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Article ; Online: Themis controls T cell activation, effector functions, and metabolism of peripheral CD8

Gautam, Namrata / Wojciech, Lukasz / Yap, Jiawei / Chua, Yen Leong / Ding, Eyan Mw / Sim, Don Cn / Tan, Alrina Sm / Ahl, Patricia J / Prasad, Mukul / Tung, Desmond Wh / Connolly, John E / Adriani, Giulia / Brzostek, Joanna / Gascoigne, Nicholas Rj

Life science alliance

2023 Volume 6, Issue 12

Abstract: Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis ... ...

Abstract	Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis deletion mouse model. We find that proliferation, effector functions including anti-tumor killing, and up-regulation of energy metabolism are severely compromised. This study reveals the phenomenon of peripheral adaptation to loss of Themis, by demonstrating direct TCR-induced defects after acute deletion of Themis that were not evident in peripheral T cells chronically deprived of Themis in dLck-Cre deletion model. Peripheral adaptation to long-term loss was compared using chronic versus acute tamoxifen-mediated deletion and with the (chronic) dLck-Cre deletion model. We found that upon chronic tamoxifen-mediated Themis deletion, there was modulation in the gene expression profile for both TCR and cytokine signaling pathways. This profile overlapped with (chronic) dLck-Cre deletion model. Hence, we found that peripheral adaptation induced changes to both TCR and cytokine signaling modules. Our data highlight the importance of Themis in the activation of CD8
MeSH term(s)	Animals ; Mice ; CD8-Positive T-Lymphocytes ; Cytokines ; Energy Metabolism ; Receptors, Antigen, T-Cell/genetics ; Tamoxifen/pharmacology
Chemical Substances	Cytokines ; Receptors, Antigen, T-Cell ; Tamoxifen (094ZI81Y45) ; themis protein, mouse
Language	English
Publishing date	2023-09-22
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.202302156
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A 3D pancreatic tumor model to study T cell infiltration.

Mollica, Hilaria / Teo, Yi Juan / Tan, Alrina Shin Min / Tan, Damien Zhi Ming / Decuzzi, Paolo / Pavesi, Andrea / Adriani, Giulia

Biomaterials science

2021 Volume 9, Issue 22, Page(s) 7420–7431

Abstract: The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including ... ...

Abstract	The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including T cell immunotherapies. We present an
MeSH term(s)	Carcinoma, Pancreatic Ductal ; Endothelial Cells ; Humans ; Pancreatic Neoplasms ; Pancreatic Stellate Cells ; T-Lymphocytes ; Tumor Microenvironment
Language	English
Publishing date	2021-11-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d1bm00210d
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Article ; Online: Fungal Symbionts Produce Prostaglandin E

Tan, Tze Guan / Lim, Ying Shiang / Tan, Alrina / Leong, Royston / Pavelka, Norman

Frontiers in cellular and infection microbiology

2019 Volume 9, Page(s) 359

Abstract: ... Candida ... ...

Abstract	Candida albicans
MeSH term(s)	Animals ; Candida albicans/physiology ; Dinoprostone/metabolism ; Fungi/physiology ; Host-Pathogen Interactions ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/microbiology ; Macrophages/metabolism ; Mice ; Mice, Knockout ; Mutation ; Phagocytes/metabolism ; Symbiosis ; Virulence/genetics
Chemical Substances	Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2019-10-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2019.00359
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Article ; Online: Aneuploidy Enables Cross-Adaptation to Unrelated Drugs.

Yang, Feng / Teoh, Flora / Tan, Alrina Shin Min / Cao, Yongbing / Pavelka, Norman / Berman, Judith

Molecular biology and evolution

2019 Volume 36, Issue 8, Page(s) 1768–1782

Abstract: Aneuploidy is common both in tumor cells responding to chemotherapeutic agents and in fungal cells adapting to antifungal drugs. Because aneuploidy simultaneously affects many genes, it has the potential to confer multiple phenotypes to the same cells. ... ...

Abstract	Aneuploidy is common both in tumor cells responding to chemotherapeutic agents and in fungal cells adapting to antifungal drugs. Because aneuploidy simultaneously affects many genes, it has the potential to confer multiple phenotypes to the same cells. Here, we analyzed the mechanisms by which Candida albicans, the most prevalent human fungal pathogen, acquires the ability to survive both chemotherapeutic agents and antifungal drugs. Strikingly, adaptation to both types of drugs was accompanied by the acquisition of specific whole-chromosome aneuploidies, with some aneuploid karyotypes recovered independently and repeatedly from very different drug conditions. Specifically, strains selected for survival in hydroxyurea, an anticancer drug, acquired cross-adaptation to caspofungin, a first-line antifungal drug, and both acquired traits were attributable to trisomy of the same chromosome: loss of trisomy was accompanied by loss of adaptation to both drugs. Mechanistically, aneuploidy simultaneously altered the copy number of most genes on chromosome 2, yet survival in hydroxyurea or caspofungin required different genes and stress response pathways. Similarly, chromosome 5 monosomy conferred increased tolerance to both fluconazole and to caspofungin, antifungals with different mechanisms of action. Thus, the potential for cross-adaptation is not a feature of aneuploidy per se; rather, it is dependent on specific genes harbored on given aneuploid chromosomes. Furthermore, pre-exposure to hydroxyurea increased the frequency of appearance of caspofungin survivors, and hydroxyurea-adapted C. albicans cells were refractory to antifungal drug treatment in a mouse model of systemic candidiasis. This highlights the potential clinical consequences for the management of cancer chemotherapy patients at risk of fungal infections.
MeSH term(s)	Adaptation, Biological ; Aneuploidy ; Animals ; Antifungal Agents ; Antineoplastic Agents ; Calcineurin ; Candida albicans/genetics ; Caspofungin ; Chromosomes, Fungal ; Drug Resistance, Fungal/genetics ; Hydroxyurea ; Mice
Chemical Substances	Antifungal Agents ; Antineoplastic Agents ; Calcineurin (EC 3.1.3.16) ; Caspofungin (F0XDI6ZL63) ; Hydroxyurea (X6Q56QN5QC)
Language	English
Publishing date	2019-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msz104
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Article: A 3D pancreatic tumor model to study T cell infiltration

Mollica, Hilaria / Teo, Yi Juan / Tan, Alrina Shin Min / Tan, Damien Zhi Ming / Decuzzi, Paolo / Pavesi, Andrea / Adriani, Giulia

Biomaterials science. 2021 Nov. 9, v. 9, no. 22

2021

Abstract	The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including T cell immunotherapies. We present an in vitro 3D PDAC-TME model to observe and quantify T cell infiltration across the vasculature. In a three-channel microfluidic device, PDAC cells are cultured in a collagen matrix in the central channel surrounded, on one side, by endothelial cells (ECs) to mimic a blood vessel and, on the opposite side, by pancreatic stellate cells (PSCs) to simulate exocrine pancreas. The migration of T cells toward the tumor is quantified based on their activation state and TME composition. The presence of EC-lining drastically reduces T cell infiltration, confirming the essential role of the vasculature in controlling T cell trafficking. We show that activated T cells migrate ∼50% more than the not-activated ones toward the cancer cells. Correspondingly, in the absence of cancer cells, both activated and not-activated T cells present similar migration toward the PSCs. The proposed approach could help researchers in testing and optimizing immunotherapies for pancreatic cancer.
Keywords	T-lymphocytes ; adenocarcinoma ; biocompatible materials ; blood vessels ; collagen ; drug therapy ; models ; pancreas ; pancreatic neoplasms
Language	English
Dates of publication	2021-1109
Size	p. 7420-7431.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d1bm00210d
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Gut-Evolved

Reales-Calderon, Jose Antonio / Tso, Gloria H W / Tan, Alrina S M / Hor, Pei Xiang / Böhme, Julia / Teng, Karen W W / Newell, Evan W / Singhal, Amit / Pavelka, Norman

Frontiers in cellular and infection microbiology

2021 Volume 11, Page(s) 743735

Abstract: Serial passaging of the human fungal ... ...

Abstract	Serial passaging of the human fungal pathogen
MeSH term(s)	Animals ; Candida albicans ; Cell Wall ; Macrophages ; Mice ; Neutrophils ; beta-Glucans
Chemical Substances	beta-Glucans
Language	English
Publishing date	2021-11-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2021.743735
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Article ; Online: Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment.

Lee, Sharon Wei Ling / Seager, R J / Litvak, Felix / Spill, Fabian / Sieow, Je Lin / Leong, Penny Hweixian / Kumar, Dillip / Tan, Alrina Shin Min / Wong, Siew Cheng / Adriani, Giulia / Zaman, Muhammad Hamid / Kamm, And Roger D

Integrative biology : quantitative biosciences from nano to macro

2020 Volume 12, Issue 4, Page(s) 90–108

Abstract: Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow ...

Abstract	Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.
MeSH term(s)	Cell Differentiation ; Cell Line, Tumor ; Cell Movement ; Cell Separation ; Chemokines/metabolism ; Coculture Techniques ; Culture Media, Conditioned ; Cytokines/metabolism ; Humans ; Immunotherapy/methods ; Lab-On-A-Chip Devices ; Macrophages/cytology ; Macrophages/metabolism ; Models, Theoretical ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Chemokines ; Culture Media, Conditioned ; Cytokines
Language	English
Publishing date	2020-03-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2480063-6
ISSN	1757-9708 ; 1757-9694
ISSN (online)	1757-9708
ISSN	1757-9694
DOI	10.1093/intbio/zyaa007
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Article ; Online: MIG1 Regulates Resistance of Candida albicans against the Fungistatic Effect of Weak Organic Acids.

Cottier, Fabien / Tan, Alrina Shin Min / Xu, Xiaoli / Wang, Yue / Pavelka, Norman

Eukaryotic cell

2015 Volume 14, Issue 10, Page(s) 1054–1061

Abstract: Candida albicans is the leading cause of fungal infections; but it is also a member of the human microbiome, an ecosystem of thousands of microbial species potentially influencing the outcome of host-fungal interactions. Accordingly, antibacterial ... ...

Abstract	Candida albicans is the leading cause of fungal infections; but it is also a member of the human microbiome, an ecosystem of thousands of microbial species potentially influencing the outcome of host-fungal interactions. Accordingly, antibacterial therapy raises the risk of candidiasis, yet the underlying mechanism is currently not fully understood. We hypothesize the existence of bacterial metabolites that normally control C. albicans growth and of fungal resistance mechanisms against these metabolites. Among the most abundant microbiota-derived metabolites found on human mucosal surfaces are weak organic acids (WOAs), such as acetic, propionic, butyric, and lactic acid. Here, we used quantitative growth assays to investigate the dose-dependent fungistatic properties of WOAs on C. albicans growth and found inhibition of growth to occur at physiologically relevant concentrations and pH values. This effect was conserved across distantly related fungal species both inside and outside the CTG clade. We next screened a library of transcription factor mutants and identified several genes required for the resistance of C. albicans to one or more WOAs. A single gene, MIG1, previously known for its role in glucose repression, conferred resistance against all four acids tested. Consistent with glucose being an upstream activator of Mig1p, the presence of this carbon source was required for WOA resistance in wild-type C. albicans. Conversely, a MIG1-complemented strain completely restored the glucose-dependent resistance against WOAs. We conclude that Mig1p plays a central role in orchestrating a transcriptional program to fight against the fungistatic effect of this class of highly abundant metabolites produced by the gastrointestinal tract microbiota.
MeSH term(s)	Acetic Acid/pharmacology ; Antifungal Agents/pharmacology ; Butyric Acid/pharmacology ; Candida albicans/drug effects ; Candida albicans/genetics ; Candida albicans/growth & development ; Candidiasis/microbiology ; Drug Resistance, Fungal/genetics ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Lactic Acid/pharmacology ; Microbial Sensitivity Tests ; Propionates/pharmacology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Antifungal Agents ; Fungal Proteins ; Propionates ; Repressor Proteins ; Butyric Acid (107-92-6) ; Lactic Acid (33X04XA5AT) ; propionic acid (JHU490RVYR) ; Acetic Acid (Q40Q9N063P)
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2077635-4
ISSN	1535-9786 ; 1535-9778
ISSN (online)	1535-9786
ISSN	1535-9778
DOI	10.1128/EC.00129-15
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Zs.A 5779: Show issues

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Article ; Online: The Transcriptional Response of

Cottier, Fabien / Tan, Alrina Shin Min / Yurieva, Marina / Liao, Webber / Lum, Josephine / Poidinger, Michael / Zolezzi, Francesca / Pavelka, Norman

G3 (Bethesda, Md.)

2017 Volume 7, Issue 11, Page(s) 3597–3604

Abstract: ... Candida ... ...

Abstract	Candida albicans
MeSH term(s)	Acetic Acid/metabolism ; Acetic Acid/pharmacology ; Antifungal Agents/metabolism ; Antifungal Agents/pharmacology ; Butyric Acid/metabolism ; Butyric Acid/pharmacology ; Candida albicans/drug effects ; Candida albicans/genetics ; Candida albicans/metabolism ; Drug Resistance, Fungal/genetics ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Glucose/metabolism ; Glucose Transport Proteins, Facilitative/genetics ; Glucose Transport Proteins, Facilitative/metabolism ; Transcriptome
Chemical Substances	Antifungal Agents ; Fungal Proteins ; Glucose Transport Proteins, Facilitative ; Butyric Acid (107-92-6) ; Glucose (IY9XDZ35W2) ; Acetic Acid (Q40Q9N063P)
Language	English
Publishing date	2017--06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1534/g3.117.300238
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Article ; Online: The transcriptional stress response of Candida albicans to weak organic acids.

Cottier, Fabien / Tan, Alrina Shin Min / Chen, Jinmiao / Lum, Josephine / Zolezzi, Francesca / Poidinger, Michael / Pavelka, Norman

G3 (Bethesda, Md.)

2015 Volume 5, Issue 4, Page(s) 497–505

Abstract: Candida albicans is the most important fungal pathogen of humans, causing severe infections, especially in nosocomial and immunocompromised settings. However, it is also the most prevalent fungus of the normal human microbiome, where it shares its ... ...

Abstract	Candida albicans is the most important fungal pathogen of humans, causing severe infections, especially in nosocomial and immunocompromised settings. However, it is also the most prevalent fungus of the normal human microbiome, where it shares its habitat with hundreds of trillions of other microbial cells. Despite weak organic acids (WOAs) being among the most abundant metabolites produced by bacterial microbiota, little is known about their effect on C. albicans. Here we used a sequencing-based profiling strategy to systematically investigate the transcriptional stress response of C. albicans to lactic, acetic, propionic, and butyric acid at several time points after treatment. Our data reveal a complex transcriptional response, with individual WOAs triggering unique gene expression profiles and with important differences between acute and chronic exposure. Despite these dissimilarities, we found significant overlaps between the gene expression changes induced by each WOA, which led us to uncover a core transcriptional response that was largely unrelated to other previously published C. albicans transcriptional stress responses. Genes commonly up-regulated by WOAs were enriched in several iron transporters, which was associated with an overall decrease in intracellular iron concentrations. Moreover, chronic exposure to any WOA lead to down-regulation of RNA synthesis and ribosome biogenesis genes, which resulted in significant reduction of total RNA levels and of ribosomal RNA in particular. In conclusion, this study suggests that gastrointestinal microbiota might directly influence C. albicans physiology via production of WOAs, with possible implications of how this fungus interacts with its host in both health and disease.
MeSH term(s)	Acids, Acyclic/pharmacology ; Candida albicans/drug effects ; Candida albicans/genetics ; Candida albicans/metabolism ; Down-Regulation/drug effects ; Iron/metabolism ; Lactic Acid/pharmacology ; RNA/biosynthesis ; RNA, Ribosomal/metabolism ; Transcriptome/drug effects ; Up-Regulation/drug effects
Chemical Substances	Acids, Acyclic ; RNA, Ribosomal ; Lactic Acid (33X04XA5AT) ; RNA (63231-63-0) ; Iron (E1UOL152H7)
Language	English
Publishing date	2015-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1534/g3.114.015941
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