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Article ; Online: SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling.

Niogret, Charlène / Birchmeier, Walter / Guarda, Greta

2019 Volume 10, Page(s) 2468

Abstract: Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby ... ...

Abstract	Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby exerting essential developmental functions. This phosphatase also deploys proto-oncogenic functions and specific inhibitors have recently been developed. With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied. The function of this phosphatase downstream of cytokines important for lymphocytes is less understood, though multiple lines of evidence suggest its importance. In addition, SHP-2 has been proposed to mediate the suppressive effects of inhibitory receptors (IRs) that sustain a dysfunctional state in anticancer T cells. Molecules involved in IR signaling are of potential pharmaceutical interest as blockade of these inhibitory circuits leads to remarkable clinical benefit. Here, we discuss the dichotomy in the functions ascribed to SHP-2 downstream of cytokine receptors and IRs, with a focus on T and NK lymphocytes. Further, we highlight the importance of broadening our understanding of SHP-2's relevance in lymphocytes, an essential step to inform on side effects and unanticipated benefits of its therapeutic blockade.
MeSH term(s)	Extracellular Signal-Regulated MAP Kinases/physiology ; Humans ; Killer Cells, Natural/immunology ; Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinases/physiology ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/physiology ; Receptors, Cytokine/physiology ; Receptors, KIR/physiology ; Signal Transduction/physiology ; T-Lymphocytes/immunology
Chemical Substances	Receptors, Cytokine ; Receptors, KIR ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2019-10-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.02468
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Article ; Online: Regulatory Factor X 7 and its Potential Link to Lymphoid Cancers.

Fischer, Berenice A / Chelbi, Sonia T / Guarda, Greta

Trends in cancer

2019 Volume 6, Issue 1, Page(s) 6–9

Abstract: Alterations in the Regulatory factor X 7 (RFX7) gene have recurrently been reported in lymphoid cancers. Uncharacterized until recently, this transcription factor regulates genes important for ciliogenesis and for limiting cellular metabolic activity. ... ...

Abstract	Alterations in the Regulatory factor X 7 (RFX7) gene have recurrently been reported in lymphoid cancers. Uncharacterized until recently, this transcription factor regulates genes important for ciliogenesis and for limiting cellular metabolic activity. Here we discuss these observations and conjecture on the links between the reported functions of RFX7 and its potential role in lymphoid cancers, encouraging future studies in these directions.
MeSH term(s)	Animals ; DNA Copy Number Variations ; Disease Models, Animal ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Genome-Wide Association Study ; Humans ; Leukemia, Lymphoid/genetics ; Leukemia, Lymphoid/pathology ; Lymphoma/genetics ; Lymphoma/pathology ; Mice ; Mutation ; Polymorphism, Single Nucleotide ; Regulatory Factor X Transcription Factors/genetics ; Regulatory Factor X Transcription Factors/metabolism
Chemical Substances	RFX7 protein, human ; Regulatory Factor X Transcription Factors ; Rfx7 protein, mouse
Language	English
Publishing date	2019-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2019.11.001
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Article: NLRC5, a promising new entry in tumor immunology.

Chelbi, Sonia T / Guarda, Greta

Journal for immunotherapy of cancer

2016 Volume 4, Page(s) 39

Abstract: The recent use of T cell-based cancer immunotherapies, such as adoptive T-cell transfer and checkpoint blockade, yields increasing clinical benefit to patients with different cancer types. However, decrease of MHC class I expression is a common mechanism ...

Abstract	The recent use of T cell-based cancer immunotherapies, such as adoptive T-cell transfer and checkpoint blockade, yields increasing clinical benefit to patients with different cancer types. However, decrease of MHC class I expression is a common mechanism transformed cells take advantage of to evade CD8(+) T cell-mediated antitumor responses, negatively impacting on the outcome of immunotherapies. Hence, there is an urgent need to develop novel approaches to overcome this limitation. NLRC5 has been recently described as a key transcriptional regulator controlling expression of MHC class I molecules. In this commentary, we summarize and put into perspective a study by Rodriguez and colleagues recently published in Oncoimmunology, addressing the role of NLRC5 in melanoma. The authors demonstrate that NLRC5 overexpression in B16 melanoma allows to recover MHC class I expression, rising tumor immunogenicity and counteracting immune evasion. Possible ways of manipulating NLRC5 activity in tumors will be discussed. Highlighting the therapeutic potential of modulating NLRC5 levels, this publication also encourages evaluation of NLRC5, and by extension MHC class I pathway, as clinical biomarker to select personalized immunotherapeutic strategies.
Language	English
Publishing date	2016-07-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2719863-7
ISSN	2051-1426
ISSN	2051-1426
DOI	10.1186/s40425-016-0143-z
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Article ; Online: The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.

Khameneh, Hanif J / Bolis, Marco / Ventura, Pedro M O / Cassanmagnago, Giada A / Fischer, Berenice A / Zenobi, Alessandro / Guerra, Jessica / Buzzago, Irene / Bernasconi, Maurizio / Zaman, Guido J R / Rinaldi, Andrea / Moro, Simone G / Sallusto, Federica / Baulier, Edouard / Pasquali, Christian / Guarda, Greta

Mucosal immunology

2024

Abstract: OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain ... ...

Abstract	OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo. Instead, in human immune cells, TLR2 and TLR4 orchestrate the response to OM-85, which binds to both receptors as shown by surface plasmon resonance assay. Ribonucleic acid-sequencing analyses of human monocyte-derived dendritic cells reveal that OM-85 triggers a pro-inflammatory signature and a unique gene set, which is not induced by canonical agonists of TLR2 or TLR4 and comprises tolerogenic genes. A largely overlapping TLR2/4-dependent gene signature was observed in individual subsets of primary human airway myeloid cells, highlighting the robust effects of OM-85. Collectively, our results suggest caution should be taken when relating murine studies on bacterial lysates to humans. Furthermore, our data shed light on how a standardized bacterial lysate shapes the response through TLR2 and TLR4, which are crucial for immune response, trained immunity, and tolerance.
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2411370-0
ISSN	1935-3456 ; 1933-0219
ISSN (online)	1935-3456
ISSN	1933-0219
DOI	10.1016/j.mucimm.2024.02.010
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Article ; Online: Myc controls NK cell development, IL-15-driven expansion, and translational machinery.

Khameneh, Hanif J / Fonta, Nicolas / Zenobi, Alessandro / Niogret, Charlène / Ventura, Pedro / Guerra, Concetta / Kwee, Ivo / Rinaldi, Andrea / Pecoraro, Matteo / Geiger, Roger / Cavalli, Andrea / Bertoni, Francesco / Vivier, Eric / Trumpp, Andreas / Guarda, Greta

Life science alliance

2023 Volume 6, Issue 7

Abstract: MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. ... ...

Abstract	MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells' ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.
MeSH term(s)	Animals ; Humans ; Mice ; Cytokines/metabolism ; Gene Expression Regulation ; Interleukin-15/genetics ; Interleukin-15/metabolism ; Killer Cells, Natural ; Signal Transduction
Chemical Substances	Cytokines ; Interleukin-15 ; IL15 protein, human ; MYC protein, human ; Myc protein, mouse
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302069
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Article ; Online: The regulatory network behind MHC class I expression.

Jongsma, Marlieke L M / Guarda, Greta / Spaapen, Robbert M

Molecular immunology

2017 Volume 113, Page(s) 16–21

Abstract: The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or ... ...

Abstract	The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or microbes. It is therefore important to identify the molecular mechanisms behind MHC class I expression, processing and antigen presentation. The identification of NLRC5 as regulator of MHC class I transcription was a huge step forward in understanding the transcriptional mechanism involved. Nevertheless, many questions concerning MHC class I transcription are yet unsolved. Here we illuminate current knowledge on MHC class I and NLRC5 transcription, we highlight some remaining questions and discuss the use of quickly developing high-content screening tools to reveal unknowns in MHC class I transcription in the near future.
MeSH term(s)	Animals ; Antigen Presentation/genetics ; Gene Regulatory Networks/genetics ; Genes, MHC Class I/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Transcription, Genetic/genetics
Chemical Substances	Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2017-12-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2017.12.005
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Article: The regulatory network behind MHC class I expression

Jongsma, Marlieke L.M / Guarda, Greta / Spaapen, Robbert M

Molecular immunology. 2019 Sept., v. 113

2019

Abstract	The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or microbes. It is therefore important to identify the molecular mechanisms behind MHC class I expression, processing and antigen presentation. The identification of NLRC5 as regulator of MHC class I transcription was a huge step forward in understanding the transcriptional mechanism involved. Nevertheless, many questions concerning MHC class I transcription are yet unsolved. Here we illuminate current knowledge on MHC class I and NLRC5 transcription, we highlight some remaining questions and discuss the use of quickly developing high-content screening tools to reveal unknowns in MHC class I transcription in the near future.
Keywords	T-lymphocytes ; antigen presentation ; major histocompatibility complex ; microorganisms ; neoplasm cells ; neoplasms ; peptides ; screening ; transcription (genetics)
Language	English
Dates of publication	2019-09
Size	p. 16-21.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2017.12.005
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Article ; Online: Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.

Ventura, Pedro M O / Gakovic, Milica / Fischer, Berenice A / Spinelli, Laura / Rota, Giorgia / Pathak, Shalini / Khameneh, Hanif J / Zenobi, Alessandro / Thomson, Sarah / Birchmeier, Walter / Cantrell, Doreen A / Guarda, Greta

EMBO reports

2022 Volume 23, Issue 11, Page(s) e55399

Abstract: Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer ... ...

Abstract	Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8
MeSH term(s)	CD8-Positive T-Lymphocytes/metabolism ; Programmed Cell Death 1 Receptor ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Signal Transduction
Chemical Substances	PTPN6 protein, human (EC 3.1.3.48) ; Programmed Cell Death 1 Receptor ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48)
Language	English
Publishing date	2022-10-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202255399
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Article ; Online: Regulation of inflammasome activity.

Guarda, Greta / So, Alexander

Immunology

2010 Volume 130, Issue 3, Page(s) 329–336

Abstract: Summary: Interleukin-1beta (IL-1beta) is a potent inflammatory cytokine, which is implicated in acute and chronic inflammatory disorders. The activity of IL-1beta is regulated by the proteolytic cleavage of its inactive precursor resulting in the mature, ...

Abstract	Summary: Interleukin-1beta (IL-1beta) is a potent inflammatory cytokine, which is implicated in acute and chronic inflammatory disorders. The activity of IL-1beta is regulated by the proteolytic cleavage of its inactive precursor resulting in the mature, bioactive form of the cytokine. Cleavage of the IL-1beta precursor is performed by the cysteine protease caspase-1, which is activated within protein complexes termed 'inflammasomes'. To date, four distinct inflammasomes have been described, based on different core receptors capable of initiating complex formation. Both the host and invading pathogens need to control IL-1beta production and this can be achieved by regulating inflammasome activity. However, we have, as yet, little understanding of the mechanisms of this regulation. In particular the negative feedbacks, which are critical for the host to limit collateral damage of the inflammatory response, remain largely unexplored. Recent exciting findings in this field have given us an insight into the potential of this research area in terms of opening up new therapeutic avenues for inflammatory disorders.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Humans ; Immunity, Innate/immunology ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Interleukin-1beta/immunology ; Interleukin-1beta/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Interleukin-1beta
Language	English
Publishing date	2010-05-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2010.03283.x
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Article: Regulation of inflammasome activity

Guarda, Greta / So, Alexander

Immunology. 2010 July, v. 130, no. 3

2010

Abstract: Interleukin-1β (IL-1β) is a potent inflammatory cytokine, which is implicated in acute and chronic inflammatory disorders. The activity of IL-1β is regulated by the proteolytic cleavage of its inactive precursor resulting in the mature, bioactive form of ...

Abstract	Interleukin-1β (IL-1β) is a potent inflammatory cytokine, which is implicated in acute and chronic inflammatory disorders. The activity of IL-1β is regulated by the proteolytic cleavage of its inactive precursor resulting in the mature, bioactive form of the cytokine. Cleavage of the IL-1β precursor is performed by the cysteine protease caspase-1, which is activated within protein complexes termed 'inflammasomes'. To date, four distinct inflammasomes have been described, based on different core receptors capable of initiating complex formation. Both the host and invading pathogens need to control IL-1β production and this can be achieved by regulating inflammasome activity. However, we have, as yet, little understanding of the mechanisms of this regulation. In particular the negative feedbacks, which are critical for the host to limit collateral damage of the inflammatory response, remain largely unexplored. Recent exciting findings in this field have given us an insight into the potential of this research area in terms of opening up new therapeutic avenues for inflammatory disorders.
Keywords	interleukin-1
Language	English
Dates of publication	2010-07
Size	p. 329-336.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2010.03283.x
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