scholarly journals 209 Genetically engineered myeloid cells (GEMys) as a platform to enhance antitumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A220-A220
Author(s):  
Sabina Kaczanowska ◽  
Daniel Beury ◽  
Haiying Qin ◽  
Rosandra Kaplan
Keyword(s):  
Immune Suppression ◽  
Antigen Processing ◽  
Immune Surveillance ◽  
Myeloid Cells ◽  
Genetically Engineered ◽  
List Type ◽  
Metastatic Progression ◽  
The Core ◽  
Immunotherapeutic Approach ◽  
Metastatic Microenvironment

BackgroundImmune suppression is a major hurdle in cancer immunotherapy for solid tumors. Innate myeloid cells are key regulators of the immune system and can dampen the antitumor response against cancer. We have identified that bone marrow-derived myeloid cells play an immunosuppressive role in the metastatic microenvironment, limiting immune surveillance and facilitating the growth of tumor cells. We hypothesized that targeting the myeloid-mediated immune suppression program in the metastatic and primary tumor microenvironment could facilitate antitumor immune activation and be a successful immunotherapeutic approach.MethodsTo take advantage of the unique capability of myeloid cells to home to and infiltrate tumor and metastatic sites, we designed an immunotherapeutic approach in which we generate genetically engineered myeloid cells (GEMys) as a platform to locally deliver modulatory factors into the tumor and metastatic microenvironment.ResultsMice treated with IL-12-secreting GEMys (IL12-GEMys) exhibited a robust IFNγ response associated with increased expression of antigen processing and presentation machinery as well as numbers of T and NK cells expressing markers associated with activation and cytotoxicity. These microenvironmental changes were associated with reduced metastasis, delayed tumor growth, and increased survival. When combined with chemotherapy pre-conditioning, IL12-GEMys cured mice of established tumors and generated long-lived T cell memory, as these mice were immune to subsequent tumor challenge. We are currently working on translating these exciting findings into the human setting.ConclusionsThis work demonstrates that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer. This approach holds promise to limit metastatic progression in patients with high risk and advanced cancers.ReferencesKaczanowska S, Beury DW, Gopalan V, Tycko AK, Qin H, Clements ME, Drake J, Nwanze C, Murgai M, Rae Z, Ju W, Alexander KA, Kline J, Contreras CF, Wessel KM, Patel S, Hannenhalli S, Kelly M, Kaplan RN. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell 2021;184:1–20.

Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Cell ◽  
2021 ◽  
Author(s):  
Sabina Kaczanowska ◽  
Daniel W. Beury ◽  
Vishaka Gopalan ◽  
Arielle K. Tycko ◽  
Haiying Qin ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Myeloid Cells ◽  
Genetically Engineered ◽  
The Core

Immature myeloid cells and cancer-associated immune suppression

2002 ◽  
Vol 51 (6) ◽  
pp. 293-298 ◽  
Author(s):  
Sergei Kusmartsev ◽  
Dmitry Gabrilovich
Keyword(s):  
Immune Suppression ◽  
Myeloid Cells ◽  
Immature Myeloid Cells

scholarly journals Can evolutionary thinking shed light on gender diversity?

2019 ◽  
Vol 25 (6) ◽  
pp. 351-362 ◽  
Author(s):  
Bernadette Wren ◽  
John Launer ◽  
Michael J. Reiss ◽  
Annie Swanepoel ◽  
Graham Music
Keyword(s):  
Gender Identity ◽  
Gender Diversity ◽  
Medical Intervention ◽  
List Type ◽  
Sex And Gender ◽  
Medical Interventions ◽  
The Core ◽  
Causal Pathways ◽  
And Gender ◽  
Shed Light

SUMMARYIssues of sexual reproduction lie at the core of evolutionary thinking, which often places an emphasis on how individuals attempt to maximise the number of successful offspring that they can produce. At first sight, it may therefore appear that individuals who opt for gender-affirming medical interventions are acting in ways that are evolutionarily disadvantageous. However, there are persuasive hypotheses that might make sense of such choices in evolutionary terms and we explore these here. It is premature to claim knowledge of the extent to which evolutionary arguments can usefully be applied to issues of gender identity, although worth reflecting on the extent to which nature tends towards diversity in matters of sex and gender. The importance of acknowledging and respecting different views in this domain, as well as recognising both the uncertainty and likely multiplicity of causal pathways, has implications for clinicians. We make some suggestions about how clinicians might best respond when faced with requests from patients in this area.LEARNING OBJECTIVESAfter reading this article you will be able to:•understand evolutionary arguments about diversity in human gender identity•identify strengths and weaknesses in evolutionary arguments applied to transgender issues•appreciate the range and diversity of gender experience and gender expression among people who present to specialist gender services, as well as the likely complexities of their reasons for requesting medical intervention.

scholarly journals A simplified analysis of the Chernobyl accident

2021 ◽  
Vol 7 ◽  
pp. 1
Author(s):  
Bertrand Mercier ◽  
Di Yang ◽  
Ziyue Zhuang ◽  
Jiajie Liang
Keyword(s):  
Numerical Models ◽  
List Type ◽  
Flash Evaporation ◽  
The Core ◽  
Large Size ◽  
Reaction Coefficient ◽  
Pressure Tubes ◽  
Void Effect ◽  
Reactivity Coefficient ◽  
Reactivity Increase

We show with simplified numerical models, that for the kind of RBMK operated in Chernobyl: The core was unstable due to its large size and to its weak power counter-reaction coefficient, so that the power of the reactor was not easy to control even with an automatic system. Xenon oscillations could easily be activated. When there was xenon poisoning in the upper half of the core, the safety rods were designed in such a way that, at least initially, they were increasing (and not decreasing) the core reactivity. This reactivity increase has been sufficient to lead to a very high pressure increase in a significant amount of liquid water in the fuel channels thus inducing a strong propagating shock wave leading to a failure of half the pressure tubes at their junction with the drum separators. The depressurization phase (flash evaporation) following this failure has produced, after one second, a significant decrease of the water density in half the pressure tubes and then a strong reactivity accident due to the positive void effect reactivity coefficient. We evaluate the fission energy released by the accident

scholarly journals Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

2020 ◽  
Author(s):  
M. Elizabeth Deerhake ◽  
Keiko Danzaki ◽  
Makoto Inoue ◽  
Emre D. Cardakli ◽  
Toshiaki Nonaka ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Oncostatin M ◽  
List Type ◽  
Autoimmune Encephalomyelitis ◽  
Protective Function ◽  
Lectin Receptor ◽  
Neurologic Disorders ◽  
Cns Autoimmunity ◽  
Experimental Autoimmune

ABSTRACTPathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.Graphical AbstractDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE)Dectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cellsOsmR signaling in astrocytes limits EAE progression and promotes remissionNon-canonical Card9-independent signaling drives a distinct Dectin-1-mediated transcriptional program to induce expression of Osm and other factors with protective or anti-inflammatory functions

Abstract TMP32: Transcriptome Changes of Brain Myeloid Cells After Ischemic Stroke in Type 2 Diabetic Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Shunsuke Omodaka ◽  
Atsushi Kanoke ◽  
Suwei Wong ◽  
Dvir Aran ◽  
Jialing Liu
Keyword(s):  
Gene Expression ◽  
Antigen Processing ◽  
Mononuclear Cells ◽  
Myeloid Cells ◽  
Enrichment Analysis ◽  
Marker Genes ◽  
Sham Operation ◽  
Altered Gene Expression ◽  
Altered Gene

Introduction: Type 2 diabetes mellitus (T2DM) is associated with poor outcome after stroke. Brain myeloid cells are considered to play a pivotal role in modulating brain damage and recovery after stroke, but how myeloid response to stroke under diabetic condition is largely unclear. We used single-cell RNA sequencing (scRNA seq) to determine the transcriptome profiles of brain myeloid cells under diabetic and ischemic conditions using T2DM mouse model. Hypothesis: The altered gene expression in the brain myeloid cells under diabetic condition leads to the aggravation of ischemic brain injury. Methods: We performed scRNA seq in Percoll gradient-isolated brain mononuclear cells from middle-aged db/db and db/+ mice three days after direct middle cerebral artery occlusion (MCAO) or sham-operation. Clusters of brain myeloid cells were predominantly annotated as macrophages (mp) or microglia (mg) according to the expression of marker genes in each cell type. We identified DM-unique differentially expressed genes (DEGs) and stroke-unique DEGs, and assessed the biological role of these DEGs by enrichment analysis. Results: Myeloid cell population was increased in DM ( db/db without MCAO; mp 37.3% mg 10.6%) and stroke ( db/+ with MCAO; mp 26.2% mg 33.2%) group compared to control ( db/+ without MCAO; mp 3.4% mg 0.8%) group. In macrophages, 91 DM-unique (64 up- and 27 down-regulated) and 464 stroke-unique (458 up- and 6 down-regulated) DEGs were identified, whereas 258 stroke-unique (254 up- and 4 down-regulated) DEGs were identified in microglia. Enrichment analysis revealed that DM-unique down-regulated DEGs in macrophages were related to MHC class II antigen processing involved in Staphylococcus aureus infection pathway, indicating a possible relationship between immunosuppression and stroke aggravation in diabetes. DM-unique and stroke-unique up-regulated DEGs were related to oxidative phosphorylation, phagocytosis, and protein metabolism. Conclusions: The present study demonstrated altered gene expression profile and molecular network of brain myeloid cells in response to diabetic and ischemic conditions by scRNA seq, providing a clue to the underlying mechanism of the adverse effect of T2DM on stroke.

scholarly journals A2B Adenosine Receptor and Cancer

2019 ◽  
Vol 20 (20) ◽  
pp. 5139 ◽  
Author(s):  
Zhan-Guo Gao ◽  
Kenneth A. Jacobson
Keyword(s):  
G Proteins ◽  
Anticancer Agents ◽  
Immune Suppression ◽  
Adenosine Receptors ◽  
Immune Surveillance ◽  
G Protein Coupled Receptors ◽  
Normal Tissues ◽  
Cancer Tissues ◽  
G Protein Coupled

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.

scholarly journals Molecular mechanisms of human herpes viruses inferring with host immune surveillance

2020 ◽  
Vol 8 (2) ◽  
pp. e000841
Author(s):  
Simon Jasinski-Bergner ◽  
Ofer Mandelboim ◽  
Barbara Seliger
Keyword(s):  
Immune Evasion ◽  
Antigen Processing ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Immune Surveillance ◽  
Host Cells ◽  
Herpes Viruses ◽  
Molecular Processes ◽  
Human Herpes ◽  
Human Herpes Viruses

Several human herpes viruses (HHVs) exert oncogenic potential leading to malignant transformation of infected cells and/or tissues. The molecular processes induced by viral-encoded molecules including microRNAs, peptides, and proteins contributing to immune evasion of the infected host cells are equal to the molecular processes of immune evasion mediated by tumor cells independently of viral infections. Such major immune evasion strategies include (1) the downregulation of proinflammatory cytokines/chemokines as well as the induction of anti-inflammatory cytokines/chemokines, (2) the downregulation of major histocompatibility complex (MHC) class Ia directly as well as indirectly by downregulation of the components involved in the antigen processing, and (3) the downregulation of stress-induced ligands for activating receptors on immune effector cells with NKG2D leading the way. Furthermore, (4) immune modulatory molecules like MHC class Ib molecules and programmed cell death1 ligand 1 can be upregulated on infections with certain herpes viruses. This review article focuses on the known molecular mechanisms of HHVs modulating the above-mentioned possibilities for immune surveillance and even postulates a temporal order linking regular tumor immunology with basic virology and offering putatively novel insights for targeting HHVs.

Identification of MHC-I Accessible Proteins from Salmonella Typhimurium

2001 ◽  
Vol 7 (S2) ◽  
pp. 616-617
Author(s):  
D. Ellefson ◽  
D. Parker ◽  
F. Heffron
Keyword(s):  
Salmonella Typhimurium ◽  
Host Cell ◽  
Antigen Processing ◽  
Bacterial Pathogens ◽  
Immune Surveillance ◽  
Class I ◽  
Whole Genome Analysis ◽  
Class I Mhc ◽  
Mhc I ◽  
Host Interaction

Intracellular bacterial pathogens such as Salmonella typhimurium secrete proteins into the host cell after infection. These proteins alter the normal structural and metabolic machinery of the host cell and benefit the bacterium by facilitating replication and avoidance of host immune surveillance. Since the host cytoplasmic localization of these proteins infers access to the class-I MHC antigen processing and presentation machinery of the host cell, we collectively refer to these proteins as Class- I Accessible Proteins (CAPs).The design of vaccines for new and emerging bacterial pathogens is often constrained by the selection of appropriate and specific antigens. While vaccine design is being greatly aided by whole genome analysis of bacterial pathogens, it has been of limited use in the assignment of function and host subcellular localization of a large percentage of bacterial proteins. in addition, analysis of the bacteria/host interaction is further complicated by the complex lifestyle of the pathogen.

scholarly journals CORE-Kids: a protocol for the development of a core outcome set for childhood fractures

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e036224 ◽  
Author(s):  
Ben Arthur Marson ◽  
Joseph C Manning ◽  
Marilyn James ◽  
Simon Craxford ◽  
Sandeep R Deshmukh ◽  
...  
Keyword(s):  
Core Outcome Set ◽  
Significant Heterogeneity ◽  
List Type ◽  
Core Outcome ◽  
The Core ◽  
Outcome Set ◽  
Study Results ◽  
Orthopaedic Literature ◽  
Registration Number ◽  
Limb Fractures

IntroductionLimb fractures in children are common yet there are few trials that compare treatments for these injuries. There is significant heterogeneity in the outcomes reported in the paediatric orthopaedic literature, which limits the ability to compare study results and draw firm conclusions. The aim of the CORE-Kids Study is to develop a core outcome set for use in research studies of childhood limb fractures. A core outcome set will provide a minimum set of outcomes to be measured in all trials to minimise the heterogeneity of outcomes reported and minimise reporting bias. A core outcome set ensures that outcomes are reported that are relevant to families as well as clinicians. The core outcome set will include additional upper and lower limb modules.MethodsThe development of the core outcome set will require four phases to evaluate:What are the outcomes that are relevant to professionals?What are the outcomes that are relevant to families?What are the most important of these outcomes?Which outcomes should be included in the core outcome set?This will be completed through a systematic review of trials to identify the outcomes domains that are relevant to trialists. A series of semi-structured interviews will be completed with families to identify the outcome domains that are relevant to families. These outcome domains will be used in a three-round Delphi Study to analyse the importance of these outcome domains to a range of stakeholders including parents, clinicians and researchers. Following this, the core outcome set will be decided at a consensus meeting.Ethics and disseminationEthical approval has been awarded HRA/REC IRAS number 262503. Date of approval 06/08/2019. Dissemination will be through scientific literature and international societies.Trial registrationCore Outcome Measures in Effectiveness Trials Initiative, registration number: 1274. Date of registration 13/12/2018.PROSPERO registration numberCRD42018106605.

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