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Article ; Online: Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity.

Abed, Anas / Greene, Michelle K / Alsa'd, Alhareth A / Lees, Andrea / Hindley, Andrew / Longley, Daniel B / McDade, Simon S / Scott, Christopher J

Molecular pharmaceutics

2024 Volume 21, Issue 3, Page(s) 1246–1255

Abstract: Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than ... ...

Abstract	Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the
MeSH term(s)	Humans ; Animals ; Mice ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Tumor Suppressor Protein p53/metabolism ; Apoptosis ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Combinations ; Proto-Oncogene Proteins c-mdm2 ; Benzamides ; Pyridines ; Pyrrolidines ; para-Aminobenzoates
Chemical Substances	Histone Deacetylase Inhibitors ; entinostat (1ZNY4FKK9H) ; RG7388 ; Tumor Suppressor Protein p53 ; Antineoplastic Agents ; Drug Combinations ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; MDM2 protein, human (EC 2.3.2.27) ; Benzamides ; Pyridines ; Pyrrolidines ; para-Aminobenzoates
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.3c00926
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Article ; Online: Real-time radial reconstruction with domain transform manifold learning for MRI-guided radiotherapy.

Waddington, David E J / Hindley, Nicholas / Koonjoo, Neha / Chiu, Christopher / Reynolds, Tess / Liu, Paul Z Y / Zhu, Bo / Bhutto, Danyal / Paganelli, Chiara / Keall, Paul J / Rosen, Matthew S

Medical physics

2023 Volume 50, Issue 4, Page(s) 1962–1974

Abstract: Background: MRI-guidance techniques that dynamically adapt radiation beams to follow tumor motion in real time will lead to more accurate cancer treatments and reduced collateral healthy tissue damage. The gold-standard for reconstruction of ... ...

Abstract	Background: MRI-guidance techniques that dynamically adapt radiation beams to follow tumor motion in real time will lead to more accurate cancer treatments and reduced collateral healthy tissue damage. The gold-standard for reconstruction of undersampled MR data is compressed sensing (CS) which is computationally slow and limits the rate that images can be available for real-time adaptation. Purpose: Once trained, neural networks can be used to accurately reconstruct raw MRI data with minimal latency. Here, we test the suitability of deep-learning-based image reconstruction for real-time tracking applications on MRI-Linacs. Methods: We use automated transform by manifold approximation (AUTOMAP), a generalized framework that maps raw MR signal to the target image domain, to rapidly reconstruct images from undersampled radial k-space data. The AUTOMAP neural network was trained to reconstruct images from a golden-angle radial acquisition, a benchmark for motion-sensitive imaging, on lung cancer patient data and generic images from ImageNet. Model training was subsequently augmented with motion-encoded k-space data derived from videos in the YouTube-8M dataset to encourage motion robust reconstruction. Results: AUTOMAP models fine-tuned on retrospectively acquired lung cancer patient data reconstructed radial k-space with equivalent accuracy to CS but with much shorter processing times. Validation of motion-trained models with a virtual dynamic lung tumor phantom showed that the generalized motion properties learned from YouTube lead to improved target tracking accuracy. Conclusion: AUTOMAP can achieve real-time, accurate reconstruction of radial data. These findings imply that neural-network-based reconstruction is potentially superior to alternative approaches for real-time image guidance applications.
MeSH term(s)	Humans ; Retrospective Studies ; Magnetic Resonance Imaging/methods ; Neural Networks, Computer ; Lung Neoplasms/diagnostic imaging ; Lung Neoplasms/radiotherapy ; Lung Neoplasms/pathology ; Motion ; Image Processing, Computer-Assisted/methods
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	188780-4
ISSN	2473-4209 ; 0094-2405
ISSN (online)	2473-4209
ISSN	0094-2405
DOI	10.1002/mp.16224
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Article ; Online: Correction to: Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.

Aly, Amr / Laszlo, Zsofia I / Rajkumar, Sandeep / Demir, Tugba / Hindley, Nicole / Lamont, Douglas J / Lehmann, Johannes / Seidel, Mira / Sommer, Daniel / Franz-Wachtel, Mirita / Barletta, Francesca / Heumos, Simon / Czemmel, Stefan / Kabashi, Edor / Ludolph, Albert / Boeckers, Tobias M / Henstridge, Christopher M / Catanese, Alberto

Acta neuropathologica

2023 Volume 146, Issue 5, Page(s) 783

Language	English
Publishing date	2023-09-12
Publishing country	Germany
Document type	Published Erratum
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02630-9
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Article ; Online: Organoids from adult liver and pancreas: Stem cell biology and biomedical utility.

Hindley, Christopher J / Cordero-Espinoza, Lucía / Huch, Meritxell

Developmental biology

2016 Volume 420, Issue 2, Page(s) 251–261

Abstract: The liver and pancreas are critical organs maintaining whole body metabolism. Historically, the expansion of adult-derived cells from these organs in vitro has proven challenging and this in turn has hampered studies of liver and pancreas stem cell ... ...

Abstract	The liver and pancreas are critical organs maintaining whole body metabolism. Historically, the expansion of adult-derived cells from these organs in vitro has proven challenging and this in turn has hampered studies of liver and pancreas stem cell biology, as well as being a roadblock to disease modelling and cell replacement therapies for pathologies in these organs. Recently, defined culture conditions have been described which allow the in vitro culture and manipulation of adult-derived liver and pancreatic material. Here we review these systems and assess their physiological relevance, as well as their potential utility in biomedicine.
MeSH term(s)	Animals ; Cell- and Tissue-Based Therapy ; Genetic Therapy ; Humans ; Liver/cytology ; Liver/embryology ; Liver/growth & development ; Liver Regeneration ; Models, Biological ; Organ Culture Techniques/methods ; Organogenesis ; Organoids/cytology ; Organoids/embryology ; Organoids/growth & development ; Pancreas/cytology ; Pancreas/embryology ; Pancreas/growth & development ; Signal Transduction ; Stem Cells/cytology
Language	English
Publishing date	2016-06-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.06.039
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Article ; Online: Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS.

Acta neuropathologica

2023 Volume 146, Issue 3, Page(s) 451–475

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely ... ...

Abstract	Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/pathology ; Neurodegenerative Diseases/pathology ; Proteomics ; Superoxide Dismutase-1/genetics ; Motor Neurons/metabolism
Chemical Substances	Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2023-07-24
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02611-y
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Article ; Online: Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex.

Laszlo, Zsofia I / Hindley, Nicole / Sanchez Avila, Anna / Kline, Rachel A / Eaton, Samantha L / Lamont, Douglas J / Smith, Colin / Spires-Jones, Tara L / Wishart, Thomas M / Henstridge, Christopher M

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 156

Abstract: Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed ... ...

Abstract	Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism ; DNA Repeat Expansion/genetics ; Proteomics ; Proteome/genetics ; Cognition ; Frontotemporal Dementia/genetics
Chemical Substances	C9orf72 Protein ; Proteome ; C9orf72 protein, human
Language	English
Publishing date	2022-10-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01455-z
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Article ; Online: The plastic liver: differentiated cells, stem cells, every cell?

Hindley, Christopher J / Mastrogiovanni, Gianmarco / Huch, Meritxell

The Journal of clinical investigation

2014 Volume 124, Issue 12, Page(s) 5099–5102

Abstract: The liver is capable of full regeneration following several types and rounds of injury, ranging from hepatectomy to toxin-mediated damage. The source of this regenerative capacity has long been a hotly debated topic. The damage response that occurs when ... ...

Abstract	The liver is capable of full regeneration following several types and rounds of injury, ranging from hepatectomy to toxin-mediated damage. The source of this regenerative capacity has long been a hotly debated topic. The damage response that occurs when hepatocyte proliferation is impaired is thought to be mediated by oval/dedifferentiated progenitor cells, which replenish the hepatocyte and ductal compartments of the liver. Recently, reports have questioned whether these oval/progenitor cells truly serve as the facultative stem cell of the liver following toxin-mediated damage. In this issue of the JCI, Kordes and colleagues use lineage tracing to follow transplanted rat hepatic stellate cells, a resident liver mesenchymal cell population, in hosts that have suffered liver damage. Transplanted stellate cells repopulated the damaged rat liver by contributing to the oval cell response. These data establish yet another cell type of mesenchymal origin as the progenitor for the oval/ductular response in the rat. The lack of uniformity between different damage models, the extent of the injury to the liver parenchyma, and potential species-specific differences might be at the core of the discrepancy between different studies. Taken together, these data imply a considerable degree of plasticity in the liver, whereby several cell types can contribute to regeneration.
MeSH term(s)	Animals ; Cell Differentiation ; Hepatic Stellate Cells ; Liver/metabolism ; Liver Regeneration ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells
Language	English
Publishing date	2014-12
Publishing country	United States
Document type	Comment ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI78372
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Article ; Online: Lgr5

Prior, Nicole / Hindley, Christopher J / Rost, Fabian / Meléndez, Elena / Lau, Winnie W Y / Göttgens, Berthold / Rulands, Steffen / Simons, Benjamin D / Huch, Meritxell

Development (Cambridge, England)

2019 Volume 146, Issue 12

Abstract: During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocytes and cholangiocytes. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous progenitor population that initiate ... ...

Abstract	During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocytes and cholangiocytes. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous progenitor population that initiate differentiation from E13.5. Recently, scRNA-seq analysis has identified sub-populations of transcriptionally distinct hepatoblasts at E11.5. Here, we show that hepatoblasts are not only transcriptionally but also functionally heterogeneous, and that a subpopulation of E9.5-E10.0 hepatoblasts exhibit a previously unidentified early commitment to cholangiocyte fate. Importantly, we also identify a subpopulation constituting 2% of E9.5-E10.0 hepatoblasts that express the adult stem cell marker
MeSH term(s)	Alleles ; Animals ; Base Sequence ; Cell Count ; Cell Culture Techniques ; Cell Differentiation ; Cell Lineage ; Cells, Cultured ; Embryonic Development ; Epithelial Cells/cytology ; Female ; Gene Expression Regulation, Developmental ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Homeostasis ; Liver/embryology ; Male ; Mice ; Microscopy, Confocal ; Receptors, G-Protein-Coupled/metabolism ; Stem Cells/cytology
Chemical Substances	Lgr5 protein, mouse ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2019-06-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.174557
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Article: Organoids from adult liver and pancreas: Stem cell biology and biomedical utility

Hindley, Christopher J / LucÃa Cordero-Espinoza / Meritxell Huch

Developmental biology. 2016,

2016

Abstract	The liver and pancreas are critical organs maintaining whole body metabolism. Historically, the expansion of adult-derived cells from these organs in vitro has proven challenging and this in turn has hampered studies of liver and pancreas stem cell biology, as well as being a roadblock to disease modelling and cell replacement therapies for pathologies in these organs. Recently, defined culture conditions have been described which allow the in vitro culture and manipulation of adult-derived liver and pancreatic material. Here we review these systems and assess their physiological relevance, as well as their potential utility in biomedicine.
Keywords	adults ; in vitro culture ; liver ; medicine ; metabolism ; models ; pancreas ; stem cells
Language	English
Size	p. .
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.06.039
Database	NAL-Catalogue (AGRICOLA)

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Book ; Online: On Real-time Image Reconstruction with Neural Networks for MRI-guided Radiotherapy

Waddington, David E. J. / Hindley, Nicholas / Koonjoo, Neha / Chiu, Christopher / Reynolds, Tess / Liu, Paul Z. Y. / Zhu, Bo / Bhutto, Danyal / Paganelli, Chiara / Keall, Paul J. / Rosen, Matthew S.

2022

Abstract: MRI-guidance techniques that dynamically adapt radiation beams to follow tumor motion in real-time will lead to more accurate cancer treatments and reduced collateral healthy tissue damage. The gold-standard for reconstruction of undersampled MR data is ... ...

Abstract	MRI-guidance techniques that dynamically adapt radiation beams to follow tumor motion in real-time will lead to more accurate cancer treatments and reduced collateral healthy tissue damage. The gold-standard for reconstruction of undersampled MR data is compressed sensing (CS) which is computationally slow and limits the rate that images can be available for real-time adaptation. Here, we demonstrate the use of automated transform by manifold approximation (AUTOMAP), a generalized framework that maps raw MR signal to the target image domain, to rapidly reconstruct images from undersampled radial k-space data. The AUTOMAP neural network was trained to reconstruct images from a golden-angle radial acquisition, a benchmark for motion-sensitive imaging, on lung cancer patient data and generic images from ImageNet. Model training was subsequently augmented with motion-encoded k-space data derived from videos in the YouTube-8M dataset to encourage motion robust reconstruction. We find that AUTOMAP-reconstructed radial k-space has equivalent accuracy to CS but with much shorter processing times after initial fine-tuning on retrospectively acquired lung cancer patient data. Validation of motion-trained models with a virtual dynamic lung tumor phantom showed that the generalized motion properties learned from YouTube lead to improved target tracking accuracy. Our work shows that AUTOMAP can achieve real-time, accurate reconstruction of radial data. These findings imply that neural-network-based reconstruction is potentially superior to existing approaches for real-time image guidance applications. Comment: 12 pages, 6 figures, 1 table. v2 has a typo in eqn 1 corrected and references added to the discussion
Keywords	Physics - Medical Physics ; Computer Science - Computer Vision and Pattern Recognition ; Electrical Engineering and Systems Science - Image and Video Processing
Subject code	004
Publishing date	2022-02-09
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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