new identifications could have potential biological significance, so this type of analysis may still be worthwhile

The phenotype represents a critical interface between the genome and the environment in which organisms live and evolve. Phenotypic characters also are a rich source of biodiversity data for tree building, and they enable scientists to reconstruct the evolutionary history of organisms, including most fossil taxa, for which genetic data are unavailable. Therefore, phenotypic data are necessary for building a comprehensive Tree of Life. In contrast to recent advances in molecular sequencing, which has become faster and cheaper through recent technological advances, phenotypic data collection remains often prohibitively slow and expensive. The next-generation phenomics project is a collaborative, multidisciplinary effort to leverage advances in image analysis, crowdsourcing, and natural language processing to develop and implement novel approaches for discovering and scoring the phenome, the collection of phentotypic characters for a species. This research represents a new approach to data collection that has the potential to transform phylogenetics research and to enable rapid advances in constructing the Tree of Life. Our goal is to assemble large phenomic datasets built using new methods and to provide the public and scientific community with tools for phenomic data assembly that will enable rapid and automated study of phenotypes across the Tree of Life.

To discover interordinal relationships of living and fossil placental mammals and the time of origin of placentals relative to the Cretaceous-Paleogene (K-Pg) boundary, we scored 4541 phenomic characters de novo for 86 fossil and living species. Combining these data with molecular sequences, we obtained a phylogenetic tree that, when calibrated with fossils, shows that crown clade Placentalia and placental orders originated after the K-Pg boundary. Many nodes discovered using molecular data are upheld, but phenomic signals overturn molecular signals to show Sundatheria (Dermoptera + Scandentia) as the sister taxon of Primates, a close link between Proboscidea (elephants) and Sirenia (sea cows), and the monophyly of echolocating Chiroptera (bats). Our tree suggests that Placentalia first split into Xenarthra and Epitheria; extinct New World species are the oldest members of Afrotheria.