Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy.
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ABSTRACT:
SUBMITTER: Anker JF
PROVIDER: S-EPMC5913311 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.
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Project description:Hosts can alter their strategy towards pathogens during their lifetime; that is, they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e., resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fecundity consequences that result from a high pathogen burden. Finally, previous exposure may also lead to life-history adjustments, such as terminal investment into reproduction. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested whether previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute-phase infection (one day post-challenge). We then asked whether previous pathogen exposure affects chronic-phase pathogen persistence and longer-term survival (28 days post-challenge). We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long-term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi-faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host-pathogen system and that infection persistence may be bacterium-specific.
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Project description:Background and aimsThe new coronavirus disease (COVID-19) is a systemic disease. Mounting evidence depict signs and symptoms involving multiple organs, most of which supported by pathological data. A plausible link to these manifestations is vascular and endothelial dysfunction/damage. However, much of the current knowledge relies on opinion and incipient evidence. We aim to objectively appraise current evidence on the association between COVID-19 and vascular disease, specifically endotheliitis and vasculitis.MethodsTwo researchers independently entered the search terms COVID-19 OR SARS-CoV-2 AND vasculitis, endotheliitis OR endothelium in the following online platforms: MedRxiv and LitCovid (PubMed). The search period was set from November 1, 2019 to August 28, 2020. Manuscripts with unavailable full texts, not in English, mainly on pre-clinical data, presenting only study designs or not directly related to the topics of this review were excluded. Retrospective and prospective studies, especially longitudinal ones, were given priority to the purpose of this review. Since there was paucity of prospective controlled evidence, case reports/series were also considered.ResultsA total of 318 manuscripts were initially found. Sixty-seven (21%) were excluded: 59 (18.5%) met exclusion criteria and 8 (2.5%) were duplicates. One hundred and forty-two manuscripts (44,6%) did not provide original data and were also excluded: 35 (11%) were comments, 108 (33.9%) reviews; 1 (0.3%) position paper. One hundred and seven (33.6%) studies were considered for the present scoping review: 81 (25,5%) case reports/series; 18 (5.7%) prospective; 8 (2.5%) retrospective. Viral inclusions in endothelial cells, mononuclear cell infiltrates in the intima of small vessels and markers of endothelial cell apoptosis were demonstrated. Specificities of COVID-19 may lead to diverse vascular manifestations in different levels of the vascular bed.ConclusionsEvidence indicates that COVID-19 targets vasculature and endothelium. However, high quality data is still lacking and studies with prospective designs and appropriately matched controls are needed.
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Project description:Impaired wound healing is an immense medical challenge, and while autologous skin grafting remains the "gold-standard" therapeutic option for repairing wounds that cannot be closed by primary or secondary intention, it is limited by substantial donor site morbidity. We previously developed the alternative approach of harvesting full-thickness skin tissue in the form of "micro skin tissue columns" (MSTCs), without causing scarring or any other long-term morbidity. In this study we investigated how MSTC treatment affects the different cellular processes involved in wound healing. We found that MSTC-derived cells were able to remodel and repopulate the wound volume, and positively impact multiple aspects of the wound healing process, including accelerating re-epithelialization by providing multiple cell sources throughout the wound area, increasing collagen deposition, enhancing dermal remodeling, and attenuating the inflammatory response. These effects combined to enhance both epidermal and dermal wound healing. This MSTC treatment approach was designed for practical clinical use, could convey many benefits of autologous skin grafting, and avoids the major drawback of donor site morbidity.
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Project description:Certain arenaviruses that circulate in rodent populations can cause life-threatening hemorrhagic fevers when they infect humans. Due to their efficient transmission, arenaviruses pose a severe risk for outbreaks and might be exploited as biological weapons. Effective countermeasures against these viruses are highly desired. Ideally, a single remedy would be effective against many or even all the pathogenic viruses in this family. However, despite the fact that all pathogenic arenaviruses from South America utilize transferrin receptor 1 (TfR1) as a cellular receptor, their viral glycoproteins are highly diversified, impeding efforts to isolate cross-neutralizing antibodies. Here we address this problem using a rational design approach to target TfR1-tropic arenaviruses with high potency and breadth. The pan-reactive molecule is highly effective against all arenaviruses that were tested, offering a universal therapeutic approach. Our design scheme avoids the shortcomings of previous immunoadhesins and can be used to combat other zoonotic pathogens.
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Project description:The mechano-bactericidal activity of nanostructured surfaces has become the focus of intensive research toward the development of a new generation of antibacterial surfaces, particularly in the current era of emerging antibiotic resistance. This work demonstrates the effects of an incremental increase of nanopillar height on nanostructure-induced bacterial cell death. We propose that the mechanical lysis of bacterial cells can be influenced by the degree of elasticity and clustering of highly ordered silicon nanopillar arrays. Herein, silicon nanopillar arrays with diameter 35 nm, periodicity 90 nm and increasing heights of 220, 360, and 420 nm were fabricated using deep UV immersion lithography. Nanoarrays of 360-nm-height pillars exhibited the highest degree of bactericidal activity toward both Gram stain-negative Pseudomonas aeruginosa and Gram stain-positive Staphylococcus aureus bacteria, inducing 95 ± 5% and 83 ± 12% cell death, respectively. At heights of 360 nm, increased nanopillar elasticity contributes to the onset of pillar deformation in response to bacterial adhesion to the surface. Theoretical analyses of pillar elasticity confirm that deflection, deformation force, and mechanical energies are more significant for the substrata possessing more flexible pillars. Increased storage and release of mechanical energy may explain the enhanced bactericidal action of these nanopillar arrays toward bacterial cells contacting the surface; however, with further increase of nanopillar height (420 nm), the forces (and tensions) can be partially compensated by irreversible interpillar adhesion that reduces their bactericidal effect. These findings can be used to inform the design of next-generation mechano-responsive surfaces with tuneable bactericidal characteristics for antimicrobial surface technologies.
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Project description:The transcription factor Gata3 is crucial for the development of several tissues and cell lineages both during development as well as postnatally. This importance is apparent from the early embryonic lethality following germline Gata3 deletion, with embryos displaying a number of phenotypes, and from the fact that Gata3 has been implicated in several cancer types. It often acts at the level of stem and progenitor cells in which it controls the expression of key lineage-determining factors as well as cell cycle genes, thus being one of the main drivers of cell fate choice and tissue morphogenesis. Gata3 is involved at various stages of haematopoiesis both in the adult as well as during development. This review summarizes the various contributions of Gata3 to haematopoiesis with a particular focus on the emergence of the first haematopoietic stem cells in the embryo-a process that appears to be influenced by Gata3 at various levels, thus highlighting the complex nature of Gata3 action.
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Project description:MotivationThe availability of large-scale curated protein interaction datasets has given rise to the opportunity to investigate higher level organization and modularity within the protein-protein interaction (PPI) network using graph theoretic analysis. Despite the recent progress, systems level analysis of high-throughput PPIs remains a daunting task because of the amount of data they present. In this article, we propose a novel PPI network decomposition algorithm called FACETS in order to make sense of the deluge of interaction data using Gene Ontology (GO) annotations. FACETS finds not just a single functional decomposition of the PPI network, but a multi-faceted atlas of functional decompositions that portray alternative perspectives of the functional landscape of the underlying PPI network. Each facet in the atlas represents a distinct interpretation of how the network can be functionally decomposed and organized. Our algorithm maximizes interpretative value of the atlas by optimizing inter-facet orthogonality and intra-facet cluster modularity.ResultsWe tested our algorithm on the global networks from IntAct, and compared it with gold standard datasets from MIPS and KEGG. We demonstrated the performance of FACETS. We also performed a case study that illustrates the utility of our approach.Supplementary informationSupplementary data are available at the Bioinformatics online.AvailabilityOur software is available freely for non-commercial purposes from: http://www.cais.ntu.edu.sg/~assourav/Facets/
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