Reducing prostaglandin E2 production to raise cancer immunogenicity

Cyclooxygenases (COX), commonly upregulated in numerous cancers, generate prostaglandin E2 (PGE2), which has been implicated in key aspects of malignant growth including proliferation, invasion and angiogenesis. Recently, we showed that production of PGE2 by cancer cells dominantly enables progressive tumor growth via immune escape and that cyclooxygenase inhibitors synergize with immunotherapy to enhance tumor eradication

Cytosolic Sensing of Viruses

Cells are equipped with mechanisms that allow them to rapidly detect and respond to viruses. These defense mechanisms rely partly on receptors that monitor the cytosol for the presence of atypical nucleic acids associated with virus infection. RIG-I-like receptors detect RNA molecules that are absent from the uninfected host. DNA receptors alert the cell to the abnormal presence of that nucleic acid in the cytosol. Signaling by RNA and DNA receptors results in the induction of restriction factors that prevent virus replication and establish cell-intrinsic antiviral immunity. In light of these formidable obstacles, viruses have evolved mechanisms of evasion, masking nucleic acid structures recognized by the host, sequestering themselves away from the cytosol or targeting host sensors, and signaling adaptors for deactivation or degradation. Here, we detail recent advances in the molecular understanding of cytosolic nucleic acid detection and its evasion by viruses

Sensing infection and tissue damage

Innate and adaptive immunity work concertedly in vertebrates to restore homoeostasis following pathogen invasion or other insults. Like all homoeostatic circuits, immunity relies on an integrated system of sensors, transducers and effectors that can be analysed in cellular or molecular terms. At the cellular level, T and B lymphocytes act as an effector arm of immunity that is mobilised in response to signals transduced by innate immune cells that detect a given insult. These innate cells are spread around the body and include dendritic cells (DCs), the chief immune sensors of pathogen invasion and tumour growth. At the molecular level, DCs possess receptors that directly sense pathogen presence and tissue damage and that signal via transduction pathways to control antigen presentation or regulate a plethora of genes encoding effector proteins that regulate immunity. Notably, molecular circuits for pathogen detection are not confined to DCs or even to immune cells. All cells express sensors and transducers that monitor invasion by viruses and bacteria and elicit suitable effector barriers to pathogen propagation. Here, I discuss work from my laboratory that has contributed to our understanding of these issues over the years

Economic Impact of Prosthetic Joint Infection - an Evaluation Within the Portuguese National Health System

Introduction: Prosthetic infection is a devastating complication of arthroplasty and carries significant economic burden. The objective of this study was to analyze the economic impact of prosthetic hip and knee infection in Portuguese National Health System. Material and Methods: Case-control study carried out from January 2014 to December 2015. The mean costs of primary arthroplasties and prosthetic revision surgeries for non-infectious reasons were compared with the costs of prosthetic infections treated with debridement and preservation of the prosthesis or with two-stage exchange arthroplasty.The reimbursement for these cases was also evaluated and compared with its real costs. Results: A total of 715 primary arthroplasties, 35 aseptic revisions, 16 surgical debridements and 15 revisions for infectious reasons were evaluated. The cost of primary arthroplasties was 3,230€ in the hips and 3,618€ in the knees. The cost of aseptic revision was 6,089€ in the hips and 7,985€ in the knees. In the cases treated with debridement and implant retention the cost was 5,528€ in the hips and 4,009€ in the knees. In cases of infections treated with a two-stage revision the cost was 11,415€ and 13,793€ for hips and knees, respectively. Conclusion: As far as we know this is the first study that analyzes the economic impact of prosthetic infection in the Portuguese context. Although direct compensation for treating infected cases is much lower than calculated costs, infected cases push the overall hospital case-mix-index upwards thus increasing financial compensation for the entire cohort of treated patients. This knowledge will allow for more informed decisions about health policies in the future.info:eu-repo/semantics/publishedVersio

Panorama do uso do BIM 4D e 5D no planejamento e gerenciamento de obras na construção civil

Trabalho de Conclusão de Curso (Graduação)O governo brasileiro instituiu metas para implementação da indústria 4.0 para alavancar os avanços na indústria da construção civil. Segundo a Agenda Brasileira para a Indústria 4.0, atualmente o setor da AEC (Arquitetura, Engenharia e Construção) ocupa o ranking de 69º lugar no índice global de inovação, e de 2010 a 2016 teve uma queda na produção de 7%, enquanto países da Europa, como a Alemanha e Itália ocupam respectivamente a primeira e segunda posição. A introdução de novas tecnologias que consigam minimizar a geração de resíduos, organizar e integrar as partes interessadas reduzindo conflitos e gerenciar o tempo e custo se faz necessária. A metodologia BIM (Building Information Modeling) fornece a interação das informações de um projeto, unindo a modelagem 3D, com o gerenciamento do tempo (BIM 4D) e a gestão de custos (BIM 5D). O interesse com relação à adoção dessa metodologia por parte das empresas vem crescendo, porém, a falta de informação, de suporte, de conhecimento, de documentos para consulta, além de profissionais qualificados e experientes na área, são fatores que geram a desistência das instituições. Este artigo visou mapear sistematicamente referências que fazem o uso do BIM 4D e 5D no planejamento e gerenciamento de obras, com o objetivo de apresentar um panorama da atualidade e as lacunas a serem preenchidas, no Brasil e no mundo. Dentre os principais tópicos identificados, a falta de expertise da mão de obra em relação ao BIM e a estagnação da indústria AEC em antigos métodos foram os mais levantados pelos estudos aderidos a este artigo, logo em seguida, a falta de padronização da metodologia por meio da criação de normas e regulamentos

Dendritic cell quiescence during systemic inflammation driven by LPS stimulation of radioresistant cells in vivo

Dendritic cell (DC) activation is a prerequisite for T cell priming. During infection, activation can ensue from signaling via pattern-recognition receptors after contact with pathogens or infected cells. Alternatively, it has been proposed that DCs can be activated indirectly by signals produced by infected tissues. To address the contribution of tissue-derived signals, we measured DC activation in a model in which radioresistant cells can or cannot respond to lipopolysaccharide (LPS). We report that recognition of LPS by the radioresistant compartment is sufficient to induce local and systemic inflammation characterized by high circulating levels of tumor necrosis factor (TNF) α, interleukin (IL) 1β, IL-6, and CC chemokine ligand 2. However, this is not sufficient to activate DCs, whether measured by migration, gene expression, phenotypic, or functional criteria, or to render DC refractory to subsequent stimulation with CpG-containing DNA. Similarly, acute or chronic exposure to proinflammatory cytokines such as TNF-α ± interferon α/β has marginal effects on DC phenotype in vivo when compared with LPS. In addition, DC activation and migration induced by LPS is unimpaired when radioresistant cells cannot respond to the stimulus. Thus, inflammatory mediators originating from nonhematopoietic tissues and from radioresistant hematopoietic cells are neither sufficient nor required for DC activation in vivo

Dendritic cells in remodeling of lymph nodes during immune responses

A critical hallmark of adaptive immune responses is the rapid and extensive expansion of lymph nodes. During this process, the complex internal structure of the organs is maintained revealing the existence of mechanisms able to balance lymph node integrity with structural flexibility. This article reviews the extensive architectural remodeling that occurs within lymph nodes during adaptive immune responses and how it is regulated by dendritic cells (DCs). In particular we focus on previously unappreciated functions of DCs in coordinating remodeling of lymph node vasculature, expansion of the fibroblastic reticular network and maintenance of lymphoid stromal phenotypes. Our increased understanding of these processes indicates that DCs need to be viewed not only as key antigen-presenting cells for lymphocytes but also as broad-acting immune sentinels that convey signals to lymphoid organ stroma and thereby facilitate immune response initiation at multiple levels

Platelet-rich blood derivatives for tendon regeneration

Tendon injuries constitute a significant healthcare problem with variable clinical outcomes. The complex interplay of tissue homeostasis, degeneration, repair, and regeneration makes the development of successful delivery therapeutic strategies challenging. Platelet-rich hemoderivatives, a source of supra-physiologic concentrations of human therapeutic factors, are a promising application to treat tendon injuries from the perspective of tendon tissue engineering, although the outcomes remain controversial.The authors acknowledge the finan-cial support from the ERC GrantCoG MagTendon nr 772817, theProject NORTE-01-0145-FEDER-000021, the Project FOOD4CELLS(Pedro Babo post-doc grant)(PTDC/CTM-BIO/4706/2014-POCI-01-0145-FEDER 016716), andHORIZON 2020 under the TEAM-ING Grant agreement no 739572—The Discoveries CTR

Clec9a-mediated ablation of conventional dendritic cells suggests a lymphoid path to generating dendritic cells In Vivo

Conventional dendritic cells (cDCs) are versatile activators of immune responses that develop as part of the myeloid lineage downstream of hematopoietic stem cells. We have recently shown that in mice precursors of cDCs, but not of other leukocytes, are marked by expression of DNGR-1/CLEC9A. To genetically deplete DNGR-1-expressing cDC precursors and their progeny, we crossed Clec9a-Cre mice to Rosa-lox-STOP-lox-diphtheria toxin (DTA) mice. These mice develop signs of age-dependent myeloproliferative disease, as has been observed in other DC-deficient mouse models. However, despite efficient depletion of cDC progenitors in these mice, cells with phenotypic characteristics of cDCs populate the spleen. These cells are functionally and transcriptionally similar to cDCs in wild type control mice but show somatic rearrangements of Ig-heavy chain genes, characteristic of lymphoid origin cells. Our studies reveal a previously unappreciated developmental heterogeneity of cDCs and suggest that the lymphoid lineage can generate cells with features of cDCs when myeloid cDC progenitors are impaired