A Type-Theoretic Account of Neg-Raising Predicates in Tree Adjoining Grammars

International audienceNeg-Raising (NR) verbs form a class of verbs with a clausal complement that show the following behavior: when a negation syntactically attaches to the matrix predicate, it can semantically attach to the embedded predicate. This paper presents an account of NR predicates within Tree Adjoining Grammar (TAG). We propose a lexical semantic interpretation that heavily relies on a Montague-like semantics for TAG and on higher-order types

Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk.

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8(+) gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Linked within-host and between-host models and data for infectious diseases: a systematic review

The observed dynamics of infectious diseases are driven by processes across multiple scales. Here we focus on two: within-host, that is, how an infection progresses inside a single individual (for instance viral and immune dynamics), and between-host, that is, how the infection is transmitted between multiple individuals of a host population. The dynamics of each of these may be influenced by the other, particularly across evolutionary time. Thus understanding each of these scales, and the links between them, is necessary for a holistic understanding of the spread of infectious diseases. One approach to combining these scales is through mathematical modeling. We conducted a systematic review of the published literature on multi-scale mathematical models of disease transmission (as defined by combining within-host and between-host scales) to determine the extent to which mathematical models are being used to understand across-scale transmission, and the extent to which these models are being confronted with data. Following the PRISMA guidelines for systematic reviews, we identified 24 of 197 qualifying papers across 30 years that include both linked models at the within and between host scales and that used data to parameterize/calibrate models. We find that the approach that incorporates both modeling with data is under-utilized, if increasing. This highlights the need for better communication and collaboration between modelers and empiricists to build well-calibrated models that both improve understanding and may be used for prediction

Mutation or loss of Wilms' tumor gene 1 (WT1) are not major reasons for immune escape in patients with AML receiving WT1 peptide vaccination

<p>Abstract</p> <p>Background</p> <p>Efficacy of cancer vaccines may be limited due to immune escape mechanisms like loss or mutation of target antigens. Here, we analyzed 10 HLA-A2 positive patients with acute myeloid leukemia (AML) for loss or mutations of the WT1 epitope or epitope flanking sequences that may abolish proper T cell recognition or epitope presentation.</p> <p>Methods</p> <p>All patients had been enrolled in a WT1 peptide phase II vaccination trial (NCT00153582) and ultimately progressed despite induction of a WT1 specific T cell response. Blood and bone marrow samples prior to vaccination and during progression were analyzed for mRNA expression level of WT1. Base exchanges within the epitope sequence or flanking regions (10 amino acids N- and C-terminal of the epitope) were assessed with melting point analysis and sequencing. HLA class I expression and WT1 protein expression was analyzed by flow cytometry.</p> <p>Results</p> <p>Only in one patient, downregulation of WT1 mRNA by 1 log and loss of WT1 detection on protein level at time of disease progression was observed. No mutation leading to a base exchange within the epitope sequence or epitope flanking sequences could be detected in any patient. Further, no loss of HLA class I expression on leukemic blasts was observed.</p> <p>Conclusion</p> <p>Defects in antigen presentation caused by loss or mutation of WT1 or downregulation of HLA molecules are not the major basis for escape from the immune response induced by WT1 peptide vaccination.</p

SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair

Breaking and sealing one strand of DNA is an inherent feature of chromosome metabolism to overcome torsional barriers. Failure to reseal broken DNA strands results in protein-linked DNA breaks, causing neurodegeneration in humans. This is typified by defects in tyrosyl DNA phosphodiesterase 1 (TDP1), which removes stalled topoisomerase 1 peptides from DNA termini. Here we show that TDP1 is a substrate for modification by the small ubiquitin-like modifier SUMO. We purify SUMOylated TDP1 from mammalian cells and identify the SUMOylation site as lysine 111. While SUMOylation exhibits no impact on TDP1 catalytic activity, it promotes its accumulation at sites of DNA damage. A TDP1 SUMOylation-deficient mutant displays a reduced rate of repair of chromosomal single-strand breaks arising from transcription-associated topoisomerase 1 activity or oxidative stress. These data identify a role for SUMO during single-strand break repair, and suggest a mechanism for protecting the nervous system from genotoxic stress

Lack of color integration in visual short-term memory binding

Bicolored objects are retained in visual short-term memory (VSTM) less efficiently than unicolored objects. This is unlike shape-color combinations, whose retention in VSTM does not differ from that observed for shapes only. It is debated whether this is due to a lack of color integration and whether this may reflect the function of separate memory mechanisms. Participants judged whether the colors of bicolored objects (each with an external and an internalcolor) were the same or different across two consecutive screens. Colors had to be remembered either individually or in combination. In Experiment 1, external colors in the combined colors condition were remembered better than the internal colors, and performance for both was worse than that in the individual colors condition. The lack of color integration observed in Experiment 1 was further supported by a reduced capacity of VSTM to retain color combinations, relative to individual colors (Experiment 2). An additional account was found in Experiment 3, which showed spared color-color binding in the presence of impaired shape-color binding in a brain-damaged patient, thus suggesting that these two memory mechanisms are different

Neoplastic transformation of breast epithelial cells by genotoxic stress

<p>Abstract</p> <p>Background</p> <p>Exposure to genotoxic stresses such as radiation and tobacco smoke can cause increased cancer incidence rate as reflected in an in depth meta-analysis of data for women and breast cancer incidence. Published reports have indicated that exposures to low dose radiation and tobacco smoke are factors that contribute to the development of breast cancer. However, there is a scarcity of information on the combinatorial effects of low dose radiation and tobacco smoke on formation and progression of breast cancer. The combination of these two genotoxic insults can induce significant damage to the genetic material of the cells resulting in neoplastic transformation.</p> <p>Methods</p> <p>To study the effects of low dose ionizing radiation and tobacco smoke on breast cells, MCF 10A cells were treated either with radiation (Rad - 0.1 Gray) or cigarette smoke condensate (Csc - 10 microgram/ml of medium) or a combination of Rad + Csc. Following treatments, cells were analyzed for cell cycle distribution patterns and the ability to extrude the Hoechst 33342 dye. In addition, <it>in vitro </it>invasion and migration as well as mammosphere formation assays were performed. Finally, differential gene expression profiles were generated from the individual and combination treatment.</p> <p>Results</p> <p>Exposure of MCF 10A cells to the combination of radiation plus cigarette smoke condensate generated a neoplastic phenotype. The transformed phenotype promoted increased mammosphere numbers, altered cell cycle phases with a doubling of the population in S phase, and increased invasion and motility. Also, exclusion of Hoechst 33342 dye, a surrogate marker for increased ABC transporters, was observed, which indicates a possible increase in drug resistance. In addition, changes in gene expression include the up regulation of genes encoding proteins involved in metabolic pathways and inflammation.</p> <p>Conclusions</p> <p>The results indicate that when normal breast cells are exposed to low dose radiation in combination with cigarette smoke condensate a phenotype is generated that exhibits traits indicative of neoplastic transformation. More importantly, this is the first study to provide a new insight into a possible etiology for breast cancer formation in individuals exposed to low dose radiation and tobacco smoke.</p