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Article ; Online: Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma

Fan Huang / Feiyang Cai / Michael S. Dahabieh / Kshemaka Gunawardena / Ali Talebi / Jonas Dehairs / Farah El-Turk / Jae Yeon Park / Mengqi Li / Christophe Goncalves / Natascha Gagnon / Jie Su / Judith H. LaPierre / Perrine Gaub / Jean-Sébastien Joyal / John J. Mitchell / Johannes V. Swinnen / Wilson H. Miller Jr. / Sonia V. del Rincón

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 20

Abstract: Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a ... ...

Abstract	Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.
Keywords	Oncology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optimized protocol for immunophenotyping of melanoma and tumor-bearing skin from mouse

Sai Sakktee Krisna / Christophe Goncalves / Natascha Gagnon / Fan Huang / Dany Plourde / Wilson H. Miller, Jr. / Jörg H. Fritz / Sonia V. del Rincon

STAR Protocols, Vol 2, Iss 3, Pp 100627- (2021)

2021

Abstract: Summary: While isolating immune cells from spleens and lungs is routinely achieved using flow cytometry, it is challenging to isolate viable immune cells from skin. Here, we describe a step-by-step protocol for skin digestion using a murine melanoma ... ...

Abstract	Summary: While isolating immune cells from spleens and lungs is routinely achieved using flow cytometry, it is challenging to isolate viable immune cells from skin. Here, we describe a step-by-step protocol for skin digestion using a murine melanoma model, which is amenable for detection of low abundant immune cell populations including group 2 innate lymphoid cells.
Keywords	Cancer ; Cell isolation ; Flow Cytometry/Mass Cytometry ; Immunology ; Model Organisms ; Science (General) ; Q1-390
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia

Jessica N. Nichol / Matthew D. Galbraith / Claudia L. Kleinman / Joaquín M. Espinosa / Wilson H. Miller Jr.

Cell Reports, Vol 14, Iss 12, Pp 2938-

2016 Volume 2949

Abstract: Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA- ...

Abstract	Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2016-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Artificial night light and anthropogenic noise interact to influence bird abundance over a continental scale.

Wilson, Ashley A / Ditmer, Mark A / Barber, Jesse R / Carter, Neil H / Miller, Eliot T / Tyrrell, Luke P / Francis, Clinton D

Global change biology

2021 Volume 27, Issue 17, Page(s) 3987–4004

Abstract: The extent of artificial night light and anthropogenic noise (i.e., "light" and "noise") impacts is global and has the capacity to threaten species across diverse ecosystems. Existing research involving impacts of light or noise has primarily focused on ... ...

Abstract	The extent of artificial night light and anthropogenic noise (i.e., "light" and "noise") impacts is global and has the capacity to threaten species across diverse ecosystems. Existing research involving impacts of light or noise has primarily focused on noise or light alone and single species; however, these stimuli often co-occur and little is known about how co-exposure influences wildlife and if and why species may vary in their responses. Here, we had three aims: (1) to investigate species-specific responses to light, noise, and the interaction between the two using a spatially explicit approach to model changes in abundance of 140 prevalent bird species across North America, (2) to investigate responses to the interaction between light exposure and night length, and (3) to identify functional traits and habitat affiliations that explain variation in species-specific responses to these sensory stimuli with phylogenetically informed models. We found species that responded to noise exposure generally decreased in abundance, and the additional presence of light interacted synergistically with noise to exacerbate its negative effects. Moreover, the interaction revealed negative emergent responses for several species that only reacted when light and noise co-occurred. Additionally, an interaction between light and night length revealed 47 species increased in abundance with light exposure during longer nights. In addition to modifying behavior with optimal temperature and potential foraging opportunities, birds might be attracted to light, yet suffer inadvertent physiological consequences. The trait that most strongly related to avian response to light and noise was habitat affiliation. Specifically, species that occupy closed habitat were less tolerant of both sensory stressors compared to those that occupy open habitat. Further quantifying the contexts and intrinsic traits that explain how species respond to noise and light will be fundamental to understanding the ecological consequences of a world that is ever louder and brighter.
MeSH term(s)	Animals ; Animals, Wild ; Birds ; Ecosystem ; Noise/adverse effects ; Species Specificity
Language	English
Publishing date	2021-06-10
Publishing country	England
Document type	Journal Article
ZDB-ID	1281439-8
ISSN	1365-2486 ; 1354-1013
ISSN (online)	1365-2486
ISSN	1354-1013
DOI	10.1111/gcb.15663
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Article ; Online: Antimicrobial resistance determinants are associated with

Microbial genomics

2024 Volume 7, Issue 11

Abstract: Staphylococcus ... ...

Abstract	Staphylococcus aureus
MeSH term(s)	Adult ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Bacteremia/microbiology ; Delivery of Health Care ; Drug Resistance, Bacterial/genetics ; Genome-Wide Association Study ; Humans ; Staphylococcal Infections/microbiology ; Staphylococcus aureus
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2024-01-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2835258-0
ISSN	2057-5858 ; 2057-5858
ISSN (online)	2057-5858
ISSN	2057-5858
DOI	10.1099/mgen.0.000700
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Retinoids inhibit measles virus through a type I IFN-dependent bystander effect

Trottier, Claire / Colombo, Myrian / Mann, Koren K / Miller, Wilson H. Jr / Ward, Brian J

FASEB journal. 2009 Sept., v. 23, no. 9

2009

Abstract: ... Miller, W. H., Jr., Ward, B. J. Retinoids inhibit measles virus through a type I IFN-dependent ... regulated by ATRA in MeV-infected U937 cell cultures starting at 12 h and reaching a plateau at 24 h ...

Abstract	Measles-associated mortality can be decreased in response to treatment with vitamin A. Our goal was to understand the mechanism by which vitamin A and other retinoids reduce measles virus (MeV) replication in vitro. MeV is known to inhibit type I interferon (IFN) signaling, and retinoids are increasingly implicated in modulating innate immunity. Type I IFN blocking antibodies abrogated the inhibitory effects of all-trans retinoic acid (ATRA) on MeV replication (EC₅₀ of ATRA: 3.17x10⁻⁸ M). IFN-stimulated genes (ISGs) are up-regulated by ATRA in MeV-infected U937 cell cultures starting at 12 h and reaching a plateau at 24 h postinfection when compared to either treatment or infection alone. We found that this increased gene expression occurs in uninfected cells by using a transwell system where the uninfected cells were separated from infected cells by a membrane with 0.02-μM pores. Uninfected bystander cells from the ATRA-treated transwells did not support substantial viral replication when subsequently infected with MeV. In the absence of ATRA, the cells from the uninfected chamber did not up-regulate ISG expression and were not protected from subsequent challenge with virus. These results demonstrate that retinoids inhibit MeV replication by up-regulating elements of the innate immune response in uninfected bystander cells, making them refractory to productive infection during subsequent rounds of viral replication.--Trottier, C., Colombo, M., Mann, K. K., Miller, W. H., Jr., Ward, B. J. Retinoids inhibit measles virus through a type I IFN-dependent bystander effect.
Language	English
Dates of publication	2009-09
Size	p. 3203-3212.
Publishing place	The Federation of American Societies for Experimental Biology
Document type	Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
Database	NAL-Catalogue (AGRICOLA)

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Article: Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

Pettersson, Filippa / Hanna, Nessrine / Lagodich, Marina / Dupéré-Richer, Daphné / Couture, Marie-Claude / Choi, Catherine / Miller, Wilson H. Jr

Journal of biological chemistry. 2008 Aug. 8, v. 283, no. 32

2008

Abstract: The steroid and xenobiotic receptor SXR (human pregnane X receptor) is a nuclear receptor that plays a key role in the body's detoxification response by regulating genes involved in drug metabolism and transport. SXR ligands include a wide range of ... ...

Abstract	The steroid and xenobiotic receptor SXR (human pregnane X receptor) is a nuclear receptor that plays a key role in the body's detoxification response by regulating genes involved in drug metabolism and transport. SXR ligands include a wide range of compounds, which induce transcription of SXR target genes via activation of a heterodimeric transcription factor consisting of SXR and the related nuclear receptor retinoid X receptor (RXR). We investigated the effect of RXR-selective ligands, rexinoids, on SXR/RXR activity. In agreement with previous reports, we found that rexinoids are weak activators of SXR, but we also found that they can antagonize SXR activation by the potent SXR agonist rifampicin. This antagonism included suppression of rifampicin-induced expression of SXR target genes, as well as reduced binding of SXR/RXR to SXR response elements both in vivo and in vitro. Interestingly, two rexinoids, bexarotene (LGD1069/Targretin®) and LG100268, caused a rapid and sustained decrease in the protein levels of both SXR and RXR. The decrease in SXR level was due to an enhanced rate of protein degradation and was dependent on calpain activity, as opposed to rexinoid-induced RXR degradation, which is mediated via the proteasome. Thus, we have demonstrated a novel, rexinoid-modulated mechanism regulating SXR protein stability, which may explain why rexinoids are only weak activators of SXR/RXR-mediated transcription, despite reports that they bind to SXR with high affinity. We suggest that the ability of rexinoids to induce degradation of both SXR and RXR, in combination with competition for binding to SXR, can also explain why rexinoids antagonize the activation of SXR by drugs like rifampicin.
Language	English
Dates of publication	2008-0808
Size	p. 21945-21952.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter

Witcher, Michael / Pettersson, Filippa / DupÃ©rÃ©-Richer, Daphne / Padovani, Alessandra / Summers-Deluca, Leslie / Baldwin, Albert S / Miller, Wilson H. Jr

Nucleic acids research. 2008 Feb., v. 36, no. 2

2008

Abstract: Transcriptional activation by nuclear hormone receptors is well characterized, but their cooperation with other signaling pathways to activate transcription remains poorly understood. Tumor necrosis factor alpha (TNFÎ±) and all-trans retinoic acid (RA) ... ...

Abstract	Transcriptional activation by nuclear hormone receptors is well characterized, but their cooperation with other signaling pathways to activate transcription remains poorly understood. Tumor necrosis factor alpha (TNFÎ±) and all-trans retinoic acid (RA) induce monocytic differentiation of acute promyelocytic leukemia (APL) cells in a synergistic manner. We used the promoter of DIF2, a gene involved in monocytic differentiation, to model the mechanism underlying the cooperative induction of target genes by RA and TNFÎ±. We show a functional RA response element in the DIF2 promoter, which is constitutively bound by PML/RARÎ± in APL cells. RA stimulates release of corepressors and recruitment of chromatin modifying proteins and additional transcription factors to the promoter, but these changes cause only a modest induction of DIF2 mRNA. Co-stimulation with RA plus TNFÎ± facilitates binding of NF-ÎºB to the promoter, which is crucial for full induction of transcription. Furthermore, RA plus TNFÎ± greatly enhanced the level of RNA Pol II phosphorylation on the DIF2 promoter, via synergistic recruitment of TFIIH. We propose that RA mediates remodeling of chromatin to facilitate binding of transcription factors, which cooperate to enhance Pol II phosphorylation, providing a mechanism whereby nuclear receptors interact with other signaling pathways on the level of transcription.
Keywords	DNA-directed RNA polymerase ; chromatin ; genes ; hormone receptors ; leukemia ; messenger RNA ; models ; phosphorylation ; retinoic acid ; signal transduction ; transcription (genetics) ; transcription factor NF-kappa B ; transcriptional activation ; tumor necrosis factor-alpha
Language	English
Dates of publication	2008-02
Size	p. 435-443.
Document type	Article
ZDB-ID	186809-3
ISSN	0301-5610 ; 0305-1048
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkm1058
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Protein target highlights in CASP15: Analysis of models by structure providers.

Alexander, Leila T / Durairaj, Janani / Kryshtafovych, Andriy / Abriata, Luciano A / Bayo, Yusupha / Bhabha, Gira / Breyton, Cécile / Caulton, Simon G / Chen, James / Degroux, Séraphine / Ekiert, Damian C / Erlandsen, Benedikte S / Freddolino, Peter L / Gilzer, Dominic / Greening, Chris / Grimes, Jonathan M / Grinter, Rhys / Gurusaran, Manickam / Hartmann, Marcus D /

Hitchman, Charlie J / Keown, Jeremy R / Kropp, Ashleigh / Kursula, Petri / Lovering, Andrew L / Lemaitre, Bruno / Lia, Andrea / Liu, Shiheng / Logotheti, Maria / Lu, Shuze / Markússon, Sigurbjörn / Miller, Mitchell D / Minasov, George / Niemann, Hartmut H / Opazo, Felipe / Phillips, George N / Davies, Owen R / Rommelaere, Samuel / Rosas-Lemus, Monica / Roversi, Pietro / Satchell, Karla / Smith, Nathan / Wilson, Mark A / Wu, Kuan-Lin / Xia, Xian / Xiao, Han / Zhang, Wenhua / Zhou, Z Hong / Fidelis, Krzysztof / Topf, Maya / Moult, John / Schwede, Torsten

Proteins

2023 Volume 91, Issue 12, Page(s) 1571–1599

Abstract: We present an in-depth analysis of selected CASP15 targets, focusing on their biological and functional significance. The authors of the structures identify and discuss key protein features and evaluate how effectively these aspects were captured in the ... ...

Abstract	We present an in-depth analysis of selected CASP15 targets, focusing on their biological and functional significance. The authors of the structures identify and discuss key protein features and evaluate how effectively these aspects were captured in the submitted predictions. While the overall ability to predict three-dimensional protein structures continues to impress, reproducing uncommon features not previously observed in experimental structures is still a challenge. Furthermore, instances with conformational flexibility and large multimeric complexes highlight the need for novel scoring strategies to better emphasize biologically relevant structural regions. Looking ahead, closer integration of computational and experimental techniques will play a key role in determining the next challenges to be unraveled in the field of structural molecular biology.
MeSH term(s)	Protein Conformation ; Models, Molecular ; Computational Biology/methods ; Proteins/chemistry
Chemical Substances	Proteins
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26545
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Book ; Online: G4CMP

Kelsey, M. H. / Agnese, R. / Alam, Y. F. / Langroudy, I. Ataee / Azadbakht, E. / Brandt, D. / Bunker, R. / Cabrera, B. / Chang, Y. -Y. / Coombes, H. / Cormier, R. M. / Diamond, M. D. / Edwards, E. R. / Figueroa-Feliciano, E. / Gao, J. / Harrington, P. M. / Hong, Z. / Hui, M. / Kurinsky, N. A. /

Lawrence, R. E. / Loer, B. / Masten, M. G. / Michaud, E. / Michielin, E. / Miller, J. / Novati, V. / Oblath, N. S. / Orrell, J. L. / Perry, W. L. / Redl, P. / Reynolds, T. / Saab, T. / Sadoulet, B. / Serniak, K. / Singh, J. / Speaks, Z. / Stanford, C. / Stevens, J. R. / Strube, J. / Toback, D. / Ullom, J. N. / VanDevender, B. A. / Vissers, M. R. / Wilson, M. J. / Wilson, J. S. / Zatschler, B. / Zatschler, S.

Condensed Matter Physics Simulation Using the Geant4 Toolkit

2023

Abstract: G4CMP simulates phonon and charge transport in cryogenic semiconductor crystals using the Geant4 toolkit. The transport code is capable of simulating the propagation of acoustic phonons as well as electron and hole charge carriers. Processes for ... ...

Abstract	G4CMP simulates phonon and charge transport in cryogenic semiconductor crystals using the Geant4 toolkit. The transport code is capable of simulating the propagation of acoustic phonons as well as electron and hole charge carriers. Processes for anisotropic phonon propagation, oblique charge-carrier propagation, and phonon emission by accelerated charge carriers are included. The simulation reproduces theoretical predictions and experimental observations such as phonon caustics, heat-pulse propagation times, and mean charge-carrier drift velocities. In addition to presenting the physics and features supported by G4CMP, this report outlines example applications from the dark matter and quantum information science communities. These communities are applying G4CMP to model and design devices for which the energy transported by phonons and charge carriers is germane to the performance of superconducting instruments and circuits placed on silicon and germanium substrates. The G4CMP package is available to download from GitHub: github.com/kelseymh/G4CMP. Comment: 21 pages, 11 figures, 10 tables
Keywords	High Energy Physics - Experiment ; Quantum Physics
Subject code	621
Publishing date	2023-02-12
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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