TNO at TRECVID 2013 : multimedia event detection and instance search

We describe the TNO system and the evaluation results for TRECVID 2013 Multimedia Event Detection (MED) and instance search (INS) tasks. The MED system consists of a bag-of-word (BOW) approach with spatial tiling that uses low-level static and dynamic visual features, an audio feature and high-level concepts. Automatic speech recognition (ASR) and optical character recognition (OCR) are not used in the system. In the MED case with 100 example training videos, support-vector machines (SVM) are trained and fused to detect an event in the test set. In the case with 0 example videos, positive and negative concepts are extracted as keywords from the textual event description and events are detected with the high-level concepts. The MED results show that the SIFT keypoint descriptor is the one which contributes best to the results, fusion of multiple low-level features helps to improve the performance, and the textual event-description chain currently performs poorly. The TNO INS system presents a baseline open-source approach using standard SIFT keypoint detection and exhaustive matching. In order to speed up search times for queries a basic map-reduce scheme is presented to be used on a multi-node cluster. Our INS results show above-median results with acceptable search times.This research for the MED submission was performed in the GOOSE project, which is jointly funded by the enabling technology program Adaptive Multi Sensor Networks (AMSN) and the MIST research program of the Dutch Ministry of Defense. The INS submission was partly supported by the MIME project of the creative industries knowledge and innovation network CLICKNL.peer-reviewe

Direct Visualization by Cryo-EM of the Mycobacterial Capsular Layer: A Labile Structure Containing ESX-1-Secreted Proteins

The cell envelope of mycobacteria, a group of Gram positive bacteria, is composed of a plasma membrane and a Gram-negative-like outer membrane containing mycolic acids. In addition, the surface of the mycobacteria is coated with an ill-characterized layer of extractable, non-covalently linked glycans, lipids and proteins, collectively known as the capsule, whose occurrence is a matter of debate. By using plunge freezing cryo-electron microscopy technique, we were able to show that pathogenic mycobacteria produce a thick capsule, only present when the cells were grown under unperturbed conditions and easily removed by mild detergents. This detergent-labile capsule layer contains arabinomannan, α-glucan and oligomannosyl-capped glycolipids. Further immunogenic and proteomic analyses revealed that Mycobacterium marinum capsule contains high amounts of proteins that are secreted via the ESX-1 pathway. Finally, cell infection experiments demonstrated the importance of the capsule for binding to cells and dampening of pro-inflammatory cytokine response. Together, these results show a direct visualization of the mycobacterial capsular layer as a labile structure that contains ESX-1-secreted proteins

M-tuberculosis and M-leprae translocate from the phagolysosome to the cytosol in myeloid cells

M. tuberculosis and M. leprae are considered to be prototypical intracellular pathogens that have evolved strategies to enable growth in the intracellular phagosomes. In contrast, we show that lysosomes rapidly fuse with the virulent M. tuberculosis- and M. leprae-containing phagosomes of human monocyte-derived dendritic cells and macrophages. After 2 days, M. tuberculosis progressively translocates from phagolysosomes into the cytosol in nonapoptotic cells. Cytosolic entry is also observed for M. leprae but not for vaccine strains such as M. bovis BCG or in heat-killed mycobacteria and is dependent upon secretion of the mycobacterial gene products CFP-10 and ESAT-6. The cytosolic bacterial localization and replication are pathogenic features of virulent mycobacteria, causing significant cell death within a week. This may also reveal a mechanism for MHC-based antigen presentation that is lacking in current vaccine strain

Time to return to work by occupational class after total hip or knee arthroplasty

AIMS: For the increasing number of working-age patients undergoing total hip or total knee arthroplasty (THA/TKA), return to work (RTW) after surgery is crucial. We investigated the association between occupational class and time to RTW after THA or TKA.METHODS: Data from the prospective multicentre Longitudinal Leiden Orthopaedics Outcomes of Osteoarthritis Study were used. Questionnaires were completed preoperatively and six and 12 months postoperatively. Time to RTW was defined as days from surgery until RTW (full or partial). Occupational class was preoperatively assessed and categorized into four categories according to the International Standard Classification of Occupations 2008 (blue-/white-collar, high-/low-skilled). Cox regression analyses were conducted separately for THA and TKA patients. Low-skilled blue-collar work was used as the reference category.RESULTS: A total of 360 THA and 276 TKA patients, preoperatively employed, were included. Patients were mainly high-skilled (THA 57%; TKA 41%) or low-skilled (THA 24%; TKA 38%) white-collar workers. Six months post-THA, RTW rates were 78% of low-skilled blue-collar workers compared to 83% to 86% within other occupational classes, increasing after 12 months to 87% to 90% in all occupational classes. Six months post-TKA, RTW rates were 58% of low-skilled and 64% of high-skilled blue-collar workers compared to 80% to 89% of white-collar workers, and after 12 months 79% of low-skilled blue-collar workers compared to 87% to 92% within other occupational classes. High-skilled white-collar workers (THA: hazard ratio (HR) 2.12 (95% confidence interval (CI) 1.32 to 3.40); TKA: HR 2.31 (95% CI 1.34 to 4.00)) and low-skilled white-collar workers (TKA: HR 1.82 (95% CI 1.04 to 3.18)) had a higher hazard to RTW within six months postoperatively.CONCLUSION: Clear differences existed in time to RTW among both THA and TKA patients in each of the groups studied. These findings may help guide tailored patient-specific information during preoperative consultation and advice postoperatively, as well as to create awareness among workers and their employers.</p

IL-1R1-Dependent Signals Improve Control of Cytosolic Virulent Mycobacteria In Vivo

International audienceMycobacterium tuberculosis infections claim more than a million lives each year, and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from phagolysosomes to the cytosol upon phagocytosis by macrophages. Translocation from the phagolysosome to the cytosol is an ESX-1-dependent process, as previously shown in vitro Here, we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillos, zebrafish, and patient material infected with M. tuberculosis, M. marinum, or M. leprae In contrast, when innate or adaptive immunity was compromised, as in severe combined immunodeficiency (SCID) or interleukin-1 receptor 1 (IL-1R1)-deficient mice, significant numbers of cytosolic M. tuberculosis bacilli were detected in the lungs of infected mice. Taken together, in vivo, translocation to the cytosol of M. tuberculosis is controlled by adaptive immune responses as well as IL-1R1-mediated signals.IMPORTANCE For decades, Mycobacterium tuberculosis has been one of the deadliest pathogens known. Despite infecting approximately one-third of the human population, no effective treatment or vaccine is available. A crucial pathogenicity factor is subcellular localization, as M. tuberculosis can translocate from phagolysosome to the cytosol in macrophages. The situation in vivo is more complicated. In this study, we establish that high-level cytosolic escape of mycobacteria can indeed occur in vivo but mainly when host resistance is compromised. The IL-1 pathway is crucial for the control of the number of cytosolic mycobacteria. The establishment that immune signals result in the clearance of cells containing cytosolic mycobacteria connects two important fields, cell biology and immunology, which is vital for the understanding of the pathology of M. tuberculosis

Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

Purpose Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.Experimental Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.Results Five out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.Conclusion The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

To improve the efficacy of immunotherapy, it is essential to better understand how cytotoxic CD8+ T cells infiltrate into tumors. Here, we examine a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) is a secreted phospholipase that produces the lipid mediator lysophosphatidic acid (LPA) to regulate multiple biological functions via specific G protein-coupled receptors, termed LPAR1-6. ATX/LPA promotes tumor cell migration via LPAR1 and T-cell motility via LPAR2, yet its actions in the tumor microenvironment remain unclear. Here, we show that tumor-intrinsic ATX suppresses T-cell infiltration to impede anti-tumor immunity, and identify LPAR6 as a T-cell migration inhibitory receptor. Hence, ATX inhibition may show clinical benefit for patients with cancer. We find that ATX secreted by melanoma cells is a chemo-repellent for ex vivo expanded tumor-infiltrating lymphocytes (TILs) and peripheral CD8+ T cells, overruling chemokine activity. Mechanistically, T-cell repulsion is mediated by G12/13-coupled LPAR6, which is highly expressed in immune cells. Contrary to prevailing notions, secreted ATX is bioactive at physiologically insignificant steady-state LPA levels, revealing its secondary function as an LPA carrier or chaperone. Upon anti-cancer vaccination of tumor-bearing mice, tumor-intrinsic ATX does not affect the induction of systemic T-cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor immune control. Moreover, ENPP2 expression in melanoma tumors – in both malignant and stromal cells – is associated with reduced T-cell infiltration, as inferred from single-cell transcriptomics. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration and anti-tumor immunity