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Article: The two faces of the inflammasome adaptor ASC in epithelial skin carcinogenesis.

Yazdi, Amir S / Drexler, Stefan K

2015 Volume 33, Issue 4 Suppl 92, Page(s) S94–6

Abstract: The development of tumours is a multistep process during which cells acquire the capability to sustain proliferation, evade growth suppressors and/or resist cell death. One factor, which is increasingly recognised to influence tumour progression, is the ... ...

Abstract	The development of tumours is a multistep process during which cells acquire the capability to sustain proliferation, evade growth suppressors and/or resist cell death. One factor, which is increasingly recognised to influence tumour progression, is the inflammatory environment of the tumour. The responsible molecular mechanisms and signalling pathways are only beginning to emerge. One major pathway able to induce potent inflammation is the activation of the inflammasome and the subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Both these cytokines have been implicated in tumour-genesis/progression. However, evidence for the role of inflammasomes in this process is still scarce and mainly derived from murine colitis associated tumour models. In this short review we discuss current knowledge on the role of inflammasomes in epithelial cancer of the gut and skin with a special focus on the complex role of the inflammasome adaptor ASC in epithelial skin carcinogenesis.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins/immunology ; Apoptosis Regulatory Proteins/metabolism ; CARD Signaling Adaptor Proteins ; Cell Transformation, Neoplastic/immunology ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Colonic Neoplasms/immunology ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Cytoskeletal Proteins/immunology ; Cytoskeletal Proteins/metabolism ; Epithelial Cells/immunology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Humans ; Inflammasomes/immunology ; Inflammasomes/metabolism ; Signal Transduction ; Skin/immunology ; Skin/metabolism ; Skin/pathology ; Skin Neoplasms/immunology ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology
Chemical Substances	Apoptosis Regulatory Proteins ; CARD Signaling Adaptor Proteins ; Cytoskeletal Proteins ; Inflammasomes ; PYCARD protein, human ; Pycard protein, mouse
Language	English
Publishing date	2015-07
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605886-3
ISSN	1593-098X ; 0392-856X
ISSN (online)	1593-098X
ISSN	0392-856X
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Article ; Online: Complex roles of inflammasomes in carcinogenesis.

Drexler, Stefan K / Yazdi, Amir S

Cancer journal (Sudbury, Mass.)

2013 Volume 19, Issue 6, Page(s) 468–472

Abstract: The central role of chronic inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. However, the molecular mechanisms converting transient inflammatory tissue reactions into a tumor-promoting ... ...

Abstract	The central role of chronic inflammation in the promotion of tumor growth is supported by a broad range of experimental and clinical evidence. However, the molecular mechanisms converting transient inflammatory tissue reactions into a tumor-promoting microenvironment remain largely elusive. Because inflammasomes have been shown to regulate the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, they have been implicated in the relationship between tumor genesis/progression and inflammation. For instance, many cancers have been directly linked to inflammasome-mediated sterile inflammation, where a blockade of IL-1β and IL-18 has been shown to inhibit tumor growth. On the other hand, inflammasome activation also has potent antitumorigenic effects, where malignant precursor cells are eliminated through pyroptotic cell death. Indeed, inflammasome activity can even increase the efficacy of certain chemotherapies. Here, we review the current understanding on the complex and sometimes contradictory role of inflammasomes in carcinogenesis.
MeSH term(s)	Animals ; Carcinogenesis/immunology ; Humans ; Inflammasomes/immunology ; Interleukin-1/immunology ; Interleukin-18/immunology ; Neoplasms/immunology ; Signal Transduction
Chemical Substances	Inflammasomes ; Interleukin-1 ; Interleukin-18
Language	English
Publishing date	2013-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2018400-1
ISSN	1540-336X ; 1528-9117 ; 1081-4442
ISSN (online)	1540-336X
ISSN	1528-9117 ; 1081-4442
DOI	10.1097/PPO.0000000000000004
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Article: Injection Molding of Encapsulated Diffractive Optical Elements.

Wagner, Stefan / Treptow, Kevin / Weser, Sascha / Drexler, Marc / Sahakalkan, Serhat / Eberhardt, Wolfgang / Guenther, Thomas / Pruss, Christof / Herkommer, Alois / Zimmermann, André

Micromachines

2023 Volume 14, Issue 6

Abstract: Microstructuring techniques, such as laser direct writing, enable the integration of microstructures into conventional polymer lens systems and may be used to generate advanced functionality. Hybrid polymer lenses combining multiple functions such as ... ...

Abstract	Microstructuring techniques, such as laser direct writing, enable the integration of microstructures into conventional polymer lens systems and may be used to generate advanced functionality. Hybrid polymer lenses combining multiple functions such as diffraction and refraction in a single component become possible. In this paper, a process chain to enable encapsulated and aligned optical systems with advanced functionality in a cost-efficient way is presented. Within a surface diameter of 30 mm, diffractive optical microstructures are integrated in an optical system based on two conventional polymer lenses. To ensure precise alignment between the lens surfaces and the microstructure, resist-coated ultra-precision-turned brass substrates are structured via laser direct writing, and the resulting master structures with a height of less than 0.002 mm are replicated into metallic nickel plates via electroforming. The functionality of the lens system is demonstrated through the production of a zero refractive element. This approach provides a cost-efficient and highly accurate method for producing complicated optical systems with integrated alignment and advanced functionality.
Language	English
Publishing date	2023-06-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2620864-7
ISSN	2072-666X
ISSN	2072-666X
DOI	10.3390/mi14061223
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Article ; Online: Regulation of interleukin 1α secretion by inflammasomes.

Yazdi, Amir S / Drexler, Stefan K

Annals of the rheumatic diseases

2013 Volume 72 Suppl 2, Page(s) ii96–9

Abstract: The crucial role of the proinflammatory cytokine interleukin 1β (IL-1β) in driving inflammatory disorders, such as Muckle-Wells syndrome and gout, has been extensively characterised. Owing to its high potency to induce inflammation the activation and ... ...

Abstract	The crucial role of the proinflammatory cytokine interleukin 1β (IL-1β) in driving inflammatory disorders, such as Muckle-Wells syndrome and gout, has been extensively characterised. Owing to its high potency to induce inflammation the activation and secretion of IL-1β is tightly regulated. The sensing of various host 'dangers', including infections and metabolic deregulation, results in the formation of large protein complexes, termed inflammasomes. Formation of the inflammasomes leads to the cleavage and activation of caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1β. Biologically active IL-1β is subsequently secreted by the cell. In contrast to IL-1β, little is known about mechanisms underlying the activation and secretion of its close homologue IL-1α. Moreover, the physiological role of IL-1α is still not well defined. Several studies hypothesise that IL-1α serves as a danger signal, which is passively released from dying cells. However, recent studies suggest a more complex function of this cytokine. Indeed, NLRP3 inflammasome agonists such as uric acid crystal or nigericin induce IL-1α cleavage and secretion, leading to the cosecretion of both IL-1β and IL-1α. Depending on the type of NLRP3 agonist, release of IL-1α is NLRP3-inflammasome/caspase-1 dependent or independent, but in both cases IL-1α processing depends on calpain protease activity. Taken together, these results suggest that the promotion and progression of inflammatory diseases is not solely due to IL-1β but also to its close relative IL-1α. This should be considered when IL-1 blockade is applied as a therapeutic strategy for diseases such as cryopyrin-associated periodic syndromes or gout.
MeSH term(s)	Animals ; Gene Expression Regulation ; Humans ; Inflammasomes/immunology ; Inflammation/immunology ; Interleukin-1alpha/genetics ; Interleukin-1alpha/metabolism ; Mice
Chemical Substances	Inflammasomes ; Interleukin-1alpha
Language	English
Publishing date	2013-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/annrheumdis-2012-202252
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Zs.MO 167: Show issues

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Article ; Online: Investigating the Function of Coronin A in the Early Starvation Response of Dictyostelium discoideum by Aggregation Assays.

Drexler, Stefan K / Brogna, Francesco / Vinet, Adrien / Pieters, Jean

Journal of visualized experiments : JoVE

2016 , Issue 112

Abstract: Dictyostelium discoideum amoeba are found in soil, feeding on bacteria. When food sources become scarce, they secrete factors to initiate a multicellular development program, during which single cells chemotax towards aggregation centers(1-4). This ... ...

Abstract	Dictyostelium discoideum amoeba are found in soil, feeding on bacteria. When food sources become scarce, they secrete factors to initiate a multicellular development program, during which single cells chemotax towards aggregation centers(1-4). This process is dependent on the release of cyclic adenosine monophosphate (cAMP)(5). cAMP is produced in waves through the concerted action of adenylate cyclase and phosphodiesterases, and binds to G protein-coupled cAMP receptors(6,7). A widely used assay to analyze the mechanisms involved in the developmental cycle of the lower eukaryote Dictyostelium discoideum is based on the observation of cell aggregation in submerged conditions(8,9). This protocol describes the analysis of the role of coronin A in the developmental cycle by starvation in tissue-culture plates submerged in balanced salt solution (BSS)(10). Coronin A is a member of the widely conserved protein family of coronins that have been implicated in a wide variety of activities(11,12). Dictyostelium cells lacking coronin A are unable to form multicellular aggregates, and this defect can be rescued by supplying pulses of cAMP, suggesting that coronin A acts upstream of the cAMP cascade(10). The techniques described in these studies provide robust tools to investigate functions of proteins during the initial stages of the developmental cycle of Dictyostelium discoideum upstream of the cAMP cascade. Therefore, utilizing this aggregation assay may allow the further study of coronin A function and advance our understanding of coronin biology.
MeSH term(s)	Adenylyl Cyclases ; Cell Aggregation ; Cyclic AMP ; Dictyostelium
Chemical Substances	Cyclic AMP (E0399OZS9N) ; Adenylyl Cyclases (EC 4.6.1.1)
Language	English
Publishing date	2016-06-18
Publishing country	United States
Document type	Journal Article
ISSN	1940-087X
ISSN (online)	1940-087X
DOI	10.3791/53972
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Article ; Online: The role of toll-like receptors in chronic inflammation.

Drexler, Stefan K / Foxwell, Brian M

The international journal of biochemistry & cell biology

2010 Volume 42, Issue 4, Page(s) 506–518

Abstract: The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been ... ...

Abstract	The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been shown to be present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands during inflammation and consequently the activation of TLR signalling pathways may be one mechanism initiating and driving autoimmune diseases. An increasing body of circumstantial evidence implicates a role of TLR signalling in systemic lupus erythematosus (SLE), atherosclerosis, asthma, type 1 diabetes, multiple sclerosis, bowl inflammation and rheumatoid arthritis (RA). Although at present their involvement is not comprehensively defined. However, future therapies targeting individual TLRs or their signalling transducers may provide a more specific way of treating inflammatory diseases without global suppression of the immune system.
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmune Diseases/metabolism ; Chronic Disease ; Genetic Predisposition to Disease ; Humans ; Immune Tolerance ; Inflammation ; MicroRNAs/immunology ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Polymorphism, Genetic ; Signal Transduction/immunology ; Toll-Like Receptors/genetics ; Toll-Like Receptors/immunology ; Toll-Like Receptors/metabolism ; Tumor Escape
Chemical Substances	Adjuvants, Immunologic ; MicroRNAs ; Toll-Like Receptors
Language	English
Publishing date	2010-04
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2009.10.009
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Article ; Online: Silencing of ASC in Cutaneous Squamous Cell Carcinoma.

Meier, Katharina / Drexler, Stefan K / Eberle, Franziska C / Lefort, Karine / Yazdi, Amir S

PloS one

2016 Volume 11, Issue 10, Page(s) e0164742

Abstract: Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis ...

Abstract	Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important adaptor protein for inflammasome activation, mediating the secretion of protumorigenic innate cytokines. However, ASC is also known to trigger apoptosis in tumor cells, acting as a tumor-suppressor gene, which is lost in several human cancers. The aim of this study was to evaluate the clinical significance of ASC in human cutaneous squamous cell carcinoma (SCC). Initially, ASC expression was immunohistochemically evaluated in non-metastic and metastatic SCC. While ASC expression does not correlate with metastatic potential, it correlates with the degree of dedifferentiation. Using methylation specific PCR we were able to demonstrate ASC silencing by promotor specific methylation and impaired inflammasome function in methylated cell lines, linking epigenetic modifications to innate immune activation in keratinocytes. Interestingly, upon ASC restoration by treatment with demethylating agents, we were able to restore AIM2 and NLRP3 activation. In summary, loss of ASC driven tumor development is counterbalanced in the identical cell by the inhibition of pro-tumorigenic inflammation in the tumor cell itself.
MeSH term(s)	Aged ; CARD Signaling Adaptor Proteins ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Cell Differentiation ; Cell Line, Tumor ; Cytoskeletal Proteins/genetics ; DNA Methylation ; Female ; Gene Silencing ; Humans ; Inflammasomes/metabolism ; Male ; Neoplasm Metastasis ; Promoter Regions, Genetic ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology
Chemical Substances	CARD Signaling Adaptor Proteins ; Cytoskeletal Proteins ; Inflammasomes ; PYCARD protein, human
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0164742
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Article: Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and

Drexler, Richard / Sauvigny, Thomas / Schüller, Ulrich / Eckhardt, Alicia / Maire, Cecile L / Khatri, Robin / Hausmann, Fabian / Hänzelmann, Sonja / Huber, Tobias B / Bonn, Stefan / Bode, Helena / Lamszus, Katrin / Westphal, Manfred / Dührsen, Lasse / Ricklefs, Franz L

Neuro-oncology practice

2023 Volume 10, Issue 5, Page(s) 462–471

Abstract: Background: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of : Methods: Patients with newly diagnosed and recurrent : Results: Of 74 ...

Abstract	Background: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection increases the percentage of complete CNS tumor resections and improves the progression-free survival of Methods: Patients with newly diagnosed and recurrent Results: Of 74 included patients, 12 (16.2%) patients had a non-fluorescent glioblastoma, which were compared to 62 glioblastomas with 5-ALA fluorescence. Clinical characteristics were equally distributed between both groups. We did not find significant differences between DNA methylation subclasses and 5-ALA fluorescence ( Conclusions: Our study demonstrates an association between non-fluorescent
Language	English
Publishing date	2023-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2768945-1
ISSN	2054-2585 ; 2054-2577
ISSN (online)	2054-2585
ISSN	2054-2577
DOI	10.1093/nop/npad025
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Article: Investigating the function of coronin a in the early starvation response of Dictyostelium discoideum by aggregation assays

Drexler, Stefan K / Brogna, Francesco / Vinet, Adrien / Pieters, Jean

Journal of visualized experiments. 2016 June 18, , no. 112

2016

Abstract	Dictyostelium discoideum amoeba are found in soil, feeding on bacteria. When food sources become scarce, they secrete factors to initiate a multicellular development program, during which single cells chemotax towards aggregation centers1-4. This process is dependent on the release of cyclic adenosine monophosphate (cAMP)5. cAMP is produced in waves through the concerted action of adenylate cyclase and phosphodiesterases, and binds to G protein-coupled cAMP receptors6,7. A widely used assay to analyze the mechanisms involved in the developmental cycle of the lower eukaryote Dictyostelium discoideum is based on the observation of cell aggregation in submerged conditions8,9. This protocol describes the analysis of the role of coronin A in the developmental cycle by starvation in tissue-culture plates submerged in balanced salt solution (BSS)10. Coronin A is a member of the widely conserved protein family of coronins that have been implicated in a wide variety of activities11,12. Dictyostelium cells lacking coronin A are unable to form multicellular aggregates, and this defect can be rescued by supplying pulses of cAMP, suggesting that coronin A acts upstream of the cAMP cascade10. The techniques described in these studies provide robust tools to investigate functions of proteins during the initial stages of the developmental cycle of Dictyostelium discoideum upstream of the cAMP cascade. Therefore, utilizing this aggregation assay may allow the further study of coronin A function and advance our understanding of coronin biology.
Keywords	Dictyostelium discoideum ; adenylate cyclase ; bacteria ; cyclic AMP ; eukaryotic cells ; proteins ; soil ; starvation ; tissue culture
Language	English
Dates of publication	2016-0618
Size	p. e53972.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/53972
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Temporal change of DNA methylation subclasses between matched newly diagnosed and recurrent glioblastoma.

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 21

Abstract: The longitudinal transition of phenotypes is pivotal in glioblastoma treatment resistance and DNA methylation emerged as an important tool for classifying glioblastoma phenotypes. We aimed to characterize DNA methylation subclass heterogeneity during ... ...

Abstract	The longitudinal transition of phenotypes is pivotal in glioblastoma treatment resistance and DNA methylation emerged as an important tool for classifying glioblastoma phenotypes. We aimed to characterize DNA methylation subclass heterogeneity during progression and assess its clinical impact. Matched tissues from 47 glioblastoma patients were subjected to DNA methylation profiling, including CpG-site alterations, tissue and serum deconvolution, mass spectrometry, and immunoassay. Effects of clinical characteristics on temporal changes and outcomes were studied. Among 47 patients, 8 (17.0%) had non-matching classifications at recurrence. In the remaining 39 cases, 28.2% showed dominant DNA methylation subclass transitions, with 72.7% being a mesenchymal subclass. In general, glioblastomas with a subclass transition showed upregulated metabolic processes. Newly diagnosed glioblastomas with mesenchymal transition displayed increased stem cell-like states and decreased immune components at diagnosis and exhibited elevated immune signatures and cytokine levels in serum. In contrast, tissue of recurrent glioblastomas with mesenchymal transition showed increased immune components but decreased stem cell-like states. Survival analyses revealed comparable outcomes for patients with and without subclass transitions. This study demonstrates a temporal heterogeneity of DNA methylation subclasses in 28.2% of glioblastomas, not impacting patient survival. Changes in cell state composition associated with subclass transition may be crucial for recurrent glioblastoma targeted therapies.
MeSH term(s)	Humans ; Glioblastoma/genetics ; Glioblastoma/therapy ; DNA Methylation ; Neoplasm Recurrence, Local/genetics ; Survival Analysis ; Brain Neoplasms
Language	English
Publishing date	2024-01-20
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02677-8
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